Niemann-Pick Type C 1 (NPC1) and NPC2 Gene Variability in Demented Patients with Evidence of Brain Amyloid Deposition. - Sorrentino, Federica; Arighi, Andrea; Serpente, Maria; Arosio, Beatrice; Arcaro, Marina; Visconte, Caterina; Rotondo, Emanuela; Vimercati, Roberto; Ferri, Evelyn; Fumagalli, Giorgio G; Pietroboni, Anna M; Carandini, Tiziana; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Variants in Niemann-Pick Type C genes (NPC1 and NPC2) have been suggested to play a role as risk or disease modifying factors for Alzheimer's disease (AD). OBJECTIVE: The aim of this study was to analyze NPC1 and NPC2 variability in demented patients with evidence of brain amyloid-β 1-42 (Aβ) deposition and to correlate genetic data with clinical phenotypes. METHODS: A targeted Next Generation Sequencing panel was customized to screen NPC1, NPC2, and main genes related to neurodegenerative dementias in a cohort of 136 demented patients with cerebrospinal fluid (CSF) low Aβ levels or positive PET with Aβ tracer and 200 non-demented geriatric subjects. RESULTS: Seven patients were carriers of NPC variants in heterozygosis. Four of them displayed pathogenic variants previously found in NPC patients and one AD patient had a novel variant. The latter was absent in 200 non-demented elderly subjects. Five of seven patients (70%) exhibited psychiatric symptoms at onset or later as compared with 43%in non-carriers (p >  0.05). CONCLUSION: The frequency of NPC1 and NPC2 heterozygous variants in patients with CSF evidence of Aβ deposition is higher than in the general population.

Physical Activity and Trajectory of Cognitive Change in Older Persons: Mayo Clinic Study of Aging. - Krell-Roesch, Janina; Syrjanen, Jeremy A; Bezold, Jelena; Trautwein, Sandra; Barisch-Fritz, Bettina; Boes, Klaus; Woll, Alexander; Forzani, Erica; Kremers, Walter K; Machulda, Mary M; Mielke, Michelle M; Knopman, David S; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Little is known about the association between physical activity (PA) and cognitive trajectories in older adults. OBJECTIVE: To examine the association between PA and change in memory, language, attention, visuospatial skills, and global cognition, and a potential impact of sex or Apolipoprotein E (APOE) ɛ4 status. METHODS: Longitudinal study derived from the population-based Mayo Clinic Study of Aging, including 2,060 cognitively unimpaired males and females aged ≥70 years. Engagement in midlife (ages 50-65) and late-life (last year) PA was assessed using a questionnaire. Neuropsychological testing was done every 15 months (mean follow-up 5.8 years). We ran linear mixed-effect models to examine whether mid- or late-life PA at three intensities (mild, moderate, vigorous) was associated with cognitive z-scores. RESULTS: Light intensity midlife PA was associated with less decline in memory function compared to the no-PA reference group (time x light PA; estimate [standard error] 0.047 [0.016], p = 0.004). Vigorous late-life PA was associated with less decline in language (0.033 [0.015], p = 0.030), attention (0.032 [0.017], p = 0.050), and global cognition (0.039 [0.016], p = 0.012). Females who were physically inactive in midlife experienced more pronounced cognitive decline than females physically active in midlife and males regardless of PA (p-values for time interaction terms with midlife PA levels and sex were all p <  0.05 for global cognition). APOE ɛ4 carriership did not moderate the association between PA and cognition. CONCLUSION: Engaging in PA, particularly of vigorous intensity in late-life, was associated with less pronounced decline in global and domain-specific cognition. This association may differ by sex.

Plasma Biomarkers of Alzheimer's Disease in African Americans. - Deniz, Kaancan; Ho, Charlotte C G; Malphrus, Kimberly G; Reddy, Joseph S; Nguyen, Thuy; Carnwath, Troy P; Crook, Julia E; Lucas, John A; Graff-Radford, Neill R; Carrasquillo, Minerva M; Ertekin-Taner, Nilufer (J Alzheimers Dis, 2021)
BACKGROUND/OBJECTIVE: The aim of this study was to determine if plasma concentrations of 5 surrogate markers of Alzheimer's disease (AD) pathology and neuroinflammation are associated with disease status in African Americans. METHODS: We evaluated 321 African Americans (159 AD, 162 controls) from the Florida Consortium for African-American Alzheimer's Disease Studies (FCA3DS). Five plasma proteins reflecting AD neuropathology or inflammation (Aβ42, tau, IL6, IL10, TNFα) were tested for associations with AD, age, sex, APOE and MAPT genotypes, and for pairwise correlations. RESULTS: Plasma tau levels were higher in AD when adjusted for biological and technical covariates. APOEɛ4 was associated with lower plasma Aβ42 and tau levels. Older age was associated with higher plasma Aβ42, tau, and TNFα. Females had lower IL10 levels. Inflammatory proteins had strong pairwise correlations amongst themselves and with Aβ42. CONCLUSION: We identified effects of demographic and genetic variants on five potential plasma biomarkers in African Americans. Plasma inflammatory biomarkers and Aβ42 may reflect correlated pathologies and elevated plasma tau may be a biomarker of AD in this population.
Keywords: African Americans; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Case-Control Studies; Female; Humans; Interleukin-10; Interleukin-6; Male; Middle Aged; Peptide Fragments; tau Proteins; Tumor Necrosis Factor-alpha

Plasma Neurofilament Light Chain Predicts Cognitive Progression in Prodromal and Clinical Dementia with Lewy Bodies. - Pilotto, Andrea; Imarisio, Alberto; Carrarini, Claudia; Russo, Mirella; Masciocchi, Stefano; Gipponi, Stefano; Cottini, Elisabetta; Aarsland, Dag; Zetterberg, Henrik; Ashton, Nicholas J; Hye, Abdul; Bonanni, Laura; et al. (J Alzheimers Dis, 2021)
Plasma neurofilament light chain (NfL) is a marker of neuronal damage in different neurological disorders and might predict disease progression in dementia with Lewy bodies (DLB). The study enrolled 45 controls and 44 DLB patients (including 17 prodromal cases) who underwent an extensive assessment at baseline and at 2 years follow-up. At baseline, plasma NfL levels were higher in both probable DLB and prodromal cases compared to controls. Plasma NfL emerged as the best predictor of cognitive decline compared to age, sex, and baseline severity variables. The study supports the role of plasma NfL as a useful prognostic biomarker from the early stages of DLB.

Porphyromonas Gingivalis Infection Induces Synaptic Failure via Increased IL-1β Production in Leptomeningeal Cells. - Huang, Wanyi; Zeng, Fan; Gu, Yebo; Jiang, Muzhou; Zhang, Xinwen; Yan, Xu; Kadowaki, Tomoko; Mizutani, Shinsuke; Kashiwazaki, Haruhiko; Ni, Junjun; Wu, Zhou (J Alzheimers Dis, 2021)
BACKGROUND: Studies have reported that synaptic failure occurs before the Alzheimer's disease (AD) onset. The systemic Porphyromonas gingivalis (P. gingivalis) infection is involved in memory decline. We previously showed that leptomeningeal cells, covering the brain, activate glial cells by releasing IL-1β in response to systemic inflammation. OBJECTIVE: In the present study, we focused on the impact of leptomeningeal cells on neurons during systemic P. gingivalis infection. METHODS: The responses of leptomeningeal cells and cortical neurons to systemic P. gingivalis infection were examined in 15-month-old mice. The mechanism of IL-1β production by P. gingivalis infected leptomeningeal cells was examined, and primary cortical neurons were treated with P. gingivalis infected leptomeningeal cells condition medium (Pg LCM). RESULTS: Systemic P. gingivalis infection increased the expression of IL-1β in leptomeninges and reduced the synaptophysin (SYP) expression in leptomeninges proximity cortex in mice. Leptomeningeal cells phagocytosed P. gingivalis resulting in lysosomal rupture and Cathepsin B (CatB) leakage. Leaked CatB mediated NLRP3 inflammasome activation inducing IL-1β secretion in leptomeningeal cells. Pg LCM decreased the expression of synaptic molecules, including SYP, which was inhibited by an IL-1 receptor antagonist pre-treatment. CONCLUSION: These observations demonstrate that P. gingivalis infection is involved in synaptic failure by inducing CatB/NLRP3 inflammasome-mediated IL-1β production in leptomeningeal cells. The periodontal bacteria-induced synaptic damage may accelerate the onset and cognitive decline of AD.

Porphyromonas gingivalis Outer Membrane Vesicles as the Major Driver of and Explanation for Neuropathogenesis, the Cholinergic Hypothesis, Iron Dyshomeostasis, and Salivary Lactoferrin in Alzheimer's Disease. - Nara, Peter L; Sindelar, Daniel; Penn, Marc S; Potempa, Jan; Griffin, W Sue T (J Alzheimers Dis, 2021)
Porphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm-induced "chronic" multi-systems inflammatory disease(s) including Alzheimer's disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention. The published literature around the role of Pg in AD highlights the bacteria's direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the "infection hypothesis" of AD. A better explanation is offered here for the discrepancy in the relatively low amounts of "Pg bacteria" residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial protein toxins. Related to this, the "Gingipains Hypothesis", AD-related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases. Thus it is hoped this paper can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention.
Keywords: Alzheimer Disease; Anti-Infective Agents; Bacterial Outer Membrane Proteins; Bacteroidaceae Infections; Brain; Cholinergic Agents; Extremophiles; Humans; Iron; Lactoferrin; Porphyromonas gingivalis; Saliva

Promoting Successful Cognitive Aging: A Ten-Year Update. - Krivanek, Taylor J; Gale, Seth A; McFeeley, Brittany M; Nicastri, Casey M; Daffner, Kirk R (J Alzheimers Dis, 2021)
A decade has passed since we published a comprehensive review in this journal addressing the topic of promoting successful cognitive aging, making this a good time to take stock of the field. Because there have been limited large-scale, randomized controlled trials, especially following individuals from middle age to late life, some experts have questioned whether recommendations can be legitimately offered about reducing the risk of cognitive decline and dementia. Despite uncertainties, clinicians often need to at least make provisional recommendations to patients based on the highest quality data available. Converging lines of evidence from epidemiological/cohort studies, animal/basic science studies, human proof-of-concept studies, and human intervention studies can provide guidance, highlighting strategies for enhancing cognitive reserve and preventing loss of cognitive capacity. Many of the suggestions made in 2010 have been supported by additional research. Importantly, there is a growing consensus among major health organizations about recommendations to mitigate cognitive decline and promote healthy cognitive aging. Regular physical activity and treatment of cardiovascular risk factors have been supported by all of these organizations. Most organizations have also embraced cognitively stimulating activities, a heart-healthy diet, smoking cessation, and countering metabolic syndrome. Other behaviors like regular social engagement, limiting alcohol use, stress management, getting adequate sleep, avoiding anticholinergic medications, addressing sensory deficits, and protecting the brain against physical and toxic damage also have been endorsed, although less consistently. In this update, we review the evidence for each of these recommendations and offer practical advice about behavior-change techniques to help patients adopt brain-healthy behaviors.
Keywords: Cognition; Cognitive Aging; Diet, Healthy; Exercise; Healthy Aging; Healthy Lifestyle; Humans

Putative Blood Somatic Mutations in Post-Traumatic Stress Disorder-Symptomatic Soldiers: High Impact of Cytoskeletal and Inflammatory Proteins. - Sragovich, Shlomo; Gershovits, Michael; Lam, Jacqueline C K; Li, Victor O K; Gozes, Illana (J Alzheimers Dis, 2021)
BACKGROUND: We recently discovered autism/intellectual disability somatic mutations in postmortem brains, presenting higher frequency in Alzheimer's disease subjects, compared with the controls. We further revealed high impact cytoskeletal gene mutations, coupled with potential cytoskeleton-targeted repair mechanisms. OBJECTIVE: The current study was aimed at further discerning if somatic mutations in brain diseases are presented only in the most affected tissue (the brain), or if blood samples phenocopy the brain, toward potential diagnostics. METHODS: Variant calling analyses on an RNA-seq database including peripheral blood samples from 85 soldiers (58 controls and 27 with symptoms of post-traumatic stress disorder, PTSD) was performed. RESULTS: High (e.g., protein truncating) as well as moderate impact (e.g., single amino acid change) germline and putative somatic mutations in thousands of genes were found. Further crossing the mutated genes with autism, intellectual disability, cytoskeleton, inflammation, and DNA repair databases, identified the highest number of cytoskeletal-mutated genes (187 high and 442 moderate impact). Most of the mutated genes were shared and only when crossed with the inflammation database, more putative high impact mutated genes specific to the PTSD-symptom cohorts versus the controls (14 versus 13) were revealed, highlighting tumor necrosis factor specifically in the PTSD-symptom cohorts. CONCLUSION: With microtubules and neuro-immune interactions playing essential roles in brain neuroprotection and Alzheimer-related neurodegeneration, the current mutation discoveries contribute to mechanistic understanding of PTSD and brain protection, as well as provide future diagnostics toward personalized military deployment strategies and drug design.

Quantifying and Examining Reserve in Symptomatic Former National Football League Players. - Foley, Éimear M; Tripodis, Yorghos; Yhang, Eukyung; Koerte, Inga K; Martin, Brett M; Palmisano, Joseph; Makris, Nikos; Schultz, Vivian; Lepage, Chris; Muehlmann, Marc; Wróbel, Paweł P; Guenette, Jeffrey P; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Repetitive head impacts (RHI) from contact sports have been associated with cognitive and neuropsychiatric disorders. However, not all individuals exposed to RHI develop such disorders. This may be explained by the reserve hypothesis. It remains unclear if the reserve hypothesis accounts for the heterogenous symptom presentation in RHI-exposed individuals. Moreover, optimal measurement of reserve in this population is unclear and likely unique from non-athlete populations. OBJECTIVE: We examined the association between metrics of reserve and cognitive and neuropsychiatric functioning in 89 symptomatic former National Football League players. METHODS: Individual-level proxies (e.g., education) defined reserve. We additionally quantified reserve as remaining residual variance in 1) episodic memory and 2) executive functioning performance, after accounting for demographics and brain pathology. Associations between reserve metrics and cognitive and neuropsychiatric functioning were examined. RESULTS: Higher reading ability was associated with better attention/information processing (β=0.25; 95% CI, 0.05-0.46), episodic memory (β=0.27; 95% CI, 0.06-0.48), semantic and phonemic fluency (β=0.24; 95% CI, 0.02-0.46; β=0.38; 95% CI, 0.17-0.59), and behavioral regulation (β=-0.26; 95% CI, -0.48, -0.03) performance. There were no effects for other individual-level proxies. Residual episodic memory variance was associated with better attention/information processing (β=0.45; 95% CI, 0.25, 0.65), executive functioning (β=0.36; 95% CI, 0.15, 0.57), and semantic fluency (β=0.38; 95% CI, 0.17, 0.59) performance. Residual executive functioning variance was associated with better attention/information processing (β=0.44; 95% CI, 0.24, 0.64) and episodic memory (β=0.37; 95% CI, 0.16, 0.58) performance. CONCLUSION: Traditional reserve proxies (e.g., years of education, occupational attainment) have limitations and may be unsuitable for use in elite athlete samples. Alternative approaches of reserve quantification may prove more suitable for this population.

Race-Related Association between APOE Genotype and Alzheimer's Disease: A Systematic Review and Meta-Analysis. - Qin, Wei; Li, Wenwen; Wang, Qi; Gong, Min; Li, Tingting; Shi, Yuqing; Song, Yang; Li, Ying; Li, Fangyu; Jia, Jianping (J Alzheimers Dis, 2021)
BACKGROUND: The global race-dependent association of Alzheimer's disease (AD) and apolipoprotein E (APOE) genotype is not well understood. Transethnic analysis of APOE could clarify the role of genetics in AD risk across populations. OBJECTIVE: This study aims to determine how race and APOE genotype affect the risks for AD. METHODS: We performed a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library since 1993 to Aug 25, 2020. A total of 10,395 reports were identified, and 133 were eligible for analysis with data on 77,402 participants. Studies contained AD clinical diagnostic and APOE genotype data. Homogeneous data sets were pooled in case-control analyses. Odds ratios and 95% confidence intervals for developing AD were calculated for populations of different races and APOE genotypes. RESULTS: The proportion of APOE genotypes and alleles differed between populations of different races. Results showed that APOEɛ4 was a risk factor for AD, whereas APOEɛ2 protected against it. The effects of APOEɛ4 and ɛ2 on AD risk were distinct in various races, and they were substantially attenuated among Black people. Sub-group analysis found a higher frequency of APOEɛ4/ɛ4 and lower frequency of APOEɛ3/ɛ3 among early-onset AD than late-onset AD in a combined group and different races. CONCLUSION: Our meta-analysis suggests that the association of APOE genotypes and AD differ among races. These results enhance our understanding of APOE-related risk for AD across race backgrounds and provide new insights into precision medicine for AD.
Keywords: Alleles; Alzheimer Disease; Apolipoprotein E2; Apolipoprotein E4; Apolipoproteins E; Genotype; Humans; Racial Groups

Relevance of a Truncated PRESENILIN 2 Transcript to Alzheimer's Disease and Neurodegeneration. - Moussavi Nik, Seyyed Hani; Porter, Tenielle; Newman, Morgan; Bartlett, Benjamin; Khan, Imran; Sabale, Miheer; Eccles, Melissa; Woodfield, Amy; Groth, David; Doré, Vincent; Villemagne, Victor L; Masters, Colin L; et al. (J Alzheimers Dis, 2021)
BACKGROUND: The PRESENILIN genes (PSEN1, PSEN2) encoding for their respective proteins have critical roles in many aspects of Alzheimer's disease (AD) pathogenesis. The PS2V transcript of PSEN2 encodes a truncated protein and is upregulated in AD brains; however, its relevance to AD and disease progression remains to be determined. OBJECTIVE: Assess transcript levels in postmortem AD and non-AD brain tissue and in lymphocytes collected under the Australian Imaging Biomarker and Lifestyle (AIBL) study. METHODS: Full length PSEN2 and PS2V transcript levels were assessed by quantitative digital PCR in postmortem brain tissue (frontal cortex and hippocampus) from control, AD, frontotemporal dementia (FTD), and Lewy body dementia (LBD). Transcript levels were also assessed in lymphocytes obtained from the Perth subset of the AIBL study (n = 160). Linear regression analysis was used to assess correlations between transcript copy number and brain volume and neocortical amyloid load. RESULTS: PS2V levels increased in AD postmortem brain but PS2V was also present at significant levels in FTD and LBD brains. PS2V transcript was detected in lymphocytes and PS2V/PSEN2 ratios were increased in mild cognitive impairment (p = 0.024) and AD (p = 0.019) groups compared to control group. Increased ratios were significantly correlated with hippocampal volumes only (n = 62, β= -0.269, p = 0.03). CONCLUSION: Taken together, these results suggest that PS2V may be a marker of overall neurodegeneration.

Research Attitudes and Interest Among Elderly Latinxs: The Impact of a Collaborative Video and Community Peers. - Sewell, Margaret C; Neugroschl, Judith; Umpierre, Mari; Chin, Shehan; Zhu, Carolyn W; Velasco, Nelly; Gonzalez, Sabrina; Acabá-Berrocal, Alexandra; Bianchetti, Luca; Silva, Gabriela; Collazo, Alma; Sano, Mary (J Alzheimers Dis, 2021)
BACKGROUND: Latinx elders are underrepresented in dementia research. In a previous study we assessed research attitudes in urban minority elders and found a significant minority expressed neutral to negative attitudes relating to trust, safety, and personal responsibility to help research. OBJECTIVE: To assess the impact of a composite intervention on attitudes toward research and research participation among elderly Latinx. The intervention was a collaboratively produced research participation video shown during presentations with our elderly community advisory board (CAB) as co-presenters. METHODS: The video was created by the ADRC and CAB. All senior center attendees were eligible to participate. Afterwards, the Research Attitudes Questionnaire (RAQ) and a brief questionnaire on the impact of the video were administered. Using Wilcoxon Rank Sum Tests, Chi Square, and OLS regressions, RAQ responses were compared to those from a historical cohort from similar centers. RESULTS: 74 in the "Historical Cohort 1" and 104 in "Intervention Cohort 2" were included. RAQ total score was higher in Cohort 2 than Cohort 1 (28.5 versus 26.1, p <  0.05) after controlling for age, education, and country of origin. In response to the question "Has the video influenced your willingness and interest to participate in research", 88.7%of the participants in Cohort 2 reported being "more" or "much more" interested in research. CONCLUSION: Tailoring community research recruitment programs to include relatable peers using novel recruitment techniques may have positive implications for improving enrollment of diverse elderly individuals in research.

The Retinal Vessel Density Can Reflect Cognitive Function in Patients with Alzheimer's Disease: Evidence from Optical Coherence Tomography Angiography. - Yan, Yibing; Wu, Xingqi; Wang, Xiaojing; Geng, Zhi; Wang, Lu; Xiao, Guixian; Wu, Yue; Zhou, Shanshan; Liao, Rongfeng; Wei, Ling; Tian, Yanghua; Wang, Kai (J Alzheimers Dis, 2021)
BACKGROUND: There is increasing evidence that Alzheimer's disease (AD) patients may present decreased cerebral blood perfusion before pathological brain changes. Using the retina as a window to the brain, we can study disorders of the central nervous system through the eyes. OBJECTIVE: This study aimed to investigate differences in retinal structure and vessel density (VD) between patients with mild AD and healthy controls (HCs). Furthermore, we explored the relationship between retinal VD and cognitive function. METHODS: We enrolled 37 patients with AD and 29 age-matched HCs who underwent standard ophthalmic optical coherence tomography angiography (OCTA) for evaluation of the retinal layer thickness and VD parameters. Cognitive function was evaluated using a battery of neuropsychological assessments. Finally, the correlations among retinal layer thickness, VD parameters, and cognitive function were evaluated. RESULTS: The retinal fiber layer thickness and retinal VD of patients with AD were significantly reduced compared with HCs. The retinal VD was significantly correlated with overall cognition, memory, executive, and visual-spatial perception functions. However, there was no significant between-group difference in the macular thickness. CONCLUSION: Our findings indicate a positive correlation between retinal VD and some, but not all, cognitive function domains. Most importantly, we demonstrated the role of OCTA in detecting early capillary changes, which could be a noninvasive biomarker for early AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cognition; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Retinal Vessels; Tomography, Optical Coherence

The Right Temporal Variant of Frontotemporal Dementia Is Not Genetically Sporadic: A Case Series. - Ulugut Erkoyun, Hulya; van der Lee, Sven J; Nijmeijer, Bas; van Spaendonk, Rosalina; Nelissen, Anne; Scarioni, Marta; Dijkstra, Anke; Samancı, Bedia; Gürvit, Hakan; Yıldırım, Zerrin; Tepgeç, Fatih; Bilgic, Basar; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Right temporal variant frontotemporal dementia (rtvFTD) has been generally considered as a right sided variant of semantic variant primary progressive aphasia (svPPA), which is a genetically sporadic disorder. Recently, we have shown that rtvFTD has a unique clinical syndrome compared to svPPA and behavioral variant frontotemporal dementia. OBJECTIVE: We challenge the assumption that rtvFTD is a sporadic, non-familial variant of FTD by identifying potential autosomal dominant inheritance and related genes in rtvFTD. METHODS: We collected all subjects with a diagnosis of FTD or primary progressive aphasia who had undergone genetic screening (n = 284) and subsequently who had a genetic variant (n = 48) with a diagnosis of rtvFTD (n = 6) in 2 specialized memory clinics. RESULTS: Genetic variants in FTD related genes were found in 33% of genetically screened rtvFTD cases; including MAPT (n = 4), GRN (n = 1), and TARDBP (n = 1) genes, whereas only one svPPA case had a genetic variant in our combined cohorts. Additionally, 4 out of 6 rtvFTD subjects had a strong family history for dementia. CONCLUSION: Our results demonstrate that rtvFTD, unlike svPPA, is not a pure sporadic, but a heterogeneous potential genetic variant of FTD, and screening for genetic causes for FTD should be performed in patients with rtvFTD.
Keywords: Aphasia, Primary Progressive; DNA-Binding Proteins; Female; Frontotemporal Dementia; Functional Laterality; Genetic Testing; Genetic Variation; Gyrus Cinguli; Humans; Male; Middle Aged; Progranulins; tau Proteins

Risk Variants in Three Alzheimer's Disease Genes Show Association with EEG Endophenotypes. - Macedo, Ana; Gómez, Carlos; Rebelo, Miguel Ângelo; Poza, Jesús; Gomes, Iva; Martins, Sandra; Maturana-Candelas, Aarón; Pablo, Víctor Gutiérrez-de; Durães, Luis; Sousa, Patrícia; Figueruelo, Manuel; Rodriguez, Maria; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Dementia due to Alzheimer's disease (AD) is a complex neurodegenerative disorder, which much of heritability remains unexplained. At the clinical level, one of the most common physiological alterations is the slowing of oscillatory brain activity, measurable by electroencephalography (EEG). Relative power (RP) at the conventional frequency bands (i.e., delta, theta, alpha, beta-1, and beta-2) can be considered as AD endophenotypes. OBJECTIVE: The aim of this work is to analyze the association between sixteen genes previously related with AD: APOE, PICALM, CLU, BCHE, CETP, CR1, SLC6A3, GRIN2 β, SORL1, TOMM40, GSK3 β, UNC5C, OPRD1, NAV2, HOMER2, and IL1RAP, and the slowing of the brain activity, assessed by means of RP at the aforementioned frequency bands. METHODS: An Iberian cohort of 45 elderly controls, 45 individuals with mild cognitive impairment, and 109 AD patients in the three stages of the disease was considered. Genomic information and brain activity of each subject were analyzed. RESULTS: The slowing of brain activity was observed in carriers of risk alleles in IL1RAP (rs10212109, rs9823517, rs4687150), UNC5C (rs17024131), and NAV2 (rs1425227, rs862785) genes, regardless of the disease status and situation towards the strongest risk factors: age, sex, and APOE ɛ4 presence. CONCLUSION: Endophenotypes reduce the complexity of the general phenotype and genetic variants with a major effect on those specific traits may be then identified. The found associations in this work are novel and may contribute to the comprehension of AD pathogenesis, each with a different biological role, and influencing multiple factors involved in brain physiology.

Stages of Objective Memory Impairment Predict Alzheimer's Disease Neuropathology: Comparison with the Clinical Dementia Rating Scale-Sum of Boxes. - Grober, Ellen; Qi, Qi; Kuo, Lynn; Hassenstab, Jason; Perrin, Richard J; Lipton, Richard B (J Alzheimers Dis, 2021)
BACKGROUND: The ultimate validation of a clinical marker for Alzheimer's disease (AD) is its association with AD neuropathology. OBJECTIVE: To examine how well the Stages of Objective Memory Impairment (SOMI) system predicts intermediate/high AD neuropathologic change and extent of neurofibrillary tangle (NFT) pathology defined by Braak stage, in comparison to the Clinical Dementia Rating (CDR) Scale sum of boxes (CDR-SB). METHODS: 251 well-characterized participants from the Knight ADRC clinicopathologic series were classified into SOMI stage at their last assessment prior to death using the free recall and total recall scores from the picture version of the Free and Cued Selective Reminding Test with Immediate Recall (pFCSRT + IR). Logistic regression models assessed the predictive validity of SOMI and CDR-SB for intermediate/high AD neuropathologic change. Receiver operating characteristics (ROC) analysis evaluated the discriminative validity of SOMI and CDR-SB for AD pathology. Ordinal logistic regression was used to predict Braak stage using SOMI and CDR-SB in separate and joint models. RESULTS: The diagnostic accuracy of SOMI for AD diagnosis was similar to that of the CDR-SB (AUC: 85%versus 83%). In separate models, both SOMI and CDR-SB predicted Braak stage. In a joint model SOMI remained a significant predictor of Braak stage but CDR-SB did not. CONCLUSION: SOMI provides a neuropathologically validated staging system for episodic memory impairment in the AD continuum and should be useful in predicting tau positivity based on its association with Braak stage.

Substance Use-Related Cognitive Decline in Families with Autosomal Dominant Alzheimer's Disease: A Cohort Study. - Ramos, Claudia; Villalba, Camilo; García, Jenny; Lanata, Serggio; López, Hugo; Aguillón, David; Cordano, Christian; Madrigal, Lucía; Aguirre-Acevedo, Daniel C; Lopera, Francisco (J Alzheimers Dis, 2021)
BACKGROUND: Cigarette smoking is a known risk factor for Alzheimer's disease (AD). However, the association between neurodegeneration and other substances has not been fully determined. It is of vital importance to evaluate this relationship in populations at high risk of dementia. Since substance use possibly modifies the progression rate of cognitive decline, we studied this association in a unique and well-phenotyped cohort from the University of Antioquia: carriers of the PSEN1-E280A genetic variant. OBJECTIVE: To determine the association between substance use and cognitive decline in carriers of the PSEN1-E280A genetic variant. METHODS: A retrospective cohort study was conducted with 94 carriers and 69 noncarriers recruited between January 2019 and April 2020. A psychiatrist interviewed the participants using the Consumption of Alcohol, Cigarettes and other Substances questionnaire. The participants were also submitted to cognitive evaluation. The relationship between cognitive decline and substance use was explored through a mixed effects regression model. RESULTS: There was an association between cigarettes and better performance on tasks related to perceptual organization, verbal fluency, and memory in carriers. Alcohol had a positive or negative effect on memory according to the type of alcoholic beverage. Results on marijuana use were no conclusive. Coffee was associated with progressive improvements in executive function and verbal fluency. CONCLUSION: Cigarette and alcohol were associated with an improvement of some cognitive assessments, possibly by a survival bias. In addition, coffee was related to improvements in executive function and language; therefore, its short-term neuroprotective potential should be studied.

A Super-Resolved View of the Alzheimer's Disease-Related Amyloidogenic Pathway in Hippocampal Neurons. - Yu, Yang; Gao, Yang; Winblad, Bengt; Tjernberg, Lars O; Schedin-Weiss, Sophia (J Alzheimers Dis, 2021)
BACKGROUND: Processing of the amyloid-β protein precursor (AβPP) is neurophysiologically important due to the resulting fragments that regulate synapse biology, as well as potentially harmful due to generation of the 42 amino acid long amyloid β-peptide (Aβ42), which is a key player in Alzheimer's disease. OBJECTIVE: Our aim was to clarify the subcellular locations of the fragments involved in the amyloidogenic pathway in primary neurons with a focus on Aβ42 and its immediate substrate AβPP C-terminal fragment (APP-CTF). To overcome the difficulties of resolving these compartments due to their small size, we used super-resolution microscopy. METHODS: Mouse primary hippocampal neurons were immunolabelled and imaged by stimulated emission depletion (STED) microscopy, including three-dimensional three-channel imaging, and quantitative image analyses. RESULTS: The first (β-secretase) and second (γ-secretase) cleavages of AβPP were localized to functionally and distally distinct compartments. The β-secretase cleavage was observed in early endosomes in soma, where we were able to show that the liberated N- and C-terminal fragments were sorted into distinct vesicles budding from the early endosomes. Lack of colocalization of Aβ42 and APP-CTF in soma suggested that γ-secretase cleavage occurs in neurites. Indeed, APP-CTF was, in line with Aβ42 in our previous study, enriched in the presynapse but absent from the postsynapse. In contrast, full-length AβPP was not detected in either the pre- or the postsynaptic side of the synapse. Furthermore, we observed that endogenously produced and endocytosed Aβ42 were localized in different compartments. CONCLUSION: These findings provide critical super-resolved insight into amyloidogenic AβPP processing in primary neurons.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Amyloidogenic Proteins; Animals; Cells, Cultured; Hippocampus; Humans; Mice; Mice, Inbred C57BL; Microscopy; Neurons; Peptide Fragments; Protein Transport

Taking the A Train? Limited Consistency of Aβ42 and the Aβ42/40 Ratio in the AT(N) Classification. - Gouilly, Dominique; Tisserand, Camille; Nogueira, Leonor; Saint-Lary, Laura; Rousseau, Vanessa; Benaiteau, Marie; Rafiq, Marie; Carlier, Jasmine; Milongo-Rigal, Emilie; Pagès, Jean-Christophe; Pariente, Jérémie (J Alzheimers Dis, 2021)
The consistency of cerebrospinal fluid amyloid-β (Aβ)42/40 ratio and Aβ 42 has not been assessed in the AT(N) classification system. We analyzed the classification changes of the dichotomized amyloid status (A+/A-) in 363 patients tested for Alzheimer's disease biomarkers after Aβ 42 was superseded by the Aβ 42/40 ratio. The consistency of Aβ 42 and the Aβ 42/40 ratio was very low. Notably, the proportions of "false" A+T-patients were considerable (74-91%) and corresponded mostly to patients not clinically diagnosed with Alzheimer's disease. Our results suggest that the interchangeability of Aβ 42/40 ratio and Aβ 42 is limited for classifying patients in clinical setting using the AT(N) scheme.

Thrombin Signaling Contributes to High Glucose-Induced Injury of Human Brain Microvascular Endothelial Cells. - Rao, Haripriya V; Bihaqi, Syed W; Iannucci, Jaclyn; Sen, Abhik; Grammas, Paula (J Alzheimers Dis, 2021)
BACKGROUND: Diabetes is one of the strongest disease-related risk factors for Alzheimer's disease (AD). In diabetics, hyperglycemia-induced microvascular complications are the major cause of end-organ injury, contributing to morbidity and mortality. Microvascular pathology is also an important and early feature of AD. The cerebral microvasculature may be a point of convergence of both diseases. Several lines of evidence also implicate thrombin in AD as well as in diabetes. OBJECTIVE: Our objective was to investigate the role of thrombin in glucose-induced brain microvascular endothelial injury. METHODS: Cultured Human brain microvascular endothelial cells (HBMVECs) were treated with 30 mM glucose±100 nM thrombin and±250 nM Dabigatran or inhibitors of PAR1, p38MAPK, MMP2, or MMP9. Cytotoxicity and thrombin activity assays on supernatants and western blotting for protein expression in lysates were performed. RESULTS: reatment of HBMVECs with 30 mM glucose increased thrombin activity and expression of inflammatory proteins TNFα, IL-6, and MMPs 2 and 9; this elevation was reduced by the thrombin inhibitor dabigatran. Direct treatment of brain endothelial cells with thrombin upregulated p38MAPK and CREB, and induced TNFα, IL6, MMP2, and MMP9 as well as oxidative stress proteins NOX4 and iNOS. Inhibition of thrombin, thrombin receptor PAR1 or p38MAPK decrease expression of inflammatory and oxidative stress proteins, implying that thrombin may play a central role in glucose-induced endothelial injury. CONCLUSION: Since preventing brain endothelial injury would preserve blood-brain barrier integrity, prevent neuroinflammation, and retain intact functioning of the neurovascular unit, inhibiting thrombin, or its downstream signaling effectors, could be a therapeutic strategy for mitigating diabetes-induced dementia.

TREM2 Deficiency Disrupts Network Oscillations Leading to Epileptic Activity and Aggravates Amyloid-β-Related Hippocampal Pathophysiology in Mice. - Stoiljkovic, Milan; Gutierrez, Karel Otero; Kelley, Craig; Horvath, Tamas L; Hajós, Mihály (J Alzheimers Dis, 2021)
BACKGROUND: Genetic mutations in triggering receptor expressed on myeloid cells-2 (TREM2) have been strongly associated with increased risk of developing Alzheimer's disease (AD) and other progressive dementias. In the brain, TREM2 protein is specifically expressed on microglia suggesting their active involvement in driving disease pathology. Using various transgenic AD models to interfere with microglial function through TREM2, several recent studies provided important data indicating a causal link between TREM2 and underlying amyloid-β (Aβ) and tau pathology. However, mechanisms by which TREM2 contributes to increased predisposition to clinical AD and influences its progression still remain largely unknown. OBJECTIVE: Our aim was to elucidate the potential contribution of TREM2 on specific oscillatory dynamic changes associated with AD pathophysiology. METHODS: Spontaneous and brainstem nucleus pontis oralis stimulation-induced hippocampal oscillation paradigm was used to investigate the impact of TREM2 haploinsufficiency TREM2(Het) or total deficiency TREM2(Hom) on hippocampal network function in wild-type and Aβ overproducing Tg2576 mice under urethane anesthesia. RESULTS: Partial (TREM2(Het)) or total (TREM2(Hom)) deletion of TREM2 led to increased incidence of spontaneous epileptiform seizures in both wild-type and Tg2576 mice. Importantly, deficiency of TREM2 in Tg2576 mice significantly diminished power of theta oscillation in the hippocampus elicited by brainstem-stimulation compared to wild-type mice. However, it did not affect hippocampal theta-phase gamma-amplitude coupling significantly, since over a 60%reduction was found in coupling in Tg2576 mice regardless of TREM2 function. CONCLUSION: Our findings indicate a role for TREM2-dependent microglial function in the hippocampal neuronal excitability in both wild type and Aβ overproducing mice, whereas deficiency in TREM2 function exacerbates disruptive effects of Aβ on hippocampal network oscillations.

Upregulation of Cortical A2A Adenosine Receptors Is Reflected in Platelets of Patients with Alzheimer's Disease. - Merighi, Stefania; Battistello, Enrica; Casetta, Ilaria; Gragnaniello, Daniela; Poloni, Tino Emanuele; Medici, Valentina; Cirrincione, Alice; Varani, Katia; Vincenzi, Fabrizio; Borea, Pier Andrea; Gessi, Stefania (J Alzheimers Dis, 2021)
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative pathology covering about 70%of all cases of dementia. Adenosine, a ubiquitous nucleoside, plays a key role in neurodegeneration, through interaction with four receptor subtypes. The A2A receptor is upregulated in peripheral blood cells of patients affected by Parkinson's and Huntington's diseases, reflecting the same alteration found in brain tissues. However, whether these changes are also present in AD pathology has not been determined. OBJECTIVE: In this study we verified any significant difference between AD cases and controls in both brain and platelets and we evaluated whether peripheral A2A receptors may reflect the status of neuronal A2A receptors. METHODS: We evaluated the expression of A2A receptors in frontal white matter, frontal gray matter, and hippocampus/entorhinal cortex, in postmortem AD patients and control subjects, through [3H]ZM 241385 binding experiments. The same analysis was performed in peripheral platelets from AD patients versus controls. RESULTS: The expression of A2A receptors in frontal white matter, frontal gray matter, and hippocampus/entorhinal cortex, revealed a density (Bmax) of 174±29, 219±33, and 358±84 fmol/mg of proteins, respectively, in postmortem AD patients in comparison to 104±16, 103±19, and 121±20 fmol/mg of proteins in controls (p < 0.01). The same trend was observed in peripheral platelets from AD patients versus controls (Bmax of 214±17 versus 95±4 fmol/mg of proteins, respectively, p < 0.01). CONCLUSION: AD subjects show significantly higher A2A receptor density than controls. Values on platelets seem to correlate with those in the brain supporting a role for A2A receptor as a possible marker of AD pathology and drug target for novel therapies able to modify the progression of dementia.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Blood Platelets; Cerebral Cortex; Female; Humans; Male; Receptor, Adenosine A2A; Up-Regulation

White Matter Connectivity in Incident Mild Cognitive Impairment: A Diffusion Spectrum Imaging Study of World Trade Center Responders at Midlife. - Huang, Chuan; Kritikos, Minos; Clouston, Sean A P; Deri, Yael; Serrano-Sosa, Mario; Bangiyev, Lev; Santiago-Michels, Stephanie; Gandy, Sam; Sano, Mary; Bromet, Evelyn J; Luft, Benjamin J (J Alzheimers Dis, 2021)
BACKGROUND: Individuals who participated in response efforts at the World Trade Center (WTC) following 9/11/2001 are experiencing elevated incidence of mild cognitive impairment (MCI) at midlife. OBJECTIVE: We hypothesized that white matter connectivity measured using diffusion spectrum imaging (DSI) would be restructured in WTC responders with MCI versus cognitively unimpaired responders. METHODS: Twenty responders (mean age 56; 10 MCI/10 unimpaired) recruited from an epidemiological study were characterized using NIA-AA criteria alongside controls matched on demographics (age/sex/occupation/race/education). Axial DSI was acquired on a 3T Siemen's Biograph mMR scanner (12-channel head coil) using a multi-band diffusion sequence. Connectometry examined whole-brain tract-level differences in white matter integrity. Fractional anisotropy (FA), mean diffusivity (MD), and quantified anisotropy were extracted for region of interest (ROI) analyses using the Desikan-Killiany atlas. RESULTS: Connectometry identified both increased and decreased connectivity within regions of the brains of responders with MCI identified in the corticothalamic pathway and cortico-striatal pathway that survived adjustment for multiple comparisons. MCI was also associated with higher FA values in five ROIs including in the rostral anterior cingulate; lower MD values in four ROIs including the left rostral anterior cingulate; and higher MD values in the right inferior circular insula. Analyses by cognitive domain revealed nominal associations in domains of response speed, verbal learning, verbal retention, and visuospatial learning. CONCLUSIONS: WTC responders with MCI at midlife showed early signs of neurodegeneration characterized by both increased and decreased white matter diffusivity in regions commonly affected by early-onset Alzheimer's disease.
Keywords: Brain; Cognitive Dysfunction; Diffusion Tensor Imaging; Emergency Responders; Female; Humans; Incidence; Male; Middle Aged; September 11 Terrorist Attacks; White Matter

ABCA7 Genotype Moderates the Effect of Aerobic Exercise Intervention on Generalization of Prior Learning in Healthy Older African Americans. - Sinha, Neha; Berg, Chelsie N; Shaw, Ashlee; Gluck, Mark A (J Alzheimers Dis, 2020)
African Americans are at elevated risk for age-related cognitive decline, with double the prevalence of Alzheimer's disease (AD) compared to Caucasians Americans. Various behavioral, biological, and lifestyle factors may underlie this health disparity, but little is known about the relative importance and interactions among these different risk factors in African Americans. While the neuroprotective effects of aerobic exercise on biomarkers are well established, few studies have examined the differential benefits of exercise based on genetic risk for AD. Furthermore, evidence is limited regarding the potential moderating effects of ABCA7, a gene known to confer significantly greater AD risk in African Americans. In a case-control matched sample of 56 healthy older African Americans, we investigated the effect of an aerobic exercise intervention on a hippocampus-related assessment of generalization following rule learning, in individuals who were carriers of the ABCA7 rs3764650 non-risk (TT) or high-risk (GG) genotypes. Following the exercise-intervention, the non-risk group made significantly fewer generalization errors, while there was no improvement in generalization for the high-risk group. For the controls, no changes in generalization scores were observed regardless of genotype status. Our results indicate that the ongoing adverse effects of ABCA7 high-risk genotype may diminish the benefits associated with aerobic exercise. As such, the potential disease-modifying effects of aerobic exercise on AD-related neuropathology may be limited to carriers of the ABCA7 rs3764650 non-risk genotype.

An Active Lifestyle Is Associated with Better Cognitive Function Over Time in APOE ɛ4 Non-Carriers. - Fernández-Matarrubia, Marta; Goni, Leticia; Rognoni, Teresa; Razquin, Cristina; Fernández-Lázaro, César Ignacio; Bes-Rastrollo, Maira; Martínez-González, Miguel Ángel; Toledo, Estefanía (J Alzheimers Dis, 2020)
BACKGROUND: Available evidence on the association of physical activity (PA) or sedentary behavior with cognitive decline is inconclusive. OBJECTIVE: To assess the association between an active lifestyle score and leisure-time physical activity (LTPA) and changes in cognitive function in the Seguimiento Universidad de Navarra (SUN) prospective cohort. METHODS: Cognitive function was evaluated in a subsample of 806 participants of the SUN cohort study using the validated Telephone Interview for Cognitive Status-modified (STICS-m) questionnaire at baseline and after 6 years. LTPA was evaluated with a previously validated 17-item self-administered questionnaire and with information on sedentary lifestyles. We also calculated a multidimensional 8-item PA score. Multivariable linear regression analysis evaluated the association between PA and changes in cognitive function and its interaction by APOE genotype. RESULTS: Mean age of participants was 66 (SD 5.3) years and 69.7% were male. When stratifying by APOE variants, no significant associations between the active lifestyle score or LTPA and changes in cognitive performance over time were found among APOE ɛ4 carriers. However, we observed that a higher adherence to an active lifestyle (high versus low PA score β= 0.76 95% CI 0.15,1.36; p trend = 0.011) and a high LTPA (Q4 versus Q1 β= 0.63; 95% CI -0.01,1.26; p trend = 0.030) were associated with more favorable changes in cognitive function over time among APOE ɛ4 non-carriers with statistically significant interactions in both cases (p for interaction = 0.042 for PA score, and p = 0.039 for LTPA). CONCLUSION: The results of the present study suggest that an active lifestyle is associated with a better status of cognitive function over time only among APOE ɛ4 non-carriers.

Age of Migration and Cognitive Function Among Older Latinos in the United States. - Garcia, Marc A; Ortiz, Kasim; Arévalo, Sandra P; Diminich, Erica D; Briceño, Emily; Vega, Irving E; Tarraf, Wassim (J Alzheimers Dis, 2020)
BACKGROUND: Age of migration has been shown to have a robust association with Latino immigrant health outcomes; however, the relationship between timing of migration and cognition is less understood. OBJECTIVE: To examine associations between race/ethnicity, nativity, age of migration, and cognitive aging among US-born (USB) non-Latino Whites (NLW) and USB and foreign-born Latinos 50 years and older. METHODS: We used longitudinal biennial data from the Health and Retirement Study (HRS; 2006-2014) to fit generalized linear and linear latent growth curve models for: 1) global cognition (Modified Telephone Interview for Cognitive Status; TICS-M); 2) memory and attention subdomains of TICS-M; and 3) cognitive dysfunction. We also tested for sex modifications. RESULTS: In age and sex adjusted models, all Latino subgroups, independent of nativity and age of migration, had lower global and domain-specific cognitive scores and higher propensity of cognitive impairment classification compared to USB-NLWs. Differences between USB Latinos, but not other Latino subgroups, and USB-NLWs remained after full covariate adjustment. Latinas, independent of nativity or age of migration, had poorer cognitive scores relative to NLW females. Differences between all Latinos and USB-NLWs were principally expressed at baseline. Racial/ethnic, nativity, and age of migration grouping was not associated with slope (nor explained variance) of cognitive decline. CONCLUSION: Older US-born Latinos, regardless of sex exhibit poorer cognitive function than older USB-NLWs and foreign-born Latinos. Social determinants that differentially affect cognitive function, particularly those that compensate for education and sex differences among US-born Latinos and foreign-born Latinos, require further exploration.

Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes. - Brewer, Gregory J; Herrera, Robert A; Philipp, Stephan; Sosna, Justyna; Reyes-Ruiz, Jorge Mauricio; Glabe, Charles G (J Alzheimers Dis, 2020)
This work provides new insight into the age-related basis of Alzheimer's disease (AD), the composition of intraneuronal amyloid (iAβ), and the mechanism of an age-related increase in iAβ in adult AD-model mouse neurons. A new end-specific antibody for Aβ45 and another for aggregated forms of Aβ provide new insight into the composition of iAβ and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iAβ levels containing aggregates of Aβ45 increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iAβ was 8 times more abundant in 3xTg-AD than non-transgenic neurons with imaged particle sizes following the same log-log distribution, suggesting a similar snow-ball mechanism of intracellular biogenesis. Pathologically misfolded and mislocalized Alz50 tau colocalized with iAβ and rapidly increased following a brief metabolic stress with glutamate. AβPP-CTF, Aβ45, and aggregated Aβ colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iAβ by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long Aβs by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iAβ processing may lead to application of countermeasures to prolong dementia-free health span.

Aggregates of RNA Binding Proteins and ER Chaperones Linked to Exosomes in Granulovacuolar Degeneration of the Alzheimer's Disease Brain. - Yamoah, Alfred; Tripathi, Priyanka; Sechi, Antonio; Köhler, Christoph; Guo, Haihong; Chandrasekar, Akila; Nolte, Kay Wilhelm; Wruck, Christoph Jan; Katona, Istvan; Anink, Jasper; Troost, Dirk; Aronica, Eleonora; et al. (J Alzheimers Dis, 2020)
Granulovacuolar degeneration (GVD) occurs in Alzheimer's disease (AD) brain due to compromised autophagy. Endoplasmic reticulum (ER) function and RNA binding protein (RBP) homeostasis regulate autophagy. We observed that the ER chaperones GRP78/BiP, Sigma receptor 1 (SigR1), and VAPB were elevated in many AD patients' subicular neurons. However, those neurons which were affected by GVD showed lower chaperone levels, and there was only minor co-localization of chaperones with GVD bodies (GVBs), suggesting that neurons lacking sufficient chaperone-mediated proteostasis enter the GVD pathway. Consistent with this notion, granular, incipient pTau aggregates in human AD and pR5 tau transgenic mouse neurons were regularly co-localized with increased chaperone immunoreactivity, whereas neurons with mature neurofibrillary tangles lacked both the chaperone buildup and significant GVD. On the other hand, APP/PS1 (APPswe/PSEN1dE9) transgenic mouse hippocampal neurons that are devoid of pTau accumulation displayed only few GVBs-like vesicles, which were still accompanied by prominent chaperone buildup. Identifying a potential trigger for GVD, we found cytoplasmic accumulations of RBPs including Matrin 3 and FUS as well as stress granules in GVBs of AD patient and pR5 mouse neurons. Interestingly, we observed that GVBs containing aggregated pTau and pTDP-43 were consistently co-localized with the exosomal marker Flotillin 1 in both AD and pR5 mice. In contrast, intraneuronal 82E1-immunoreactive amyloid-β in human AD and APP/PS1 mice only rarely co-localized with Flotillin 1-positive exosomal vesicles. We conclude that altered chaperone-mediated ER protein homeostasis and impaired autophagy manifesting in GVD are linked to both pTau and RBP accumulation and that some GVBs might be targeted to exocytosis.

Aluminum and Amyloid-β in Familial Alzheimer's Disease. - Mold, Matthew; Linhart, Caroline; Gómez-Ramírez, Johana; Villegas-Lanau, Andrés; Exley, Christopher (J Alzheimers Dis, 2020)
Genetic predispositions associated with metabolism of the amyloid-β protein precursor underlie familial Alzheimer's disease; a form of dementia characterized by early disease onset and elevated levels of cortical amyloid-β. Human exposure to aluminum is linked to the etiology of Alzheimer's disease and recent research measured a high content of aluminum in brain tissue in familial Alzheimer's disease. To elaborate upon this finding, we have obtained brain tissues from a Colombian cohort of donors with familial Alzheimer's disease. We have used established methods to measure the aluminum content of these tissues and we have compared the data with a recently measured dataset for control brain tissues. We report significantly higher levels of aluminum in brain tissues in donors with familial Alzheimer's disease than in control tissues from donors without neurological impairment or neurodegeneration. We have used aluminum-specific fluorescence microscopy along with complementary imaging for amyloid-β to demonstrate a very high degree of co-localization of these two risk factors in brain tissue in familial Alzheimer's disease. Aluminum and amyloid-β were co-located in senile plaques as well as vasculature, the latter resembling cerebral amyloid angiopathy. Aluminum was also found separately from amyloid-β in intracellular compartments including glia and neuronal axons. The research has identified an arguably unique association between high brain aluminum content and amyloid-β and allows postulation that genetic predispositions defining familial Alzheimer's disease underlie this relationship.

The Amyloid, Tau, and Neurodegeneration (A/T/N) Classification Applied to a Clinical Research Cohort with Long-Term Follow-Up. - Grøntvedt, Gøril Rolfseng; Lauridsen, Camilla; Berge, Guro; White, Linda R; Salvesen, Øyvind; Bråthen, Geir; Sando, Sigrid Botne (J Alzheimers Dis, 2020)
BACKGROUND: The unbiased amyloid, tau, and neurodegeneration (A/T/N) classification is designed to characterize individuals in the Alzheimer continuum and is currently little explored in clinical cohorts. OBJECTIVE: A retrospective comparison of the A/T/N classification system with the results of a two-year clinical study, with extended follow-up up to 10 years after inclusion. METHODS: Patients (n = 102) clinically diagnosed as Alzheimer's disease (AD) with dementia or amnestic mild cognitive impairment (MCI), and 61 cognitively healthy control individuals were included. Baseline cerebrospinal fluid core biomarkers for AD (Aβ42, phosphorylated tau, and total tau) were applied to the A/T/N classification using the final clinical diagnosis at extended follow-up as the gold standard. RESULTS: A + T + N+ was a strong predictor for AD dementia, even among cognitively healthy individuals. Amnestic MCI was heterogenous, considering both clinical outcome and distribution within A/T/N. Some individuals with amnestic MCI progressed to clinical AD dementia within all four major A/T/N groups. The highest proportion of progression was among triple positive cases, but progression was also common in individuals with suspected non-Alzheimer pathophysiology (A-T + N+), and those with triple negative status. A-T-N- individuals who were cognitively healthy overwhelmingly remained cognitively intact over time, but in amnestic MCI the clinical outcome was heterogenous, including AD dementia, other dementias, and recovery. CONCLUSION: The A/T/N framework accentuates biomarkers over clinical status. However, when selecting individuals for research, a combination of the two may be necessary since the prognostic value of the A/T/N framework depends on clinical status.

Amyloid-β Causes Mitochondrial Dysfunction via a Ca2+-Driven Upregulation of Oxidative Phosphorylation and Superoxide Production in Cerebrovascular Endothelial Cells. - Quintana, Dominic D; Garcia, Jorge A; Anantula, Yamini; Rellick, Stephanie L; Engler-Chiurazzi, Elizabeth B; Sarkar, Saumyendra N; Brown, Candice M; Simpkins, James W (J Alzheimers Dis, 2020)
Cerebrovascular pathology is pervasive in Alzheimer's disease (AD), yet it is unknown whether cerebrovascular dysfunction contributes to the progression or etiology of AD. In human subjects and in animal models of AD, cerebral hypoperfusion and hypometabolism are reported to manifest during the early stages of the disease and persist for its duration. Amyloid-β is known to cause cellular injury in both neurons and endothelial cells by inducing the production of reactive oxygen species and disrupting intracellular Ca2+ homeostasis. We present a mechanism for mitochondrial degeneration caused by the production of mitochondrial superoxide, which is driven by increased mitochondrial Ca2+ uptake. We found that persistent superoxide production injures mitochondria and disrupts electron transport in cerebrovascular endothelial cells. These observations provide a mechanism for the mitochondrial deficits that contribute to cerebrovascular dysfunction in patients with AD.

Anterior Cingulate Structure and Perfusion Is Associated with Cerebrospinal Fluid Tau Among Cognitively Normal Older Adult APOEɛ4 Carriers. - Hays, Chelsea C; Zlatar, Zvinka Z; Meloy, M J; Osuna, Jessica; Liu, Thomas T; Galasko, Douglas R; Wierenga, Christina E (J Alzheimers Dis, 2020)
Evidence suggests the ɛ4 allele of the apolipoprotein E gene (APOE) may accelerate an age-related process of cortical thickening and cerebral blood flow (CBF) reduction in the anterior cingulate cortex (ACC). Although the neural basis of this association remains unclear, evidence suggests it might reflect early neurodegenerative processes. However, to date, associations between cerebrospinal fluid (CSF) biomarkers of neurodegeneration, such as CSF tau, and APOE-related alterations in ACC cortical thickness (CTH) and CBF have yet to be explored. The current study explored the interaction of CSF tau and APOE genotype (ɛ4+, ɛ4-) on FreeSurfer-derived CTH and arterial spin labeling MRI-measured resting CBF in the ACC (caudal ACC [cACC] and rostral ACC [rACC]) among a sample of 45 cognitively normal older adults. Secondary analyses also examined associations between APOE, CTH/CBF, and cognitive performance. In the cACC, higher CSF tau was associated with higher CTH and lower CBF in ɛ4+, whereas these relationships were not evident in ɛ4-. In the rACC, higher CSF tau was associated with higher CTH for both ɛ4+ and ɛ4-, and with lower CBF only in ɛ4+. Significant interactions of CSF tau and APOE on CTH/CBF were not observed in two posterior reference regions implicated in Alzheimer's disease. Secondary analyses revealed a negative relationship between cACC CTH and executive functioning in ɛ4+ and a positive relationship in ɛ4-. Findings suggest the presence of an ɛ4-related pattern of increased CTH and CBF reduction in the ACC that is associated with biomarkers of neurodegeneration and subtle decrements in cognition.

The Association of Post-Stroke Cognitive Impairment and Gut Microbiota and its Corresponding Metabolites. - Liu, Yongqiang; Kong, Cheng; Gong, Li; Zhang, Xiaohui; Zhu, Yuefei; Wang, Haichao; Qu, Xiao; Gao, Renyuan; Yin, Fang; Liu, Xueyuan; Qin, Huanlong (J Alzheimers Dis, 2020)
BACKGROUND: Post-stroke cognitive impairment (PSCI) is an important factor causing disabilities after acute ischemic stroke (AIS). Emerging evidence suggested that gut microbiota play an important role in cognitive impairment. OBJECTIVE: This study aimed to explore the association between PSCI and gut microbiota. METHOD: 65 patients with newly diagnostic AIS finished the fecal collection on admission and cognitive assessment 3 months later in the clinic. Fecal samples were subjected to 16SrRNA gene sequencing and gas chromatography-mass spectrometry analysis. Additionally, we enrolled new 18 AIS patients, whose treatment was supplemented by probiotics, to assess the potential of microbial treatment in PSCI. RESULTS: PSCI patients were characterized by the significantly decreased alpha-diversity, disturbed microbial composition, and corresponding metabolites compared with non-PSCI patients. Increased Fusobacterium and deficiency of microbial metabolized short-chain fatty acids (SCFAs) were significantly associated with PSCI. A model based on gut microbiota and SCFAs could predict 3 months or longer PSCI early and accurately after stroke onset. While traditional probiotic administration had little effect on PSCI, it could ameliorate patients' mood, including depression and anxiety in the 3 months after stroke. CONCLUSION: Our study revealed the association between PSCI and gut microbiota and its corresponding metabolites for the first time, suggesting the potential for applying microbiota and its corresponding metabolites to early clinical diagnosis and treatment of PSCI.

Brain Volume Predicts Behavioral and Psychological Symptoms in Alzheimer's Disease. - Boublay, Nawele; Bouet, Romain; Dorey, Jean-Michel; Padovan, Catherine; Makaroff, Zaza; Federico, Denis; Gallice, Isabelle; Barrellon, Marie-Odile; Robert, Philippe; Moreaud, Olivier; Rouch, Isabelle; Krolak-Salmon, Pierre (J Alzheimers Dis, 2020)
BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are frequent and troublesome for patients and caregivers. Considering possible preventive approaches, a better understanding of underlying neural correlates of BPSD is crucial. OBJECTIVE: The aim is to assess whether brain regional volume predicts behavioral changes in mild AD. METHODS: This work took part from the PACO study, a multicenter and prospective study that included 252 patients with mild AD from 2009 to 2014. Fifty-three patients were retained. Forty healthy matched control subjects from the ADNI cohort were included as controls. Voxel-based morphometry analysis was conducted to assess regional brain volume using baseline MRI scans as a predictor of future behavioral changes over a period of 18 months. Behavior was assessed at baseline and longitudinally at 6-month intervals using the shortened form of the Neuropsychiatric Inventory (NPI). RESULTS: The volume of 23 brain structures in frontal, temporal, parietal, occipital, subcortical regions and cerebellum predicted the evolution of NPI scores. Frontal volume was the most powerful predictor with frontal gyri, anterior cingulate cortex, and orbital gyri being particularly involved. CONCLUSION: To our knowledge, this is the first study assessing regional brain volumes as predictors of behavioral changes considered at earlier stages of AD. Up to 23 brain structures were associated with an increased risk of developing BPSD. Frontal lobe volume was the strongest predictor of future evolution of NPI. The involvement of multiple structures in the prediction of behavior suggests a role of the main large-scale networks involved in cognition.

Cerebrospinal Fluid Metals and the Association with Cerebral Small Vessel Disease. - Shams, Mana; Martola, Juha; Charidimou, Andreas; Granberg, Tobias; Ferreira, Daniel; Westman, Eric; Wintermark, Max; Iv, Michael; Larvie, Mykol; Kristoffersen Wiberg, Maria; Kaijser, Magnus; Forsgard, Niklas; et al. (J Alzheimers Dis, 2020)
BACKGROUND: Brain metal homeostasis is essential for brain health, and deregulation can result in oxidative stress on the brain parenchyma. OBJECTIVE: Our objective in this study was to focus on two hemorrhagic MRI manifestations of small vessel disease [cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS)] and associations with cerebrospinal fluid (CSF) iron levels. In addition, we aimed to analyze CSF biomarkers for dementia and associations with CSF metal levels. METHODS: This is a cross-sectional study of 196 patients who underwent memory clinic investigation, including brain MRI. CSF was collected and analyzed for metals, amyloid-β (Aβ) 42, total tau (T-tau), and phosphorylated tau (P-tau), and CSF/serum albumin ratios. Statistical analyses were performed using generalized linear models. RESULTS: No significant difference was found between CSF metal levels across diagnostic groups. Higher iron and copper levels were associated with higher CSF levels of Aβ42, T-tau, P-tau, and CSF/serum albumin ratios (p < 0.05). Zinc was associated with higher CSF/serum albumin ratios. There was no significant association between CMBs or cSS and CSF iron levels. An increase in CSF iron with the number of CMBs was seen in APOEɛ4 carriers. CONCLUSION: CSF iron levels are elevated with cerebral microbleeds in APOEɛ4 carriers, with no other association seen with hemorrhagic markers of small vessel disease. The association of elevated CSF iron and copper with tau could represent findings of increased neurodegeneration in these patients.

Cognitive Impairment Is a Common Comorbidity in Deceased COVID-19 Patients: A Hospital-Based Retrospective Cohort Study. - Martín-Jiménez, Paloma; Muñoz-García, Mariana I; Seoane, David; Roca-Rodríguez, Lucas; García-Reyne, Ana; Lalueza, Antonio; Maestro, Guillermo; Folgueira, Dolores; Blanco-Palmero, Víctor A; Herrero-San Martín, Alejandro; Llamas-Velasco, Sara; Pérez-Martínez, David A; et al. (J Alzheimers Dis, 2020)
We analyzed the frequency of cognitive impairment (CI) in deceased COVID-19 patients at a tertiary hospital in Spain. Among the 477 adult cases who died after admission from March 1 to March 31, 2020, 281 had confirmed COVID-19. CI (21.1% dementia and 8.9% mild cognitive impairment) was a common comorbidity. Subjects with CI were older, tended to live in nursing homes, had shorter time from symptom onset to death, and were rarely admitted to the ICU, receiving palliative care more often. CI is a frequent comorbidity in deceased COVID-19 subjects and is associated with differences in care.
Keywords: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Cognitive Dysfunction; Comorbidity; COVID-19; Female; Hospital Mortality; Hospitals; Humans; Male; Middle Aged; Palliative Care; Patient Admission; Retrospective Studies; Spain; Young Adult

A Community-Based Study Identifying Metabolic Biomarkers of Mild Cognitive Impairment and Alzheimer's Disease Using Artificial Intelligence and Machine Learning. - Yilmaz, Ali; Ustun, Ilyas; Ugur, Zafer; Akyol, Sumeyya; Hu, William T; Fiandaca, Massimo S; Mapstone, Mark; Federoff, Howard; Maddens, Michael; Graham, Stewart F (J Alzheimers Dis, 2020)
BACKGROUND: Currently, there is no objective, clinically available tool for the accurate diagnosis of Alzheimer's disease (AD). There is a pressing need for a novel, minimally invasive, cost friendly, and easily accessible tool to diagnose AD, assess disease severity, and prognosticate course. Metabolomics is a promising tool for discovery of new, biologically, and clinically relevant biomarkers for AD detection and classification. OBJECTIVE: Utilizing artificial intelligence and machine learning, we aim to assess whether a panel of metabolites as detected in serum can be used as an objective and clinically feasible tool for the diagnosis of mild cognitive impairment (MCI) and AD. METHODS: Using a community-based sample cohort acquired from different sites across the US, we adopted an approach combining Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR), Liquid Chromatography coupled with Mass Spectrometry (LC-MS). and various machine learning statistical approaches to identify a biomarker panel capable of identifying those patients with AD and MCI from healthy controls. RESULTS: Of the 212 measured metabolites, 5 were identified as optimal to discriminate between controls, and individuals with MCI or AD. Our models performed with AUC values in the range of 0.72-0.76, with the sensitivity and specificity values ranging from 0.75-0.85 and 0.69-0.81, respectively. Univariate and pathway analysis identified lipid metabolism as the most perturbed biochemical pathway in MCI and AD. CONCLUSION: A comprehensive method of acquiring metabolomics data, coupled with machine learning techniques, has identified a strong panel of diagnostic biomarkers capable of identifying individuals with MCI and AD. Further, our data confirm what other groups have reported in that lipid metabolism is significantly perturbed in those individuals suffering with dementia. This work may provide additional insight into AD pathogenesis and encourage more in-depth analysis of the AD lipidome.

Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia. - Shiells, Helen; Schelter, Bjoern O; Bentham, Peter; Baddeley, Thomas C; Rubino, Christopher M; Ganesan, Harish; Hammel, Jeffrey; Vuksanovic, Vesna; Staff, Roger T; Murray, Alison D; Bracoud, Luc; Wischik, Damon J; et al. (J Alzheimers Dis, 2020)
BACKGROUND: Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins. OBJECTIVE: To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD. METHODS: We undertook a 52-week Phase III study in 220 bvFTD patients randomized to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control). The principal outcomes were change on the Addenbrookes Cognitive Examination - Revised (ACE-R), the Functional Activities Questionnaire (FAQ), and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 175 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug. RESULTS: There were no significant differences between the two doses as randomized. There were steep concentration-response relationships for plasma levels in the range 0.3-0.6 ng/ml at the 8 mg/day dose on clinical and MRI outcomes. There were significant exposure-dependent differences at 8 mg/day for FAQ, Modified-CGIC, and whole brain atrophy comparing patients with plasma levels greater than 0.346 ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200 mg/day. CONCLUSIONS: Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8 mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20-60 mg/day. A confirmatory placebo-controlled trial is now planned.

COVID-19: Review of a 21st Century Pandemic from Etiology to Neuro-psychiatric Implications. - Yamamoto, Vicky; Bolanos, Joe F; Fiallos, John; Strand, Susanne E; Morris, Kevin; Shahrokhinia, Sanam; Cushing, Tim R; Hopp, Lawrence; Tiwari, Ambooj; Hariri, Robert; Sokolov, Rick; Wheeler, Christopher; et al. (J Alzheimers Dis, 2020)
COVID-19 is a severe infectious disease that has claimed >150,000 lives and infected millions in the United States thus far, especially the elderly population. Emerging evidence has shown the virus to cause hemorrhagic and immunologic responses, which impact all organs, including lungs, kidneys, and the brain, as well as extremities. SARS-CoV-2 also affects patients', families', and society's mental health at large. There is growing evidence of re-infection in some patients. The goal of this paper is to provide a comprehensive review of SARS-CoV-2-induced disease, its mechanism of infection, diagnostics, therapeutics, and treatment strategies, while also focusing on less attended aspects by previous studies, including nutritional support, psychological, and rehabilitation of the pandemic and its management. We performed a systematic review of >1,000 articles and included 425 references from online databases, including, PubMed, Google Scholar, and California Baptist University's library. COVID-19 patients go through acute respiratory distress syndrome, cytokine storm, acute hypercoagulable state, and autonomic dysfunction, which must be managed by a multidisciplinary team including nursing, nutrition, and rehabilitation. The elderly population and those who are suffering from Alzheimer's disease and dementia related illnesses seem to be at the higher risk. There are 28 vaccines under development, and new treatment strategies/protocols are being investigated. The future management for COVID-19 should include B-cell and T-cell immunotherapy in combination with emerging prophylaxis. The mental health and illness aspect of COVID-19 are among the most important side effects of this pandemic which requires a national plan for prevention, diagnosis and treatment.
Keywords: Coronavirus Infections; COVID-19; Humans; Immunotherapy; Mental Health; Nutritional Support; Pandemics; Pneumonia, Viral

Dementia Care in Times of COVID-19: Experience at Fundació ACE in Barcelona, Spain. - Benaque, Alba; Gurruchaga, Miren Jone; Abdelnour, Carla; Hernandez, Isabel; Cañabate, Pilar; Alegret, Montserrat; Rodríguez, Isabel; Rosende-Roca, Maitee; Tartari, Juan Pablo; Esteban, Ester; López, Rogelio; Gil, Silvia; et al. (J Alzheimers Dis, 2020)
BACKGROUND: Fundació ACE is a non-profit organization providing care based on a holistic model to persons with cognitive disorders and their families for 25 years in Barcelona, Spain. Delivering care to this vulnerable population amidst the COVID-19 pandemic has represented a major challenge to our institution. OBJECTIVE: To share our experience in adapting our model of care to the new situation to ensure continuity of care. METHODS: We detail the sequence of events and the actions taken within Fundació ACE to swiftly adapt our face-to-face model of care to one based on telemedicine consultations. We characterize individuals under follow-up by the Memory Unit from 2017 to 2019 and compare the number of weekly visits in 2020 performed before and after the lockdown was imposed. RESULTS: The total number of individuals being actively followed by Fundació ACE Memory Unit grew from 6,928 in 2017 to 8,147 in 2019. Among those newly diagnosed in 2019, most patients had mild cognitive impairment or mild dementia (42% and 25%, respectively). Weekly visits dropped by 60% following the suspension of face-to-face activity. However, by April 24 we were able to perform 78% of the visits we averaged in the weeks before confinement began. DISCUSSION: We have shown that Fundació ACE model of care has been able to successfully adapt to a health and social critical situation as COVID-19 pandemic. Overall, we were able to guarantee the continuity of care while preserving the safety of patients, families, and professionals. We also seized the opportunity to improve our model of care.
Keywords: Aged; Aged, 80 and over; Betacoronavirus; Coronavirus Infections; COVID-19; Dementia; Female; Follow-Up Studies; Holistic Health; Humans; Male; Pandemics; Patient-Centered Care; Pneumonia, Viral; SARS-CoV-2; Spain; Telemedicine

Detection of Mild Cognitive Impairment in an At-Risk Group of Older Adults: Can a Novel Self-Administered Serious Game-Based Screening Test Improve Diagnostic Accuracy? - Zygouris, Stelios; Iliadou, Paraskevi; Lazarou, Eftychia; Giakoumis, Dimitrios; Votis, Konstantinos; Alexiadis, Anastasios; Triantafyllidis, Andreas; Segkouli, Sofia; Tzovaras, Dimitrios; Tsiatsos, Thrasyvoulos; Papagianopoulos, Sotirios; Tsolaki, Magda (J Alzheimers Dis, 2020)
BACKGROUND: Literature supports the use of serious games and virtual environments to assess cognitive functions and detect cognitive decline. This promising assessment method, however, has not yet been translated into self-administered screening instruments for pre-clinical dementia. OBJECTIVE: The aim of this study is to assess the performance of a novel self-administered serious game-based test, namely the Virtual Supermarket Test (VST), in detecting mild cognitive impairment (MCI) in a sample of older adults with subjective memory complaints (SMC), in comparison with two well-established screening instruments, the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). METHODS: Two groups, one of healthy older adults with SMC (N = 48) and one of MCI patients (N = 47) were recruited from day centers for cognitive disorders and administered the VST, the MoCA, the MMSE, and an extended pencil and paper neuropsychological test battery. RESULTS: The VST displayed a correct classification rate (CCR) of 81.91% when differentiating between MCI patients and older adults with SMC, while the MoCA displayed of CCR of 72.04% and the MMSE displayed a CCR of 64.89%. CONCLUSION: The three instruments assessed in this study displayed significantly different performances in differentiating between healthy older adults with SMC and MCI patients. The VST displayed a good CCR, while the MoCA displayed an average CCR and the MMSE displayed a poor CCR. The VST appears to be a robust tool for detecting MCI in a population of older adults with SMC.

Development and Validation of a High Sensitivity Assay for Measuring p217 + tau in Cerebrospinal Fluid. - Triana-Baltzer, Gallen; Van Kolen, Kristof; Theunis, Clara; Moughadam, Setareh; Slemmon, Randy; Mercken, Marc; Galpern, Wendy; Sun, Hong; Kolb, Hartmuth (J Alzheimers Dis, 2020)
BACKGROUND: Early and accurate detection and staging is critical to managing Alzheimer's disease (AD) and supporting clinical trials. Cerebrospinal fluid (CSF) biomarkers for amyloid-β peptides, tau species, and various neurodegenerative and inflammatory analytes are leading the way in this regard, yet there is room for improved sensitivity and specificity. In particular tau is known to be present in many different fragments, conformations, and post-translationally modified forms. While the exact tau species that might best reflect AD pathology is unknown, a growing body of evidence suggests that forms with high levels of phosphorylation in the mid-region may be especially enriched in AD. OBJECTIVE: Develop an assay for measuring p217tau in CSF. METHODS: Here we describe the development and validation of a novel sELISA for measuring CSF tau species containing phosphorylation at threonines 212 & 217, aka p217 + tau, using the PT3 antibody. RESULTS: While the analyte is present at extremely low levels the assay is sufficiently sensitive and specific to quantitate p217 + tau with excellent precision, accuracy, and dilution linearity, allowing good differentiation between diagnostic subgroups. The p217 + tau measurements appear to track AD pathology better than the commonly used p181tau epitope, suggesting superior diagnostic and staging performance. Finally, the assay can also be configured to differentiate antibody-bound versus antibody-free tau, and therefore can be used to measure target engagement by p217 + tau-targeting immunotherapeutics. CONCLUSION: The assay for measuring p217 + tau described here is highly sensitive, accurate, precise, dilution linear, and shows good potential for identifying and staging AD.

Development of Classification Models for the Prediction of Alzheimer's Disease Utilizing Circulating Sex Hormone Ratios. - Hayashi, Kentaro; Gonzales, Tina K; Kapoor, Amita; Ziegler, Toni E; Meethal, Sivan Vadakkadath; Atwood, Craig S (J Alzheimers Dis, 2020)
BACKGROUND: While sex hormones are essential for normal cognitive health, those individuals with greater endocrine dyscrasia around menopause and with andropause are more likely to develop cognitive loss and Alzheimer's disease (AD). OBJECTIVE: To assess whether circulating sex hormones may provide an etiologically significant, surrogate biomarker, for cognitive decline. METHODS: Plasma (n = 152) and serum (n = 107) samples from age- and gender-matched AD and control subjects from the Wisconsin Alzheimer's Disease Research Center (ADRC) were analyzed for11 steroids and follicle-stimulating hormone. Logistic regression (LR), correlation analyses, and recursive partitioning (RP) were used to examine the interactions of hormones and hormone ratios and their association with AD. Models generated were then tested on an additional 43 ADRC samples. RESULTS: The wide variation and substantial overlap in the concentrations of all circulating sex steroids across control and AD groups precluded their use for predicting AD. Classification tree analyses (RP) revealed interactions among single hormones and hormone ratios that associated with AD status, the most predictive including only the hormone ratios identified by LR. The strongest associations were observed between cortisol, cortisone, and androstenedione with AD, with contributions from progesterone and 17β-estradiol. Utilizing this model, we correctly predicted 81% of AD test cases and 64% of control test cases. CONCLUSION: We have developed a diagnostic model for AD, the Wisconsin Hormone Algorithm Test for Cognition (WHAT-Cog), that utilizes classification tree analyses of hormone ratios. Further refinement of this technology could provide a quick and cheap diagnostic method for screening those with AD.

Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology. - Shi, Liu; Winchester, Laura M; Liu, Benjamine Y; Killick, Richard; Ribe, Elena M; Westwood, Sarah; Baird, Alison L; Buckley, Noel J; Hong, Shengjun; Dobricic, Valerija; Kilpert, Fabian; Franke, Andre; et al. (J Alzheimers Dis, 2020)
BACKGROUND: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. OBJECTIVE: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. METHODS: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). RESULTS: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. CONCLUSIONS: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.

The Effects of Confinement on Neuropsychiatric Symptoms in Alzheimer's Disease During the COVID-19 Crisis. - Boutoleau-Bretonnière, Claire; Pouclet-Courtemanche, Hélene; Gillet, Aurelie; Bernard, Amelie; Deruet, Anne Laure; Gouraud, Ines; Mazoue, Aurelien; Lamy, Estelle; Rocher, Laetitia; Kapogiannis, Dimitrios; El Haj, Mohamad (J Alzheimers Dis, 2020)
BACKGROUND: Neuropsychiatric symptoms, such as depression, anxiety, apathy, agitation, and hallucinations, are frequent in Alzheimer's disease (AD) and their prevalence tends to increase with external stressors. OBJECTIVE: We offer the first investigation of the effects of confinement during the COVID-19 crisis on neuropsychiatric symptoms in patients with AD. METHODS: We contacted caregivers of 38 patients with AD who were confined to their homes for nearly two months and asked them to report whether patients experienced any change in neuropsychiatric symptoms during, compared to before, the confinement and rate its severity and impact on themselves using the Neuropsychiatric Inventory-Questionnaire. RESULTS: Among the 38 patients, only 10 demonstrated neuropsychiatric changes during the confinement. Cognitive function of these 10 patients, assessed with the Mini-Mental State Examination, was worse than that of patients who did not demonstrate neuropsychiatric changes. Interestingly, among the 10 patients with neuropsychiatric changes, the duration of confinement significantly correlated with the severity of symptoms as well as with their caregivers' distress. DISCUSSION: The confinement seems to impact neuropsychiatric symptomatology in AD patients with low baseline cognitive function.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Betacoronavirus; Cohort Studies; Coronavirus Infections; COVID-19; Female; Humans; Male; Mental Disorders; Mental Status and Dementia Tests; Middle Aged; Pandemics; Pneumonia, Viral; Quarantine; SARS-CoV-2

Effects of Probiotic Supplementation on Short Chain Fatty Acids in the AppNL-G-F Mouse Model of Alzheimer's Disease. - Kaur, Harpreet; Golovko, Svetlana; Golovko, Mikhail Y; Singh, Surjeet; Darland, Diane C; Combs, Colin K (J Alzheimers Dis, 2020)
BACKGROUND: The intestinal microbiota and its metabolites, particularly short-chain fatty acids (SCFAs), have been implicated in immune function, host metabolism, and even behavior. OBJECTIVE: This study was performed to investigate whether probiotic administration influences levels of intestinal microbiota and their metabolites in a fashion that may attenuate brain changes in a mouse model of Alzheimer's disease (AD). METHODS: C57BL/6 wild-type (WT) mice were compared to AppNL-G-Fmice. The animals were treated with either vehicle or probiotic (VSL#3) for 8 weeks. Fecal microbiome analysis along with Aβ, GFAP, Iba-1, c-Fos, and Ki-67 immunohistochemistry was done. SCFAs were analyzed in serum and brains using UPLC-MS/MS. RESULTS: Probiotic (VSL#3) supplementation for 2 months resulted in altered microbiota in both WT and AppNL-G-Fmice. An increase in serum SCFAs acetate, butyrate, and lactate were found in both genotypes following VSL#3 treatment. Propionate and isobutyrate were only increased in AppNL-G-Fmice. Surprisingly, VSL#3 only increased lactate and acetate in brains of AppNL-G-Fmice. No significant differences were observed between vehicle and VSL#3 fed AppNL-G-Fhippocampal immunore activities of Aβ, GFAP, Iba-1, and Ki-67. However, hippocampal c-Fos staining increased in VSL#3 fed AppNL-G-Fmice. CONCLUSION: These data demonstrate intestinal dysbiosis in the AppNL-G-Fmouse model of AD. Probiotic VSL#3 feeding altered both serum and brain levels of lactate and acetate in AppNL-G-Fmice correlating with increased expression of the neuronal activity marker, c-Fos.

Environmental Nanoparticles, SARS-CoV-2 Brain Involvement, and Potential Acceleration of Alzheimer's and Parkinson's Diseases in Young Urbanites Exposed to Air Pollution. - Calderón-Garcidueñas, Lilian; Torres-Jardón, Ricardo; Franco-Lira, Maricela; Kulesza, Randy; González-Maciel, Angelica; Reynoso-Robles, Rafael; Brito-Aguilar, Rafael; García-Arreola, Berenice; Revueltas-Ficachi, Paula; Barrera-Velázquez, Juana Adriana; García-Alonso, Griselda; García-Rojas, Edgar; et al. (J Alzheimers Dis, 2020)
Alzheimer's and Parkinson's diseases (AD, PD) have a pediatric and young adult onset in Metropolitan Mexico City (MMC). The SARS-CoV-2 neurotropic RNA virus is triggering neurological complications and deep concern regarding acceleration of neuroinflammatory and neurodegenerative processes already in progress. This review, based on our MMC experience, will discuss two major issues: 1) why residents chronically exposed to air pollution are likely to be more susceptible to SARS-CoV-2 systemic and brain effects and 2) why young people with AD and PD already in progress will accelerate neurodegenerative processes. Secondary mental consequences of social distancing and isolation, fear, financial insecurity, violence, poor health support, and lack of understanding of the complex crisis are expected in MMC residents infected or free of SARS-CoV-2. MMC residents with pre-SARS-CoV-2 accumulation of misfolded proteins diagnostic of AD and PD and metal-rich, magnetic nanoparticles damaging key neural organelles are an ideal host for neurotropic SARS-CoV-2 RNA virus invading the body through the same portals damaged by nanoparticles: nasal olfactory epithelium, the gastrointestinal tract, and the alveolar-capillary portal. We urgently need MMC multicenter retrospective-prospective neurological and psychiatric population follow-up and intervention strategies in place in case of acceleration of neurodegenerative processes, increased risk of suicide, and mental disease worsening. Identification of vulnerable populations and continuous effort to lower air pollution ought to be critical steps.
Keywords: Adult; Air Pollution; Alzheimer Disease; Brain Diseases; Coronavirus Infections; COVID-19; Disease Progression; Environmental Pollutants; Humans; Middle Aged; Nanoparticles; Pandemics; Parkinson Disease; Pneumonia, Viral; Suicide; Urban Population

Epilepsy in Neurodegenerative Dementias: A Clinical, Epidemiological, and EEG Study. - Arnaldi, Dario; Donniaquio, Andrea; Mattioli, Pietro; Massa, Federico; Grazzini, Matteo; Meli, Riccardo; Filippi, Laura; Grisanti, Stefano; Famá, Francesco; Terzaghi, Michele; Girtler, Nicola; Brugnolo, Andrea; et al. (J Alzheimers Dis, 2020)
BACKGROUND: Seizures are common in patients with dementia but precise epidemiologic data of epilepsy in neurodegenerative dementia is lacking. OBJECTIVE: The first aim of the study was to investigate prevalence and clinical characteristics of epilepsy in a large cohort of patients with neurodegenerative dementias. Subsequently, we explored clinical, neuropsychological, and quantitative electroencephalogram (qEEG) data of Alzheimer's disease (AD) patients with epilepsy (AD-EPI) as compared to AD patients without epilepsy (AD-CTR). METHODS: We retrospectively evaluated consecutive patients with a diagnosis of a neurodegenerative dementia and a clinically diagnosed epilepsy that required antiepileptic drugs (AED). All patients underwent baseline comprehensive neuropsychological assessment. A follow-up of at least one year was requested to confirm the dementia diagnosis. In AD patients, qEEG power band analysis was performed. AD-CTR and AD-EPI patients were matched for age, Mini-Mental State Examination score, and gender. RESULTS: Thirty-eight out of 2,054 neurodegenerative dementia patients had epilepsy requiring AED. The prevalence of epilepsy was 1.82% for AD, 1.28% for the behavioral variant of frontotemporal dementia (bvFTD), 2.47% for dementia with Lewy bodies (DLB), and 12% for primary progressive aphasia. Epilepsy were more drug-responsive in AD than in non-AD dementias. Finally, no significant differences were found in neuropsychological and qEEG data between AD-EPI and AD-CTR patients. CONCLUSION: In our cohort, AD, FTD, and DLB dementias have similar prevalence of epilepsy, even if AD patients were more responsive to AED. Moreover, AD-EPI patients did not have significant clinical, neuropsychological qEEG differences compared with AD-CTR patients.

Estrogens Inhibit Amyloid-β-Mediated Paired Helical Filament-Like Conformation of Tau Through Antioxidant Activity and miRNA 218 Regulation in hTau Mice. - Guglielmotto, Michela; Manassero, Giusi; Vasciaveo, Valeria; Venezia, Marika; Tabaton, Massimo; Tamagno, Elena (J Alzheimers Dis, 2020)
BACKGROUND: The risk of developing Alzheimer's disease as well as its progression and severity are known to be different in men and women, and cognitive decline is greater in women than in men at the same stage of disease and could be correlated at least in part on estradiol levels. OBJECTIVE: In our work we found that biological sex influences the effect of amyloid-β42 (Aβ42) monomers on pathological tau conformational change. METHODS: In this study we used transgenic mice expressing the wild-type human tau (hTau) which were subjected to intraventricular (ICV) injections of Aβ peptides in nanomolar concentration. RESULTS: We found that Aβ42 produces pathological conformational changes and hyperphosphorylation of tau protein in male or ovariectomized female mice but not in control females. The treatment of ovariectomized females with estradiol replacement protects against the pathological conformation of tau and seems to be mediated by antioxidant activity as well as the ability to modulate the expression of miRNA 218 linked to tau phosphorylation. CONCLUSION: Our study indicates that factors as age, reproductive stage, hormone levels, and the interplay with other risk factors should be considered in women, in order to identify the best appropriate therapeutic approach in prevention of cognitive impairment.

An Exploratory Phase IIa Study of the PPAR delta/gamma Agonist T3D-959 Assessing Metabolic and Cognitive Function in Subjects with Mild to Moderate Alzheimer's Disease. - Chamberlain, Stanley; Gabriel, Hoda; Strittmatter, Warren; Didsbury, John (J Alzheimers Dis, 2020)
BACKGROUND: T3D-959 is a chemically unique, brain penetrant, dual PPAR delta/gamma agonist with 15-fold higher PPAR delta selectivity. Ubiquitous brain expression of PPAR delta, its critical role in regulating glucose and lipid metabolism, and the Alzheimer's disease (AD)-like phenotype of PPAR delta null mice motivated this study. OBJECTIVE: To determine safety and tolerability of multiple doses of T3D-959 in subjects with mild to moderate AD, examine systemic and central drug pharmacology and in an exploratory manner, perform cognitive assessments. METHODS: Thirty-four subjects with mild-to-moderate AD were orally administered 3, 10, 30, or 90 mg of T3D-959 daily for 14 days. There was no inclusion of a placebo arm. Safety and tolerability were monitored. Systemic drug pharmacology was examined via plasma metabolomics LC-MS-MS analysis, cerebral drug pharmacology via FDG-PET measures of changes in Relative CMRgl (R CMRgl, AD-effected regions relative to brain reference regions), and cognitive function assessed before and after drug treatment and again one week after completion of drug treatment, by ADAS-cog11 and the Digit Symbol Substitution Test (DSST). RESULTS: T3D-959 was in general safe and well tolerated. Single point pharmacokinetics at the Tmax showed dose dependent exposure. Plasma metabolome profile changes showed dose-dependent systemic effects on lipid metabolism and metabolism related to insulin sensitization. Relative FDG-PET imaging demonstrated dose-dependent, regional, effects of T3D-959 on R CMRgl based on the use of multiple reference regions. ADAS-cog11 and DSST cognitive assessments showed improvements with possible ApoE genotype association and pharmacodynamics related to the mechanism of drug action. CONCLUSIONS: Exploratory data from this Phase IIa clinical trial supports further clinical investigation of T3D-959 in a larger placebo-controlled clinical study.

Falls Associate with Neurodegenerative Changes in ATN Framework of Alzheimer's Disease. - Keleman, Audrey; Wisch, Julie K; Bollinger, Rebecca M; Grant, Elizabeth A; Benzinger, Tammie L; Morris, John C; Ances, Beau M; Stark, Susan L (J Alzheimers Dis, 2020)
BACKGROUND: Behavioral markers for Alzheimer's disease (AD) are not included within the widely used amyloid-tau-neurodegeneration framework. OBJECTIVE: To determine when falls occur among cognitively normal (CN) individuals with and without preclinical AD. METHODS: This cross-sectional study recorded falls among CN participants (n = 83) over a 1-year period. Tailored calendar journals recorded falls. Biomarkers including amyloid positron emission tomography (PET) and structural and functional magnetic resonance imaging were acquired within 2 years of fall evaluations. CN participants were dichotomized by amyloid PET (using standard cutoffs). Differences in amyloid accumulation, global resting state functional connectivity (rs-fc) intra-network signature, and hippocampal volume were compared between individuals who did and did not fall using Wilcoxon rank sum tests. Among preclinical AD participants (amyloid-positive), the partial correlation between amyloid accumulation and global rs-fc intra-network signature was compared for those who did and did not fall. RESULTS: Participants who fell had smaller hippocampal volumes (p = 0.04). Among preclinical AD participants, those who fell had a negative correlation between amyloid uptake and global rs-fc intra-network signature (R = -0.75, p = 0.012). A trend level positive correlation was observed between amyloid uptake and global rs-fc intra-network signature (R = 0.70, p = 0.081) for preclinical AD participants who did not fall. CONCLUSION: Falls in CN older adults correlate with neurodegeneration biomarkers. Participants without falls had lower amyloid deposition and preserved global rs-fc intra-network signature. Falls most strongly correlated with presence of amyloid and loss of brain connectivity and occurred in later stages of preclinical AD.

Functional Connectivity Alterations of the Temporal Lobe and Hippocampus in Semantic Dementia and Alzheimer's Disease. - Schwab, Simon; Afyouni, Soroosh; Chen, Yan; Han, Zaizhu; Guo, Qihao; Dierks, Thomas; Wahlund, Lars-Olof; Grieder, Matthias (J Alzheimers Dis, 2020)
BACKGROUND: Semantic memory impairments in semantic dementia are attributed to atrophy and functional disruption of the anterior temporal lobes. In contrast, the posterior medial temporal neurodegeneration found in Alzheimer's disease is associated with episodic memory disturbance. The two dementia subtypes share hippocampal deterioration, despite a relatively spared episodic memory in semantic dementia. OBJECTIVE: To unravel mutual and divergent functional alterations in Alzheimer's disease and semantic dementia, we assessed functional connectivity between temporal lobe regions in Alzheimer's disease (n = 16), semantic dementia (n = 23), and healthy controls (n = 17). METHODS: In an exploratory study, we used a functional parcellation of the temporal cortex to extract time series from 66 regions for correlation analysis. RESULTS: Apart from differing connections between Alzheimer's disease and semantic dementia that yielded reduced functional connectivity, we identified a common pathway between the right anterior temporal lobe and the right orbitofrontal cortex in both dementia subtypes. This disconnectivity might be related to social knowledge deficits as part of semantic memory decline. However, such interpretations are preferably made in a holistic context of disease-specific semantic impairments and functional connectivity changes. CONCLUSION: Despite a major limitation owed to unbalanced databases between study groups, this study provides a preliminary picture of the brain's functional disconnectivity in Alzheimer's disease and semantic dementia. Future studies are needed to replicate findings of a common pathway with consistent diagnostic criteria and neuropsychological evaluation, balanced designs, and matched data MRI acquisition procedures.

An Immunomodulatory Therapeutic Vaccine Targeting Oligomeric Amyloid-β. - Song, Ge; Yang, Haiqiang; Shen, Ning; Pham, Phillip; Brown, Breanna; Lin, Xiaoyang; Hong, Yuzhu; Sinu, Paul; Cai, Jianfeng; Li, Xiaopeng; Leon, Michael; Gordon, Marcia; et al. (J Alzheimers Dis, 2020)
BACKGROUND: Aging is considered the most important risk factor for Alzheimer's disease (AD). Recent research supports the theory that immunotherapy targeting the "oligomeric" forms of amyloid-β (Aβ) may halt the progression of AD. However, previous clinical trial of the vaccine against Aβ, called AN1792, was suspended due to cases of meningoencephalitis in patients. OBJECTIVE: To develop a peptide sensitized dendritic cells (DCs) vaccine that would target oligomer Aβ and prevent an autoimmune response. METHODS: Double transgenic APPswe/PS1ΔE9 (Tg) and C57BL/6J control mice were used in this study. Cytokine expression profile detection, characterization of antisera, brain GSK-3β, LC3 expression, and spatial working memory testing before and post-vaccination were obtained. RESULTS: Epitope prediction indicated that E22W42 could generate 13 new T cell epitopes which can strengthen immunity in aged subjects and silence several T cell epitopes of the wild type Aβ. The silenced T cell epitope could help avoid the autoimmune response that was seen in some patients of the AN-1792 vaccine. The E22W42 not only helped sensitize bone marrow-derived DCs for the development of an oligomeric Aβ-specific antibody, but also delayed memory impairment in the APP/PS1 mouse model. Most importantly, this E22W42 peptide will not alter the DC's natural immunomodulatory properties. CONCLUSION: The E22W42 vaccine is possibly safer for patients with impaired immune systems. Since there is increasing evidence that oligomeric form of Aβ are the toxic species to neurons, the E22W42 antibody's specificity for these "oligomeric" Aβ species could provide the opportunity to produce some clinical benefits in AD subjects.

lncRNA SNHG1 Knockdown Alleviates Amyloid-β-Induced Neuronal Injury by Regulating ZNF217 via Sponging miR-361-3p in Alzheimer's Disease. - Gao, Yiwen; Zhang, Nan; Lv, Chunmei; Li, Na; Li, Xueqin; Li, Weiwei (J Alzheimers Dis, 2020)
BACKGROUND: Long noncoding RNAs have been proven to play an important role in the progression of Alzheimer's disease (AD). However, the function of small nucleolar RNA host gene 1 (SNHG1) in AD progression remains to be studied. OBJECTIVE: To explore the role of SNHG1 in AD progression and clarify its potential mechanism. METHODS: Amyloid β-protein (Aβ) was used to construct an AD cell model in vitro. The expression levels of SNHG1 and miR-361-3p were determined by quantitative real-time polymerase chain reaction. Cell viability and apoptosis were measured by cell counting kit 8 assay and flow cytometry. The levels of apoptosis-related proteins and zinc finger gene 217 (ZNF217) protein were evaluated by western blot analysis. Additionally, the contents of inflammatory cytokines and oxidative stress markers were tested by enzyme-linked immunosorbent assay. Furthermore, dual-luciferase reporter and RNA immunoprecipitation assays were used to verify the interaction between miR-361-3p and SNHG1 or ZNF217. RESULTS: Aβ could induce cell injury, while resveratrol could reverse this effect. SNHG1 expression was positively regulated by Aβ and negatively regulated by resveratrol. SNHG1 knockdown could reverse the promotion effect of Aβ on cell injury. Moreover, SNHG1 sponged miR-361-3p, and miR-361-3p targeted ZNF217. Additionally, miR-361-3p overexpression reversed the promotion effect of SNHG1 overexpression on cell injury, and ZNF217 silencing also reversed the promotion effect of miR-361-3p inhibitor on cell injury. CONCLUSION: SNHG1 promoted cell injury by regulating the miR-361-3p/ZNF217 axis, which might provide a theoretical basis for molecular therapy of AD.

Metabolic Changes Detected by 18F-FDG PET in the Preclinical Stage of Familial Creutzfeldt-Jakob Disease. - Lu, Hui; Jing, Donglai; Chen, Yaojing; Cui, Chunlei; Gao, Ran; Wang, Lin; Liang, Zhigang; Chen, Kewei; Wu, Liyong (J Alzheimers Dis, 2020)
BACKGROUND: Pathologic processes in Creutzfeldt-Jakob disease (CJD) are not fully understood. Familial CJD (fCJD) gives opportunities to discover pathologic changes in the preclinical stage. OBJECTIVE: To investigate cerebral glucose metabolism in the preclinical stage via 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in fCJD. METHODS: Seven asymptomatic carriers of G114V mutation and six family members without PRNP mutation from the same fCJD kindred were included, and were followed for 2 years. Ten symptomatic CJD patients were also recruited. All subjects underwent standardized clinical examinations and 18F-FDG PET scans. Results were compared in three groups: baseline carriers against non-carriers (baseline analysis), changes after 2 years in carriers (follow-up analysis), and differences between symptomatic CJD patients and healthy controls (CJD patients analysis). RESULTS: No carriers developed any neurological symptoms during 2-year follow-up. Baseline analysis: carriers demonstrates decreased metabolism (p < 0.001) in left and right postcentral, left fusiform, left superior temporal, left lingual, left superior parietal, and left Heschl gyrus. Follow-up analysis shows metabolic decline (p < 0.001) in right inferior temporal, left supra-marginal and left postcentral lobe, and increased metabolism (p < 0.001) in left fusiform, left angular, left thalamus, left Heschl's, right Rolandic operculum, and left superior parietal gyrus. CJD patients demonstrates decreased metabolism in right inferior triangularis frontal gyrus, right middle occipital gyrus, right putamen, right thalamus, and right middle temporal gyrus. CONCLUSION: Hypo-metabolism of parietal and temporal lobe can be detected by 18F-FDG PET in the preclinical stage of CJD. Subcortical area might compensate in the preclinical stage and decompensate in the symptomatic stage.

Mitochondrial DNA Manipulations Affect Tau Oligomerization. - Weidling, Ian W; Wilkins, Heather M; Koppel, Scott J; Hutfles, Lewis; Wang, Xiaowan; Kalani, Anuradha; Menta, Blaise W; Ryan, Benjamin; Perez-Ortiz, Judit; Gamblin, T Chris; Swerdlow, Russell H (J Alzheimers Dis, 2020)
BACKGROUND: Mitochondrial dysfunction and tau aggregation occur in Alzheimer's disease (AD), and exposing cells or rodents to mitochondrial toxins alters their tau. OBJECTIVE: To further explore how mitochondria influence tau, we measured tau oligomer levels in human neuronal SH-SY5Y cells with different mitochondrial DNA (mtDNA) manipulations. METHODS: Specifically, we analyzed cells undergoing ethidium bromide-induced acute mtDNA depletion, ρ0 cells with chronic mtDNA depletion, and cytoplasmic hybrid (cybrid) cell lines containing mtDNA from AD subjects. RESULTS: We found cytochrome oxidase activity was particularly sensitive to acute mtDNA depletion, evidence of metabolic re-programming in the ρ0 cells, and a relatively reduced mtDNA content in cybrids generated through AD subject mitochondrial transfer. In each case tau oligomer levels increased, and acutely depleted and AD cybrid cells also showed a monomer to oligomer shift. CONCLUSION: We conclude a cell's mtDNA affects tau oligomerization. Overlapping tau changes across three mtDNA-manipulated models establishes the reproducibility of the phenomenon, and its presence in AD cybrids supports its AD-relevance.

Music Playlists for People with Dementia: Trialing A Guide for Caregivers. - Garrido, Sandra; Dunne, Laura; Stevens, Catherine J; Chang, Esther (J Alzheimers Dis, 2020)
BACKGROUND: Music programs have the potential to provide an effective non-pharmacological tool for caregivers to reduce depression and agitation and increase quality of life in people with dementia. However, where such programs are not facilitated by a trained music therapist, caregivers need greater access to information about how to use music most effectively in response to key challenges to care, and how to pre-empt and manage adverse responses. OBJECTIVE: This study reports on the trial of a Guide for use of music with 45 people with dementia and their caregivers in residential care facilities and home-based care. METHODS: The study used a pre-post experimental design in which participants were randomly allocated to a treatment group or a waitlist control group. RESULTS: Improvements to quality of life were found in the experimental group over the 6-week period. Significant increases in Interest, Responsiveness, Initiation, Involvement, and Enjoyment were reported for individual listening sessions. CONCLUSION: The Guide can provide an effective protocol for caregivers to follow in selecting music to manage particular challenges to care, confirming the need for caregivers to be prepared to monitor and manage potential negative responses.

Novel Markers of Angiogenesis in the Setting of Cognitive Impairment and Dementia. - Callahan, Christopher M; Apostolova, Liana G; Gao, Sujuan; Risacher, Shannon L; Case, Jamie; Saykin, Andrew J; Lane, Kathleen A; Swinford, Cecily G; Yoder, Mervin C (J Alzheimers Dis, 2020)
BACKGROUND: Aberrant angiogenesis may play a role in the development of Alzheimer's disease and related dementia. OBJECTIVE: To explore the relationship between angiogenesis activity and evidence of neurodegeneration among older adults. METHODS: Cross-sectional study of 49 older adults clinically characterized as cognitively normal, mild cognitive impairment, or early Alzheimer's disease. In addition to neuroimaging, we completed assays on peripheral blood, including: vascular endothelial growth factor, tumor necrosis factor, fibroblast growth factor, and amyloid-β peptide 40. We used advanced polychromatic flow cytometry to phenotype circulating mononuclear cells to assess angiogenesis activity. RESULTS: Although we documented differences in cognitive performance, structural changes on neuroimaging, and burden of amyloid and tau on positron emission tomography, angiogenesis activity did not vary by group. Interestingly, VEGF levels were shown to be increased among subjects with mild cognitive impairment. In ANCOVA models controlling for age, sex, intracranial volume, and monocyte subpopulations, angiogenesis activity was correlated with increased white matter hyperintensities. CONCLUSION: We demonstrate a significant association between angiogenesis activity and cerebrovascular disease. To better understand the potential of angiogenesis as an intervention target, longitudinal studies are needed.

Older Patients with Alzheimer's Disease-Related Cortical Atrophy Who Develop Post-Operative Delirium May Be at Increased Risk of Long-Term Cognitive Decline After Surgery. - Racine, Annie M; Touroutoglou, Alexandra; Abrantes, Tatiana; Wong, Bonnie; Fong, Tamara G; Cavallari, Michele; Travison, Thomas G; Gou, Yun; Marcantonio, Edward R; Alsop, David C; Jones, Richard N; Inouye, Sharon K; et al. (J Alzheimers Dis, 2020)
BACKGROUND: Older surgical patients with Alzheimer's disease (AD) dementia and delirium are at increased risk for accelerated long-term cognitive decline. OBJECTIVE: Investigate associations between a probabilistic marker of preclinical AD, delirium, and long-term cognitive decline. METHODS: The Successful Aging after Elective Surgery cohort includes older adults (≥70 years) without dementia who underwent elective surgery. 140 patients underwent preoperative magnetic resonance imaging and had≥6 months cognitive follow-up. Cortical thickness was measured in 'AD-Signature' regions. Delirium was evaluated each postoperative day by the Confusion Assessment Method. Cognitive performance was assessed using a detailed neuropsychological battery at baseline; months 1, 2, and 6; and every 6 months thereafter until 36 months. Using either a General Cognitive Performance composite (GCP) or individual test scores as outcomes, we performed linear mixed effects models to examine main effects of AD-signature atrophy and the interaction of AD-signature atrophy and delirium on slopes of cognitive change from post-operative months 2-36. RESULTS: Reduced baseline AD-signature cortical thickness was associated with greater 36-month cognitive decline in GCP (standardized beta coefficient, β = -0.030, 95% confidence interval [-0.060, -0.001]). Patients who developed delirium who also had thinner AD signature cortex showed greater decline on a verbal learning test (β = -0.100 [-0.192, -0.007]). CONCLUSION: Patients with the greatest baseline AD-related cortical atrophy who develop delirium after elective surgery appear to experience the greatest long-term cognitive decline. Thus, atrophy suggestive of preclinical AD and the development of delirium may be high-risk indicators for long-term cognitive decline following surgery.

Patterns of Regional Cerebral Blood Flow as a Function of Obesity in Adults. - Amen, Daniel G; Wu, Joseph; George, Noble; Newberg, Andrew (J Alzheimers Dis, 2020)
BACKGROUND: While obesity has been shown to be a risk factor for Alzheimer's disease, the potential mechanisms underlying this risk may be clarified with better understanding of underlying physiology in obese persons. OBJECTIVE: To identify patterns of cerebral perfusion abnormality in adults as a function of body mass index (BMI) defined weight categories, including overweight or obese status. METHODS: A large psychiatric cohort of 35,442 brain scans across 17,721 adults (mean age 40.8±16.2 years, range 18-94 years) were imaged with SPECT during baseline and concentration scans, the latter done after each participant completed the Connors Continuous Performance Test II. ANOVA was done to identify patterns of perfusion abnormality in this cohort across BMI designations of underweight (BMI < 18.5), normal weight (BMI = 18.5 to 24.9), overweight (BMI 24.9 to 29.9), obesity (BMI≥30), and morbid obesity (BMI≥40). This analysis was done for 128 brain regions quantifying SPECT perfusion using the automated anatomical labeling (AAL) atlas. RESULTS: Across adulthood, higher BMI correlated with decreased perfusion on both resting and concentration brain SPECT scans. These are seen in virtually all brain regions, including those influenced by AD pathology such as the hippocampus. CONCLUSION: Greater BMI is associated with cerebral perfusion decreases in both resting and concentration SPECT scans across adulthood.

Perceived Stress is Associated with Alzheimer's Disease Cerebrospinal Fluid Biomarkers in African Americans with Mild Cognitive Impairment. - Trammell, Antoine R; McDaniel, Darius J; Obideen, Malik; Okafor, Maureen; Thomas, Tiffany L; Goldstein, Felicia C; Shaw, Leslie M; Hajjar, Ihab M (J Alzheimers Dis, 2020)
BACKGROUND: African Americans (AA) have a higher Alzheimer's disease (AD) prevalence and report more perceived stress than White Americans. The biological basis of the stress-AD link is unclear. This study investigates the connection between stress and AD biomarkers in a biracial cohort. OBJECTIVE: Establish biomarker evidence for the observed association between stress and AD, especially in AA. METHODS: A cross-sectional study (n = 364, 41.8% AA) administering cognitive tests and the perceived stress scale (PSS) questionnaire. A subset (n = 309) provided cerebrospinal fluid for measurement of Aβ42, Tau, Ptau, Tau/Aβ42 (TAR), and Ptau/Aβ42 (PTAR). Multivariate linear regression, including factors that confound racial differences in AD, was performed. RESULTS: Higher PSS scores were associated with higher Ptau (β= 0.43, p = 0.01) and PTAR (β= 0.005, p = 0.03) in AA with impaired cognition (mild cognitive impairment). CONCLUSION: Higher PSS scores were associated with Tau-related AD biomarker indices in AA/MCI, suggesting a potential biological connection for stress with AD and its racial disparity.

Performance of Validated MicroRNA Biomarkers for Alzheimer's Disease in Mild Cognitive Impairment. - Sandau, Ursula S; Wiedrick, Jack T; Smith, Sierra J; McFarland, Trevor J; Lusardi, Theresa A; Lind, Babett; Harrington, Christina A; Lapidus, Jodi A; Galasko, Douglas R; Quinn, Joseph F; Saugstad, Julie A (J Alzheimers Dis, 2020)
BACKGROUND: Cerebrospinal fluid (CSF) microRNA (miRNA) biomarkers of Alzheimer's disease (AD) have been identified, but have not been evaluated in prodromal AD, including mild cognitive impairment (MCI). OBJECTIVE: To assess whether a set of validated AD miRNA biomarkers in CSF are also sensitive to early-stage pathology as exemplified by MCI diagnosis. METHODS: We measured the expression of 17 miRNA biomarkers for AD in CSF samples from AD, MCI, and cognitively normal controls (NC). We then examined classification performance of the miRNAs individually and in combination. For each miRNA, we assessed median expression in each diagnostic group and classified markers as trending linearly, nonlinearly, or lacking any trend across the three groups. For trending miRNAs, we assessed multimarker classification performance alone and in combination with apolipoprotein E ɛ4 allele (APOEɛ4) genotype and amyloid-β42 to total tau ratio (Aβ42:T-Tau). We identified predicted targets of trending miRNAs using pathway analysis. RESULTS: Five miRNAs showed a linear trend of decreasing median expression across the ordered diagnoses (control to MCI to AD). The trending miRNAs jointly predicted AD with area under the curve (AUC) of 0.770, and MCI with AUC of 0.705. Aβ42:T-Tau alone predicted MCI with AUC of 0.758 and the AUC improved to 0.813 (p = 0.051) after adding the trending miRNAs. Multivariate correlation of the five trending miRNAs with Aβ42:T-Tau was weak. CONCLUSION: Selected miRNAs combined with Aβ42:T-Tau improved classification performance (relative to protein biomarkers alone) for MCI, despite a weak correlation with Aβ42:T-Tau. Together these data suggest that that these miRNAs carry novel information relevant to AD, even at the MCI stage. Preliminary target prediction analysis suggests novel roles for these biomarkers.

Plasma High Density Lipoprotein Small Subclass is Reduced in Alzheimer's Disease Patients and Correlates with Cognitive Performance. - Pedrini, Steve; Hone, Eugene; Gupta, Veer B; James, Ian; Teimouri, Elham; Bush, Ashley I; Rowe, Christopher C; Villemagne, Victor L; Ames, David; Masters, Colin L; Rainey-Smith, Stephanie; Verdile, Giuseppe; et al. (J Alzheimers Dis, 2020)
BACKGROUND: The link between cholesterol and Alzheimer's disease (AD) has received much attention, as evidence suggests high levels of cholesterol might be an AD risk factor. The carriage of cholesterol and lipids through the body is mediated via lipoproteins, some of which, particularly apolipoprotein E (ApoE), are intimately linked with AD. In humans, high density lipoprotein (HDL) is regarded as a "good" lipid complex due to its ability to enable clearance of excess cholesterol via 'cholesterol reverse transport', although its activities in the pathogenesis of AD are poorly understood. There are several subclasses of HDL; these range from the newly formed small HDL, to much larger HDL. OBJECTIVE: We examined the major subclasses of HDL in healthy controls, mild cognitively impaired, and AD patients who were not taking statins to determine whether there were HDL profile differences between the groups, and whether HDL subclass levels correlated with plasma amyloid-β (Aβ) levels or brain Aβ deposition. METHODS: Samples from AIBL cohort were used in this study. HDL subclass levels were assessed by Lipoprint while Aβ1-42 levels were assessed by ELISA. Brain Aβ deposition was assessed by PET scan. Statistical analysis was performed using parametric and non-parametric tests. RESULTS: We found that small HDL subclass is reduced in AD patients and it correlates with cognitive performance while plasma Aβ concentrations do not correlate with lipid profile or HDL subfraction levels. CONCLUSION: Our data indicate that AD patients exhibit altered plasma HDL profile and that HDL subclasses correlate with cognitive performances.

Plasma Tau Variants Detected by a Novel Anti-Tau Monoclonal Antibody: A Potential Biomarker for Alzheimer's Disease. - Gonzlez, Andrea; Guzmn-Martínez, Leonardo; Maccioni, Ricardo B (J Alzheimers Dis, 2020)
BACKGROUND: A major drawback in Alzheimer's disease (AD) is the lack of validated biomarkers for routine clinical diagnostic. We have reported earlier a novel blood biomarker, named Alz-tau®, based on variants of platelet tau. This marker evaluates the ratio of high molecular weight tau (HMWtau) and the low molecular weight (LMWtau) tau. OBJECTIVE: To analyze a potential novel source of antigen for Alz-tau®, plasma tau, detected by immunoreactivity with the novel monoclonal antibody, tau51. METHODS: We evaluated tau variants in plasma precipitated with ammonium sulfate from 36 AD patients and 15 control subjects by western blot with this novel monoclonal antibody. RESULTS: The HMW/LMWtau ratio was statistically different between AD patients and controls. CONCLUSIONS: Plasma tau variants are suitable to be considered as a novel antigen source for the Alz-tau® biomarker for AD.

The Rhythmicity of Clock Genes is Disrupted in the Choroid Plexus of the APP/PS1 Mouse Model of Alzheimer's Disease. - Furtado, André; Astaburuaga, Rosario; Costa, Ana; Duarte, Ana C; Gonçalves, Isabel; Cipolla-Neto, José; Lemos, Manuel C; Carro, Eva; Relógio, Angela; Santos, Cecília R A; Quintela, Telma (J Alzheimers Dis, 2020)
BACKGROUND: The choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, was recently identified as an important component of the circadian clock system. OBJECTIVE: The fact that circadian rhythm disruption is closely associated to Alzheimer's disease (AD) led us to investigate whether AD pathology can contribute to disturbances of the circadian clock in the CP. METHODS: For this purpose, we evaluated the expression of core-clock genes at different time points, in 6- and 12-month-old female and male APP/PS1 mouse models of AD. In addition, we also assessed the effect of melatonin pre-treatment in vitro before amyloid-β stimulus in the daily pattern of brain and muscle Arnt-like protein 1 (Bmal1) expression. RESULTS: Our results showed a dysregulation of circadian rhythmicity of Bmal1 expression in female and male APP/PS1 transgenic 12-month-old mice and of Period 2 (Per2) expression in male mice. Besides, a significant circadian pattern of Bmal1 occurs in the intermittent melatonin pre-treatment group, showing that melatonin can reset the CP circadian clock. CONCLUSION: These results demonstrated a connection between AD and the disruption of circadian rhythm in the CP, representing an attractive target for disease prevention and/or treatment.

Role of Executive Functions in the Conversion from Mild Cognitive Impairment to Dementia. - Junquera Fernández, Almudena; García-Zamora, Estefanía; Olazarán Rodríguez, Javier; Parra Rodríguez, Mario A; Fernández-Guinea, Sara (J Alzheimers Dis, 2020)
BACKGROUND: Recent research pointed to executive dysfunction as a potential early predictor of the progression of mild cognitive impairment (MCI)-dementia in Alzheimer's clinical syndrome (ACS). Such cognitive impairments account for functional impairments in instrumental activities of daily living (IADL). OBJECTIVE: The present study analyzes the contributions of executive functions to predict MCI-dementia progression in ACS. METHODS: We assessed 145 participants, 51 cognitively unimpaired and 94 MCI. The latter were divided using the traditional, memory-based MCI classification (single domain amnestic, multidomain amnestic, and non-amnestic). Eight tests assessing executive functions were administered at baseline and at 1-year follow-up, together with cognitive screening tools and IADL measures. MCI patients were reclassified based on the outcomes from a K-mean cluster analysis which identified three groups. A simple lineal regression model was used to examine whether the classification based on executive functioning could more accurately predict progression to dementia a year later. RESULTS: Clusters based on executive function deficits explained a significant proportion of the variance linked to MCI-dementia conversion, even after controlling for the severity of MCI at baseline (F(1, 68) = 116.25, p = 0.000, R2 = 0.63). Classical memory-based MCI classification failed to predict such a conversion (F(1, 68) = 5.09, p = 0.955, R2 = 0.07). Switching, categories generation, and planning were the executive functions that best distinguished between MCI converters and stable. CONCLUSION: MCI with a dysexecutive phenotype significantly predicts conversion to dementia in ACS a year later. Switching abilities and verbal fluency (categories) must be evaluated in MCI patients to assess risk of future dementia.

Selective Peripheral Taste Dysfunction in APP/PS1 Mutant Transgenic Mice. - Wood, Ryan M; Garcia, Zacnite; Daniels, Nathan; Landon, Shannon M; Humayun, Saima; Lee, Hyoung-gon; Macpherson, Lindsey J (J Alzheimers Dis, 2020)
BACKGROUND: Previous studies indicate that taste dysfunction occurs early in the development of Alzheimer's disease. It is debatable whether the deficit in taste is due primarily to peripheral sensory mechanisms or to central processing, or a combination of the two. OBJECTIVE: The aim of our current study is to combine behavior and histological data in APP/PS1 transgenic mice to determine whether APP/PS1 transgenic mice show deficits in unconditioned taste preference and avoidance behaviors and whether taste impairments are due to defects in the peripheral taste system and/or problems with central processing of taste information. METHODS: The APP/PS1 transgenic mutant mice were used as a model of Alzheimer's disease. We employed a brief-access gustometer test to assess immediate orosensory taste responses of APP/PS1 mice. We used immunohistochemistry to examine tongue, gustatory ganglion, and brain tissues to determine a cytological basis for behavioral deficits. RESULTS: There is a significant, selective reduction of bitter taste sensitivity in APP/PS1 mice. These mice also have a loss of TRPM5-expressing taste receptor cells in the circumvallate papillae of the tongue. While we observed no overt loss of neuron cell bodies within the primary gustatory sensory neurons, degeneration of the neurons' peripheral axons innervating the taste bud may play a role in the observed loss of TRPM5-expressing taste receptor cells. CONCLUSION: This data supports a potential role for peripheral taste dysfunction in AD through the selective loss of taste receptor cells. Further study is necessary to delineate the mechanisms and pathological significance of this deficit in AD.

Serum Hepcidin Levels in Cognitively Normal Older Adults with High Neocortical Amyloid-β Load. - Chatterjee, Pratishtha; Mohammadi, Maryam; Goozee, Kathryn; Shah, Tejal M; Sohrabi, Hamid R; Dias, Cintia B; Shen, Kaikai; Asih, Prita R; Dave, Preeti; Pedrini, Steve; Ashton, Nicholas J; Hye, Abdul; et al. (J Alzheimers Dis, 2020)
BACKGROUND/OBJECTIVE: Hepcidin, an iron-regulating hormone, suppresses the release of iron by binding to the iron exporter protein, ferroportin, resulting in intracellular iron accumulation. Given that iron dyshomeostasis has been observed in Alzheimer's disease (AD) together with elevated serum hepcidin levels, the current study examined whether elevated serum hepcidin levels are an early event in AD pathogenesis by measuring the hormone in cognitively normal older adults at risk of AD, based on high neocortical amyloid-β load (NAL). METHODS: Serum hepcidin levels in cognitively normal participants (n = 100) aged between 65-90 years were measured using ELISA. To evaluate NAL, all participants underwent 18F-florbetaben positron emission tomography. A standard uptake value ratio (SUVR) RESULTS: Serum hepcidin was significantly higher in participants with high NAL compared to those with low NAL before and after adjusting for covariates: age, gender, and APOEɛ4 carriage (p < 0.05). A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve, AUC = 0.766), but was outperformed when serum hepcidin was added to the base model (AUC = 0.794) and further improved with plasma Aβ42/40 ratio (AUC = 0.829). CONCLUSION: The present findings indicate that serum hepcidin is increased in individuals at risk for AD and contribute to the body of evidence supporting iron dyshomeostasis as an early event of AD. Further, hepcidin may add value to a panel of markers that contribute toward identifying individuals at risk of AD; however, further validation studies are required.

Severity Distribution of Alzheimer's Disease Dementia and Mild Cognitive Impairment in the Framingham Heart Study. - Yuan, Jing; Maserejian, Nancy; Liu, Yulin; Devine, Sherral; Gillis, Cai; Massaro, Joseph; Au, Rhoda (J Alzheimers Dis, 2020)
BACKGROUND: Studies providing Alzheimer's disease (AD) prevalence data have largely neglected to characterize the proportion of AD that is mild, moderate, or severe. Estimates of the severity distribution along the AD continuum, including the mild cognitive impairment (MCI) stage, are important to plan research and allocate future resources, particularly resources targeted at particular stages of disease. OBJECTIVE: To characterize the distribution of severity of AD dementia and MCI among prevalent cases in the population-based Framingham Heart Study. METHODS: Participants (aged 50-94) with prevalent MCI or AD dementia clinical syndrome were cross-sectionally selected from three time-windows of the population-based Framingham Heart Study in 2004-2005 (n = 381), 2006-2007 (n = 422), and 2008-2009 (n = 389). Summary estimates of the severity distribution were achieved by pooling results across time-windows. Diagnosis and severity were assessed by consensus dementia review. MCI-progressive was determined if the participant had documented progression to AD dementia clinical syndrome using longitudinal data. RESULTS: Among AD dementia participants, the pooled percentages were 50.4%for mild, 30.3%for moderate, and 19.3%for severe. Among all MCI and AD participants, the pooled percentages were 29.5%, 19.6%, 25.7%, and 45.2%for MCI-not-progressive, MCI-progressive, mild AD dementia, and the combined group of MCI-progressive and mild AD dementia, respectively. Distributions by age and sex were presented. CONCLUSION: The finding that half of the people living with AD have mild disease underscores the need for research and interventions to slow decline or prevent progression of this burdensome disease.

Structural Brain Changes in Pre-Clinical FTD MAPT Mutation Carriers. - Domínguez-Vivero, Clara; Wu, Liwen; Lee, Seonjoo; Manoochehri, Masood; Cines, Sarah; Brickman, Adam M; Rizvi, Batool; Chesebro, Anthony; Gazes, Yunglin; Fallon, Emer; Lynch, Timothy; Heidebrink, Judith L; et al. (J Alzheimers Dis, 2020)
BACKGROUND: Frontotemporal dementia (FTD) is the second most common cause of early-onset neurodegenerative dementia. Several studies have focused on early imaging changes in FTD patients, but once subjects meet full criteria for the FTD diagnosis, structural changes are generally widespread. OBJECTIVE: This study aims to determine the earliest structural brain changes in asymptomatic MAPT MUTATION carriers. METHODS: This is a cross-sectional multicenter study comparing global and regional brain volume and white matter integrity in a group of MAPT mutation preclinical carriers and controls. Participants belong to multiple generations of six families with five MAPT mutations. All participants underwent a medical examination, neuropsychological tests, genetic analysis, and a magnetic resonance scan (3T, scout, T1-weighted image followed by EPI (BOLD), MPRAGE, DTI, FLAIR, and ASL sequences). RESULTS: Volumes of five cortical and subcortical areas were strongly correlated with mutation status: temporal lobe (left amygdala, left temporal pole), cingulate cortex (left rostral anterior cingulate gyrus, right posterior cingulate), and the lingual gyrus in the occipital lobe. We did not find significant differences in whole brain volume, white matter hyperintensities volume, and white matter integrity using DTI analysis. CONCLUSION: Temporal lobe, cingulate cortex and the lingual gyrus seem to be early targets of the disease and may serve as biomarkers for FTD prior to overt symptom onset.

Structural Brain Magnetic Resonance Imaging to Rule Out Comorbid Pathology in the Assessment of Alzheimer's Disease Dementia: Findings from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) Study and Clinical Trials Over the Past 10 Years. - Kapoor, Arunima; Bartha, Robert; Black, Sandra E; Borrie, Michael; Freedman, Morris; Gao, Fuqiang; Herrmann, Nathan; Mandzia, Jennifer; Ozzoude, Miracle; Ramirez, Joel; Scott, Christopher J M; Symons, Sean; et al. (J Alzheimers Dis, 2020)
BACKGROUND/OBJECTIVE: Structural brain magnetic resonance imaging (MRI) is not mandatory in Alzheimer's disease (AD) research or clinical guidelines. We aimed to explore the use of structural brain MRI in AD/mild cognitive impairment (MCI) trials over the past 10 years and determine the frequency with which inclusion of standardized structural MRI acquisitions detects comorbid vascular and non-vascular pathologies. METHODS: We systematically searched ClinicalTrials.gov for AD clinical trials to determine their neuroimaging criteria and then used data from an AD/MCI cohort who underwent standardized MRI protocols, to determine type and incidence of clinically relevant comorbid pathologies. RESULTS: Of 210 AD clinical trials, 105 (50%) included structural brain imaging in their eligibility criteria. Only 58 (27.6%) required MRI. 16,479 of 53,755 (30.7%) AD participants were in trials requiring MRI. In the observational AD/MCI cohort, 141 patients met clinical criteria; 22 (15.6%) had relevant MRI findings, of which 15 (10.6%) were exclusionary for the study. DISCUSSION: In AD clinical trials over the last 10 years, over two-thirds of participants could have been enrolled without brain MRI and half without even a brain CT. In a study sample, relevant comorbid pathology was found in 15% of participants, despite careful screening. Standardized structural MRI should be incorporated into NIA-AA diagnostic guidelines (when available) and research frameworks routinely to reduce diagnostic heterogeneity.

Using Machine Learning to Predict Dementia from Neuropsychiatric Symptom and Neuroimaging Data. - Gill, Sascha; Mouches, Pauline; Hu, Sophie; Rajashekar, Deepthi; MacMaster, Frank P; Smith, Eric E; Forkert, Nils D; Ismail, Zahinoor (J Alzheimers Dis, 2020)
BACKGROUND: Machine learning (ML) is a promising technique for patient-specific prediction of mild cognitive impairment (MCI) and dementia development. Neuropsychiatric symptoms (NPS) might improve the accuracy of ML models but have barely been used for this purpose. OBJECTIVES: To investigate if baseline mild behavioral impairment (MBI) status used for NPS quantification along with brain morphology features are predictive of follow-up diagnosis, median 40 months later in patients with normal cognition (NC) or MCI. METHOD: Baseline neuroimaging, neuropsychiatric, and clinical data from 102 individuals with NC and 239 with MCI were extracted from the Alzheimer's Disease Neuroimaging Initiative database. Neuropsychiatric inventory questionnaire items were transformed to MBI domains using a published algorithm. Diagnosis at latest follow-up was used as the outcome variable and ground truth classification. A logistic model tree classifier combined with information gain feature selection was trained to predict follow-up diagnosis. RESULTS: In the binary classification (NC versus MCI/AD), the optimal ML model required only two features from over 200, MBI total score and left hippocampal volume. These features correctly classified participants as remaining normal or developing cognitive impairment with 84.4% accuracy (area under the receiver operating characteristics curve [ROC-AUC] = 0.86). Seven features were selected for the three-class model (NC versus MCI versus dementia) achieving an accuracy of 58.8% (ROC-AUC=0.73). CONCLUSION: Baseline NPS, categorized for MBI domain and duration, have prognostic utility in addition to brain morphology measures for predicting diagnosis change using ML. MBI total score, followed by impulse dyscontrol and affective dysregulation were most predictive of future diagnosis.

Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort. - Westwood, Sarah; Baird, Alison L; Anand, Sneha N; Nevado-Holgado, Alejo J; Kormilitzin, Andrey; Shi, Liu; Hye, Abdul; Ashton, Nicholas J; Morgan, Angharad R; Bos, Isabelle; Vos, Stephanie J B; Baker, Susan; et al. (J Alzheimers Dis, 2020)
We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.

Adverse Vascular Risk Relates to Cerebrospinal Fluid Biomarker Evidence of Axonal Injury in the Presence of Alzheimer's Disease Pathology. - Osborn, Katie E; Alverio, Jonathan M; Dumitrescu, Logan; Pechman, Kimberly R; Gifford, Katherine A; Hohman, Timothy J; Blennow, Kaj; Zetterberg, Henrik; Jefferson, Angela L (J Alzheimers Dis, 2019)
BACKGROUND: Vascular risk factors promote cerebral small vessel disease and neuropathological changes, particularly in white matter where large-caliber axons are located. How Alzheimer's disease pathology influences the brain's vulnerability in this regard is not well understood. OBJECTIVE: Systemic vascular risk was assessed in relation to cerebrospinal fluid concentrations of neurofilament light, a biomarker of large-caliber axonal injury, evaluating for interactions by clinical and protein markers of Alzheimer's disease. METHODS: Among Alzheimer's Disease Neuroimaging Initiative participants with normal cognition (n = 117), mild cognitive impairment (n = 190), and Alzheimer's disease (n = 95), linear regression related vascular risk (as measured by the modified Framingham Stroke Risk Profile) to neurofilament light, adjusting for age, sex, education, and cognitive diagnosis. Interactions were assessed by cognitive diagnosis, and by cerebrospinal fluid markers of Aβ42, hyperphosphorylated tau, and total tau. RESULTS: Vascular risk and neurofilament light were not related in the main effect model (p = 0.08). However, interactions emerged for total tau (p = 0.01) and hyperphosphorylated tau (p = 0.002) reflecting vascular risk becoming more associated with cerebrospinal fluid neurofilament light in the context of greater concentrations of tau biomarkers. An interaction also emerged for the Alzheimer's disease biomarker profiles (p = 0.046) where in comparison to the referent 'normal' biomarker group, individuals with abnormal levels of both Aβ42 and total tau showed stronger associations between vascular risk and neurofilament light. CONCLUSION: Older adults may be more vulnerable to axonal injury in response to higher vascular risk burdens in the context of concomitant Alzheimer's disease pathology.

Alzheimer's and Parkinson's Diseases and the Risk of Cancer: A Cohort Study. - Ording, Anne G; Veres, Katalin; Horváth-Puhó, Erzsébet; Glymour, M Maria; Rørth, Mikael; Henderson, Victor W; Sørensen, Henrik T (J Alzheimers Dis, 2019)
Observational studies have shown inverse associations between neurological diseases, particularly dementia, and subsequent cancer risk, but is unknown whether this association is valid or arises from bias. We conducted a Danish nationwide cohort study using population-based health registries (1980-2012). The study included patients with dementia (n = 173,434) and with Parkinson's disease (n = 28,835). We followed patients for 10 years to assess subsequent cancer diagnoses. We computed absolute reduction in cancer risk attributable to dementia or Parkinson's disease (expected minus the observed number of cancer cases divided by the person time) and standardized incidence rate ratios (SIRs) as the observed to expected number of cancers, based on sex-, age-, and calendar year-standardized national incidence rates. During 10 years, the reduction in cancer cases were 79.9 per 10,000 person-years for Alzheimer's disease [SIR = 0.68 (95% CI: 0.66, 0.70)], 74.4 per 10,000 person-years for vascular dementia [SIR = 0.71 (95% CI: 0.67, 0.74)], 55.8 per 10,000 person-years [SIR = 0.77 (95% CI: 0.75, 0.78)] for all-cause dementia, and 4.0 per 10,000 person-years [SIR = 0.98 (95% CI: 0.95, 1.02) for Parkinson's disease. Associations were nearly similar for solid tumors diagnosed at localized, regional, or distant stages. We found an inverse association between dementia and cancer risk, with similar associations when considering only cancers diagnosed at distant stage. The cancer risk varied by type of dementia, with a gradient toward a stronger protective effect associated with Alzheimer's disease and vascular dementia, which may favor a biological explanation. Overall results do not show an inverse association between Parkinson's disease and cancer.

Amyloidogenic Nanoplaques in Blood Serum of Patients with Alzheimer's Disease Revealed by Time-Resolved Thioflavin T Fluorescence Intensity Fluctuation Analysis. - Tiiman, Ann; Jelic, Vesna; Jarvet, Jüri; Järemo, Petter; Bogdanovic, Nenad; Rigler, Rudolf; Terenius, Lars; Gräslund, Astrid; Vukojević, Vladana (J Alzheimers Dis, 2019)
BACKGROUND: Biomarkers are central to current research on molecular mechanisms underlying Alzheimer's disease (AD). Their further development is of paramount importance for understanding pathophysiological processes that eventually lead to disease onset. Biomarkers are also crucial for early disease detection, before clinical manifestation, and for development of new disease modifying therapies. OBJECTIVE: The overall aim of this work is to develop a minimally invasive method for fast, ultra-sensitive and cost-effective detection of structurally modified peptide/protein self-assemblies in the peripheral blood and in other biological fluids. Specifically, we focus here on using this method to detect structured amyloidogenic oligomeric aggregates in the blood serum of apparently healthy individuals and patients in early AD stage, and measure their concentration and size. METHODS: Time-resolved detection of Thioflavin T (ThT) fluorescence intensity fluctuations in a sub-femtoliter observation volume element was used to identify in blood serum ThT-active structured amyloidogenic oligomeric aggregates, hereafter called nanoplaques, and measure with single-particle sensitivity their concentration and size. RESULTS: The concentration and size of structured amyloidogenic nanoplaques are significantly higher in the blood serum of individuals diagnosed with AD than in control subjects. CONCLUSION: A new method with the ultimate, single-particle sensitivity was successfully developed. The proposed approach neither relies on the use of immune-based probes, nor on the use of radiotracers, signal-amplification or protein separation techniques, and provides a minimally invasive test for fast and cost-effective early determination of structurally modified peptides/proteins in the peripheral blood, as shown here, but also in other biological fluids.

APOE ɛ4 Carriers Show Delayed Recovery of Verbal Memory and Smaller Entorhinal Volume in the First Year After Ischemic Stroke. - Werden, Emilio; Khlif, Mohamed Salah; Bird, Laura J; Cumming, Toby; Bradshaw, Jennifer; Khan, Wasim; Pase, Matthew; Restrepo, Carolina; Veldsman, Michele; Egorova, Natalia; Patel, Sheila K; Gottlieb, Elie; et al. (J Alzheimers Dis, 2019)
BACKGROUND: The apolipoprotein E (APOE) gene ɛ4 allele is a risk factor for Alzheimer's disease and cardiovascular disease. However, its relationship with cognition and brain volume after stroke is not clear. OBJECTIVE: We compared cognition and medial temporal lobe volumes in APOEɛ4 carriers and non-carriers in the first year after ischemic stroke. METHODS: We sampled 20 APOEɛ4 carriers and 20 non-carriers from a larger cohort of 135 ischemic stroke participants in the longitudinal CANVAS study. Participants were matched on a range of demographic and stroke characteristics. We used linear mixed-effect models to compare cognitive domain z-scores (attention, processing speed, executive function, verbal and visual memory, language, visuospatial function) and regional medial temporal lobe volumes (hippocampal, entorhinal cortex) between groups at each time-point (three, 12-months post-stroke), and within groups across time-points. APOE gene single nucleotide polymorphisms (SNPs; rs7412, rs429358) were genotyped on venous blood. RESULTS: APOEɛ4 carriers and non-carriers did not differ on any demographic, clinical, or stroke variable. Carriers performed worse than non-carriers in verbal memory at three months post-stroke (p = 0.046), but were better in executive function at 12 months (p = 0.035). Carriers demonstrated a significant improvement in verbal memory (p = 0.012) and executive function (p = 0.015) between time-points. Non-carriers demonstrated a significant improvement in visual memory (p = 0.0005). Carriers had smaller bilateral entorhinal cortex volumes (p <  0.05), and larger-right-sided and contralesional hippocampal volumes, at both time-points (p <  0.05). CONCLUSION: APOE ɛ4 is associated with delayed recovery of verbal memory function and reduced entorhinal cortex volumes in the first year after ischemic stroke.

Can Subjective Memory Complaints Identify Aβ Positive and Aβ Negative Amnestic Mild Cognitive Impairment Patients? - Mendes, Tiago; Cardoso, Sandra; Guerreiro, Manuela; Maroco, João; Silva, Dina; Alves, Luísa; Schmand, Ben; Gerardo, Bianca; Lima, Marisa; Santana, Isabel; de Mendonça, Alexandre (J Alzheimers Dis, 2019)
BACKGROUND: The use of biomarkers, in particular amyloid-β (Aβ) changes, has allowed the possibility to identify patients with subjective memory complaints (SMCs) and amnestic mild cognitive impairment (aMCI) who suffer from Alzheimer's disease (AD). Since it is unfeasible that all patients with aMCI could presently undergo biomarkers assessment, it would be important that SMCs might contribute to identify the aMCI patients who have AD amyloid pathology. OBJECTIVES: To know whether aMCI patients with amyloid biomarkers (Aβ+) present greater SMCs as compared to those without amyloid biomarkers (Aβ-). METHODS: Participants were selected from a cohort of nondemented patients with cognitive complaints and a comprehensive neuropsychological evaluation, on the basis of 1) diagnosis of aMCI; 2) detailed assessment of memory difficulties with the SMC Scale; and 3) known amyloid status. The amyloid status was determined on the basis of either CSF Aβ1-42 concentration or amyloid PET imaging. RESULTS: Of the 176 patients with aMCI studied, 90 were Aβ+ and 86 were Aβ-. The two groups did not differ in terms of age, gender, and education. The SMC total score was not significantly different in the Aβ+ aMCI patients (9.48±4.18) when compared to the Aβ- aMCI patients (10.52±4.57). The Aβ+ aMCI patients had lower scores on the MMSE and memory/learning tests, but not on the Geriatric Depression Scale, when comparing to the Aβ- aMCI patients. CONCLUSIONS: Evaluating SMCs does not seem helpful to identify, among patients with aMCI, those who have AD.

Cerebrospinal Fluid Level of Aquaporin4: A New Window on Glymphatic System Involvement in Neurodegenerative Disease? - Arighi, Andrea; Di Cristofori, Andrea; Fenoglio, Chiara; Borsa, Stefano; D'Anca, Marianna; Fumagalli, Giorgio Giulio; Locatelli, Marco; Carrabba, Giorgio; Pietroboni, Anna Margherita; Ghezzi, Laura; Carandini, Tiziana; Colombi, Annalisa; et al. (J Alzheimers Dis, 2019)
Aquaporin4 (AQP4) is a water channel protein located at astrocyte foot processes that plays a role in glymphatic system, a highly organized fluid transport pathway which seems to be involved in Alzheimer's disease (AD) and normal pressure hydrocephalus (NPH) pathophysiology. Cerebrospinal fluid (CSF) AQP4 levels were determined in 11 patients with AD, 10 patients with NPH, and 9 controls. We found significantly reduced AQP4 in AD patients, a trend in reduction in NPH patients, and a correlation between AQP4 and amyloid-β CSF levels. This study indicates the potential role of AQP4 and glymphatic system in neurodegenerative diseases pathophysiology.

The Clinical Phenotype of Vascular Cognitive Impairment in Patients with Type 2 Diabetes Mellitus. - Groeneveld, Onno N; Moneti, Costanza; Heinen, Rutger; de Bresser, Jeroen; Kuijf, Hugo J; Exalto, Lieza G; Boomsma, Jooske M F; Kappelle, L Jaap; Barkhof, Frederik; Prins, Niels D; Scheltens, Philip; van der Flier, Wiesje M; et al. (J Alzheimers Dis, 2019)
BACKGROUND: Type 2 diabetes mellitus (T2DM) increases the risk of vascular cognitive impairment (VCI). It is unknown which type of vascular lesions and co-morbid etiologies, in particular Alzheimer's disease pathology, are associated with T2DM in patients with VCI, and how this relates to cognition and prognosis. OBJECTIVE: To compare brain MRI and cerebrospinal fluid (CSF) markers, cognition, and prognosis in patients with possible VCI with and without T2DM. METHODS: We included 851 memory clinic patients with vascular brain injury on MRI (i.e., possible VCI) from a prospective cohort study (T2DM: n = 147, 68.4±7.9 years, 63% men; no T2DM: n = 704, 67.6±8.5 years, 52% men). At baseline, we assessed between-group differences in brain MRI abnormalities, CSF markers of Alzheimer's disease, and cognitive profile. After two years follow-up, we compared occurrence of cognitive decline, stroke, and death. RESULTS: The distribution of clinical diagnoses did not differ between patients with and without T2DM. T2DM patients had more pronounced brain atrophy (total and white matter volume), and more lacunar infarcts, whereas microbleeds were less common (all p <  0.05). CSF amyloid-β levels were similar between the groups. T2DM patients performed worse on working memory (effect size: - 0.17, p = 0.03) than those without, whereas performance on other domains was similar. During follow-up, risk of further cognitive decline was not increased in T2DM.∥Conclusion: In patients with possible VCI, presence of T2DM is related to more pronounced brain atrophy and a higher burden of lacunar infarcts, but T2DM does not have a major impact on cognitive profile or prognosis.∥.

A Comparison of Partial Volume Correction Techniques for Measuring Change in Serial Amyloid PET SUVR. - Schwarz, Christopher G; Gunter, Jeffrey L; Lowe, Val J; Weigand, Stephen; Vemuri, Prashanthi; Senjem, Matthew L; Petersen, Ronald C; Knopman, David S; Jack, Clifford R (J Alzheimers Dis, 2019)
Longitudinal PET studies in aging and Alzheimer's disease populations rely on accurate and precise measurements of change over time from serial PET scans. Various methods for partial volume correction (PVC) are commonly applied to such studies, but existing comparisons and validations of these PVC methods have focused on cross-sectional measurements. Rate of change measurements inherently have smaller magnitudes than cross-sectional measurements, so levels of noise amplification due to PVC must be smaller, and it is necessary to re-evaluate methods in this context. Here we compare the relative precision in longitudinal measurements from serial amyloid PET scans when using geometric transfer matrix (GTM) PVC versus the traditional two-compartment (Meltzer-style), three-compartment (Müller-Gärtner-style), and no-PVC approaches. We used two independent implementations of standardized uptake value ratio (SUVR) measurement and PVC (one in-house pipeline based on SPM12 and ANTs, and one using FreeSurfer 6.0). For each approach, we also tested longitudinal-specific variants. Overall, we found that measurements using GTM PVC had significantly worse relative precision (unexplained within-subject variability ≈4-8%) than those using two-compartment, three-compartment, or no PVC (≈2-4%). Longitudinally-stabilized approaches did not improve these properties. This data suggests that GTM PVC methods may be less suitable than traditional approaches when measuring within-person change over time in longitudinal amyloid PET.

Evaluation of Medicare Claims Data as a Tool to Identify Dementia. - Lee, Eunjung; Gatz, Margaret; Tseng, Chiuchen; Schneider, Lon S; Pawluczyk, Sonia; Wu, Anna H; Deapen, Dennis (J Alzheimers Dis, 2019)
BACKGROUND: Medicare claims record linkage has been used to identify diagnosed dementia cases in order to estimate dementia prevalence and cost of care. Claims records in the 1990 s and early 2000 s have been found to provide 85% - ∼90% sensitivity and specificity. OBJECTIVE: Considering that dementia awareness has improved over time, we sought to examine sensitivity and specificity of more recent Medicare claims records against a standard criterion, clinical diagnosis of dementia. METHODS: For a sample of patients evaluated at the University of Southern California Alzheimer Disease Research Center (ADRC), we performed database linkage with Medicare claims files for a six-year period, 2007-2012. We used clinical diagnosis at the ADRC as the criterion diagnosis in order to calculate sensitivity and specificity. RESULTS: Medicare claims correctly identified 85% of dementia patients and 77% of individuals with normal cognition. About half of patients clinically diagnosed with mild cognitive impairment had dementia diagnoses in Medicare claims. Misclassified dementia patients (i.e., missed diagnosis by Medicare claims) had more favorable Mini-Mental State Examination and Clinical Dementia Rating scores and were less likely to present behavioral symptoms than correctly-classified dementia patients. CONCLUSIONS: Database linkage to Medicare claims records is an efficient and reasonably accurate tool to identify dementia cases in a population-based cohort. However, possibilities of obtaining biased results due to misclassification of dementia status need to be carefully considered to use Medicare claims diagnosis for etiologic research studies. Additional confirmation of dementia diagnosis may also be considered. A larger study is warranted to confirm our findings.

Exercise Training in Amnestic Mild Cognitive Impairment: A One-Year Randomized Controlled Trial. - Tarumi, Takashi; Rossetti, Heidi; Thomas, Binu P; Harris, Thomas; Tseng, Benjamin Y; Turner, Marcel; Wang, Ciwen; German, Zohre; Martin-Cook, Kristin; Stowe, Ann M; Womack, Kyle B; Mathews, Dana; et al. (J Alzheimers Dis, 2019)
BACKGROUND: The current evidence is inconclusive to support the benefits of aerobic exercise training (AET) for preventing neurocognitive decline in patients with amnestic mild cognitive impairment (aMCI). OBJECTIVE: To examine the effect of a progressive, moderate-to-high intensity AET program on memory and executive function, brain volume, and cortical amyloid-β (Aβ) plaque deposition in aMCI patients. METHODS: This is a proof-of-concept trial that randomized 70 aMCI patients to 12 months of AET or stretching and toning (SAT, active control) interventions. Primary neuropsychological outcomes were assessed by using the California Verbal Learning Test-second edition (CVLT-II) and the Delis-Kaplan Executive Function System (D-KEFS). Secondary outcomes were the global and hippocampal brain volumes and the mean cortical and precuneus Aβ deposition. RESULTS: Baseline cognitive scores were similar between the groups. Memory and executive function performance improved over time but did not differ between the AET and SAT groups. Brain volume decreased and precuneus Aβ plaque deposition increased over time but did not differ between the groups. Cardiorespiratory fitness was significantly improved in the AET compared with SAT group. In amyloid positive patients, AET was associated with reduced hippocampal atrophy when compared with the SAT group. CONCLUSION: The AET and SAT groups both showed evidence of slightly improved neuropsychological scores in previously sedentary aMCI patients. However, these interventions did not prevent brain atrophy or increases in cortical Aβ deposition over 12 months. In amyloid positive patients, AET reduced hippocampal atrophy when compared with the SAT group.

Geographical Variation in the Diagnostic Rate and Quality of Dementia Diagnoses. - Zakarias, Johanne Købstrup; Jensen-Dahm, Christina; Nørgaard, Ane; Roos, Peter; Gasse, Christiane; Phung, Thien Kieu Thi; Waldemar, Gunhild (J Alzheimers Dis, 2019)
BACKGROUND: Early and accurate diagnosis of dementia opens the door to appropriate treatment, support, and counseling. Despite availability of evidence-based guidelines for diagnostic evaluation of dementia, the diagnostic rate in people with dementia is low and the quality of dementia diagnoses is unknown. OBJECTIVE: The overall aim of this register-based study was to analyze the quality of diagnostic evaluation of dementia by assessing nationwide geographical variations in a range of indicators. METHODS: A register-based cross-sectional study of the entire Danish population aged 65 years or older in 2015 was conducted. The surrogate indicators for diagnostic quality included 1) prevalence rates of dementia diagnoses, 2) incidence rates of dementia diagnoses, 3) age at first diagnosis of dementia, 4) medical specialty responsible for diagnosis, 5) diagnostic rate of dementia subtypes, and 6) use of anti-dementia medication. The indicators were compared across the five Danish regions. RESULTS: The national prevalence and incidence of registered dementia diagnoses was 3.0% and 0.5%, respectively. The proportion of patients diagnosed at a dementia specialist department ranged from 60.9% to 90.5% across the five regions, subtype specific diagnosis ranged from 45.3% to 75.5%, and use of anti-dementia medication ranged from 29.2% to 58.3%. CONCLUSION: The observed geographical variations in dementia diagnoses and treatment indicate inequality in the access to appropriate diagnostic evaluation and care for patients with dementia. Our findings call for more awareness of the benefits of timely diagnosis and for improvement in the quality of diagnostic evaluation of dementia.

Glial Fibrillary Acidic Protein in Serum is Increased in Alzheimer's Disease and Correlates with Cognitive Impairment. - Oeckl, Patrick; Halbgebauer, Steffen; Anderl-Straub, Sarah; Steinacker, Petra; Huss, André M; Neugebauer, Hermann; von Arnim, Christine A F; Diehl-Schmid, Janine; Grimmer, Timo; Kornhuber, Johannes; Lewczuk, Piotr; Danek, Adrian; et al. (J Alzheimers Dis, 2019)
Reliable blood biomarkers for Alzheimer's disease (AD) are missing. We measured astroglial GFAP in patients with AD (n = 28), frontotemporal dementia (bvFTD, n = 35), Parkinson's disease (n = 11), Lewy body dementias (n = 19), and controls (n = 34). Serum GFAP was increased in AD (p < 0.001) and DLB/PDD (p < 0.01), and cerebrospinal fluid GFAP was increased in all neurodegenerative diseases (p < 0.001). Serum GFAP correlated with the Mini-Mental State Examination score (r= -0.42, p < 0.001) and might be a follow-up marker in clinical trials. Sensitivity and specificity of serum GFAP for AD versus bvFTD was 89% and 79% and might be the first blood biomarker in the differential diagnosis of AD and bvFTD.

Head Position During Sleep: Potential Implications for Patients with Neurodegenerative Disease. - Levendowski, Daniel J; Gamaldo, Charlene; St Louis, Erik K; Ferini-Strambi, Luigi; Hamilton, Joanne M; Salat, David; Westbrook, Philip R; Berka, Chris (J Alzheimers Dis, 2019)
BACKGROUND: The characterization of sleep in those with neurodegenerative disease (NDD) is essential in understanding the potential neurobiological mechanisms that underlie the connection between sleep disruption and NDD manifestations and progression. OBJECTIVE: Explore the inter-relationships between NDD and age, sex, diagnosis of obstructive sleep apnea, snoring, and duration of sleep time with the head in the supine and non-supine positions. METHODS: A case-control design was used to evaluate differences in sleep position obtained from multi-night, in-home Sleep Profiler recordings in 45 patients with diagnosed NDD (24 with mild cognitive impairment, 15 with Alzheimer's disease, and 6 with Lewy Body, Parkinson's, or other dementias) and 120 age-sex matched controls with normal cognition (NC). RESULTS: The frequency of supine sleep >2 h/night was significantly greater in the NDD than in the NC group (p < 0.001, odds ratio = 3.7), and remained significant after controlling for age, sex, snoring, and obstructive sleep apnea diagnosis (p = 0.01). There were no group differences in nocturnal mobility i.e., number of head position changes/h. CONCLUSION: This study demonstrates the utility of in-home measurements of sleep in defining the association of supine sleep position with neurodegenerative disorders. Our findings warrant further investigation, particularly in light of the recent evidence suggesting that sleep may an active role in the brain's ability to clear CNS neurotoxins and metabolites.

Higher Body Mass Index Is Associated with Lower Cortical Amyloid-β Burden in Cognitively Normal Individuals in Late-Life. - Thirunavu, Vineeth; McCullough, Austin; Su, Yi; Flores, Shaney; Dincer, Aylin; Morris, John C; Cruchaga, Carlos; Benzinger, Tammie L S; Gordon, Brian A (J Alzheimers Dis, 2019)
BACKGROUND: Both low and high body mass index (BMI) have been associated with an increased risk of dementia, including that caused by Alzheimer's disease (AD). Specifically, high middle-age BMI or a low late-age BMI has been considered a predictor for the development of AD dementia. Less studied is the relationship between BMI and AD pathology. OBJECTIVE: We explored the association between BMI and cortical amyloid-β (Aβ) burden in cognitively normal participants that were either in mid-life (45-60 years) or late-life (>60). METHODS: We analyzed cross-sectional baseline data from the Knight Alzheimer Disease Research Center (ADRC) at Washington University. Aβ pathology was measured in 373 individuals with Aβ PET imaging and was quantified using Centiloid units. We split the cohort into mid- and late-life groups for analyses (n = 96 and n = 277, respectively). We ran general linear regression models to predict Aβ levels from BMI while controlling for age, sex, years of education, and APOE4 status. Analyses were also conducted to test the interaction between BMI and APOE4 genotype and between BMI and sex. RESULTS: Higher BMI was associated with lower cortical Aβ burden in late-life (β= -0.81, p = 0.0066), but no relationship was found in mid-life (β= 0.04, p > 0.5). The BMI×APOE4+ and BMI×male interaction terms were not significant in the mid-life (β= 0.28, p = 0.41; β= 0.64, p = 0.13) or the late-life (β= 0.17, p > 0.5; β= 0.50, p = 0.43) groups. CONCLUSION: Higher late-life BMI is associated with lower cortical Aβ burden in cognitively normal individuals.

Impaired Glucose Tolerance and Reduced Plasma Insulin Precede Decreased AKT Phosphorylation and GLUT3 Translocation in the Hippocampus of Old 3xTg-AD Mice. - Griffith, Chelsea M; Macklin, Lauren N; Cai, Yan; Sharp, Andrew A; Yan, Xiao-Xin; Reagan, Lawrence P; Strader, April D; Rose, Gregory M; Patrylo, Peter R (J Alzheimers Dis, 2019)
Several studies have demonstrated that mouse models of Alzheimer's disease (AD) can exhibit impaired peripheral glucose tolerance. Further, in the APP/PS1 mouse model, this is observed prior to the appearance of AD-related neuropathology (e.g., amyloid-β plaques; Aβ) or cognitive impairment. In the current study, we examined whether impaired glucose tolerance also preceded AD-like changes in the triple transgenic model of AD (3xTg-AD). Glucose tolerance testing (GTT), insulin ELISAs, and insulin tolerance testing (ITT) were performed at ages prior to (1-3 months and 6-8 months old) and post-pathology (16-18 months old). Additionally, we examined for altered insulin signaling in the hippocampus. Western blots were used to evaluate the two-primary insulin signaling pathways: PI3K/AKT and MAPK/ERK. Since the PI3K/AKT pathway affects several downstream targets associated with metabolism (e.g., GSK3, glucose transporters), western blots were used to examine possible alterations in the expression, translocation, or activation of these targets. We found that 3xTg-AD mice display impaired glucose tolerance as early as 1 month of age, concomitant with a decrease in plasma insulin levels well prior to the detection of plaques (∼14 months old), aggregates of hyperphosphorylated tau (∼18 months old), and cognitive decline (≥18 months old). These alterations in peripheral metabolism were seen at all time points examined. In comparison, PI3K/AKT, but not MAPK/ERK, signaling was altered in the hippocampus only in 18-20-month-old 3xTg-AD mice, a time point at which there was a reduction in GLUT3 translocation to the plasma membrane. Taken together, our results provide further evidence that disruptions in energy metabolism may represent a foundational step in the development of AD.

Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers. - Khoonsari, Payam Emami; Shevchenko, Ganna; Herman, Stephanie; Remnestål, Julia; Giedraitis, Vilmantas; Brundin, RoseMarie; Degerman Gunnarsson, Malin; Kilander, Lena; Zetterberg, Henrik; Nilsson, Peter; Lannfelt, Lars; Ingelsson, Martin; et al. (J Alzheimers Dis, 2019)
BACKGROUND: Alzheimer's disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD. OBJECTIVE: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects. METHODS: We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4-9 years and 21 of these converted to AD, whereas 53 remained stable. RESULTS: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCI/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively. CONCLUSIONS: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects.

Inhibition of Calpain Protects Against Tauopathy in Transgenic P301S Tau Mice. - Liu, Mengyu; Wang, Luwen; Gao, Ju; Dong, Qing; Perry, George; Ma, Xuemei; Wang, Xinglong (J Alzheimers Dis, 2019)
Alzheimer's disease (AD) and other tauopathies are characterized by intracellular accumulation of microtubule-associated tau protein leading to neurodegeneration. Calpastatin is the endogenous inhibitor of calpain, a calcium-dependent cysteine protease that has been increasingly implicated in tauopathies. In this study, we generated a neuron specific calpastatin overexpressing knock-in transgenic mouse model and crossed it with the PS19 tauopathy mouse model expressing human P301S mutant tau protein. The forced expression of calpastatin in neurons significantly alleviated tau hyperphosphorylation measured by immunocytochemistry and immunoblot. The genetic inhibition of calpain by calpastatin also greatly suppressed characteristic hippocampal neuron loss and widespread astrogliosis and microgliosis in PS19 mice. Consistently, PS19 mice with neuronal calpastatin overexpression exhibited remarkably alleviated cognitive deficits, muscle weakness, skeletal muscle atrophy, and neuromuscular denervation, together implying the neuroprotective effects of neuronal calpastatin in PS19 mice of tauopathy. In sum, this study provides additional evidence supporting the pathological role of calpain in neurodegenerative diseases associated with tau pathology, and suggests that targeting calpain is likely a promising therapeutic approach for these devastating diseases.

Lipopolysaccharide Induced Opening of the Blood Brain Barrier on Aging 5XFAD Mouse Model. - Barton, Shawn M; Janve, Vaibhav A; McClure, Richard; Anderson, Adam; Matsubara, Joanne A; Gore, John C; Pham, Wellington (J Alzheimers Dis, 2019)
The development of neurotherapeutics for many neurodegenerative diseases has largely been hindered by limited pharmacologic penetration across the blood-brain barrier (BBB). Previous attempts to target and clear amyloid-β (Aβ) plaques, a key mediator of neurodegenerative changes in Alzheimer's disease (AD), have had limited clinical success due to low bioavailability in the brain because of the BBB. Here we test the effects of inducing an inflammatory response to disrupt the BBB in the 5XFAD transgenic mouse model of AD. Lipopolysaccharide (LPS), a bacterial endotoxin recognized by the innate immune system, was injected at varying doses. 24 hours later, mice were injected with either thioflavin S, a fluorescent Aβ-binding small molecule or 30 nm superparamagnetic iron oxide (SPIO) nanoparticles, both of which are unable to penetrate the BBB under normal physiologic conditions. Our results showed that when pretreated with 3.0 mg/kg LPS, thioflavin S can be found in the brain bound to Aβ plaques in aged 5XFAD transgenic mice. Following the same LPS pretreatment, SPIO nanoparticles could also be found in the brain. However, when done on wild type or young 5XFAD mice, limited SPIO was detected. Our results suggest that the BBB in aged 5XFAD mouse model is susceptible to increased permeability mediated by LPS, allowing for improved delivery of the small molecule thioflavin S to target Aβ plaques and SPIO nanoparticles, which are significantly larger than antibodies used in clinical trials for immunotherapy of AD. Although this approach demonstrated efficacy for improved delivery to the brain, LPS treatment resulted in significant weight loss even at low doses, resulting from the induced inflammatory response. These findings suggest inducing inflammation can improve delivery of small and large materials to the brain for improved therapeutic or diagnostic efficacy. However, this approach must be balanced with the risks of systemic inflammation.

Maintain Your Brain: Protocol of a 3-Year Randomized Controlled Trial of a Personalized Multi-Modal Digital Health Intervention to Prevent Cognitive Decline Among Community Dwelling 55 to 77 Year Olds. - Heffernan, Megan; Andrews, Gavin; Fiatarone Singh, Maria A; Valenzuela, Michael; Anstey, Kaarin J; Maeder, Anthony J; McNeil, John; Jorm, Louisa; Lautenschlager, Nicola T; Sachdev, Perminder S; Ginige, Jeewani A; Hobbs, Megan J; et al. (J Alzheimers Dis, 2019)
BACKGROUND: Maintain Your Brain (MYB) is a randomized controlled trial of an online multi-modal lifestyle intervention targeting modifiable dementia risk factors with its primary aim being to reduce cognitive decline in an older age cohort. METHODS: MYB aims to recruit 8,500 non-demented community dwelling 55 to 77 year olds from the Sax Institute's 45 and Up Study in New South Wales, Australia. Participants will be screened for risk factors related to four modules that comprise the MYB intervention: physical activity, nutrition, mental health, and cognitive training. Targeting risk factors will enable interventions to be personalized so that participants receive the most appropriate modules. MYB will run for three years and up to four modules will be delivered sequentially each quarter during year one. Upon completing a module, participants will continue to receive less frequent booster activities for their eligible modules (except for the mental health module) until the end of the trial. DISCUSSION: MYB will be the largest internet-based trial to attempt to prevent cognitive decline and potentially dementia. If successful, MYB will provide a model for not just effective intervention among older adults, but an intervention that is scalable for broad use.

Mild Cognitive Impairment and Dementia Involving Multiple Cognitive Domains in Mexican Urbanites. - Calderón-Garcidueñas, Lilian; Mukherjee, Partha S; Kulesza, Randy J; Torres-Jardón, Ricardo; Hernández-Luna, Jacqueline; Ávila-Cervantes, Rodrigo; Macías-Escobedo, Edgar; González-González, Oscar; González-Maciel, Angelica; García-Hernández, Kevin; Hernández-Castillo, Ariatna; Villarreal-Ríos, Rodolfo (J Alzheimers Dis, 2019)
Exposures to fine particulate matter PM2.5 and ozone O3 are associated with Alzheimer's disease (AD) risk. Mexico City residents have lifetime exposures to PM2.5 and O3 above annual USEPA standards and their brains contain high redox, combustion, and friction-derived magnetite nanoparticles. AD pathological changes with subcortical pre-tangle stages in infancy and cortical tau pre-tangles, NFT Stages I-II, and amyloid phases 1-2 are identified by the 2nd decade. Given their AD continuum, a reliable identification of cognitive impairment is of utmost importance. The Montreal Cognitive Assessment (MoCA) was administered to 517 urbanites, age 21.60±5.88 years, with 13.69±1.28 formal education years, in Mexican PM2.5 polluted cities. MoCA score was 23.92±2.82, and 24.7% and 30.3% scored ≤24 and ≤22, respectively (MCI≤24, AD≤22). Cognitive deficits progressively targeted Visuospatial, Executive, Language, and Memory domains, body mass index (BMI) impacting total scores negatively (p = 0.0008), aging driving down Executive, Visuospatial, and Language index scores (p <  0.0001, 0.0037, and 0.0045), and males performing better in Executive tasks. Average age for AD MoCA scores was 22.38±7.7 years. Residency in polluted cities is associated with progression of multi-domain cognitive impairment affecting 55% of Mexican seemingly healthy youth. Normal BMI ought to be a neuroprotection goal. MoCA provides guidance for further mandatory neuropsychological testing in young populations. Identifying and lowering key neurotoxicants impacting neural risk trajectories in the developing brain and monitoring cognitive performance would greatly facilitate multidisciplinary early diagnosis and prevention of AD in high risk young populations. Cognitive deficits hinder development of those representing the force moving the country in future years.

Mitophagy Failure in APP and Tau Overexpression Model of Alzheimer's Disease. - Martín-Maestro, Patricia; Gargini, Ricardo; García, Esther; Simón, Diana; Avila, Jesús; García-Escudero, Vega (J Alzheimers Dis, 2019)
Mitochondrial alterations and oxidative stress are common features of Alzheimer's disease brain and peripheral tissues. Moreover, mitochondrial recycling process by autophagy has been found altered in the sporadic form of the disease. However, the contribution of the main proteins involved in this pathology such as amyloid-β protein precursor (AβPP) and tau needs to be achieved. With this aim, human unmodified fibroblasts were transduced with lentivectors encoding APP and Tau and treated with CCCP to study the mitophagy process. Both AβPP and tau separately increased autophagy flux mainly by improving degradation phase. However, in the specific case of mitophagy, labeling of mitochondria by PINK1 and PARK2 to be degraded by autophagy seemed reduced, which correlates with the long-term accumulation of mitochondria. Nevertheless, the combination of tau and AβPP was necessary to cause a mitophagy functional impairment reflected in the accumulation of depolarized mitochondria labeled by PINK1. The overexpression of Tau and APP recapitulates the mitophagy failure previously found in sporadic Alzheimer's disease.

Neurodegenerative Disease-Related Proteins within the Epidermal Layer of the Human Skin. - Akerman, S Can; Hossain, Shireen; Shobo, Adeola; Zhong, Yifei; Jourdain, Roland; Hancock, Mark A; George, Kelly; Breton, Lionel; Multhaup, Gerhard (J Alzheimers Dis, 2019)
There is increasing evidence suggesting that amyloidogenic proteins might form deposits in non-neuronal tissues in neurodegenerative disorders such as Alzheimer's or Parkinson's diseases. However, the detection of these aggregation-prone proteins within the human skin has been controversial. Using immunohistochemistry (IHC) and mass spectrometry tissue imaging (MALDI-MSI), fresh frozen human skin samples were analyzed for the expression and localization of neurodegenerative disease-related proteins. While α-synuclein was detected throughout the epidermal layer of the auricular samples (IHC and MALDI-MSI), tau and Aβ34 were also localized to the epidermal layer (IHC). In addition to Aβ peptides of varying length (e.g., Aβ40, Aβ42, Aβ34), we also were able to detect inflammatory markers within the same sample sets (e.g., thymosin β-4, psoriasin). While previous literature has described α-synuclein in the nucleus of neurons (e.g., Parkinson's disease), our current detection of α-synuclein in the nucleus of skin cells is novel. Imaging of α-synuclein or tau revealed that their presence was similar between the young and old samples in our present study. Future work may reveal differences relevant for diagnosis between these proteins at the molecular level (e.g., age-dependent post-translational modifications). Our novel detection of Aβ34 in human skin suggests that, just like in the brain, it may represent a stable intermediate of the Aβ40 and Aβ42 degradation pathway.

Neuropsychological Deficit Profiles, Vascular Risk Factors, and Neuropathological Findings in Hispanic Older Adults with Autopsy-Confirmed Alzheimer's Disease. - Weissberger, Gali H; Gollan, Tamar H; Bondi, Mark W; Nation, Daniel A; Hansen, Lawrence A; Galasko, Douglas; Salmon, David P (J Alzheimers Dis, 2019)
This study aimed to determine if patterns of neuropsychological deficits, vascular risk factors, and neuropathology differ in Hispanic and Non-Hispanic patients with autopsy-confirmed Alzheimer's disease (AD). Participants were enrolled in a longitudinal study at the Shiley-Marcos AD Research Center at the University of California, San Diego. Hispanic (n = 14) and Non-Hispanic (n = 20) patients with autopsy-confirmed AD who scored ≥95 on the Dementia Rating Scale (DRS) were included. Patient groups were matched on age, education, global mental status, and severity of functional decline; they were compared to Hispanic (n = 14) or Non-Hispanic (n = 20) cognitively-normal controls of similar age and education. Ethnicity (Hispanic, Non-Hispanic) by disease state (autopsy-confirmed AD or cognitively normal) comparisons were made for cognitive test performance and vascular risk factors. Patient groups were further compared on measures of AD (Braak stage, neuritic plaques, neurofibrillary tangles), vascular neuropathology, and performance across cognitive domains of memory, language, attention, executive functions, and visuospatial abilities after scores were z-transformed based on respective culturally-appropriate control groups. Patient groups had similar overall AD pathology burden, whereas Hispanics with AD had more small parenchymal arteriolar disease and amyloid angiopathy than Non-Hispanics with AD. Despite largely similar pathology, Hispanics with AD were less cognitively impaired (relative to respective NC groups) than Non-Hispanics with AD, and exhibited a different pattern of deficits across cognitive domains. Findings suggest that cognitive deficits that are usually prominent in AD may be less salient in Hispanic patients and this may adversely impact the ability to clinically detect the disease in mild to moderate stages.

Present Algorithms and Future Treatments for Alzheimer's Disease. - Grossberg, George T; Tong, Gary; Burke, Anna D; Tariot, Pierre N (J Alzheimers Dis, 2019)
An estimated 47 million people live with Alzheimer's disease (AD) and other forms of dementia worldwide. Although no disease-modifying treatments are currently available for AD, earlier diagnosis and proper management of the disease could have considerable impact on patient and caregiver quality of life and functioning. Drugs currently approved for AD treat the cognitive, behavioral, and functional symptoms of the disease and consist of three cholinesterase inhibitors (ChEIs) and the N-methyl-D-aspartate receptor antagonist memantine. Treatment of patients with mild to moderate AD is generally initiated with a ChEI. Patients who show progression of symptoms while on ChEI monotherapy may be switched to another ChEI and/or memantine can be added to the treatment regimen. In recent years, putative disease-modifying therapies have emerged that aim to slow the progression of AD instead of only addressing its symptoms. However, many therapies have failed in clinical trials in patients with established AD, suggesting that, once developed, disease-modifying agents may need to be deployed earlier in the course of illness. The goal of this narrative literature review is to discuss present treatment algorithms and potential future therapies in AD.

A Randomized, Double-Blind, Placebo-Controlled, Phase II Study Assessing Safety, Tolerability, and Efficacy of Bryostatin in the Treatment of Moderately Severe to Severe Alzheimer's Disease. - Farlow, Martin R; Thompson, Richard E; Wei, Lee-Jen; Tuchman, Alan J; Grenier, Elaine; Crockford, David; Wilke, Susanne; Benison, Jeffrey; Alkon, Daniel L (J Alzheimers Dis, 2019)
BACKGROUND: Bryostatin-activated PKC epsilon pre-clinically induces synaptogenesis, anti-apoptosis, anti-amyloid-β oligomers, and anti-hyperphosphorylated tau. OBJECTIVES: To investigate bryostatin safety, tolerability, and efficacy to improve cognition in advanced Alzheimer's disease (AD) patients. METHODS: A double-blind, randomized, placebo-controlled Phase II, 12-week trial of i.v. bryostatin for 150 advanced AD patients (55-85) with MMSE-2 of 4-15, randomized 1:1:1 into 20 μg and 40 μg bryostatin, and placebo arms. The Full Analysis Set (FAS) and the Completer Analysis Set (CAS) were pre-specified alternative assessments (1-sided, p < 0.1 for primary efficacy, and 2-sided, p < 0.05 for pre-specified and post hoc exploratory analyses). RESULTS: The safety profile was similar for 20 μg treatment and placebo patients. The 40 μg patients showed safety and drop-out issues, but no efficacy. Primary improvement of Severe Impairment Battery (SIB) scores at 13 weeks was not significant (p = 0.134) in the FAS, although in the CAS, the SIB comparison favored 20 μg bryostatin compared to placebo patients (p < 0.07). Secondary analyses at weeks 5 and 15 (i.e., 30 days post-final dosing) also favored 20 μg bryostatin compared to placebo patients. A pre-specified ANCOVA for baseline memantine blocking bryostatin and positive post-hoc trend analyses were statistically significant (2-sided, p < 0.05). CONCLUSION: Although the primary endpoint was not significant in the FAS, primary and secondary analyses in the CAS, and pre-specified and post-hoc exploratory analyses did favor bryostatin 20 μg compared to the placebo cohort. These promising Phase II results support further trials of 20 μg bryostatin- without memantine- to treat AD.

Risk Factors for and Clinical Relevance of Incident and Progression of Cerebral Small Vessel Disease Markers in an Asian Memory Clinic Population. - Gyanwali, Bibek; Shaik, Muhammad Amin; Tan, Boon Yeow; Venketasubramanian, Narayanaswamy; Chen, Christopher; Hilal, Saima (J Alzheimers Dis, 2019)
BACKGROUND: Cerebral small vessel disease (SVD) is one of the major contributors to cognitive impairment and dementia. However, data on the incidence and progression of SVD in an Asian population are lacking. OBJECTIVE: The present study aims to investigate the incidence, progression, associated risk factors, and clinical relevance of SVD in a memory clinic setting. METHODS: A prospective case-control study, where 346 patients underwent repeated brain MRI with a mean interval of 24.5 months, accessing white matter hyperintensities (WMH), lacunes and cerebral microbleeds (CMBs). Severity of cognitive impairment was assessed using Clinical Dementia Rating scale and change in clinical diagnosis. Data on demographics, vascular risk factors, and clinical history were collected at baseline. RESULTS: The prevalence of significant WMH (Fazekas ≥2) was 56.6% at baseline which progressed to 59.0% at follow-up. Overall prevalence of CMBs increased from 42.2% to 47.4% (9% new cases) and lacunes increased from 31.8% to 33.2% (2.1% new cases). Hypertension was associated with WMH progression (OR: 1.78, 95% CI: 1.01, 2.99) and increasing age was associated with incident CMBs (OR: 1.04, 95% CI: 1.01, 1.08). Moreover, the use of lipid-lowering medications decreased the incidence of lacunes (OR: 0.15, 95% CI: 0.04, 0.61). The major risk factor for incident SVD was baseline SVD lesion load. WMH progression was associated with increased severity of cognitive impairment (OR: 1.95, 95% CI: 1.16, 3.23). CONCLUSION: Vascular risk factors and baseline severity of SVD lesion load were associated with progression of SVD. Furthermore, WMH progression was linked with increased severity of cognitive impairment. Future studies should be aimed to slow cognitive deterioration by preventing SVD related brain damage by targeting vascular risk factors.

Sirtuin 3 Mediates Tau Deacetylation. - Li, Shiping; Yin, Junxiang; Nielsen, Megan; Beach, Thomas G; Guo, Li; Shi, Jiong (J Alzheimers Dis, 2019)
BACKGROUND: Emerging evidence shows tau acetylation has been observed in Alzheimer's disease (AD) brain at early Braak stages and is involved in regulating tau early accumulation. However, the effects of deacetylase Sirtuin 3 (Sirt3) on tau acetylation and its aggregations are unclear. OBJECTIVE: We studied the effects of Sirt3 on tau acetylation and its aggregations. METHODS: We investigated the protein levels of Sirt3 and tangle tau in human postmortem brains slices from AD, mild cognitive impairment, and age- and education-matched cognitively normal subjects, and AD model mice. We also measured tau acetylation levels in hippocampal HT22 cells after Sirt3 knockdown or overexpression. RESULTS: The level of Sirt3 was inversely related with tau protein in brain slices from both human being and AD model mice. Mechanistically, tau acetylation decreased dramatically with Sirt3 overexpression, while tau acetylation increased after Sirt3 knockdown in hippocampal HT22 cells. CONCLUSIONS: Sirt3 may play a role in tau acetylation and could be a potential target for novel therapy to alleviate tau accumulation.

Telomere Shortening in the Alzheimer's Disease Neuroimaging Initiative Cohort. - Nudelman, Kelly N H; Lin, Jue; Lane, Kathleen A; Nho, Kwangsik; Kim, Sungeun; Faber, Kelley M; Risacher, Shannon L; Foroud, Tatiana M; Gao, Sujuan; Davis, Justin W; Weiner, Michael W; Saykin, Andrew J (J Alzheimers Dis, 2019)
BACKGROUND: Although shorter telomeres have been associated with Alzheimer's disease (AD), it is unclear whether longitudinal change in telomere length is associated with AD progression. OBJECTIVE: To investigate the association of telomere length change with AD diagnosis and progression. METHODS: In 653 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, T/S ratio (telomere versus single copy gene), a proxy of telomere length, was measured for up to five visits per participant (N = 1918 samples post-QC) using quantitative PCR (qPCR). T/S ratio was adjusted for batch effects and DNA storage time. A mixed effects model was used to evaluate association of telomere length with AD diagnostic group and interaction of age and diagnosis. Another mixed effects model was used to compare T/S ratio changes pre- to post-conversion to MCI or AD to telomere change in participants with stable diagnoses. RESULTS: Shorter telomeres were associated with older age (Effect Size (ES) = -0.23) and male sex (ES = -0.26). Neither baseline T/S ratio (ES = -0.036) nor T/S ratio change (ES = 0.046) differed significantly between AD diagnostic groups. MCI/AD converters showed greater, but non-significant, telomere shortening compared to non-converters (ES = -0.186). CONCLUSIONS: Although AD compared to controls showed small, non-significant effects for baseline T/S ratio and T/S ratio shortening, we did observe a larger, though still non-significant effect for greater telomere shortening in converters compared to non-converters. Although our results do not support telomere shortening as a robust biomarker of AD progression, further investigation in larger samples and for subgroups of participants may be informative.

TSPO Ligands Boost Mitochondrial Function and Pregnenolone Synthesis. - Lejri, Imane; Grimm, Amandine; Hallé, François; Abarghaz, Mustapha; Klein, Christian; Maitre, Michel; Schmitt, Martine; Bourguignon, Jean-Jacques; Mensah-Nyagan, Ayikoe Guy; Bihel, Frederic; Eckert, Anne (J Alzheimers Dis, 2019)
Translocator protein 18 kDa (TSPO) is located in the mitochondrial outer membrane and plays an important role in steroidogenesis and cell survival. In the central nervous system (CNS), its expression is upregulated in neuropathologies such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands based on an imidazoquinazolinone termed 2a and 2b, stimulated pregnenolone synthesis and ATP production in vitro. In the present study, we compared their effects to those of TSPO ligands described in the literature (XBD173, SSR-180,575, and Ro5-4864) by profiling the mitochondrial bioenergetic phenotype before and after treatment and investigating the protective effects of these ligands after oxidative injury in a cellular model of AD overexpressing amyloid-β (Aβ). Of note, ATP levels increased with rising pregnenolone levels suggesting that the energetic performance of mitochondria is linked to an increased production of this neurosteroid via TSPO modulation. Our results further demonstrate that the TSPO ligands 2a and 2b exerted neuroprotective effects by improving mitochondrial respiration, reducing reactive oxygen species and thereby decreasing oxidative stress-induced cell death as well as lowering Aβ levels. The compounds 2a and 2b show similar or even better functional effects than those obtained with the reference TSPO ligands XBD173 and SSR-180.575. These findings indicate that the new TSPO ligands modulate mitochondrial bioenergetic phenotype and protect against oxidative injury probably through the de novo synthesis of neurosteroids, suggesting that these compounds could be potential new therapeutic tools for the treatment of neurodegenerative disease.

Two Year Outcomes, Cognitive and Behavioral Markers of Decline in Healthy, Cognitively Normal Older Persons with Global Deterioration Scale Stage 2 (Subjective Cognitive Decline with Impairment). - Reisberg, Barry; Torossian, Carol; Shulman, Melanie B; Monteiro, Isabel; Boksay, Istvan; Golomb, James; Guillo Benarous, Francoise; Ulysse, Anaztasia; Oo, Thet; Vedvyas, Alok; Rao, Julia A; Marsh, Karyn; et al. (J Alzheimers Dis, 2019)
BACKGROUND: Little is known with respect to behavioral markers of subjective cognitive decline (SCD), a condition initially described in association with Global Deterioration Scale (GDS) stage 2. OBJECTIVE: Two-year interval behavioral markers were investigated herein. METHODS: Subjects from a published 7-year outcome study of GDS stage 2 subjects were selected. This study had demonstrated a hazard ratio of 4.5 for progression of GDS stage 2, in comparison with GDS stage 1 (no subjective or objective cognitive decline) subjects, after controlling for demographic and temporal variables. Because GDS 2 subjects have previously demonstrated impairment in comparison with healthy persons free of complaints, we herein suggest the terminology "SCD(I)" for these persons. 98 SCD(I) persons, 63 women and 35 men, mean baseline age, 67.12±8.75 years, with a mean educational background of 15.55±2.60 years, and mean baseline MMSE scores of 28.9±1.24 were followed for 2.13±0.30 years. RESULTS: Observed annual decline on the GDS was 6.701% per annum, very close to a 1986 published estimate. At follow up, the MMSE, and 7 of 8 psychometric tests did not decline significantly. Of 21 Hamilton Depression Scale items, 2 improved and the remainder were unchanged. Anxieties declined from multiple perspectives. The Brief Cognitive Rating Scale (BCRS) declined significantly (p < 0.001), with component declines in Remote memory (p < 0.01), and Functioning/self-care (p = 0.01). CONCLUSION: SCD(I) persons decline at an annual rate of approximately 6.7% /year from several recent studies. The BCRS assessments and the Digit Symbol Substitution Test can be sensitive measures for future studies of progression mitigation.

Ultrasensitive Detection of Plasma Amyloid-β as a Biomarker for Cognitively Normal Elderly Individuals at Risk of Alzheimer's Disease. - Chatterjee, Pratishtha; Elmi, Mitra; Goozee, Kathryn; Shah, Tejal; Sohrabi, Hamid R; Dias, Cintia B; Pedrini, Steve; Shen, Kaikai; Asih, Prita R; Dave, Preeti; Taddei, Kevin; Vanderstichele, Hugo; et al. (J Alzheimers Dis, 2019)
BACKGROUND: Aberrant amyloid-β (Aβ) deposition in the brain occurs two decades prior to the manifestation of Alzheimer's disease (AD) clinical symptoms and therefore brain Aβ load measured using PET serves as a gold standard biomarker for the early diagnosis of AD. However, the uneconomical nature of PET makes blood markers, that reflect brain Aβ deposition, attractive candidates for investigation as surrogate markers. OBJECTIVE: Investigation of plasma Aβ as a surrogate marker for brain Aβ deposition in cognitively normal elderly individuals. METHODS: Plasma Aβ40 and Aβ42 concentrations were measured using the ultrasensitive Single Molecule Array (Simoa) assay in 95 cognitively normal elderly individuals, who have all undergone PET to assess brain Aβ deposition. Based on the standard uptake value ratios (SUVR) obtained from PET imaging, using the tracer 18F-Florbetaben, plasma Aβ was compared between 32 participants assessed to have low brain Aβ load (Aβ-, SUVR <1.35) and 63 assessed to have high brain Aβ load (Aβ+, SUVR ≥1.35). RESULTS: Plasma Aβ42/Aβ40 ratios were lower in the Aβ+ group compared to the Aβ-group. Plasma Aβ40 and Aβ42 levels were not significantly different between Aβ-and Aβ+ groups, although a trend of higher plasma Aβ40 was observed in the Aβ+ group. Additionally, plasma Aβ42/Aβ40 ratios along with the known AD risk factors, age and APOEɛ4 status, resulted in Aβ+ participants being distinguished from Aβ-participants based on an area under the receiver operating characteristic curve shown to be 78%. CONCLUSION: Plasma Aβ ratios in this study are a potential biomarker for brain Aβ deposition and therefore, for preclinical AD. However, this method to measure plasma Aβ needs further development to increase the accuracy of this promising AD blood biomarker.

An UNC5C Allele Predicts Cognitive Decline and Hippocampal Atrophy in Clinically Normal Older Adults. - Yang, Hyun-Sik; Chhatwal, Jasmeer P; Xu, Jishu; White, Charles C; Hanseeuw, Bernard; Rabin, Jennifer S; Papp, Kathryn V; Buckley, Rachel F; Schultz, Aaron P; Properzi, Michael J; Gatchel, Jennifer R; Amariglio, Rebecca E; et al. (J Alzheimers Dis, 2019)
BACKGROUND: The UNC5C rs3846455G allele has been linked to poor cognitive resilience against age-related neuropathologies, but this association remains to be replicated, and the allele's effect on hippocampal neurodegeneration needs to be examined. OBJECTIVE: To further validate the association between rs3846455G and faster cognitive decline, especially among cognitively normal older adults, and to assess whether rs3846455G predicts accelerated hippocampal volume loss in older adults. METHODS: We assessed participants in the Harvard Aging Brain Study (HABS), a longitudinal cohort study of older adults who were clinically normal at baseline. To avoid bias from population admixture, analyses were limited to participants of European descent with longitudinal neuroimaging data (n = 174). Linear mixed effect models were used to examine the effect of rs3846455G on longitudinal change of the Preclinical Alzheimer Cognitive Composite (PACC) and MRI-measured bilateral hippocampal volume, adjusting for baseline amyloid-β (Aβ) measured by the cortical Pittsburgh Compound B PET distributed volume ratio. We also tested whether hippocampal atrophy mediates the association between rs3846455G and greater PACC decline through a mediation analysis. RESULTS: rs3846455G was associated with greater PACC decline (β= -0.087/year, 95% CI -0.169 to -0.005, p = 0.039) after controlling for baseline Aβ. Further, rs3846455G predicted accelerated hippocampal atrophy after controlling for baseline Aβ (β= -57.3 mm3/year, 95% CI -102.8 to -11.9, p = 0.014). The association between rs3846455G and greater PACC decline was partially mediated by accelerated hippocampal atrophy (mediated effect (relative scale) = -0.014, 95% CI -0.032 to -6.0×10-4, p = 0.039). CONCLUSION: UNC5C rs3846455G predicts greater cognitive decline and accelerated hippocampal atrophy in clinically normal older adults.

Vital Exhaustion and Incidence of Dementia: Results from the Copenhagen City Heart Study. - Islamoska, Sabrina; Ishtiak-Ahmed, Kazi; Hansen, Åse Marie; Grynderup, Matias Brødsgaard; Mortensen, Erik Lykke; Garde, Anne Helene; Gyntelberg, Finn; Prescott, Eva Irene Bossano; Török, Eszter; Waldemar, Gunhild; Nabe-Nielsen, Kirsten (J Alzheimers Dis, 2019)
BACKGROUND: Psychological distress is potentially linked to the risk of dementia through neurologic and cardiovascular mechanisms. Vital exhaustion (VE) is a mental state of psychological distress, which could be a risk factor for dementia. OBJECTIVE: To investigate whether VE is a risk factor for dementia in later life. METHODS: We used data from 6,807 participants attending the third survey of the Copenhagen City Heart Study in 1991-1994. VE was assessed by 17 symptoms (score: 0-17) from the Maastricht Questionnaire. Information on dementia was obtained from national registers. Risk time for dementia was counted from five years after VE assessment for participants > 55 years at the time of VE assessment. For younger participants, risk time for dementia was counted from the year they turned 60 years and onwards. Participants were followed until 2016. We used Poisson regression to calculate incidence rate ratios (IRR) and their 95% confidence intervals (CI). RESULTS: During an average follow-up of 10 years, 872 participants were registered with dementia. We found a dose-response relation between the number of VE symptoms and the incidence of dementia. For every additional VE symptom, the dementia incidence increased by 2% (IRR = 1.024; 95% CI: 1.004-1.043). Adjustment for socio-demographic and health-related factors did not change the results substantially. Neither did stratification by age, sex, educational level, and marital status. CONCLUSION: We found evidence that VE is a risk factor for dementia. Our sensitivity analyses supported that this association was not only due to VE being a potential prodromal sign of dementia.

Why Is Amyloid-β PET Requested After Performing Cerebrospinal Fluid Biomarkers? - Reimand, Juhan; Groot, Colin; Teunissen, Charlotte E; Windhorst, Albert D; Boellaard, Ronald; Barkhof, Frederik; Nazarenko, Sergei; van der Flier, Wiesje M; van Berckel, Bart N M; Scheltens, Philip; Ossenkoppele, Rik; Bouwman, Femke (J Alzheimers Dis, 2019)
BACKGROUND: Amyloid-β PET and cerebrospinal fluid (CSF) Aβ42 are considered interchangeable for clinical diagnosis of Alzheimer's disease. OBJECTIVE: To explore the clinical reasoning for requesting additional amyloid-β PET after performing CSF biomarkers. METHODS: We retrospectively identified 72 memory clinic patients who underwent amyloid-β PET after CSF biomarkers analysis for clinical diagnostic evaluation between 2011 and 2019. We performed patient chart reviews to identify factors which led to additional amyloid-β PET. Additionally, we assessed accordance with appropriate-use-criteria (AUC) for amyloid-β PET. RESULTS: Mean patient age was 62.0 (SD = 8.1) and mean Mini-Mental State Exam score was 23.6 (SD = 3.8). CSF analysis conflicting with the clinical diagnosis was the most frequent reason for requesting an amyloid-β PET scan (n = 53, 74%), followed by incongruent MRI (n = 16, 22%), unusual clinical presentation (n = 11, 15%) and young age (n = 8, 11%). An amyloid-β PET scan was rarely (n = 5, 7%) requested in patients with a CSF Aβ+/tau+ status. Fifteen (47%) patients with a post-PET diagnosis of AD had a predominantly non-amnestic presentation. In n = 11 (15%) cases, the reason that the clinician requested amyloid-β was not covered by AUC. This happened most often (n = 7) when previous CSF analysis did not support current clinical diagnosis, which led to requesting amyloid-β PET. CONCLUSION: In this single-center study, the main reason for requesting an amyloid-β PET scan after performing CSF biomarkers was the occurrence of a mismatch between the primary clinical diagnosis and CSF Aβ/tau results.

A 10-Year Follow-Up of Adiposity and Dementia in Swedish Adults Aged 70 Years and Older. - Arnoldussen, Ilse A C; Sundh, Valter; Bäckman, Kristoffer; Kern, Silke; Östling, Svante; Blennow, Kaj; Zetterberg, Henrik; Skoog, Ingmar; Kiliaan, Amanda J; Gustafson, Deborah R (J Alzheimers Dis, 2018)
BACKGROUND: Adiposity measured in mid- or late-life and estimated using anthropometric measures such as body mass index (BMI) and waist-to-hip ratio (WHR), or metabolic markers such as blood leptin and adiponectin levels, is associated with late-onset dementia risk. However, during later life, this association may reverse and aging- and dementia-related processes may differentially affect adiposity measures. OBJECTIVE: We explored associations of concurrent BMI, WHR, and blood leptin and high molecular weight adiponectin levels with dementia occurrence. METHODS: 924 Swedish community-dwelling elderly without dementia, aged 70 years and older, systematically-sampled by birth day and birth year population-based in the Gothenburg city region of Sweden. The Gothenburg Birth Cohort Studies are designed for evaluating risk and protective factors for dementia. All dementias diagnosed after age 70 for 10 years were identified. Multivariable logistic regression models were used to predict dementia occurrence between 2000-2005, 2005-2010, and 2000-2010 after excluding prevalent baseline (year 2000) dementias. Baseline levels of BMI, WHR, leptin, and adiponectin were used. RESULTS: Within 5 years of baseline, low BMI (<20 kg/m2) was associated with higher odds of dementia compared to those in the healthy BMI category (≥ 20-24.9 kg/m2). Compared to the lowest quartile, leptin levels in the second quartile were associated with lower odds of dementia in women (p < 0.05). CONCLUSION: In late-life, anthropometric and metabolic adiposity measures appear to be differentially associated with dementia risk. While BMI and leptin levels are highly positively correlated, our results show that their association with dementia at age ≥70 years, is asynchronous. These data suggest that with aging, the complexity of the adiposity exposure may increase and suggests metabolic dysregulation. Additional studies are needed to better understand this complexity.

18F-Flortaucipir Binding in Choroid Plexus: Related to Race and Hippocampus Signal. - Lee, Christopher M; Jacobs, Heidi I L; Marquié, Marta; Becker, John A; Andrea, Nicolas V; Jin, David S; Schultz, Aaron P; Frosch, Matthew P; Gómez-Isla, Teresa; Sperling, Reisa A; Johnson, Keith A (J Alzheimers Dis, 2018)
BACKGROUND: On target 18F-Flortaucipir (FTP) binding of Alzheimer's disease tau aggregates and off-target binding of melanocytes have been demonstrated with autoradiography. OBJECTIVE: We aimed to investigate the hypothesis that if binding in choroid plexus (CP) is due to melanocytes, the signal would be elevated in Black/African American (B/AA) compared to White (W) participants. In addition, we examined whether CP signal affects measurements in adjacent regions, and whether correcting for spill-in effects has an influence on associations between hippocampus (HC) FTP and amyloid or cognition. METHODS: FTP race differences in 147 Harvard Aging Brain Study participants (23 B/AA, 124W) were examined in CP, HC, HC covaried for CP, amygdala, inferior temporal gyrus, entorhinal cortex, and fusiform regions. Associations between CP FTP and other regions-of-interest (ROIs) were probed to assess spill-in effects. A statistical regression approach to attenuate CP spill-in was tested by relating adjusted HC SUVR residuals and unadjusted HC SUVR to race, cognition and amyloid. All analyses were covaried for age, sex, education and amyloid deposition, and Bonferroni-corrected for multiple comparisons. RESULTS: B/AA individuals had elevated CP and HC SUVR (p < 0.007), whereas other ROI SUVR and HC SUVR covaried for CP SUVR did not show race differences (p > 0.05). CP SUVR was associated with HC SUVR (p < 10-14), but with no other ROI SUVR (p > 0.05). When adjusting HC SUVR for CP SUVR, no race differences in residual HC SUVR were detected, and relationships with amyloid and memory became apparent. CONCLUSION: Melanocyte FTP binding may account partially for high CP signal. This off-target binding affects mainly HC FTP measurements, which should be interpreted with caution.

ABCA7 Downregulation Modifies Cellular Cholesterol Homeostasis and Decreases Amyloid-β Peptide Efflux in an in vitro Model of the Blood-Brain Barrier. - Lamartinière, Yordenca; Boucau, Marie-Christine; Dehouck, Lucie; Krohn, Markus; Pahnke, Jens; Candela, Pietra; Gosselet, Fabien; Fenart, Laurence (J Alzheimers Dis, 2018)
The role of ABCA7 in brain homeostasis and Alzheimer's disease (AD) is currently under intense scrutiny, since it has been reported that polymorphisms in the Abca7 gene and a loss of function of the protein are closely linked to excessive accumulation of amyloid peptides and disturbed cholesterol homeostasis. The blood-brain barrier (BBB), which isolates the brain from the blood compartment, is involved in both of these processes. We therefore hypothesized that ABCA7 downregulation might affect cholesterol and amyloid exchanges at the BBB. Using siRNA and primary cultures of mouse endothelial cells purified from brain microvessels and seeded on Transwell ® inserts, we investigated the role of ABCA7 in cholesterol and amyloid exchanges across the BBB. Our results showed that a decrease in ABCA7 expression at the BBB provokes in vitro a reduction in ABCA1 expression and a decrease in APOE secretion. In vitro, these decreases reduce cholesterol exchange across the BBB, particularly for high-density lipoproteins and ApoA-I particles. When ABCA7 was absent, we observed a reduction in Aβ peptide basolateral-to-apical transport in the presence of ApoA-I, with non-significant changes in the expression levels of Rage, Lrp1, Abcb1, Abcc1, and Abcg2. Our study in murine BBB model highlighted a putative new role for ABCA7 in AD via the protein's involvement in cholesterol metabolism and amyloid clearance at the BBB.

Abnormal Functional Brain Networks in Mild Cognitive Impairment and Alzheimer's Disease: A Minimum Spanning Tree Analysis. - Wang, Bin; Miao, Liwen; Niu, Yan; Cao, Rui; Li, Dandan; Yan, Pengfei; Guo, Hao; Yan, Tianyi; Wu, Jinglong; Xiang, Jie (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) disrupts the topological architecture of whole-brain connectivity. Minimum spanning tree (MST), which captures the most important connections in a network, has been considered an unbiased method for brain network analysis. However, the alterations in the MST of functional brain networks during the progression of AD remain unclear. Here, we performed an MST analysis to examine the alterations in functional networks among normal controls (NCs), mild cognitive impairment (MCI) patients, and AD patients. We identified substantial differences in the connections among the three groups. The maximum betweenness centrality, leaf number, and tree hierarchy of the MSTs showed significant group differences, indicating a more star-like topology in the MCI patients and a more line-like topology in the NCs and AD patients. These findings may correspond to changes in the core of the functional brain networks. For nodal properties (degree and betweenness centrality), we determined that brain regions around the cingulate gyrus, occipital lobes, subcortex, and inferior temporal gyrus showed significant differences among the three groups and contributed to the global topological alterations. The leaf number and tree hierarchy, as well as the nodal properties, were significantly correlated with clinical features in the MCI and AD patients, which demonstrated that more star-to-line topology changes were associated with worse cognitive performance in these patients. These findings indicated that MST properties could capture slight alterations in network topology, particularly for the differences between NCs and MCI patients, and may be applicable as neuroimaging markers of the early stage of AD.

Abnormalities of Resting State Cortical EEG Rhythms in Subjects with Mild Cognitive Impairment Due to Alzheimer's and Lewy Body Diseases. - Babiloni, Claudio; Del Percio, Claudio; Lizio, Roberta; Noce, Giuseppe; Lopez, Susanna; Soricelli, Andrea; Ferri, Raffaele; Pascarelli, Maria Teresa; Catania, Valentina; Nobili, Flavio; Arnaldi, Dario; Famá, Francesco; et al. (J Alzheimers Dis, 2018)
The present study tested the hypothesis that cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) and dementia with Lewy bodies (DLBMCI) as compared to cognitively normal elderly (Nold) subjects. Clinical and rsEEG data in 30 ADMCI, 23 DLBMCI, and 30 Nold subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) score was matched between the ADMCI and DLBMCI groups. Individual alpha frequency peak (IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROCC) classified these sources across individuals. Compared to Nold, IAF showed marked slowing in DLBMCI and moderate in ADMCI. Furthermore, the posterior alpha 2 and alpha 3 source activities were more abnormal in the ADMCI than the DLBMCI group, while widespread delta source activities were more abnormal in the DLBMCI than the ADMCI group. The posterior delta and alpha sources correlated with the MMSE score and correctly classified the Nold and MCI individuals (area under the ROCC >0.85). In conclusion, the ADMCI and DLBMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test the clinical validity of these rsEEG markers.

Accuracy of Inferred APOE Genotypes for a Range of Genotyping Arrays and Imputation Reference Panels. - Lupton, Michelle K; Medland, Sarah E; Gordon, Scott D; Goncalves, Tabatha; MacGregor, Stuart; Mackey, David A; Young, Terri L; Duffy, David L; Visscher, Peter M; Wray, Naomi R; Nyholt, Dale R; Bain, Lisa; et al. (J Alzheimers Dis, 2018)
Cohort studies investigating aging and dementia require APOE genotyping. We compared directly measured APOE genotypes to 'hard-call' genotypes derived from imputing genome-wide genotyping data from a range of platforms using several imputation panels. Older GWAS arrays imputed to 1000 Genomes Project (1KGP) phases and the Haplotype Reference Consortium (HRC) reference panels were able to achieve concordance rates of over 98% with stringent quality control (hard-call-threshold 0.8). However, this resulted in high levels of missingness (>12% with 1KGP and 5% with HRC). With recent GWAS arrays, concordance of 99% could be obtained with relatively lenient QC, resulting in no missingness.

Acute Stroke Care in Dementia: A Cohort Study from the Swedish Dementia and Stroke Registries. - Zupanic, Eva; Kåreholt, Ingemar; Norrving, Bo; Secnik, Juraj; von Euler, Mia; Winblad, Bengt; Religa, Dorota; Kramberger, Milica Gregoric; Johnell, Kristina; Eriksdotter, Maria; Garcia-Ptacek, Sara (J Alzheimers Dis, 2018)
BACKGROUND: Previous studies have shown that patients with dementia receive less testing and treatment for stroke. OBJECTIVES: Our aim was to investigate hospital management of acute ischemic stroke in patients with and without dementia. METHODS: Retrospective analysis of prospectively collected data 2010-2014 from the Swedish national dementia registry (SveDem) and the Swedish national stroke registry (Riksstroke). Patients with dementia who suffered an acute ischemic stroke (AIS) (n = 1,356) were compared with matched non-dementia AIS patients (n = 6,755). Outcomes included length of stay in a stroke unit, total length of hospitalization, and utilization of diagnostic tests and assessments. RESULTS: The median age at stroke onset was 83 years. While patients with dementia were equally likely to be directly admitted to a stroke unit as their non-dementia counterparts, their stroke unit and total hospitalization length were shorter (10.5 versus 11.2 days and 11.6 versus 13.5, respectively, p < 0.001). Dementia patients were less likely to receive carotid ultrasound (OR 0.36, 95% CI [0.30-0.42]) or undergo assessments by the interdisciplinary team members (physiotherapists, speech therapists, occupational therapists; p < 0.05 for all adjusted models). However, a similar proportion of patients received CT imaging (97.4% versus 98.6%, p = 0.001) and a swallowing assessment (90.7% versus 91.8%, p = 0.218). CONCLUSIONS: Patients with dementia who suffer an ischemic stroke have equal access to direct stroke unit care compared to non-dementia patients; however, on average, their stay in a stroke unit and total hospitalization are shorter. Dementia patients are also less likely to receive specific diagnostic tests and assessments by the interdisciplinary stroke team.

Added Diagnostic Value of Cerebrospinal Fluid Biomarkers for Differential Dementia Diagnosis in an Autopsy-Confirmed Cohort. - Niemantsverdriet, Ellis; Feyen, Bart F E; Le Bastard, Nathalie; Martin, Jean-Jacques; Goeman, Johan; De Deyn, Peter Paul; Bjerke, Maria; Engelborghs, Sebastiaan (J Alzheimers Dis, 2018)
BACKGROUND: Differential dementia diagnosis remains a challenge due to overlap of clinical profiles, which often results in diagnostic doubt. OBJECTIVE: Determine the added diagnostic value of cerebrospinal fluid (CSF) biomarkers for differential dementia diagnosis as compared to autopsy-confirmed diagnosis. METHODS: Seventy-one dementia patients with autopsy-confirmed diagnoses were included in this study. All neuropathological diagnoses were established according to standard neuropathological criteria and consisted of Alzheimer's disease (AD) or other dementias (NONAD). CSF levels of Aβ1 - 42, T-tau, and P-tau181 were determined and interpreted based on the IWG-2 and NIA-AA criteria, separately. A panel of three neurologists experienced with dementia made clinical consensus dementia diagnoses. Clinical and CSF biomarker diagnoses were compared to the autopsy-confirmed diagnoses. RESULTS: Forty-two patients (59%) had autopsy-confirmed AD, whereas 29 patients (41%) had autopsy-confirmed NONAD. Of the 24 patients with an ambiguous clinical dementia diagnosis, a correct diagnosis would have been established in 67% of the cases applying CSF biomarkers in the context of the IWG-2 or the NIA-AA criteria respectively. CONCLUSION: AD CSF biomarkers have an added diagnostic value in differential dementia diagnosis and can help establishing a correct dementia diagnosis in case of ambiguous clinical dementia diagnoses.

The Added Value of Diffusion-Weighted MRI-Derived Structural Connectome in Evaluating Mild Cognitive Impairment: A Multi-Cohort Validation1. - Wang, Qi; Guo, Lei; Thompson, Paul M; Jack, Clifford R; Dodge, Hiroko; Zhan, Liang; Zhou, Jiayu (J Alzheimers Dis, 2018)
T1-weighted MRI has been extensively used to extract imaging biomarkers and build classification models for differentiating Alzheimer's disease (AD) patients from healthy controls, but only recently have brain connectome networks derived from diffusion-weighted MRI been used to model AD progression and various stages of disease such as mild cognitive impairment (MCI). MCI, as a possible prodromal stage of AD, has gained intense interest recently, since it may be used to assess risk factors for AD. Little work has been done to combine information from both white matter and gray matter, and it is unknown how much classification power the diffusion-weighted MRI-derived structural connectome could provide beyond information available from T1-weighted MRI. In this paper, we focused on investigating whether diffusion-weighted MRI-derived structural connectome can improve differentiating healthy controls subjects from those with MCI. Specifically, we proposed a novel feature-ranking method to build classification models using the most highly ranked feature variables to classify MCI with healthy controls. We verified our method on two independent cohorts including the second stage of Alzheimer's Disease Neuroimaging Initiative (ADNI2) database and the National Alzheimer's Coordinating Center (NACC) database. Our results indicated that 1) diffusion-weighted MRI-derived structural connectome can complement T1-weighted MRI in the classification task; 2) the feature-rank method is effective because of the identified consistent T1-weighted MRI and network feature variables on ADNI2 and NACC. Furthermore, by comparing the top-ranked feature variables from ADNI2, NACC, and combined dataset, we concluded that cross-validation using independent cohorts is necessary and highly recommended.

Aging-Related Calcium Dysregulation in Rat Entorhinal Neurons Homologous with the Human Entorhinal Neurons in which Alzheimer's Disease Neurofibrillary Tangles First Appear. - Gant, John C; Kadish, Inga; Chen, Kuey-Chu; Thibault, Olivier; Blalock, Eric M; Porter, Nada M; Landfield, Philip W (J Alzheimers Dis, 2018)
Aging is the leading risk factor for idiopathic Alzheimer's disease (AD), indicating that normal aging processes promote AD and likely are present in the neurons in which AD pathogenesis originates. In AD, neurofibrillary tangles (NFTs) appear first in entorhinal cortex, implying that aging processes in entorhinal neurons promote NFT pathogenesis. Using electrophysiology and immunohistochemistry, we find pronounced aging-related Ca2 + dysregulation in rat entorhinal neurons homologous with the human neurons in which NFTs originate. Considering that humans recapitulate many aspects of animal brain aging, these results support the hypothesis that aging-related Ca2 + dysregulation occurs in human entorhinal neurons and promotes NFT pathogenesis.

Alterations in the Plasma Levels of Specific Choline Phospholipids in Alzheimer's Disease Mimic Accelerated Aging. - Dorninger, Fabian; Moser, Ann B; Kou, Jianqiu; Wiesinger, Christoph; Forss-Petter, Sonja; Gleiss, Andreas; Hinterberger, Margareta; Jungwirth, Susanne; Fischer, Peter; Berger, Johannes (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is the most common neurodegenerative disease and of continuously rising prevalence. The identification of easy-to-measure biomarkers capable to assist in the prediction and early diagnosis of AD is currently a main research goal. Lipid metabolites in peripheral blood of human patients have recently gained major attention in this respect. Here, we analyzed plasma of 174 participants (not demented at baseline; mean age: 75.70±0.44 years) of the Vienna Transdanube Aging (VITA) study, a longitudinal, population-based birth cohort study, at baseline and after 90 months or at diagnosis of probable AD. We determined the levels of specific choline phospholipids, some of which have been suggested as potential biomarkers for the prediction of AD. Our results show that during normal aging the levels of lysophosphatidylcholine, choline plasmalogen, and lyso-platelet activating factor increase significantly. Notably, we observed similar but more pronounced changes in the group that developed probable AD. Thus, our results imply that, in terms of choline-containing plasma phospholipids, the conversion to AD mimics an accelerated aging process. We conclude that age, even in the comparatively short time frame between 75 and 82.5 years, is a crucial factor in the quest for plasma lipid biomarkers for AD that must be carefully considered in future studies and trials.

Alterations of Effective Connectivity Patterns in Mild Cognitive Impairment: An MEG Study. - Gómez, Carlos; Juan-Cruz, Celia; Poza, Jesús; Ruiz-Gómez, Saúl J; Gomez-Pilar, Javier; Núñez, Pablo; García, María; Fernández, Alberto; Hornero, Roberto (J Alzheimers Dis, 2018)
Neuroimaging techniques have demonstrated over the years their ability to characterize the brain abnormalities associated with different neurodegenerative diseases. Among all these techniques, magnetoencephalography (MEG) stands out by its high temporal resolution and noninvasiveness. The aim of the present study is to explore the coupling patterns of resting-state MEG activity in subjects with mild cognitive impairment (MCI). To achieve this goal, five minutes of spontaneous MEG activity were acquired with a 148-channel whole-head magnetometer from 18 MCI patients and 26 healthy controls. Inter-channel relationships were investigated by means of two complementary coupling measures: coherence and Granger causality. Coherence is a classical method of functional connectivity, while Granger causality quantifies effective (or causal) connectivity. Both measures were calculated in the five conventional frequency bands: delta (δ, 1-4 Hz), theta (θ, 4-8 Hz), alpha (α, 8-13 Hz), beta (β, 13-30 Hz), and gamma (γ, 30-45 Hz). Our results showed that connectivity values were lower for MCI patients than for controls in all frequency bands. However, only Granger causality revealed statistically significant differences between groups (p-values < 0.05, FDR corrected Mann-Whitney U-test), mainly in the beta band. Our results support the role of MCI as a disconnection syndrome, which elicits early alterations in effective connectivity patterns. These findings can be helpful to identify the neural substrates involved in prodromal stages of dementia.

Altered Expression of Circulating Cdc42 in Frontotemporal Lobar Degeneration. - Saraceno, Claudia; Catania, Marcella; Paterlini, Anna; Fostinelli, Silvia; Ciani, Miriam; Zanardini, Roberta; Binetti, Giuliano; Di Fede, Giuseppe; Caroppo, Paola; Benussi, Luisa; Ghidoni, Roberta; Bolognin, Silvia (J Alzheimers Dis, 2018)
The term frontotemporal lobar degeneration (FTLD) defines a group of heterogeneous conditions histologically characterized by neuronal degeneration, inclusions of various proteins, and synaptic loss. However, the molecular mechanisms contributing to these alterations are still unknown. As the Rho-GTPase family member Cell division cycle 42 (Cdc42) plays a key role in the regulation of actin cytoskeleton dynamics and spine formation, we investigated whether Cdc42 protein levels were altered in the disease. Cdc42 was increased in the frontal cortex of FTLD patients compared to age-matched controls, but also in Alzheimer's disease (AD) patients included in the data-set. On the other hand, the pool of circulating Cdc42 in the plasma was altered in FTLD but not in AD patients. Interestingly, the stratification of the FTLD patients according to the different clinical variants showed a specific decrease of Cdc42 expression in the behavioral subgroup. This data support a role of Cdc42 in FTLD and specifically in the behavioral variant.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Case-Control Studies; cdc42 GTP-Binding Protein; Female; Frontotemporal Lobar Degeneration; Humans; Male; Middle Aged

Altered Expression of Urea Cycle Enzymes in Amyloid-β Protein Precursor Overexpressing PC12 Cells and in Sporadic Alzheimer's Disease Brain. - Jęśko, Henryk; Lukiw, Walter J; Wilkaniec, Anna; Cieślik, Magdalena; Gąssowska-Dobrowolska, Magdalena; Murawska, Emilia; Hilgier, Wojciech; Adamczyk, Agata (J Alzheimers Dis, 2018)
Urea cycle enzymes may play important yet poorly characterized roles in Alzheimer's disease (AD). Our previous results showed that amyloid-β (Aβ) affects urea cycle enzymes in rat pheochromocytoma (PC12) cells. The aim of the present study was to investigate the changes in arginases, other urea cycle enzymes, and nitric oxide synthases (NOSs) in PC12 cells transfected with AβPP bearing the double 'Swedish' mutation (APPsw, K670M/N671L) and in postmortem sporadic AD brain hippocampus; the mutation intensifies Aβ production and strongly associates with AD neuropathology. mRNA expression was analyzed using real-time PCR in cell cultures and DNA microarrays in hippocampal CA1 area of human AD brains. Arginase activity was measured spectrophotometrically, and arginine, ornithine, and citrulline levels by high-performance liquid chromatography. Our data demonstrated that the expression and activity of arginases (Arg1 and Arg2), as well as the expression of argininosuccinate synthase (Ass) were significantly reduced in APPsw cells compared to control. However, argininosuccinate lyase (Asl) was upregulated in APPsw cells. Real-time PCR analysis revealed significant elevation of neuronal nitric oxide synthase (Nnos) mRNA in APPsw cells, without changes in the endothelial Enos, whereas inducible Inos was undetectable. The changes were found to follow closely those observed in the human hippocampal CA1 region of sporadic AD brains. The changes in enzyme expression were accompanied in APPsw cells by significantly elevated citrulline, ornithine, and arginine. Our findings demonstrate that AβPP/Aβ alters arginine metabolism and induces a shift of cellular homeostasis that may support the oxidative/nitrosative stress observed in AD.

Alzheimer's Amyloid-β is an Antimicrobial Peptide: A Review of the Evidence. - Gosztyla, Maya L; Brothers, Holly M; Robinson, Stephen R (J Alzheimers Dis, 2018)
The amyloid-β (Aβ) peptide has long been considered to be the driving force behind Alzheimer's disease (AD). However, clinical trials that have successfully reduced Aβ burden in the brain have not slowed the cognitive decline, and in some instances, have resulted in adverse outcomes. While these results can be interpreted in different ways, a more nuanced picture of Aβ is emerging that takes into account the facts that the peptide is evolutionarily conserved and is present throughout life in cognitively normal individuals. Recent evidence indicates a role for Aβ as an antimicrobial peptide (AMP), a class of innate immune defense molecule that utilizes fibrillation to protect the host from a wide range of infectious agents. In humans and in animal models, infection of the brain frequently leads to increased amyloidogenic processing of the amyloid-β protein precursor (AβPP) and resultant fibrillary aggregates of Aβ. Evidence from in vitro and in vivo studies demonstrates that Aβ oligomers have potent, broad-spectrum antimicrobial properties by forming fibrils that entrap pathogens and disrupt cell membranes. Importantly, overexpression of Aβ confers increased resistance to infection from both bacteria and viruses. The antimicrobial role of Aβ may explain why increased rates of infection have been observed in some of the AD clinical trials that depleted Aβ. Perhaps progress toward a cure for AD will accelerate once treatment strategies begin to take into account the likely physiological functions of this enigmatic peptide.

Alzheimer's Disease: A Journey from Amyloid Peptides and Oxidative Stress, to Biomarker Technologies and Disease Prevention Strategies-Gains from AIBL and DIAN Cohort Studies. - Martins, Ralph N; Villemagne, Victor; Sohrabi, Hamid R; Chatterjee, Pratishtha; Shah, Tejal M; Verdile, Giuseppe; Fraser, Paul; Taddei, Kevin; Gupta, Veer B; Rainey-Smith, Stephanie R; Hone, Eugene; Pedrini, Steve; et al. (J Alzheimers Dis, 2018)
Worldwide there are over 46 million people living with dementia, and this number is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-β peptide (also known as Aβ or A4 peptide) extracted from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aβ peptide in Alzheimer's disease (AD) brain to the establishment of pre-clinical AD using PET amyloid tracers, a method now serving as the gold standard for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E ɛ4, as well as better understanding the role of lifestyle factors particularly diet, physical activity and sleep to cognitive decline and the accumulation of cerebral Aβ.

Alzheimer's Disease: Advances in Drug Development. - Piton, Morgane; Hirtz, Christophe; Desmetz, Caroline; Milhau, Jacqueline; Lajoix, Anne Dominique; Bennys, Karim; Lehmann, Sylvain; Gabelle, Audrey (J Alzheimers Dis, 2018)
As of 2018, Alzheimer's disease (AD) is the most common form of neurodegenerative dementia. It contributes to a progressive neuron loss, deterioration of memory, and cognitive impairment. Current therapies may provide a symptomatic benefit, but do not treat the underlying process. Ongoing researches focus on understanding the causal mechanisms and finding neuropathological hallmarks of AD. Therapeutic approaches targeting senile plaques or neurofibrillary tangles have not yet resulted in a significant cognitive improvement. However, recent data according to the analysis of AD clinical trials (clinicaltrials.gov database) show promising results. This literature review aims at summarizing the recent advances and at highlighting the most promising results of the ongoing researches. It compares the merits of small-molecules, antibodies, cell, and gene-based therapies and emphasizes the need for treatment at earlier stages of the disease.

Alzheimer's Disease Can Be Spared by Nonsteroidal Anti-Inflammatory Drugs. - McGeer, Patrick L; Guo, Jian Ping; Lee, Moonhee; Kennedy, Krista; McGeer, Edith G (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is characterized by deposits of amyloid-β protein (Aβ) in brain which become foci of inflammation. Neurons are destroyed by this inflammatory process, leading to the cognitive deficits which define AD clinical onset. Epidemiological studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) can ameliorate this destructive process if they are started well before clinical signs develop. Biomarker studies indicate that the disease process starts at least a decade before cognitive deficits appear. This pre-clinical onset explains the NSAID effect. It also opens a window of opportunity for preventive treatment that can be met with a simple diagnostic test. Salivary levels of Aβ42 may fulfill that need. They can be measured by a simple ELISA test we have developed using commercially available reagents. By this ELISA test, normal controls, who are not at risk for AD, have levels of Aβ42 close to 20 pg/ml. AD cases, as well as high level controls, secrete levels in the range of 40-85 pg/ml. Widespread application of this test to detect high level controls, followed by NSAID consumption, could substantially reduce the prevalence of AD.

Alzheimer's Disease Computer-Aided Diagnosis: Histogram-Based Analysis of Regional MRI Volumes for Feature Selection and Classification. - Ruiz, Elena; Ramírez, Javier; Górriz, Juan Manuel; Casillas, Jorge (J Alzheimers Dis, 2018)
This paper proposes a novel fully automatic computer-aided diagnosis (CAD) system for the early detection of Alzheimer's disease (AD) based on supervised machine learning methods. The novelty of the approach, which is based on histogram analysis, is twofold: 1) a feature extraction process that aims to detect differences in brain regions of interest (ROIs) relevant for the recognition of subjects with AD and 2) an original greedy algorithm that predicts the severity of the effects of AD on these regions. This algorithm takes account of the progressive nature of AD that affects the brain structure with different levels of severity, i.e., the loss of gray matter in AD is found first in memory-related areas of the brain such as the hippocampus. Moreover, the proposed feature extraction process generates a reduced set of attributes which allows the use of general-purpose classification machine learning algorithms. In particular, the proposed feature extraction approach assesses the ROI image separability between classes in order to identify the ones with greater discriminant power. These regions will have the highest influence in the classification decision at the final stage. Several experiments were carried out on segmented magnetic resonance images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) in order to show the benefits of the overall method. The proposed CAD system achieved competitive classification results in a highly efficient and straightforward way.

Amyloid-β and Tau in Alzheimer's Disease: Novel Pathomechanisms and Non-Pharmacological Treatment Strategies. - Nisbet, Rebecca M; Götz, Jürgen (J Alzheimers Dis, 2018)
Accumulation of the peptide amyloid-β (Aβ) and the protein tau in Alzheimer's disease (AD) brains is a gradual process that involves the post-translational modification and assembly of monomeric forms into larger structures that eventually form fibrillar inclusions. This process is thought to both drive and initiate AD. However, why the axonally enriched tau in the course of AD accumulates in the somatodendritic domain is not fully understood. We discuss new data that provide a possible explanation that involves de novo protein synthesis, induced by Aβ and mediated through the kinase Fyn. We further discuss how in a pathological state, tau, being a scaffolding protein, impairs nuclear and mitochondrial functions and reduces action potential generation at the axon initial segment. Pathological tau can further be packaged into exosomes, released by one neuron and taken up by another, contributing to its pathogenicity. We also present our new work that suggests ultrasound as a new treatment modality to clear pathological Aβ and tau. We put this work into perspective, discussing current vaccination strategies and improved brain delivery methods involving antibody engineering and viral approaches. We propose that rather than reducing post-translational modifications of tau, its levels and de novo synthesis need to be reduced. We anticipate a surge in combinatorial strategies, simultaneously targeting multiple pathologies, and an improved drug delivery to the brain facilitated by emerging technologies such as ultrasound.

Amyloid-β Induces AMPA Receptor Ubiquitination and Degradation in Primary Neurons and Human Brains of Alzheimer's Disease. - Zhang, Yanmin; Guo, Ouyang; Huo, Yuda; Wang, Guan; Man, Heng-Ye (J Alzheimers Dis, 2018)
As the primary mediator for synaptic transmission, AMPA receptors (AMPARs) are crucial for synaptic plasticity and higher brain functions. A downregulation of AMPAR expression has been indicated as one of the early pathological molecular alterations in Alzheimer's disease (AD), presumably via amyloid-β (Aβ). However, the molecular mechanisms leading to the loss of AMPARs remain less clear. We report that in primary neurons, application of Aβ triggers AMPAR internalization accompanied with a decrease in cell-surface AMPAR expression. Importantly, in both Aβ-treated neurons and human brain tissue from AD patients, we observed a significant decrease in total AMPAR amount and an enhancement in AMPAR ubiquitination. Consistent with facilitated receptor degradation, AMPARs show higher turnover rates in the presence of Aβ. Furthermore, AD brain lysates and Aβ-incubated neurons show increased expression of the AMPAR E3 ligase Nedd4 and decreased expression of AMPAR deubiquitinase USP46. Changes in these enzymes are responsible for the Aβ-dependent AMPAR reduction. These findings indicate that AMPAR ubiquitination acts as the key molecular event leading to the loss of AMPARs and thus suppressed synaptic transmission in AD.

Analyses of Clinical Features and Investigations on Potential Mechanisms in Patients with Alzheimer's Disease and Olfactory Dysfunction. - Zuo, Li-Jun; Guo, Peng; Liu, Li; Yu, Shu-Yang; Lian, Teng-Hong; Yu, Qiu-Jin; Hu, Yang; Jin, Zhao; Wang, Rui-Dan; Piao, Ying-Shan; Li, Li-Xia; Wang, Ya-Jie; et al. (J Alzheimers Dis, 2018)
BACKGROUND: OD is common in patients with Alzheimer's disease (AD). However, the relationship between OD and clinical symptoms and the potential mechanisms of OD in AD patients are still unknown. OBJECTIVE: To explore the relationship between OD and clinical symptoms and the potential mechanisms of OD in AD patients. METHODS: We evaluated OD using the Hyposmia Rating Scale (HRS), classified patients into AD with OD (AD-OD) and AD with no OD (AD-NOD) groups, and detected the levels of free radicals and inflammatory factors, including hydroxyl radical (•OH), hydrogen peroxide (H2O2), nitric oxide, interleukin-1β, interleukin-6, tumor necrosis factor-α, and prostaglandin E2 in serum from AD patients. RESULTS: It was shown that the scores of the Mini-Mental State Examination, Animal Fluency Test, Boston Naming Test (BNT), and Auditory Verbal Learning Test-delayed recall were all significantly lower and the score of overall activity of daily living (ADL) and instrumental ADL were significantly higher in AD-OD group than those in AD-NOD group. Compared with AD-NOD group, •OH level in serum was prominently elevated, and H2O2 level was dramatically declined in AD-OD group. In the correlation analysis, HRS score was significantly and positively correlated with the score of BNT, and negatively correlated with •OH level in serum. CONCLUSIONS: AD-OD patients suffered from severe cognitive impairment in the domain of language. Oxidative stress might be correlated with AD-OD featured by the drastically increased •OH level in serum.

Analysis of Brain Donors' Demographic and Medical Characteristics to Facilitate the Construction of a Human Brain Bank in China. - Zhang, Hanlin; Chen, Kang; Wang, Naili; Zhang, Di; Yang, Qian; Zhang, Qing; Liu, Pan; Wan, Mengyao; Gong, Changlin; Hong, Xinyu; Qiu, Wenying; Qian, Xiaojing; et al. (J Alzheimers Dis, 2018)
The Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS/PUMC) Human Brain Bank was established in December 2012 and had accomplished 197 brain donations by November 2017. The brain bank was based on a large-scale willed body donation program in CAMS/PUMC starting from 1999. Demographic and medical characteristic analysis of brain donors was conducted to facilitate the construction of the brain bank. The average postmortem delay of brain donors was 17.7 h and 77.7% of these donors died less than 15 km away from the brain bank. Donors were predominantly with higher-level education (p < 0.001) and at an older age when registration (p < 0.001) and donation (p < 0.001) occurred. Our results elucidated the characteristics of donors in the CAMS/PUMC Human Brain Bank, which may provide useful information to target potential donors and improve the quality and quantity of brain specimens. The current study may pave the way for the construction of a nationwide network of standardized human brain banks in China.

Antibodies to Multiple Receptors are Associated with Neuropsychiatric Symptoms and Mortality in Alzheimer's Disease: A Longitudinal Study. - Giil, Lasse M; Aarsland, Dag; Hellton, Kristoffer; Lund, Anders; Heidecke, Harald; Schulze-Forster, Kai; Riemekasten, Gabriela; Vik-Mo, Audun Osland; Kristoffersen, Einar K; Vedeler, Christian A; Nordrehaug, Jan Erik (J Alzheimers Dis, 2018)
BACKGROUND: Endogenous antibodies to signaling molecules and receptors (Abs) are associated with Alzheimer's disease (AD). OBJECTIVES: To investigate the association of 33 Abs to dopaminergic, serotoninergic, muscarinic, adrenergic, vascular, and immune receptors with cognitive, neuropsychiatric, and mortality outcomes. METHODS: Ninety-one patients with mild AD were followed annually for 5 years with the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI; composite outcomes: "psychosis" (item 1 + 2), "mood" (item 4 + 5 + 7), and "agitation" (item 3 + 8 + 9)). Abs were quantified in sera obtained at baseline by ELISA and reduced to principal components (PCs). Associations between Abs and outcomes were assessed by a mixed model (MMSE decline), zero-inflated fixed effects count models (composite NPI scores), and Cox regression (mortality). The resulting p-values were adjusted for multiple testing according to a false discovery rate of 0.05 (Benjamini-Hochberg). RESULTS: The measured levels of the 33 Abs formed four PCs. PC1 (dopaminergic and serotonergic Abs) was associated with increased mortality (Hazard ratio 2.57, p < 0.001), PC2 (serotonergic, immune, and vascular Abs) with decreased agitation symptoms (β - 0.19, p < 0.001), and PC3 (cholinergic receptor Abs) with increased mood symptoms (β 0.04, p = 0.002), over time. There were no associations between Abs and MMSE decline. CONCLUSION: The associations between Abs, mortality, and neuropsychiatric symptoms reported in this cohort are intriguing. They cannot, however, be generalized. Validation in independent sample sets is required.

Anticholinergic Burden and Risk of Stroke and Death in People with Different Types of Dementia. - Tan, Edwin C K; Eriksdotter, Maria; Garcia-Ptacek, Sara; Fastbom, Johan; Johnell, Kristina (J Alzheimers Dis, 2018)
BACKGROUND: Anticholinergic burden is associated with poorer cognitive and functional outcomes in people with dementia. However, the impact of anticholinergics on significant adverse outcomes such as stroke has not been studied previously. OBJECTIVE: To investigate the association between total anticholinergic cognitive burden (ACB) and risk of stroke and death in people with different dementia subtypes. METHODS: This was a cohort study of 39,107 people with dementia and no prior history of stroke registered in the Swedish Dementia Registry (SveDem) from 2008-2014. Data were extracted from the Swedish Prescribed Drug Register, the Swedish National Patient Register, and the Swedish Total Population Register. Competing risk regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between time-varying ACB score and risk of stroke and all-cause mortality. RESULTS: During a mean follow-up period of 2.31 (standard deviation 1.66) years, 11,224 (28.7%) individuals had a stroke or died. Compared with non-users of anticholinergic medications, ACB score of 1 (HR 1.09, 95% CI 1.04-1.14) and ACB score of ≥2 (HR 1.20, 95% CI 1.14-1.26) increased the risk of developing the composite outcome of stroke and death. When stratifying by dementia disorder, the association remained significant in Alzheimer's disease, mixed dementia, and vascular dementia. CONCLUSIONS: The use of anticholinergic medicines may be associated with an increased risk of stroke and death in people with dementia. A dose-response relationship was observed. Careful consideration should be made when prescribing medications with anticholinergic properties to people with dementia.

Argyrophilic Grain Pathology in Frontotemporal Lobar Degeneration: Demographic, Clinical, Neuropathological, and Genetic Features. - Gil, María José; Manzano, María Sagrario; Cuadrado, María Luz; Fernández, Cristina; Góméz, Elena; Matesanz, Carmen; Calero, Miguel; Rábano, Alberto (J Alzheimers Dis, 2018)
Frontotemporal lobar degeneration (FTLD) is a clinically, pathologically, and genetically heterogeneous group of disorders that affect the frontal and temporal lobes of the brain. FTLD classification distinguishes three main neuropathological groups: FTLD-tau, FTLD-TDP, and FTLD-FUS. As a four-repeat tauopathy, argyrophilic grain disease (AGD) is included in the FTLD-tau group. AGD may also appear in association with other neuropathological disorders. We describe the demographic, clinical, neuropathological, and genetic characteristics of a series of FTLD cases presenting with AGD. For this purpose, a clinico-pathological study of 71 autopsy-confirmed FTLD cases from different tissue banks was performed. AGD was found in 52.1% of FTLD cases. The presence of AGD increased with the increasing age (up to 88.9% in cases older than 80 years; p < 0.001) and was associated with higher ages at onset (p < 0.001) and death (p < 0.001). In AGD cases, progressive supranuclear palsy (PSP) was the most frequent clinical diagnosis (29.7%) and gait disturbance was the most common symptom (64.5%); behavioral and language symptoms were less frequent as compared with non-AGD cases (p = 0.055; p = 0.012). PSP was the most frequent neuropathological diagnosis among cases with AGD (32.4%). This group also showed less brain atrophy (p = 0.094) and higher prevalence of Alzheimer (p = 0.002) and vascular pathology (p = 0.047) as compared to the non-AGD group. We also observed that H1/H1 genotype was overrepresented in AGD cases (p = 0.018) and that there was no association with any specific APOE allele. A subanalysis of PSP cases according to the AGD status was carried out, yielding no significant differences.

Assessing Mild Cognitive Impairment Progression using a Spherical Brain Mapping of Magnetic Resonance Imaging. - Martinez-Murcia, Francisco Jesus; Górriz, Juan Manuel; Ramírez, Javier; Segovia, Fermín; Salas-Gonzalez, Diego; Castillo-Barnes, Diego; Ortiz, Andrés (J Alzheimers Dis, 2018)
BACKGROUND: The early diagnosis of Alzheimer's Disease (AD), particularly in its prodromal stage, mild cognitive impairment (MCI), still remains a challenge. Many computational tools have been developed to successfully explore and predict the disease progression. In this context, the Spherical Brain Mapping (SBM) proved its ability in detecting differences between AD and aged subjects without symptoms of dementia. Being a very visual tool, its application in predicting MCI conversion to AD could be of great help to understand neurodegeneration and the disease progression. OBJECTIVE: In this work, we aim at predicting the conversion of MCI affected subjects to AD more than 6 months in advance of their conversion session and understanding the progression of the disease by predicting neuropsychological test outcomes from MRI data. METHODS: In order to do so, SBM is applied to a series of MRI scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The resulting spherical brain maps show statistical and morphological information of the brain in a bidimensional plane, performing at the same time a significant feature reduction that provides a feature vector used in classification analysis. RESULTS: The study achieves up to 92.3% accuracy in the AD versus normal controls (CTL) detection, and up to a 77.6% in detection a of MCI conversions when trained with AD and CTL subjects. The prediction of neuropsychological test outcomes achieved R2 rates up to more than 0.5. Significant regions according to t-test and correlation analysis match reported brain areas in the literature. CONCLUSION: The results prove that Spherical Brain Mapping offers good ability to predict conversion patterns and cognitive state, at the same time that provides an additional aid for visualizing a two-dimensional abstraction map of the brain.

Assessing Working Memory in Mild Cognitive Impairment with Serial Order Recall. - Emrani, Sheina; Libon, David J; Lamar, Melissa; Price, Catherine C; Jefferson, Angela L; Gifford, Katherine A; Hohman, Timothy J; Nation, Daniel A; Delano-Wood, Lisa; Jak, Amy; Bangen, Katherine J; Bondi, Mark W; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Working memory (WM) is often assessed with serial order tests such as repeating digits backward. In prior dementia research using the Backward Digit Span Test (BDT), only aggregate test performance was examined. OBJECTIVE: The current research tallied primacy/recency effects, out-of-sequence transposition errors, perseverations, and omissions to assess WM deficits in patients with mild cognitive impairment (MCI). METHODS: Memory clinic patients (n = 66) were classified into three groups: single domain amnestic MCI (aMCI), combined mixed domain/dysexecutive MCI (mixed/dys MCI), and non-MCI where patients did not meet criteria for MCI. Serial order/WM ability was assessed by asking participants to repeat 7 trials of five digits backwards. Serial order position accuracy, transposition errors, perseverations, and omission errors were tallied. RESULTS: A 3 (group)×5 (serial position) repeated measures ANOVA yielded a significant group×trial interaction. Follow-up analyses found attenuation of the recency effect for mixed/dys MCI patients. Mixed/dys MCI patients scored lower than non-MCI patients for serial position 3 (p < 0.003) serial position 4 (p < 0.002); and lower than both group for serial position 5 (recency; p < 0.002). Mixed/dys MCI patients also produced more transposition errors than both groups (p < 0.010); and more omissions (p < 0.020), and perseverations errors (p < 0.018) than non-MCI patients. CONCLUSIONS: The attenuation of a recency effect using serial order parameters obtained from the BDT may provide a useful operational definition as well as additional diagnostic information regarding working memory deficits in MCI.
Keywords: Aged; Aged, 80 and over; Cognitive Dysfunction; Executive Function; Female; Humans; Male; Memory Disorders; Memory, Short-Term; Mental Recall; Neuropsychological Tests; Regression Analysis; Serial Learning

Assessment of the Genetic Architecture of Alzheimer's Disease Risk in Rate of Memory Decline. - Del-Aguila, Jorge L; Fernández, Maria Victoria; Schindler, Suzanne; Ibanez, Laura; Deming, Yuetiva; Ma, Shengmei; Saef, Ben; Black, Kathleen; Budde, John; Norton, Joanne; Chasse, Rachel; Harari, Oscar; et al. (J Alzheimers Dis, 2018)
Many genetic studies for Alzheimer's disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University, and we calculated PRS (polygenic risk score) based on the IGAP study to compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (β= 0.146, p = 0.03). In the case of rare variants, TREM2 (β= 0.309, p = 0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients.
Keywords: Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease; Dementia; Disease Progression; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Heterozygote; Humans; Longitudinal Studies; Male; Membrane Glycoproteins; Memory Disorders; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Immunologic; Risk Assessment

Association between Hippocampal Shape, Neuroinflammation, and Cognitive Decline in Alzheimer's Disease. - Cabinio, Monia; Saresella, Marina; Piancone, Federica; LaRosa, Francesca; Marventano, Ivana; Guerini, Franca; Nemni, Raffaello; Baglio, Francesca; Clerici, Mario (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition characterized by memory impairment and general decrease in cognitive functions and daily living competences, that leads to a complete loss of autonomy. The pathogenesis of AD is characterized by the deposition of amyloid-β plaques (Aβ plaques) and neurofibrillary tangles, initially involving cortical and hippocampal structures, and neuroinflammation. To date, no studies have investigated the topological association between neuroinflammation and hippocampal shape in AD. OBJECTIVE: The aim of the present study is to assess the association between hippocampal shape, cognitive profile, and neuroinflammation in a group of AD patients in the mild stage of the disease. METHODS: Thirty-one patients with typical onset AD (mild stage) underwent MRI examination (1.5T scanner); hippocampal structures were segmented using a vertex-wise analysis (FSL-FIRST). Immune parameters were evaluated on peripheral blood mononuclear cells by flow-cytometry. Correlation analyses were performed between hippocampal shape and both cognitive profile (ADAS-Cog and MMSE scores), and neuro-inflammatory variables (i.e., circulating monocytes, cytokines). RESULTS: Statistically significant correlations (p < 0.05FWE) between right hippocampal shape and cognitive measurements and between left hippocampal shape and inflammatory indices were detected. The hippocampal field mostly involved was the lateral portion of bilateral hippocampi, mainly overlapping with Cornu Ammonis, extending along the entire longitudinal axis. CONCLUSIONS: A topological relationship between hippocampal atrophy and both cognitive profile and neuroinflammation is found; the association with neuroinflammatory indices is in line with the pattern of AD-associated neuronal death, whereas the association with cognitive test might account for residual cognitive functions.

Association between Peripheral Leptin and Adiponectin Levels and Cognitive Decline in Patients with Neurocognitive Disorders ≥65 Years. - Gilbert, Thomas; Roche, Sylvain; Blond, Emilie; Bar, Jean-Yves; Drai, Jocelyne; Cuerq, Charlotte; Haution-Bitker, Marine; Ecochard, René; Bonnefoy, Marc (J Alzheimers Dis, 2018)
BACKGROUND: There is evidence that adipokines have roles in brain functioning and cognitive decline. OBJECTIVE: Assess the role of leptin and adiponectin levels in predicting changes in neuro-cognitive disorders (NCD). METHODS: The study included 205 patients over 65 years of age presenting for a one-day hospitalization for current assessment of cognitive function. Peripheral blood leptin and adiponectin levels were measured at admission. Demographic variables, body mass index (BMI), and history of hypertension were also recorded. Cognitive function was assessed by the Mini-Mental State Examination (MMSE) at admission and at later scheduled visits over a median follow-up period of 14.5 months. Conventional univariate comparisons were made between diagnosis groups (Alzheimer's disease (AD), mild NCD, vascular/mixed dementia). Changes in MMSE scores over time were examined with regard to the above variables using a linear mixed model. RESULTS: The mean BMI was significantly lower (by 2 kg/m2, p = 0.01) in patients with AD than in patients with either mild-NCD or vascular/mixed dementia. Leptin levels were significantly higher (p = 0.043) and adiponectin levels significantly lower (p = 0.045) in patients with mild-NCD than in patients with major-NCD (AD or vascular/mixed dementia). However, the mixed model suggested no influence of the baseline levels of these two biomarkers on the course of cognitive decline. CONCLUSION: The present study confirms the associations between leptin and adiponectin and AD or AD-related disorders but did not confirm that these peptides may be used as predictive biomarkers of cognitive decline.

Association between Plasma Levels of PAI-1, tPA/PAI-1 Molar Ratio, and Mild Cognitive Impairment in Chinese Patients with Type 2 Diabetes Mellitus. - Wang, Jiaqi; Yuan, Yang; Cai, Rongrong; Huang, Rong; Tian, Sai; Lin, Hongyan; Guo, Dan; Wang, Shaohua (J Alzheimers Dis, 2018)
BACKGROUND: Plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (tPA) are involved in the complications of type 2 diabetes mellitus (T2DM) and early pathology of Alzheimer's disease. OBJECTIVE: This study aimed to investigate the association between plasma PAI-1, tPA/PAI-1 molar ratio, and mild cognitive impairment (MCI) in Chinese T2DM patients. METHODS: A total of 162 Chinese T2DM patients were recruited and divided into two groups according to the Montreal Cognitive Assessment score. Demographic data were collected, plasma PAI-1 and tPA levels were measured through enzyme-linked immunosorbent assay, tPA/PAI-1 molar ratio was calculated, and neuropsychological test results were examined. The association between PAI-1, tPA/PAI-1 molar ratio, and cognition was analyzed. RESULTS: There were 66 diabetic MCI patients and 96 healthy cognition participants (controls). T2DM patients with MCI displayed significantly increased plasma PAI-1 levels (p = 0.016) and decreased tPA/PAI-1 molar ratio (p = 0.021) compared with the controls. High PAI-1 levels and low tPA/PAI-1 molar ratio were associated with MCI in T2DM patients, e.g., plasma level of PAI-1 were negatively correlated (r = -0.343, p = 0.007) with logic memory in T2DM patients with MCI. Linear regression analysis further revealed that PAI-1 concentration was an independent factor of diabetic MCI (p = 0.001). CONCLUSIONS: High PAI-1 levels and low tPA/PAI-1 molar ratio were significantly correlated with T2DM-associated cognitive impairment, especially memory function, in Chinese patients.

Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease. - Geijselaers, Stefan L C; Aalten, Pauline; Ramakers, Inez H G B; De Deyn, Peter Paul; Heijboer, Annemieke C; Koek, Huiberdina L; OldeRikkert, Marcel G M; Papma, Janne M; Reesink, Fransje E; Smits, Lieke L; Stehouwer, Coen D A; Teunissen, Charlotte E; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD). OBJECTIVE: To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype. METHODS: From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42, total (t-)Tau, and phosphorylated (p-)Tau. RESULTS: CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient -0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029). CONCLUSION: Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Brain; Cognition Disorders; Female; Humans; Insulin; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Peptide Fragments; Signal Transduction; tau Proteins

Association of Low-Level Ozone with Cognitive Decline in Older Adults. - Cleary, Ekaterina Galkina; Cifuentes, Manuel; Grinstein, Georges; Brugge, Doug; Shea, Thomas B (J Alzheimers Dis, 2018)
Increasing evidence points to an association of airborne pollutant exposure with respiratory, cardiovascular, and neurological pathology. We examined whether or not ground-level ozone or fine particulate matter ≤ 2.5 μm in diameter (PM2.5) was associated with accelerated cognitive decline. Using repeated measures mixed regression modeling, we analyzed cognitive performance of a geographically diverse sampling of individuals from the National Alzheimer's Coordinating Center between 2004-2008. Ambient air concentrations of ozone and PM2.5 were established using a space-time Hierarchical Bayesian Model that statistically merged air monitor data and modeled air quality estimates. We then compared the ambient regional concentrations of ozone and PM2.5 with the rate of cognitive decline in residents within those regions. Increased levels of ozone correlated with an increased rate of cognitive decline, following adjustment for key individual and community-level risk factors. Furthermore, individuals harboring one or more APOE4 alleles exhibited a faster rate of cognitive decline. The deleterious association of ozone was confined to individuals with normal cognition who eventually became cognitively impaired as opposed to those who entered the study with baseline impairment. In contrast to ozone, we did not observe any correlation between ambient PM2.5 and cognitive decline at regulatory limits set by the Environmental Protection Agency. Our findings suggest that prolonged exposure to ground-level ozone may accelerate cognitive decline during the initial stages of dementia development.
Keywords: Age Distribution; Aged; Aged, 80 and over; Aging; Air Pollutants; Cognitive Dysfunction; Female; Humans; Male; Mental Status and Dementia Tests; Middle Aged; Ozone; Regression Analysis; Retrospective Studies; United States

The Association of Mid- and Late-Life Systemic Inflammation with Brain Amyloid Deposition: The ARIC-PET Study. - Walker, Keenan A; Windham, B Gwen; Brown, Charles H; Knopman, David S; Jack, Clifford R; Mosley, Thomas H; Selvin, Elizabeth; Wong, Dean F; Hughes, Timothy M; Zhou, Yun; Gross, Alden L; Gottesman, Rebecca F (J Alzheimers Dis, 2018)
BACKGROUND: Although inflammation has been implicated in the pathogenesis of Alzheimer's disease, the effects of systemic inflammation on brain amyloid deposition remain unclear. OBJECTIVE: We examined the association of midlife and late-life systemic inflammation with late-life brain amyloid levels in a community sample of non-demented older adults from the Atherosclerosis Risk in Communities (ARIC) - PET Study. METHODS: 339 non-demented participants (age: 75 [SD 5]) were recruited from the ARIC Study to undergo florbetapir PET (amyloid) imaging. Blood levels of high sensitivity C-reactive protein (CRP), a marker of systemic inflammation, were measured 22 years (Visit 2), 16 years (Visit 4), and up to 2 years before PET imaging (Visit 5). Elevated brain amyloid deposition (standardized uptake value ratio >1.2) was the primary outcome. RESULTS: Our primary analyses found no association of midlife and late-life CRP with late-life brain amyloid levels. However, in secondary stratified analyses, we found that higher midlife (Visit 2) CRP was associated with elevated amyloid among males (OR 1.65, 95% CI: 1.13-2.42), and among white (OR 1.33, 95% CI: 1.02-1.75), but not African American, participants (p-interactions<0.05). Among male participants, those who maintained high CRP levels (≥3 mg/L) throughout mid- and late-life were most likely to have elevated brain amyloid (OR, 8.81; 95% CI: 1.23, 62.91). CONCLUSIONS: Although our primary analysis does not support an association between systemic inflammation and brain amyloid deposition, we found evidence for sex- and race-dependent associations. However, findings from subgroup analyses should be interpreted with caution.

Association of Motoric Cognitive Risk Syndrome with Cardiovascular Disease and Risk Factors: Results from an Original Study and Meta-Analysis. - Beauchet, Olivier; Sekhon, Harmehr; Barden, John; Liu-Ambrose, Teresa; Chester, Victoria L; Szturm, Tony; Grenier, Sébastien; Léonard, Guillaume; Bherer, Louis; Allali, Gilles (J Alzheimers Dis, 2018)
BACKGROUND: Motoric cognitive risk (MCR) syndrome, a recently described pre-dementia syndrome, has been associated with cardiovascular disease and their risk factors (CVDRF). OBJECTIVE: To determine whether MCR syndrome was associated with CVDRF in French community-dwelling older adults, and to quantitatively evaluate, with a systematic review and meta-analysis, the association of MCR syndrome with CVDRF. METHODS: Based on a cross-sectional design, 238 older adults without dementia were selected from the French GAIT study. An English and French systematic Medline and Embase search (without limiting date of publication) was also conducted in February 2017 using the terms "motoric cognitive risk syndrome" OR "motoric cognitive risk" OR "motoric risk". The systematic review and meta-analysis included 8 studies. CVDRF were defined as cardiovascular diseases, hypertension, diabetes, stroke, obesity and abnormal waist-hip ratio (WHR). RESULTS: The prevalence of MCR syndrome in the current original study was 16.8%. MCR syndrome was associated with abnormalWHR(Odds ratio [OR] >2.8 with p < 0.020) and high blood pressure (OR >2.5 with p < 0.025). Of the 202 originally identified abstracts, 7 (3.5%) were selected for the systematic review. The meta-analysis showed that all pooled OR were significant with a p-value <0.001 (OR = 1.41 for cardiovascular diseases, 1.21 for hypertension, 1.44 for diabetes, 2.05 for stroke, and 1.34 for obesity). When pooling all CVDRF, the overall OR was 1.38 (95% CI, 1.33-1.45) with p-value <0.001. CONCLUSION: MCR syndrome is significantly associated with CVDRF. These findings suggest that a vascular mechanism may underlie the pathophysiology of MCR syndrome.

Association of Plasma Neurofilament Light Chain with Neocortical Amyloid-β Load and Cognitive Performance in Cognitively Normal Elderly Participants. - Chatterjee, Pratishtha; Goozee, Kathryn; Sohrabi, Hamid R; Shen, Kaikai; Shah, Tejal; Asih, Prita R; Dave, Preeti; ManYan, Candice; Taddei, Kevin; Chung, Roger; Zetterberg, Henrik; Blennow, Kaj; et al. (J Alzheimers Dis, 2018)
BACKGROUND: The disruption of neurofilament, an axonal cytoskeletal protein, in neurodegenerative conditions may result in neuronal damage and its release into the cerebrospinal fluid and blood. In Alzheimer's disease (AD), neurofilament light chain (NFL), a neurofilament subunit, is elevated in the cerebrospinal fluid and blood. OBJECTIVE: Investigate the association of plasma NFL with preclinical-AD features, such as high neocortical amyloid-β load (NAL) and subjective memory complaints, and cognitive performance in cognitively normal older adults. METHODS: Plasma NFL concentrations were measured employing the single molecule array platform in participants from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort, aged 65- 90 years. Participants underwent a battery of neuropsychological testing to evaluate cognitive performance and were categorized as low NAL (NAL-, n = 65) and high NAL (NAL+, n = 35) assessed via PET, and further stratified into subjective memory complainers (SMC; nNAL- = 51, nNAL+ = 25) and non-SMC (nNAL- = 14, nNAL+ = 10) based on the Memory Assessment Clinic- Questionnaire. RESULTS: Plasma NFL inversely correlated with cognitive performance. No significant difference in NFL was observed between NAL+ and NAL- participants; however, within APOEɛ4 non-carriers, higher NAL was observed in individuals with NFL concentrations within quartiles 3 and 4 (versus quartile 1). Additionally, within the NAL+ participants, SMC had a trend of higher NFL compared to non-SMC. CONCLUSION: Plasma NFL is inversely associated with cognitive performance in elderly individuals. While plasma NFL may not reflect NAL in individuals with normal global cognition, the current observations indicate that onset of axonal injury, reflected by increased plasma NFL, within the preclinical phase of AD may contribute to the pathogenesis of AD.

Associations between the Frailty Index and Brain Atrophy: The Treviso Dementia (TREDEM) Registry. - Gallucci, Maurizio; Piovesan, Cinzia; Di Battista, Maria Elena (J Alzheimers Dis, 2018)
BACKGROUND: Frailty is a condition which is characterized by a reduction in the homeostatic reserves of the individual and which entails an increased vulnerability to stressful endogenous and exogenous agents. The Frailty Index (FI), proposed by Rockwood, was designed following an accumulation of deficits model: the greater the number of deficits in a given individual, the greater the degree of frailty. OBJECTIVE: The aim of this study was to verify the existence of associations between FI and cerebral atrophy. METHODS: The TREDEM Register (Treviso Dementia) provided retrospective observational data from 1,584 patients. The FI was calculated based on 50 variables comprising diseases, disability, behavioral disturbances, and blood chemistry parameters. The severity of atrophy in the cortical and subcortical regions, such as the amplitude of the lateral ventricles, were detected by computerized axial tomography (CAT). Multiple logistic regression models using the stepwise backward method were used to analyze possible associations between FI and atrophy. RESULTS: For each increment of one hundredth of the FI, the probability of cortical atrophy increases by 2%. The female gender is a protective factor for cortical and subcortical atrophy. At each increase of one percent of the FI, the probability of a severe degree of cortical atrophy increases by 3%. The FI was significantly associated with frontal and temporal cortical atrophy. The relationship between overall subcortical atrophy and the FI was not significant, whereas it was the one with the severe degree of subcortical atrophy. The FI is significantly associated with the atrophy of the peri-insular subcortical region. Similar associations were found considering only demented patients. CONCLUSION: The FI is associated with the presence, degree, and some localization of cerebral atrophy in a population of cognitive-decline patients.

Associations of Dietary Protein and Fiber Intake with Brain and Blood Amyloid-β. - Fernando, W M A D Binosha; Rainey-Smith, Stephanie R; Gardener, Samantha L; Villemagne, Victor L; Burnham, Samantha C; Macaulay, S Lance; Brown, Belinda M; Gupta, Veer Bala; Sohrabi, Hamid R; Weinborn, Michael; Taddei, Kevin; Laws, Simon M; et al. (J Alzheimers Dis, 2018)
Accumulating evidence suggests a diet high in protein and fiber may confer some protection against Alzheimer's disease (AD). However, no human studies to-date have assessed the relationship between protein and fiber intake, and plasma and brain amyloid-β (Aβ). Consequently, this cross-sectional study, investigated the association of self-reported dietary intakes of protein and fiber, with plasma and brain Aβ burden (n = 541, and n = 162 respectively), in a well-characterized cohort of cognitively normal older adults, drawn from the larger Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. We observed 12.59 and 8.43 higher odds of 'high' brain Aβ burden (PiB PET SUVR≥1.5) if protein intake fell in the lowest and middle tertile, respectively, compared to the highest tertile (p = 0.008; p = 0.013). Thus, in this cohort, the more protein consumed, the less likelihood of 'high' Aβ burden in the brain. No other significant associations were observed. The results of this study highlight the potentially protective impact of high dietary protein intake on brain Aβ burden in older adults, before objective memory decline is apparent. While longitudinal validation is required, these findings may assist in the development of dietary approaches aimed at preventing or delaying AD onset.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Australia; Biomarkers; Brain; Cognition; Cohort Studies; Cross-Sectional Studies; Dietary Fiber; Dietary Proteins; Female; Humans; Logistic Models; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography

Automated Multi-Atlas Segmentation of Hippocampal and Extrahippocampal Subregions in Alzheimer's Disease at 3T and 7T: What Atlas Composition Works Best? - Xie, Long; Shinohara, Russell T; Ittyerah, Ranjit; Kuijf, Hugo J; Pluta, John B; Blom, Kim; Kooistra, Minke; Reijmer, Yael D; Koek, Huiberdina L; Zwanenburg, Jaco J M; Wang, Hongzhi; Luijten, Peter R; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Multi-atlas segmentation, a popular technique implemented in the Automated Segmentation of Hippocampal Subfields (ASHS) software, utilizes multiple expert-labelled images ("atlases") to delineate medial temporal lobe substructures. This multi-atlas method is increasingly being employed in early Alzheimer's disease (AD) research, it is therefore becoming important to know how the construction of the atlas set in terms of proportions of controls and patients with mild cognitive impairment (MCI) and/or AD affects segmentation accuracy. OBJECTIVE: To evaluate whether the proportion of controls in the training sets affects the segmentation accuracy of both controls and patients with MCI and/or early AD at 3T and 7T. METHODS: We performed cross-validation experiments varying the proportion of control subjects in the training set, ranging from a patient-only to a control-only set. Segmentation accuracy of the test set was evaluated by the Dice similarity coeffiecient (DSC). A two-stage statistical analysis was applied to determine whether atlas composition is linked to segmentation accuracy in control subjects and patients, for 3T and 7T. RESULTS: The different atlas compositions did not significantly affect segmentation accuracy at 3T and for patients at 7T. For controls at 7T, including more control subjects in the training set significantly improves the segmentation accuracy, but only marginally, with the maximum of 0.0003 DSC improvement per percent increment of control subject in the training set. CONCLUSION: ASHS is robust in this study, and the results indicate that future studies investigating hippocampal subfields in early AD populations can be flexible in the selection of their atlas compositions.

Aβ42/Aβ40 and Aβ42/Aβ38 Ratios Are Associated with Measures of Gait Variability and Activities of Daily Living in Mild Alzheimer's Disease: A Pilot Study. - Koychev, Ivan; Galna, Brook; Zetterberg, Henrik; Lawson, Jennifer; Zamboni, Giovanna; Ridha, Basil H; Rowe, James B; Thomas, Alan; Howard, Robert; Malhotra, Paresh; Ritchie, Craig; Lovestone, Simon; et al. (J Alzheimers Dis, 2018)
Gait disturbances are some of the earliest changes in dementia and their monitoring presents an opportunity for early diagnosis. The exact relationship between gait and well-established biomarkers of Alzheimer's disease (AD) remains to be clarified. In this study we compared gait-related measures with cerebrospinal fluid (CSF) markers of AD pathology. We recruited seventeen participants with mild AD in a multi-site study and performed gait assessment as well as lumbar punctures to obtain CSF. CSF Aβ42/Aβ40 and Aβ42/Aβ38 correlated positively with measures of variability (step time and step length) in the clinic-based assessments. This was driven by a negative relationship between gait variability and Aβ40 and Aβ38 but not Aβ42.The amyloid ratios and gait variability measures were also associated with more severe functional impairment. We interpret these data as an indication that increasing amyloid production (i.e., increasing Aβ40 and Aβ38) is associated with diminishing cognitive-motor control of gait. These preliminary results suggest that the two amyloid ratios may be a marker of the earliest disturbances in the interplay between cognitive and motor control which characterize dementia.

The Behavioral and Psychological Symptoms of Dementia in Down Syndrome (BPSD-DS) Scale: Comprehensive Assessment of Psychopathology in Down Syndrome. - Dekker, Alain D; Sacco, Silvia; Carfi, Angelo; Benejam, Bessy; Vermeiren, Yannick; Beugelsdijk, Gonny; Schippers, Mieke; Hassefras, Lyanne; Eleveld, José; Grefelman, Sharina; Fopma, Roelie; Bomer-Veenboer, Monique; et al. (J Alzheimers Dis, 2018)
People with Down syndrome (DS) are prone to develop Alzheimer's disease (AD). Behavioral and psychological symptoms of dementia (BPSD) are core features, but have not been comprehensively evaluated in DS. In a European multidisciplinary study, the novel Behavioral and Psychological Symptoms of Dementia in Down Syndrome (BPSD-DS) scale was developed to identify frequency and severity of behavioral changes taking account of life-long characteristic behavior. 83 behavioral items in 12 clinically defined sections were evaluated. The central aim was to identify items that change in relation to the dementia status, and thus may differentiate between diagnostic groups. Structured interviews were conducted with informants of persons with DS without dementia (DS, n = 149), with questionable dementia (DS+Q, n = 65), and with diagnosed dementia (DS+AD, n = 67). First exploratory data suggest promising interrater, test-retest, and internal consistency reliability measures. Concerning item relevance, group comparisons revealed pronounced increases in frequency and severity in items of anxiety, sleep disturbances, agitation & stereotypical behavior, aggression, apathy, depressive symptoms, and eating/drinking behavior. The proportion of individuals presenting an increase was highest in DS+AD, intermediate in DS+Q, and lowest in DS. Interestingly, among DS+Q individuals, a substantial proportion already presented increased anxiety, sleep disturbances, apathy, and depressive symptoms, suggesting that these changes occur early in the course of AD. Future efforts should optimize the scale based on current results and clinical experiences, and further study applicability, reliability, and validity. Future application of the scale in daily care may aid caregivers to understand changes, and contribute to timely interventions and adaptation of caregiving.

Beneficial Effects of Sideritis scardica and Cichorium spinosum against Amyloidogenic Pathway and Tau Misprocessing in Alzheimer's Disease Neuronal Cell Culture Models. - Chalatsa, Ioanna; Arvanitis, Demetrios A; Mikropoulou, Eleni V; Giagini, Athina; Papadopoulou-Daifoti, Zeta; Aligiannis, Nektarios; Halabalaki, Maria; Tsarbopoulos, Anthony; Skaltsounis, Leandros A; Sanoudou, Despina (J Alzheimers Dis, 2018)
BACKGROUND: Natural products are a significantly underutilized source of potential treatments against human disease. Alzheimer's disease (AD) is a prime example of conditions that could be amenable to such treatments as suggested by recent findings. OBJECTIVE: Aiming to identify novel potentially therapeutic approaches against AD, we assessed the effects of Cichorium spinosum and Sideritis scardica extracts, both distinct components of the Mediterranean diet. METHODS/RESULTS: After the detailed characterization of the extracts' composition using LC-HRMS methods, they were evaluated on two AD neuronal cell culture models, namely the AβPP overexpressing SH-SY5Y-AβPP and the hyperphosphorylated tau expressing PC12-htau. Initially their effect on cell viability of SH-SY5Y and PC12 cells was examined, and subsequently their downstream effects on AβPP and tau processing pathways were investigated in the SH-SY5Y-AβPP and PC12-htau cells. We found that the S. scardica and C. spinosum extracts have similar effects on tau, as they both significantly decrease total tau, the activation of the GSK3β, ERK1 and/or ERK2 kinases of tau, as well as tau hyperphosphorylation. Furthermore, both extracts appear to promote AβPP processing through the alpha, non-amyloidogenic pathway, albeit through partly different mechanisms. CONCLUSIONS: These findings suggest that C. spinosum and S. scardica could have a notable potential in the prevention and/or treatment of AD, and merit further investigations at the in vivo level.

Biallelic Loss of Function of SORL1 in an Early Onset Alzheimer's Disease Patient. - Le Guennec, Kilan; Tubeuf, Hélène; Hannequin, Didier; Wallon, David; Quenez, Olivier; Rousseau, Stéphane; Richard, Anne-Claire; Deleuze, Jean-François; Boland, Anne; Frebourg, Thierry; Gaildrat, Pascaline; Campion, Dominique; et al. (J Alzheimers Dis, 2018)
Heterozygous SORL1 protein truncating variants (PTV) are a strong risk factor for early-onset Alzheimer's disease (EOAD). In case control studies performed at the genome-wide level, PTV definition is usually straightforward. Regarding splice site variants, only those affecting canonical sites are typically included. Some other variants, not annotated as PTV, could, however, affect splicing and hence result in a loss of SORL1 function. We took advantage of the whole exome sequencing data from the 9/484 patients with a previously reported SORL1 PTV in the French EOAD series and searched for a second variant which may affect splicing and eventually result in more than 50% loss of function overall. We found that one patient, known to carry a variant predicted to disrupt the canonical 5' splice site of exon 8, also carried a second novel intronic variant predicted to affect SORL1 splicing of exon 29. Segregation analysis showed that the second variant was located in trans from the known PTV. We performed ex vivo minigene splicing assays and showed that both variants led to the generation of transcripts containing a premature stop codon. This is therefore the first evidence of a human carrying biallelic SORL1 PTV. This patient had a family history of dementia in both maternal and paternal lineages with later ages of onset than the proband himself. However, his 55 years age at onset was in the same ranges as previously published SORL1 heterozygous PTV carriers. This suggests that biallelic loss of SORL1 function is an extremely rare event that was not associated with a dramatically earlier age at onset than heterozygous SORL1 loss-of-function variant carriers, in this single patient.
Keywords: Alzheimer Disease; Case-Control Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Humans; LDL-Receptor Related Proteins; Male; Membrane Transport Proteins; Middle Aged; Risk Factors

Bioactive Food Abates Metabolic and Synaptic Alterations by Modulation of Gut Microbiota in a Mouse Model of Alzheimer's Disease. - Syeda, Tauqeerunnisa; Sanchez-Tapia, Mónica; Pinedo-Vargas, Laura; Granados, Omar; Cuervo-Zanatta, Daniel; Rojas-Santiago, Eleazar; Díaz-Cintra, Sof A; Torres, Nimbe; Perez-Cruz, Claudia (J Alzheimers Dis, 2018)
Recent investigations have demonstrated an important role of gut microbiota (GM) in the pathogenesis of Alzheimer's disease (AD). GM modulates a host's health and disease by production of several substances, including lipopolysaccharides (LPS) and short-chain fatty acids (SCFAs), among others. Diet can modify the composition and diversity of GM, and ingestion of a healthy diet has been suggested to lower the risk to develop AD. We have previously shown that bioactive food (BF) ingestion can abate neuroinflammation and oxidative stress and improve cognition in obese rats, effects associated with GM composition. Therefore, BF can impact the gut-brain axis and improved behavior. In this study, we aim to explore if inclusion of BF in the diet may impact central pathological markers of AD by modulation of the GM. Triple transgenic 3xTg-AD (TG) female mice were fed a combination of dried nopal, soy, chia oil, and turmeric for 7 months. We found that BF ingestion improved cognition and reduced Aβ aggregates and tau hyperphosphorylation. In addition, BF decreased MDA levels, astrocyte and microglial activation, PSD-95, synaptophysin, GluR1 and ARC protein levels in TG mice. Furthermore, TG mice fed BF showed increased levels of pGSK-3β. GM analysis revealed that pro-inflammatory bacteria were more abundant in TG mice compared to wild-type, while BF ingestion was able to restore the GM's composition, LPS, and propionate levels to control values. Therefore, the neuroprotective effects of BF may be mediated, in part, by modulation of GM and the release of neurotoxic substances that alter brain function.

Biological, Neuroimaging, and Neurophysiological Markers in Frontotemporal Dementia: Three Faces of the Same Coin. - Borroni, Barbara; Benussi, Alberto; Premi, Enrico; Alberici, Antonella; Marcello, Elena; Gardoni, Fabrizio; Di Luca, Monica; Padovani, Alessandro (J Alzheimers Dis, 2018)
Frontotemporal dementia (FTD) is a heterogeneous clinical, genetic, and neuropathological disorder. Clinical diagnosis and prediction of neuropathological substrates are hampered by heterogeneous pictures. Diagnostic markers are key in clinical trials to differentiate FTD from other neurodegenerative dementias. In the same view, identifying the neuropathological hallmarks of the disease is key in light of future disease-modifying treatments. The aim of the present review is to unravel the progress in biomarker discovery, discussing the potential applications of available biological, imaging, and neurophysiological markers.

Brimapitide Reduced Neuronal Stress Markers and Cognitive Deficits in 5XFAD Transgenic Mice. - Gourmaud, Sarah; Thomas, Priscilla; Thomasseau, Sylvie; Tible, Marion; Abadie, Claire; Paquet, Claire; Hugon, Jacques (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is characterized by accumulations of amyloid-β (Aβ42) and hyperphosphorylated tau proteins, associated with neuroinflammation, synaptic loss, and neuronal death. Several studies indicate that c-Jun N-terminal kinase (JNK) is implicated in the pathological features of AD. We have investigated in 5XFAD mice, the therapeutic effects of Brimapitide, a JNK-specific inhibitory peptide previously tested with higher concentrations in another AD model (TgCRND8). Three-month-old 5XFAD and wild-type littermate mice were treated by intravenous injections of low doses (10 mg/kg) of Brimapitide every 3 weeks, for 3 or 6 months (n = 6-9 per group). Cognitive deficits and brain lesions were assessed using Y-maze, fear-conditioning test, and histological and biochemical methods. Chronic treatment of Brimapitide for 3 months resulted in a reduction of Aβ plaque burden in the cortex of 5XFAD treated mice. After 6 months of treatment, cognitive deficits were reduced but also a significant reduction of cell death markers and the pro-inflammatory IL-1β cytokine in treated mice were detected. The Aβ plaque burden was not anymore modified by the 6 months of treatment. In addition to modulating cognition and amyloid plaque accumulation, depending on the treatment duration, Brimapitide seems experimentally to reduce neuronal stress in 5XFAD mice.

Calpain I Activation Causes GLUT3 Proteolysis and Downregulation of O-GlcNAcylation in Alzheimer's Disease Brain. - Gu, Jianlan; Jin, Nana; Ma, Denglei; Chu, Dandan; Iqbal, Khalid; Gong, Cheng-Xin; Liu, Fei (J Alzheimers Dis, 2018)
Impairment of cerebral glucose uptake/metabolism in individuals with Alzheimer's disease (AD) is believed to lead to downregulation of protein O-GlcNAcylation, which contributes to tau pathogenesis through tau hyperphosphorylation. Level of glucose transporter 3 (GLUT3), a neuronal specific glucose transporter, is decreased in AD brain, which may contribute to impaired brain glucose uptake/metabolism. However, what causes the reduction of GLUT3 in AD brain is not fully understood. Here, we report 1) that decrease of GLUT3 is associated with the reduction of protein O-GlcNAcylation in AD brain, 2) that GLUT3 level is negatively correlated with calpain I activation in human brain, 3) that calpain I proteolyzes GLUT3 at the N-terminus in vitro, and 4) that activation of calpain I is negatively correlated with protein O-GlcNAcylation in AD brain. Furthermore, we found that overexpression of GLUT3 enhances protein O-GlcNAcylation in N2a cells. Overexpression of calpain I suppresses protein O-GlcNAcylation in these cells. These findings suggest a novel mechanism by which calpain I overactivation leads to GLUT3 degradation and the consequent down-regulation of protein O-GlcNAcylation in AD brain.

Can a Novel High-Density EEG Approach Disentangle the Differences of Visual Event Related Potential (N170), Elicited by Negative Facial Stimuli, in People with Subjective Cognitive Impairment? - Lazarou, Ioulietta; Adam, Katerina; Georgiadis, Kostas; Tsolaki, Anthoula; Nikolopoulos, Spiros; Yiannis Kompatsiaris, Ioannis; Tsolaki, Magda (J Alzheimers Dis, 2018)
BACKGROUND: Studies on subjective cognitive impairment (SCI) and neural activation report controversial results. OBJECTIVE: To evaluate the ability to disentangle the differences of visual N170 ERP, generated by facial stimuli (Anger & Fear) as well as the cognitive deterioration of SCI, mild cognitive impairment (MCI), and Alzheimer's disease (AD) compared to healthy controls (HC). METHOD: 57 people took part in this study. Images corresponding to facial stimuli of "Anger" and "Fear" were presented to 12 HC, 14 SCI, 17 MCI and 14 AD participants. EEG data were recorded by using a HD-EEG HydroCel with 256 channels. RESULTS: Results showed that the amplitude of N170 can contribute in distinguishing the SCI group, since statistically significant differences were observed with the HC (p < 0.05) and the MCI group from HC (p < 0.001), as well as AD from HC (p = 0.05) during the processing of facial stimuli. Noticeable differences were also observed in the topographic distribution of the N170 amplitude, while localization analysis by using sLORETA images confirmed the activation of superior, middle-temporal, and frontal lobe brain regions. Finally, in the case of "Fear", SCI and HC demonstrated increased activation in the orbital and inferior frontal gyrus, respectively, MCI in the inferior temporal gyrus, and AD in the lingual gyrus. CONCLUSION: These preliminary findings suggest that the amplitude of N170 elicited after negative facial stimuli could be modulated by the decline related to pathological cognitive aging and can contribute in distinguishing HC from SCI, MCI, and AD.

Caregiving and Caregiver Burden in Dementia Home Care: Results from the Prospective Dementia Registry (PRODEM) of the Austrian Alzheimer Society. - Ransmayr, Gerhard; Hermann, Philipp; Sallinger, Katharina; Benke, Thomas; Seiler, Stephan; Dal-Bianco, Peter; Marksteiner, Josef; Defrancesco, Michaela; Sanin, Günter; Struhal, Walter; Guger, Michael; Vosko, Milan; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Comprehensive studies on caregiver burden (CB) of persons caring for dementia patients differ methodologically and show variable results. OBJECTIVE: Analysis of known and hypothesized factors of CB in home care of dementia patients. METHODS: Multicenter longitudinal study comprising 585 persons caring mostly for Alzheimer's disease patients (age median 77.25 years, Mini-Mental State Examination raw score median 23) using the Zarit Caregiver Burden Interview (CBI). Known patient-related determinants of CB were studied, such as dementia severity (Clinical Dementia Rating, CDR), neuropsychological deficits (CERAD-Plus), neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI), disability (Disability Assessment for Dementia, DAD), dependency (Dependency Scale, DS), and moreover, unclarified potential factors (age, sex, education of patients; age, sex, occupational status of the caregivers; family relationship). Psychological and somatic effects of CB were analyzed (factor analysis). RESULTS: Caregiver age was median 61. Female caregivers prevailed (67.8%). Median CBI sum score (CBIss) was 16 at baseline. After two years, CBIss was 22 and 37% of the caregivers reported mild to moderate (CBIss 21-40), 16.8% moderate to severe or severe (≥41), and 46.2% absent to little CB (CBIss ≤ 20). CB correlated positively with NPI, CDR, DS scores, disability (DAD), years of education of the patients, and proximity of patient and caregiver sex (female), and negatively with caregiver age. Caregivers reported restrictions of time, health problems, and negative emotions. CONCLUSION: The findings are applicable to identify persons at risk for substantial CB and its consequences. There is demand for personal, psychological, and medical support of caregivers and increasing male participation.

Cerebral Amyloid Angiopathy and Cerebral Amyloid Angiopathy-Related Inflammation: Comparison of Hemorrhagic and DWI MRI Features. - Renard, Dimitri; Tatu, Lavinia; Collombier, Laurent; Wacongne, Anne; Ayrignac, Xavier; Charif, Mahmoud; Boukriche, Yassine; Chiper, Laura; Fourcade, Genevieve; Azakri, Souhayla; Gaillard, Nicolas; Mercier, Erick; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Cerebral amyloid angiopathy (CAA) can be associated with primary vasculitis of small/medium-sized leptomeningeal and cortical arteries, called CAA-related inflammation (CAA-ri). OBJECTIVE: To compare hemorrhagic and diffusion-weighted imaging (DWI) MRI features in CAA and CAA-ri. METHODS: We prospectively scored in a consecutive CAA and CAA-ri cohort: presence/number of chronic intracerebral hemorrhage (ICH), cerebral microbleeds (CMB), and cortical superficial siderosis (CSS) on initial T2*-weighted imaging, and DWI lesions on both initial and follow-up imaging. In a subgroup, ApoE, CSF, and 18F-florbetaben-positron emission tomography (FBB-PET) were also analyzed. RESULTS: In CAA-ri, CMB presence was more frequent (100% versus 40%, p < 0.001) and CMB numbers higher (mean 137 versus 8, p < 0.001). No difference was observed for chronic ICH or CSS. DWI lesions were more frequent in acute compared to chronic CAA-ri (p = 0.025), whereas no such difference was observed between acute and chronic CAA (p = 0.18). Both ApoE4 (genotyping available in 22 CAA-ri and 48 CAA patients) carriers and homozygosity were more frequent in CAA-ri (48% versus 19% [p = 0.014] and 32% versus 2% [p < 0.001] respectively). CSF biomarker analyses (performed in 20 CAA-ri and 45 CAA patients) showed lower Aβ42 levels in CAA-ri compared to CAA (median 312 versus 422 pg/mL, p = 0.0032). FBB-PET (performed in 11 CAA-ri and 20 CAA patients) showed higher standardized uptake value ratios in CAA-ri compared with CAA, only significant when the pons was used as reference (p = 0.037). CONCLUSION: Compared to CAA, CAA-ri was associated with higher CMB numbers, more frequent ApoE4 carriers and homozygotes, lower CSF Aβ42 levels, and more severe amyloid load on FBB-PET.

Cerebral Amyloid Angiopathy: Similarity in African-Americans and Caucasians with Alzheimer's Disease. - Kamara, Dennis M; Gangishetti, Umesh; Gearing, Marla; Willis-Parker, Monica; Zhao, Liping; Hu, William T; Walker, Lary C (J Alzheimers Dis, 2018)
Cerebral amyloid angiopathy (CAA) of the Aβ type is variably present in the brains of patients with Alzheimer's disease (AD). CAA contributes to cognitive decline and increases the risk of lobar hemorrhage; because both AD-typical dementia and lobar hemorrhage are more common in African-Americans than in Caucasians, we postulated that African-Americans with AD might be particularly susceptible to CAA. To test this hypothesis, we analyzed CAA histopathologically in the large vessels and capillaries of autopsy-derived frontal, temporal, parietal, and occipital cortical samples from African-Americans (n = 18) and Caucasians (n = 19) with end-stage AD. In the combined cohort of 37 subjects, 22% of the subjects had severe CAA in large vessels, and 11% had severe CAA in capillaries. However, the prevalence and histopathologic characteristics of CAA were similar in the African-Americans and Caucasians. This conclusion was substantiated in an independent sample from the National Alzheimer's Coordinating Center database, in which the degree of CAA was comparable in 1,554 Caucasians and 68 African-Americans with end-stage AD. These findings support a growing consensus that the fundamental histopathologic features of AD are largely impartial to the race of the afflicted.

Cerebrospinal Fluid Amyloid-β Levels are Increased in Patients with Insomnia. - Chen, Dong-Wan; Wang, Jun; Zhang, Li-Li; Wang, Yan-Jiang; Gao, Chang-Yue (J Alzheimers Dis, 2018)
Previous studies demonstrate that patients with sleep disorders are at risk of developing Alzheimer's disease (AD), with the mechanism unknown. It is suggested that acute sleep deprivation induces an increase of amyloid-β (Aβ), the major pathological agent in AD, in the cerebrospinal fluid (CSF). In the present study, we recruited 23 patients with chronic insomnia aged between 46 to 67 years and 23 healthy controls aged between 43 to 67 years. We investigated the CSF levels of Aβ and tau, another pathological hallmark in the AD pathogenesis. We found that CSF Aβ42 levels were significantly increased in insomnia patients. However, no significant difference was found in Aβ40, total tau (t-Tau), and phosphorylated tau (p-Tau) between the two groups. Furthermore, we found that CSF Aβ40 and Aβ42 levels are significantly correlated with the sleep quality, as reflected by the Pittsburgh Sleep Quality Index (PSQI) scores. But no significant correlation was found in CSF t-Tau and p-Tau levels with PSQI. Our results indicate that chronic sleep disorders may induce the disruption of Aβ metabolism in the brain, thus increase the risk for developing AD.
Keywords: Adult; Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Female; Humans; Male; Middle Aged; Phosphorylation; Sleep Initiation and Maintenance Disorders; tau Proteins

Cerebrospinal Fluid Levels of Angiotensin-Converting Enzyme Are Associated with Amyloid-β42 Burden in Alzheimer's Disease. - Rocha, Natalia P; Toledo, Andre; Corgosinho, Laiane T S; de Souza, Leonardo C; Guimarães, Henrique C; Resende, Elisa P F; Braz, Nayara F T; Gomes, Karina B; Simoes E Silva, Ana C; Caramelli, Paulo; Teixeira, Antônio L (J Alzheimers Dis, 2018)
This study was designed to determine whether the levels of renin-angiotensin system (RAS) components are associated with Alzheimer's disease (AD) pathology. Cerebrospinal fluid levels of Angiotensin (Ang) II, Ang-(1-7), angiotensin-converting enzyme (ACE), ACE2, Amyloid-β (Aβ)40, Aβ42, total tau (hTau), and phospho-tau (pTau) were measured in 18 patients with AD and 10 controls. Patients with AD presented decreased levels of ACE when compared with controls. We found a significant positive correlation between ACE and Aβ42 levels among patients. Our results strengthen the hypothesis that ACE is associated with Aβ pathology in AD.

Cerebrospinal Fluid, MRI, and Florbetaben-PET in Cerebral Amyloid Angiopathy-Related Inflammation. - Renard, Dimitri; Collombier, Laurent; Demattei, Christophe; Wacongne, Anne; Charif, Mahmoud; Ayrignac, Xavier; Azakri, Souhayla; Gaillard, Nicolas; Boudousq, Vincent; Lehmann, Sylvain; Menjot de Champfleur, Nicolas; Thouvenot, Eric (J Alzheimers Dis, 2018)
BACKGROUND: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is associated with a cerebrospinal fluid (CSF) biomarker profile similar to that observed in CAA. Few CAA-ri patients have been studied by fibrillar amyloid-β (Aβ) imaging (using 11C-Pittsburgh compound B and 18F-florbetapir, but not 18F-florbetaben). OBJECTIVE: To describe CSF biomarkers, magnetic resonance imaging (MRI), and 18F-florbetaben (FBB)-positron emission tomography (PET) changes in CAA-ri patients. METHODS: CSF levels of total tau, phosphorylated tau, Aβ1-42, and Aβ1-40, MRI (cerebral microbleeds count on susceptibility-weighted imaging and semi-quantitative analysis of fluid-attenuation inversion recovery white matter hyperintensities), and FBB-PET (using both cerebellar cortex and pons to calculate standardized uptake value ratios) were analyzed in nine consecutive CAA-ri patients. RESULTS: A median number of 769 cerebral microbleeds/patient were counted on MRI. When using the pons as reference region, amyloid load on FBB-PET was very strongly correlated to CSF Aβ1-40 levels (rho = -0.83, p = 0.008) and moderately correlated to cerebral microbleed numbers in the occipital lobes (rho = 0.59, p = 0.001), while comparisons with other CSF biomarkers were not statistically significant (total tau, rho = -0.63, p = 0.076; phosphorylated tau, rho = -0.68, p = 0.05; Aβ1-42, rho = -0.59, p = 0.09). All correlations were weaker, and not statistically significant, when using the cerebellum as reference region. A non-significant correlation (rho = -0.50, p = 0.18) was observed between CSF Aβ1-40 levels and cerebral microbleed numbers. CONCLUSION: In CAA-ri, CSF Aβ1-40 levels correlated well with amyloid load assessed by FBB-PET when the pons was used as reference, and to a lesser degree with cerebral microbleeds count on MRI. This confirms earlier data on CSF Aβ1-40 as an in vivo marker for CAA and CAA-ri.
Keywords: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Cerebral Amyloid Angiopathy; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multivariate Analysis; Positron-Emission Tomography; Prospective Studies; Stilbenes; tau Proteins; Vasculitis, Central Nervous System

Cerebrovascular Disease and Neurodegeneration in Alzheimer's Disease with and without a Strong Family History: A Pilot Magnetic Resonance Imaging Study in Dominican Republic. - Piriz, Angel; Reyes, Dolly; Narkhede, Atul; Guzman, Vanessa A; Viqar, Fawad; Meier, Irene B; Budge, Mariana; Mena, Pedro; Dashnaw, Stephen; Lee, Joseph; Reitz, Christiane; Gutierrez, Jose; et al. (J Alzheimers Dis, 2018)
The incidence and prevalence of Alzheimer's disease (AD) dementia are higher among Caribbean Hispanics than among non-Hispanic Whites. The causes of this health disparity remain elusive, partially because of the relative limited capacity for biomedical research in the developing countries that comprise Caribbean Latin America. To begin to address this issue, we were awarded a Development Research Award from the US NIH and Fogarty International Center in order to establish the local capacity to integrate magnetic resonance imaging (MRI) into studies of cognitive aging and dementia in Dominican Republic, establish collaborations with Dominican investigators, and conduct a pilot study on the role of cerebrovascular markers in the clinical expression of AD. Ninety older adult participants with and without AD dementia and with and without a strong family history of AD dementia received MRI scans and clinical evaluation. We quantified markers of cerebrovascular disease (white matter hyperintensities [WMH], presence of infarct, and presence of microbleed) and neurodegeneration (entorhinal cortex volume) and compared them across groups. Patients with AD dementia had smaller entorhinal cortex and greater WMH volumes compared with controls, regardless of family history status. This study provides evidence for the capacity to conduct MRI studies of cognitive aging and dementia in Dominican Republic. The results are consistent with the hypothesis that small vessel cerebrovascular disease represents a core feature of AD dementia, as affected participants had elevated WMH volumes irrespective of family history status.

Characterization of Music and Photograph Evoked Autobiographical Memories in People with Alzheimer's Disease. - Baird, Amee; Brancatisano, Olivia; Gelding, Rebecca; Thompson, William Forde (J Alzheimers Dis, 2018)
BACKGROUND: Music evoked autobiographical memories (MEAMs) have been documented in people with Alzheimer's disease (AD), but it is unclear whether music is more effective than other familiar stimuli at evoking memories. OBJECTIVE: To explore the frequency and specificity of memories in response to famous songs compared with photographs of famous events (photograph evoked autobiographical memories, PEAMs), and whether stimuli from the period of the reminiscence bump (10-30 years of age) were more likely to elicit memories. METHODS: 10 participants with AD and 10 aged-matched healthy elderly people reported memories following exposure to 2 songs (longest time at number one in Australian music charts) and 2 photographs (of prominent famous events) from each decade from 1930 to 2010. RESULTS: PEAMs were more frequent than MEAMs in healthy elderly (p < 0.05), but no such differences were observed among people with AD. There was no difference in the frequency of MEAMs between groups, but people with AD showed a significant decline in the frequency of PEAMs. In both groups, MEAMs were typically less specific than PEAMs and comprised semantic knowledge or repeated/extended events. Stimuli from when participants were aged 10-30 years triggered more frequent memories compared with stimuli from later decades, but this was only statistically significant for MEAMs. CONCLUSION: Our findings indicate a preserved mnemonic effect of music relative to pictures in this patient population, corroborating suggestions that MEAMs represent an island of preservation during the progression of AD.

Chinese Herbal Medicine Xueshuantong Enhances Cerebral Blood Flow and Improves Neural Functions in Alzheimer's Disease Mice. - Huang, Yangmei; Guo, Baihong; Shi, Bihua; Gao, Qingtao; Zhou, Qiang (J Alzheimers Dis, 2018)
Reduced cerebral blood flow in Alzheimer's disease (AD) may occur in early AD, which contributes to the pathogenesis and/or pathological progression of AD. Reversing this deficit may have therapeutic potential. Certain traditional Chinese herbal medicines (e.g., Saponin and its major component Xueshuantong [XST]) increase blood flow in humans, but whether they could be effective in treating AD patients has not been tested. We found that systemic XST injection elevated cerebral blood flow in APP/PS1 transgenic mice using two-photon time-lapse imaging in the same microvessels before and after injection. Subchronic XST treatment led to improved spatial learning and memory and motor performance in the APP/PS1 mice, suggesting improved neural plasticity and functions. Two-photon time lapse imaging of the same plaques revealed a reduction in plaque size after XST treatment. In addition, western blots experiments showed that XST treatment led to reduced processing of amyloid-β protein precursor (AβPP) and enhanced clearance of amyloid-β (Aβ) without altering the total level of AβPP. We also found increased synapse density in the immediate vicinity of amyloid plaques, suggesting enhanced synaptic function. We conclude that targeting cerebral blood flow can be an effective strategy in treating AD.

Chronic Lithium Treatment Increases Telomere Length in Parietal Cortex and Hippocampus of Triple-Transgenic Alzheimer's Disease Mice. - Cardillo, Giancarlo de Mattos; De-Paula, Vanessa de Jesus Rodrigues; Ikenaga, Eliza Hiromi; Costa, Luciana Rodrigues; Catanozi, Sergio; Schaeffer, Evelin Lisete; Gattaz, Wagner Farid; Kerr, Daniel Shikanai; Forlenza, Orestes Vicente (J Alzheimers Dis, 2018)
Telomere length (TL) is a biomarker of cell aging, and its shortening has been linked to several age-related diseases. In Alzheimer's disease (AD), telomere shortening has been associated with neuroinflammation and oxidative stress. The majority of studies on TL in AD were based on leucocyte DNA, with little information about its status in the central nervous system. In addition to other neuroprotective effects, lithium has been implicated in the maintenance of TL. The present study aims to determine the effect of chronic lithium treatment on TL in different regions of the mouse brain, using a triple-transgenic mouse model (3xTg-AD). Eighteen transgenic and 22 wild-type (Wt) male mice were treated for eight months with chow containing 1.0 g (Li1) or 2.0 g (Li2) of lithium carbonate/kg, or standard chow (Li0). DNA was extracted from parietal cortex, hippocampus and olfactory epithelium and TL was quantified by real-time PCR. Chronic lithium treatment was associated with longer telomeres in the hippocampus (Li2, p = 0.0159) and in the parietal cortex (Li1, p = 0.0375) of 3xTg-AD compared to Wt. Our findings suggest that chronic lithium treatment does affect telomere maintenance, but the magnitude and nature of this effect depend on the working concentrations of lithium and characteristics of the tissue. This effect was observed when comparing 3xTg-AD with Wt mice, suggesting that the presence of AD pathology was required for the lithium modulation of TL.

Circulating miR-127-3p as a Potential Biomarker for Differential Diagnosis in Frontotemporal Dementia. - Piscopo, Paola; Grasso, Margherita; Puopolo, Maria; D'Acunto, Emanuela; Talarico, Giuseppina; Crestini, Alessio; Gasparini, Marina; Campopiano, Rosa; Gambardella, Stefano; Castellano, Anna Elisa; Bruno, Giuseppe; Denti, Michela A; et al. (J Alzheimers Dis, 2018)
Given the heterogeneous nature of frontotemporal dementia (FTD), sensitive biomarkers are greatly needed for the accurate diagnosis of this neurodegenerative disorder. Circulating miRNAs have been reported as promising biomarkers for neurodegenerative disorders and processes affecting the central nervous system, especially in aging. The objective of the study was to evaluate if some circulating miRNAs linked with apoptosis (miR-29b-3p, miR-34a-5p, miR-16-5p, miR-17-5p, miR-107, miR-19b-3p, let-7b-5p, miR-26b-5p, and 127-3p) were able to distinguish between FTD patients and healthy controls. For this study, we enrolled 127 subjects, including 54 patients with FTD, 20 patients with Alzheimer's disease (AD), and 53 healthy controls. The qRT-PCR analysis showed a downregulation of miR-127-3p in FTD compared to controls, while the levels of other miRNAs remained unchanged. Then, miR-127-3p expression was also analyzed in AD patients, finding a different expression between two patient groups. A receiver operating characteristic curve was then created for miR-127-3p to discriminate FTD versus AD (AUC: 0.8986), and versus healthy controls (AUC: 0.8057). In conclusion, miR-127-3p could help to diagnose FTD and to distinguish it from AD.

Circulating Plasma microRNAs are Altered with Amyloidosis in a Mouse Model of Alzheimer's Disease. - Ryan, Margaret M; Guévremont, Diane; Mockett, Bruce G; Abraham, Wickliffe C; Williams, Joanna M (J Alzheimers Dis, 2018)
Pathological changes underlying Alzheimer's disease (AD) begin decades before the classical symptoms of memory loss become evident. As microRNAs are released from neurons and enter the bloodstream, circulating microRNAs may be reflective of AD progression and are ideal candidates as biomarkers for early-stage disease detection. Here, we provide a novel, in-depth analysis of how plasma microRNAs alter with aging, the most prominent risk factor for AD, and with development of amyloid-β (Aβ) plaque deposition. We assessed the circulating microRNAs in APPswe/PSEN1dE9 transgenic mice and wild-type controls at 4, 8 and 15 m (n = 8-10) using custom designed Taqman arrays representing 185 neuropathology-related microRNAs. We performed a linear mixed-effects model to investigate the effects of age and genotype on plasma microRNAs expression. Following this analysis, we found 8 microRNAs were significantly affected by age alone in wild-type animals and 12 microRNAs altered in APPswe/PSEN1dE9 mice, either prior to Aβ plaque deposition (4 m) or during the development of AD-like pathogenesis (8 m or 15 m). Importantly, we found that differing sets of microRNAs were identified at each time point. Functional analysis of these data revealed that while common biological pathways, such as Inflammatory Response, were enriched throughout the disease process, Free Radical Scavenging, Immunological Disease, and Apoptosis Signaling were specifically enriched later in the disease process. Overall, this study reinforces that distinct biological processes underpin the early versus late stages of AD-like pathogenesis and highlights potential pre-symptomatic microRNAs biomarkers of neurodegeneration.

Circulating Progenitor Cells Correlate with Memory, Posterior Cortical Thickness, and Hippocampal Perfusion. - Nation, Daniel A; Tan, Alick; Dutt, Shubir; McIntosh, Elissa C; Yew, Belinda; Ho, Jean K; Blanken, Anna E; Jang, Jung Yun; Rodgers, Kathleen E; Gaubert, Aimée (J Alzheimers Dis, 2018)
BACKGROUND: Bone marrow-derived progenitor cells survey the vasculature and home to sites of tissue injury where they can promote repair and regeneration. It has been hypothesized that these cells may play a protective role neurodegenerative and vascular cognitive impairment. OBJECTIVE: To evaluate progenitor cell levels in older adults with and without mild cognitive impairment (MCI), and to relate circulating levels to memory, brain volume, white matter lesion volume, and cerebral perfusion. METHOD: Thirty-two older adults, free of stroke and cardiovascular disease, were recruited from the community and evaluated for diagnosis of MCI versus cognitively normal (CN). Participants underwent brain MRI and blood samples were taken to quantify progenitor reserve using flow cytometry (CD34+, CD34+CD133+, and CD34+CD133+CD309+ cells). RESULTS: Participants with MCI (n = 10) exhibited depletion of all CPC markers relative to those who were CN (n = 22), after controlling for age, sex, and education. Post-hoc age, sex, and education matched comparisons (n = 10 MCI, n = 10 CN) also revealed the same pattern of results. Depletion of CD34+ cells correlated with memory performance, left posterior cortical thickness, and bilateral hippocampal perfusion. Participants exhibited low levels of vascular risk and white matter lesion burden that did not correlate with progenitor levels. CONCLUSIONS: Circulating progenitor cells are associated with cognitive impairment, memory, cortical atrophy, and hippocampal perfusion. We hypothesize that progenitor depletion contributes to, or is triggered by, cognitive decline and cortical atrophy. Further study of progenitor cell depletion in older adults may benefit efforts to prevent or delay dementia.
Keywords: Aged; Aged, 80 and over; Antigens, CD; Apolipoproteins E; Cerebral Cortex; Cognitive Dysfunction; Female; Flow Cytometry; Hippocampus; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Perfusion; Stem Cells; White Matter

A Clinically-Translatable Machine Learning Algorithm for the Prediction of Alzheimer's Disease Conversion in Individuals with Mild and Premild Cognitive Impairment. - Grassi, Massimiliano; Perna, Giampaolo; Caldirola, Daniela; Schruers, Koen; Duara, Ranjan; Loewenstein, David A (J Alzheimers Dis, 2018)
BACKGROUND: Available therapies for Alzheimer's disease (AD) can only alleviate and delay the advance of symptoms, with the greatest impact eventually achieved when provided at an early stage. Thus, early identification of which subjects at high risk, e.g., with MCI, will later develop AD is of key importance. Currently available machine learning algorithms achieve only limited predictive accuracy or they are based on expensive and hard-to-collect information. OBJECTIVE: The current study aims to develop an algorithm for a 3-year prediction of conversion to AD in MCI and PreMCI subjects based only on non-invasively and effectively collectable predictors. METHODS: A dataset of 123 MCI/PreMCI subjects was used to train different machine learning techniques. Baseline information regarding sociodemographic characteristics, clinical and neuropsychological test scores, cardiovascular risk indexes, and a visual rating scale for brain atrophy was used to extract 36 predictors. Leave-pair-out-cross-validation was employed as validation strategy and a recursive feature elimination procedure was applied to identify a relevant subset of predictors. RESULTS: 16 predictors were selected from all domains excluding sociodemographic information. The best model resulted a support vector machine with radial-basis function kernel (whole sample: AUC = 0.962, best balanced accuracy = 0.913; MCI sub-group alone: AUC = 0.914, best balanced accuracy = 0.874). CONCLUSIONS: Our algorithm shows very high cross-validated performances that outperform the vast majority of the currently available algorithms, and all those which use only non-invasive and effectively assessable predictors. Further testing and optimization in independent samples will warrant its application in both clinical practice and clinical trials.
Keywords: Aged; Aged, 80 and over; Algorithms; Alzheimer Disease; Area Under Curve; Atrophy; Brain; Cognitive Dysfunction; Disease Progression; Female; Humans; Logistic Models; Machine Learning; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Predictive Value of Tests; Prognosis; Regression Analysis; Sensitivity and Specificity; Support Vector Machine

Clinical-Neuropathological Correlations of Alzheimer's Disease and Related Dementias in Latino Volunteers. - Soria, Jose A; Huisa, Branko N; Edland, Steven D; Litvan, Irene; Peavy, Guerry M; Salmon, David P; Hansen, Lawrence A; Galasko, Douglas R; Brewer, James B; González, Hector M; Rissman, Robert A (J Alzheimers Dis, 2018)
Clinical, neuropsychological, and neurological procedures used to diagnose Alzheimer's disease (AD) and related dementias were largely developed and validated in well-educated, non-Latino, English-speaking populations. Sociocultural and genetic differences in Latinos might influence the accuracy of clinical diagnosis of AD and other dementias. We aim to compare the accuracy of the clinical diagnosis of AD and related dementias in Latinos with the corresponding neuropathological diagnosis. From the UCSD Alzheimer's Disease Research Center longitudinal cohort, we selected all Latino participants who had autopsy neuropathological studies from 1991 to 2017. Participants underwent annual neurological clinical evaluations, standard neuropsychological tests, neuroimaging, and genotyping of Apolipoprotein E. We calculated the sensitivity and specificity of the clinical diagnosis of AD against the primary pathological diagnosis. Of the 34 participants with a primary neuropathological diagnosis of AD, 33 (97.1%) were correctly clinically diagnosed as having AD at the last clinical evaluation, and 1 was incorrectly diagnosed with dementia with Lewy bodies. Of the 19 participants without a primary neuropathological diagnosis of AD, 8 were incorrectly clinically diagnosed with probable AD at the last clinic evaluation. The clinical diagnosis of AD at the last clinical evaluation had 97.1% sensitivity and 57.9% specificity for autopsy-verified AD. In this Latino cohort, clinicians predicted AD pathological findings with high sensitivity but moderate specificity. Tangle-only dementia was the most common misdiagnosis. Our study suggests that current procedures and instruments to clinically determine AD in Latinos have high sensitivity compared with neuropathology, but specificity needs to be improved.

Clinic-Based Validation of Cerebrospinal Fluid Biomarkers with Florbetapir PET for Diagnosis of Dementia. - Álvarez, Ignacio; Aguilar, Miquel; González, Jose Manuel; Ysamat, Montse; Lorenzo-Bosquet, Carles; Alonso, Alvaro; Tartari, Juan Pablo; Romero, Silvia; Diez-Fairen, Monica; Carcel, Maria; Pujalte, Francisco; Pastor, Pau (J Alzheimers Dis, 2018)
BACKGROUND: Cerebrospinal fluid (CSF) biomarker studies have shown variable accuracy for diagnosis of Alzheimer's disease (AD); therefore, internal validation is recommended. OBJECTIVE: To investigate the correlation between CSF biomarkers and cerebral 18-Florbetapir positron emission tomography (Amyloid-PET) and calculate their sensitivity and specificity to obtain the optimal clinical cut-off points to diagnose the etiology of cognitive impairment. METHODS: We performed Amyloid-PET scans and CSF biomarker levels analyses in 68 subjects (50 with mild cognitive impairment, 11 with AD dementia, and 7 with non-AD dementia). Visual examination of Amyloid-PET scans was performed. CSF analyses were performed using standard sandwich ELISA. RESULTS: Amyloid-PET was positive in 36 subjects, negative in 26, and inconclusive in 6. Optimal clinical cut-off points for CSF markers were the following: amyloid-β 1-42 (Aβ42) = 629 pg/ml, total tau (t-tau) = 532 pg/ml, phosphorylated tau (p-tau) = 88 pg/ml, and t-tau/Aβ42 ratio = 0.58. T-tau/Aβ42 ratio showed the best sensitivity and specificity (92 and 84%, respectively). T-tau and p-tau CSF levels (r2 = 0.867) followed by the t-tau and t-tau/Aβ42 CSF ratio (r2 = 0.666) showed the strongest inter-marker correlation. Interestingly, subjects with inconclusive Amyloid-PET showed intermediate values for all CSF markers between negative and positive Amyloid-PET groups. CONCLUSIONS: CSF t-tau/Aβ42 ratio appears to be the most accurate AD CSF marker. The presence of intermediate values for CSF markers among the subjects with inconclusive Amyloid-PET suggests the presence of other dementias associated with AD pathology or intermediate phenotypes.
Keywords: Aged; Amyloid beta-Peptides; Analysis of Variance; Aniline Compounds; Apolipoproteins E; Biomarkers; Cognition Disorders; Dementia; Ethylene Glycols; Female; Humans; Male; Middle Aged; Peptide Fragments; Positron-Emission Tomography; tau Proteins

Co-Expression of Glia Maturation Factor and Apolipoprotein E4 in Alzheimer's Disease Brain. - Thangavel, Ramasamy; Bhagavan, Sachin M; Ramaswamy, Swathi Beladakere; Surpur, Spurthi; Govindarajan, Raghav; Kempuraj, Duraisamy; Zaheer, Smita; Raikwar, Sudhanshu; Ahmed, Mohammad E; Selvakumar, Govindhasamy Pushpavathi; Iyer, Shankar S; Zaheer, Asgar (J Alzheimers Dis, 2018)
Apolipoprotein E4 (ApoE4) is a major genetic risk factor for Alzheimer's disease (AD). The E4 allele of ApoE plays a crucial role in the inflammatory and neurodegenerative processes associated with AD. This is evident from the multiple effects of the ApoE isoforms in amyloid-β (Aβ) aggregation. Glia maturation factor (GMF) is a brain-specific neuroinflammatory protein that we have previously demonstrated to be significantly upregulated in various regions of AD brains compared to non-AD control brains and that it induces neurodegeneration. We have previously reported that GMF is predominantly expressed in the reactive astrocytes surrounding amyloid plaques (APs) in AD brain. In the present study, using immunohistochemical and dual immunofluorescence staining, we show the expression and colocalization of GMF and ApoE4 in AD brains. Our results show that ApoE4 is present within the APs of AD brain. Further, we found that GMF and ApoE4 were strongly expressed and co-associated in APs and in the reactive astrocytes surrounding APs in AD. An increased expression of GMF in APs and neurofibrillary tangles in the AD brain, and the co-localization of GMF and ApoE4 in APs suggest that GMF and ApoE4 together should be contributing to the neuropathological changes associated with AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Brain; Case-Control Studies; Fluorescent Antibody Technique; Glia Maturation Factor; Humans; Neurofibrillary Tangles; Plaque, Amyloid

Cognitive Impairment is Associated with Mortality in Hemodialysis Patients. - Angermann, Susanne; Schier, Johannes; Baumann, Marcus; Steubl, Dominik; Hauser, Christine; Lorenz, Georg; Günthner, Roman; Braunisch, Matthias C; Kemmner, Stephan; Satanovskij, Robin; Haller, Bernhard; Heemann, Uwe; et al. (J Alzheimers Dis, 2018)
BACKGROUND: The prevalence of cognitive impairment in hemodialysis patients is notably high. In previous studises performed in the general population, cognitive impairment has been associated with increased mortality. OBJECTIVE: We evaluated the relationship between global cognitive function tested by a short screening instrument and mortality in hemodialysis patients. METHODS: Cognitive testing was performed in 242 maintenance hemodialysis patients under standardized conditions at baseline using the Montreal Cognitive Assessment (MoCA).Cognitive impairment was defined as a MoCA test score ≤24 points, as published previously. All-cause mortality was monitored during a median follow-up of 3.54 years. Kaplan-Meier plot and Cox regression model adjusted for known risk factors for mortality in hemodialysis patients were used to examine a possible association between global cognitive function and all-cause mortality. RESULTS: A MoCA test score ≤24 points resulted in a significant almost 3-fold higher hazard for all-cause mortality (unadjusted hazard ratio [HR]: 2.812; 95% confidence interval [95% CI]: 1.683-4.698; p < 0.001). After adjustment, this association was attenuated but remained significant (adjusted HR: 1.749; 95% CI: 1.007-3.038; p = 0.047). CONCLUSION: Impairment of global cognitive function measured by a short screening instrument was identified for the first time as an independent predictor of all-cause mortality in hemodialysis patients. Thus, implementing the MoCA test in clinical routine could contribute to a better risk stratification of this patient population.

Cognitive Variability Predicts Incident Alzheimer's Disease and Mild Cognitive Impairment Comparable to a Cerebrospinal Fluid Biomarker. - Gleason, Carey E; Norton, Derek; Anderson, Eric D; Wahoske, Michelle; Washington, Danielle T; Umucu, Emre; Koscik, Rebecca L; Dowling, N Maritza; Johnson, Sterling C; Carlsson, Cynthia M; Asthana, Sanjay (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) biomarkers are emerging as critically important for disease detection and monitoring. Most biomarkers are obtained through invasive, resource-intense procedures. A cognitive marker, intra-individual cognitive variability (IICV) may provide an alternative or adjunct marker of disease risk for individuals unable or disinclined to undergo lumbar puncture. OBJECTIVE: To contrast risk of incident AD and mild cognitive impairment (MCI) associated with IICV to risk associated with well-established biomarkers: cerebrospinal fluid (CSF) phosphorylated tau protein (p-tau181) and amyloid-β 42 (Aβ42) peptide. METHODS: Dispersion in cognitive performance, IICV, was estimated with a published algorithm, and included Trail Making Test A and B, Rey Auditory Verbal Learning Test (RAVLT), and the American National Adult Reading Test (ANART). CSF biomarkers were expressed as a ratio: p-tau181/Aβ42, wherein high values signified pathognomonic profiles. Logistic regression models included longitudinal data from 349 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who completed lumbar puncture. All subjects were cognitively healthy (n = 105) or diagnosed with MCI (n = 244) at baseline. We examined odds of conversion associated with baseline elevations in IICV and/or ratio of CSF p-tau181/Aβ42. RESULTS: When included in models alone or in combination with CSF p-tau181/Aβ42, one standard IICV unit higher was associated with an estimated odds ratio for incident AD or MCI of 2.81 (95% CI: 1.83-4.33) in the most inclusive sample, and an odds ratio of 3.41 (95% CI: 2.03-5.73) when restricted to participants with MCI. Iterative analyses suggested that IICV independently improved model fit even when individual index components were included in comparative models. CONCLUSIONS: These analyses provide preliminary support for IICV as a marker of incident AD and MCI. This easily-disseminated, non-invasive marker compared favorably to well-established CSF biomarkers.
Keywords: Aged; Aged, 80 and over; Algorithms; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Female; Humans; Incidence; Logistic Models; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Statistics, Nonparametric; tau Proteins

Combined Socio-Behavioral Evaluation Improves the Differential Diagnosis Between the Behavioral Variant of Frontotemporal Dementia and Alzheimer's Disease: In Search of Neuropsychological Markers. - Dodich, Alessandra; Cerami, Chiara; Cappa, Stefano F; Marcone, Alessandra; Golzi, Valeria; Zamboni, Michele; Giusti, Maria Cristina; Iannaccone, Sandro (J Alzheimers Dis, 2018)
BACKGROUND: Current diagnostic criteria for behavioral variant of frontotemporal dementia (bvFTD) and typical Alzheimer's disease (AD) include a differential pattern of neuropsychological impairments (episodic memory deficit in typical AD and dysexecutive syndrome in bvFTD). There is, however, large evidence of a frequent overlap in neuropsychological features, making the differential diagnosis extremely difficult. OBJECTIVES: In this retrospective study, we evaluated the diagnostic value of different cognitive and neurobehavioral markers in bvFTD and AD patient groups. METHODS: We included 95 dementia patients with a clinical and biomarker evidence of bvFTD (n = 48) or typical AD (n = 47) pathology. A clinical 2-year follow-up confirmed clinical classification. Performances at basic cognitive tasks (memory, executive functions, visuo-spatial, language) as well as social cognition skills and neurobehavioral profiles have been recorded. A stepwise logistic regression model compared the neuropsychological profiles between groups and assessed the accuracy of cognitive and neurobehavioral markers in discriminating bvFTD from AD. RESULTS: Statistical comparison between patient groups proved social cognition and episodic memory impairments as main cognitive signatures of bvFTD and AD neuropsychological profiles, respectively. Only half of bvFTD patients showed attentive/executive deficits, questioning their role as cognitive marker of bvFTD. Notably, the large majority of bvFTD sample (i.e., 70%) poorly performed at delayed recall tasks. Logistic regression analysis identified social cognition performances, Frontal Behavioral Inventory and Mini-Mental State Examination scores as the best combination in distinguishing bvFTD from AD. CONCLUSION: Social cognition tasks and socio-behavioral questionnaires are recommended in clinical settings to improve the accuracy of early diagnosis of bvFTD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Cognition; Diagnosis, Differential; Female; Frontotemporal Dementia; Humans; Logistic Models; Male; Memory, Episodic; Mental Recall; Middle Aged; Neuropsychological Tests; Retrospective Studies; Social Skills

Comparison of Different Hypotheses Regarding the Spread of Alzheimer's Disease Using Markov Random Fields and Multimodal Imaging. - Dyrba, Martin; Grothe, Michel J; Mohammadi, Abdolreza; Binder, Harald; Kirste, Thomas; Teipel, Stefan J (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is characterized by a cascade of pathological processes that can be assessed in vivo using different neuroimaging methods. Recent research suggests a systematic sequence of pathogenic events on a global biomarker level, but little is known about the associations and dependencies of distinct lesion patterns on a regional level. Markov random fields are a probabilistic graphical modeling approach that represent the interaction between individual random variables by an undirected graph. We propose the novel application of this approach to study the interregional associations and dependencies between multimodal imaging markers of AD pathology and to compare different hypotheses regarding the spread of the disease. We retrieved multimodal imaging data from 577 subjects enrolled in the Alzheimer's Disease Neuroimaging Initiative. Mean amyloid load (AV45-PET), glucose metabolism (FDG-PET), and gray matter volume (MRI) were calculated for the six principle nodes of the default mode network- a functional network of brain regions that appears to be preferentially targeted by AD. Multimodal Markov random field models were developed for three different hypotheses regarding the spread of the disease: the "intraregional evolution model", the "trans-neuronal spread" hypothesis, and the "wear-and-tear" hypothesis. The model likelihood to reflect the given data was evaluated using tenfold cross-validation with 1,000 repetitions. The most likely graph structure contained the posterior cingulate cortex as main hub region with edges to various other regions, in accordance with the "wear-and-tear" hypothesis of disease vulnerability. Probabilistic graphical models facilitate the analysis of interactions between several variables in a network model and therefore afford great potential to complement traditional multiple regression analyses in multimodal neuroimaging research.

Complexity and Selectivity of γ-Secretase Cleavage on Multiple Substrates: Consequences in Alzheimer's Disease and Cancer. - Medoro, Alessandro; Bartollino, Silvia; Mignogna, Donatella; Passarella, Daniela; Porcile, Carola; Pagano, Aldo; Florio, Tullio; Nizzari, Mario; Guerra, Germano; Di Marco, Roberto; Intrieri, Mariano; Raimo, Gennaro; et al. (J Alzheimers Dis, 2018)
The processing of the amyloid-β protein precursor (AβPP) by β- and γ-secretases is a pivotal event in the genesis of Alzheimer's disease (AD). Besides familial mutations on the AβPP gene, or upon its overexpression, familial forms of AD are often caused by mutations or deletions in presenilin 1 (PSEN1) and 2 (PSEN2) genes: the catalytic components of the proteolytic enzyme γ-secretase (GS). The "amyloid hypothesis", modified over time, states that the aberrant processing of AβPP by GS induces the formation of specific neurotoxic soluble amyloid-β (Aβ) peptides which, in turn, cause neurodegeneration. This theory, however, has recently evidenced significant limitations and, in particular, the following issues are debated: 1) the concept and significance of presenilin's "gain of function" versus "loss of function"; and 2) the presence of several and various GS substrates, which interact with AβPP and may influence Aβ formation. The latter consideration is suggestive: despite the increasing number of GS substrates so far identified, their reciprocal interaction with AβPP itself, even in the AD field, is significantly unexplored. On the other hand, GS is also an important pharmacological target in the cancer field; inhibitors or GS activity are investigated in clinical trials for treating different tumors. Furthermore, the function of AβPP and PSENs in brain development and in neuronal migration is well known. In this review, we focused on a specific subset of GS substrates that directly interact with AβPP and are involved in its proteolysis and signaling, by evaluating their role in neurodegeneration and in cell motility or proliferation, as a possible connection between AD and cancer.
Keywords: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Humans; Neoplasms; Presenilin-1

Consent to Medical Procedures of Patients with Neurodegenerative Diseases: A Comparative Study of Legal Regulations in Selected European Countries and in the United States. - Guzik-Makaruk, Ewa M; Pływaczewski, Emil W; Mroczko, Piotr; Olesiuk-Okomska, Magda; Kulczyńska-Przybik, Agnieszka (J Alzheimers Dis, 2018)
According to the projections of the statistical office of the European Union, Eurostat, nearly one third of EU citizens will be at least 65 in 2060. The U.S. population age 65 and older continues to increase and is projected to nearly double from 48 million to 88 million by 2050. Elderly people are especially exposed to neurodegenerative diseases (NDs). The most common ND is Alzheimer's disease (AD), a chronic and progressive disorder with a variety of pathological changes within neuronal tissue, which begin even 10-15 years before the onset of cognitive impairment symptoms. AD is perceived as a disease continuum and considered to include three basic phases: preclinical (asymptomatic) stage, mild cognitive impairment (MCI), and dementia due to AD. A very important issue, from medical and legal perspectives, is the NDs patient's consent to medical procedures, including diagnostic procedures, such as lumber puncture. NDs patients are not always able to express their consent and do not always understand the information provided by a physician. This applies to a group of patients in the final stages of NDs. This paper presents legal regulations of selected European countries and signalizes the U.S. legal solutions on the issue of NDs patients' informed consent to medical procedures.

Constructing a Local Potential Participant Registry to Improve Alzheimer's Disease Clinical Research Recruitment. - Grill, Joshua D; Hoang, Dan; Gillen, Daniel L; Cox, Chelsea G; Gombosev, Adrijana; Klein, Kirsten; O'Leary, Steve; Witbracht, Megan; Pierce, Aimee (J Alzheimers Dis, 2018)
Potential participant registries are tools to address the challenge of slow recruitment to clinical research. In particular, registries may aid recruitment to secondary prevention clinical trials for Alzheimer's disease (AD), which enroll cognitively normal older individuals meeting specific genetic or biomarker criteria. Evidence of registry effectiveness is sparse, as is guidance on optimal designs or methods of conduct. We report our experiences of developing a novel local potential participant registry that implemented online enrollment and data collection. In the first year of operation, 957 individuals submitted email addresses to the registry, of whom 592 self-reported demographic, family history, and medical data. In addition, registrants provided information related to their interest and willingness to be contacted about studies. Local earned media and community education were the most effective methods of recruitment into the registry. Seventy-six (26%) of 298 registrants contacted about studies in the first year enrolled in those studies. One hundred twenty-nine registrants were invited to enroll in a preclinical AD trial, of whom 25 (18%) screened and 6 were randomized. These results indicate that registries can aid recruitment and provide needed guidance for investigators initiating new local registries.

Crosstalk between Peripheral Small Vessel Properties and Anxious-like Profiles: Sex, Genotype, and Interaction Effects in Mice with Normal Aging and 3×Tg-AD mice at Advanced Stages of Disease. - Jiménez-Altayó, Francesc; Sánchez-Ventura, Judith; Vila, Elisabet; Giménez-Llort, Lydia (J Alzheimers Dis, 2018)
Cardiovascular disease resulting from oxidative stress and inflammation can exacerbate Alzheimer's disease. This brief report provides the first evidence of compromised small peripheral mesenteric resistance artery (MRA) properties in 15-month-old 3xTg-AD mice. Females showed worse physiologically relevant MRA structural (increased passive external and internal diameters, cross sectional area) and functional (increased active internal diameters) alterations suggesting sex-dependent dysfunctions. At both physiological and high intraluminal pressures, vascular alterations correlated with the anxious-like behavioral profile, in a sex-dependent manner. Finally, the results unveil a crosstalk between peripheral small vessel properties and behavior in both 3xTg-AD mice and age-matched counterparts with normal aging.

Cysteine-Rich Repeat Domains 2 and 4 are Amyloid-β Binding Domains of Neurotrophin Receptor p75NTR and Potential Targets to Block Amyloid-β Neurotoxicity. - Wang, Ye-Ran; Wang, Jun; Liu, Yu-Hui; Hu, Gong-Ling; Gao, Chang-Yue; Wang, Yan-Jiang; Zhou, Xin-Fu; Zeng, Fan (J Alzheimers Dis, 2018)
The p75 neurotrophin receptor (p75NTR) is an amyloid-β (Aβ) receptor that both mediates Aβ neurotoxicity and regulates Aβ production and deposition, thus playing an important role in the pathogenesis of Alzheimer's disease (AD). The extracellular domain of p75NTR (p75ECD), consisting of four cysteine-rich repeat domains (CRDs), was recently reported to be an endogenous anti-Aβ scavenger to block p75NTR-mediated neuronal death and neurite degeneration signaling of Aβ and pro-neurotrophins. Identification of the specific Aβ binding domains of p75NTR is crucial for illuminating their interactions and the etiology of AD. CRDs of p75ECD were obtained by expression of recombinant plasmids or direct synthesis. Aβ aggregation inhibiting test and immunoprecipitation assay were applied to locate the specific binding domains of Aβ to p75ECD. The Aβ neurotoxicity antagonistic effects of different CRDs were examined by cytotoxicity experiments including neurite outgrowth assay, propidium iodide (PI) staining, and MTT assay. In the Aβ aggregation inhibiting test, the fluorescence intensity in the CRD2 and CRD4 treatment groups was significantly lower than that in the CRD1 and CRD3 treatment groups. Immunoprecipitation assay and western blot confirmed that Aβ could bind to CRD2 and CRD4. Besides, CRD2 and CRD4 antagonized Aβ neurotoxicity suggested by longer neurite length, less PI labelled cells, and higher cell viability than the control group. Our results indicate that CRD2 and CRD4 are Aβ binding domains of p75NTR and capable of antagonizing Aβ neurotoxicity, and therefore are potential therapeutic targets to block the interaction of Aβ and p75NTR in the pathogenesis of AD.

Decoupling of Local Metabolic Activity and Functional Connectivity Links to Amyloid in Alzheimer's Disease. - Scherr, Martin; Pasquini, Lorenzo; Benson, Gloria; Nuttall, Rachel; Gruber, Martin; Neitzel, Julia; Brandl, Felix; Sorg, Christian (J Alzheimers Dis, 2018)
BACKGROUND: Both ongoing local metabolic activity (LMA) and corresponding functional connectivity (FC) with remote brain regions are progressively impaired in Alzheimer's disease (AD), particularly in the posterior default mode network (pDMN); however, it is unknown how these impairments interact. It is well known that decreasing mean synaptic activity of a region, i.e., decreasing LMA, reduces the region's sensitivity to afferent input from other regions, i.e., FC. OBJECTIVE: We hypothesized progressive decoupling between LMA and FC in AD, which is linked to amyloid-β pathology (Aβ). METHODS: Healthy adults (n=20) and Aβ+patients without memory impairment (n=9), early MCI (n=21), late MCI (n=18) and AD (n=22) were assessed by resting-state fMRI, FDG-PET, and AV-45-PET to measure FC, LMA, and Aβ of the pDMN. Coupling between LMA and FC (rLA/FC) was estimated by voxelwise correlation. RESULTS: RLMA/FC decreased with disease severity (F=20.09, p<0.001). This decrease was specifically associated with pDMN Aβ (r=-0.273, p=0.029) but not global Aβ (r=-0.112, p=0.378) and with the impact of Aβ on FC (i.e., rAβ/FC,r=-0.339; p=0.006). In multiple regression models rLMA/FC was also associated with memory impairment, reduced cognitive speed and flexibility, outperforming global Aβ, pDMN Aβ, pDMN LMA, and pDMN FC, respectively. CONCLUSION: Results demonstrate increasing decoupling of LMA from its FC in AD. Data suggest that decoupling is driven by local Aβ and contributes to memory decline.

Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation. - Leoutsakos, Jeannie-Marie S; Yan, Haijuan; Anderson, William S; Asaad, Wael F; Baltuch, Gordon; Burke, Anna; Chakravarty, M Mallar; Drake, Kristen E; Foote, Kelly D; Fosdick, Lisa; Giacobbe, Peter; Mari, Zoltan; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants≥65 years. OBJECTIVE: To examine the long-term safety and clinical effects of sustained and delayed-on DBS-f treatment of mild AD after two years. METHODS: 42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial. RESULTS: DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants. CONCLUSION: DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65.

Delirium Severity Post-Surgery and its Relationship with Long-Term Cognitive Decline in a Cohort of Patients without Dementia. - Vasunilashorn, Sarinnapha M; Fong, Tamara G; Albuquerque, Asha; Marcantonio, Edward R; Schmitt, Eva M; Tommet, Douglas; Gou, Yun; Travison, Thomas G; Jones, Richard N; Inouye, Sharon K (J Alzheimers Dis, 2018)
BACKGROUND: Delirium has been associated with more rapid cognitive decline. However, it is unknown whether increased delirium severity is associated with a higher rate of long-term cognitive decline. OBJECTIVE: To evaluate delirium severity and the presence and rate of cognitive decline over 36 months following surgery. METHODS: We examined patients from the Successful Aging after Elective Surgery Study, who were age ≥70 years undergoing major elective surgery (N = 560). Delirium severity was determined by the peak Confusion Assessment Method-Severity (CAM-S) score for each patient's hospitalization and grouped based on the sample distribution: scores of 0-2, 3-7, and 8-19. A neuropsychological composite, General Cognitive Performance (GCP), and proxy-reported Informant Questionnaire for Cognitive Decline (IQCODE) were used to examine cognitive outcomes following surgery at 0, 1, and 2 months, and then every 6 months for up to 3 years. RESULTS: No significant cognitive decline was observed for patients with peak CAM-S scores 0-2 (-0.17 GCP units/year, 95% confidence interval [CI] -0.35, 0.01). GCP scores decreased significantly in the group with peak CAM-S scores 3-7 (-0.30 GCP units/year, 95% CI -0.51, -0.09), and decreased almost three times faster in the highest delirium severity group (peak CAM-S scores 8-19; -0.82 GCP units/year, 95% CI -1.28, -0.37). A similar association was found for delirium severity and the proportion of patients who developed IQCODE impairment over time. CONCLUSION: Patients with the highest delirium severity experienced the greatest rate of cognitive decline, which exceeds the rate previously observed for patients with dementia, on serial neuropsychological testing administered over 3 years, with a dose-response relationship between delirium severity and long-term cognitive decline.
Keywords: Aged; Aged, 80 and over; Cognitive Dysfunction; Cohort Studies; Delirium; Elective Surgical Procedures; Female; Humans; Male; Neuropsychological Tests; Postoperative Complications; Severity of Illness Index

Depressive Symptoms Are Associated with Cognitive Function in the Elderly with Type 2 Diabetes. - Guerrero-Berroa, Elizabeth; Ravona-Springer, Ramit; Schmeidler, James; Heymann, Anthony; Soleimani, Laili; Sano, Mary; Leroith, Derek; Preiss, Rachel; Zukran, Ruth; Silverman, Jeremy M; Beeri, Michal Schnaider (J Alzheimers Dis, 2018)
BACKGROUND: Type 2 diabetes (T2D) is a metabolic condition associated with poor clinical and cognitive outcomes including vascular disease, depressive symptoms, cognitive impairment, and dementia. In the general elderly population, depression has been consistently identified as a risk factor for cognitive impairment/decline. However, the association between depression and cognitive function in T2D has been understudied. OBJECTIVE: We investigated the association between depression and cognitive function in a large sample of cognitively normal elderly with T2D. METHODS: In this cross-sectional study, we examined 738 participants, aged 65-88 years old, enrolled in the Israel Diabetes and Cognitive Decline study. For each cognitive domain (Episodic Memory, Executive Function, Attention/Working Memory, Language/Semantic Categorization) and Overall Cognition, multiple linear regressions assessed its association with depression (score greater than 5 on the 15-item version of the Geriatric Depression Scale [GDS]), adjusting for age, sex, and education. RESULTS: Depression (n = 66, 8.9%) was associated with worse performance on tasks of Executive Function (p = 0.004), Language/Semantic Categorization (p < 0.001), and Overall Cognition (p < 0.002), but not Episodic Memory (p = 0.643) or Attention/Working Memory (p = 0.488). Secondary analyses using GDS as a continuous variable did not substantially change the results. Adjusting also for a history of antidepressant medication use slightly weakened the findings. CONCLUSION: Significant associations of depression with several cognitive domains and Overall Cognition even in cognitively normal elderly with T2D, suggest that depression may have a role in impaired cognitive function in T2D, which may be attenuated by antidepressants.

Designing an Internet-Based Multidomain Intervention for the Prevention of Cardiovascular Disease and Cognitive Impairment in Older Adults: The HATICE Trial. - Barbera, Mariagnese; Mangialasche, Francesca; Jongstra, Susan; Guillemont, Juliette; Ngandu, Tiia; Beishuizen, Cathrien; Coley, Nicola; Brayne, Carol; Andrieu, Sandrine; Richard, Edo; Soininen, Hilkka; Kivipelto, Miia (J Alzheimers Dis, 2018)
BACKGROUND: Many dementia and cardiovascular disease (CVD) cases in older adults are attributable to modifiable vascular and lifestyle-related risk factors, providing opportunities for prevention. In the Healthy Aging Through Internet Counselling in the Elderly (HATICE) randomized controlled trial, an internet-based multidomain intervention is being tested to improve the cardiovascular risk (CVR) profile of older adults. OBJECTIVE: To design a multidomain intervention to improve CVR, based on the guidelines for CVR management, and administered through a coach-supported, interactive, platform to over 2500 community-dwellers aged 65+ in three European countries. METHODS: A comparative analysis of national and European guidelines for primary and secondary CVD prevention was performed. Results were used to define the content of the intervention. RESULTS: The intervention design focused on promoting awareness and self-management of hypertension, dyslipidemia, diabetes mellitus, and overweight, and supporting smoking cessation, physical activity, and healthy diet. Overall, available guidelines lacked specific recommendations for CVR management in older adults. The comparative analysis of the guidelines showed general consistency for lifestyle-related recommendations. Key differences, identified mostly in methods used to assess the overall CVR, did not hamper the intervention design. Minor country-specific adaptations were implemented to maximize the intervention feasibility in each country. CONCLUSION: Despite differences in CVR management within the countries considered, it was possible to design and implement the HATICE multidomain intervention. The study can help define preventative strategies for dementia and CVD that are applicable internationally.
Keywords: Aged; Aged, 80 and over; Cardiovascular Diseases; Cognitive Dysfunction; Counseling; Europe; Exercise; Female; Healthy Aging; Humans; Internet; Life Style; Male; Practice Guidelines as Topic; Risk Factors; Telemedicine

Detection of Dementia Cases in Two Swedish Health Registers: A Validation Study. - Rizzuto, Debora; Feldman, Adina L; Karlsson, Ida K; Dahl Aslan, Anna K; Gatz, Margaret; Pedersen, Nancy L (J Alzheimers Dis, 2018)
BACKGROUND: Population-based health registers are potential assets in epidemiological research; however, the quality of case ascertainment is crucial. OBJECTIVE: To compare the case ascertainment of dementia, from the National Patient Register (NPR) and the Cause of Death Register (CDR) with dementia diagnoses from six Swedish population based studies. METHODS: Sensitivity, specificity, and positive predictive value (PPV) of dementia identification in NPR and CDR were estimated by individual record linkage with six Swedish population based studies (n = 19,035). Time to detection in NPR was estimated using data on dementia incidence from longitudinal studies with more than two decades of follow-up. RESULTS: Barely half of the dementia cases were ever detected by NPR or CDR. Using data from longitudinal studies we estimated that a record with a dementia diagnosis appears in the NPR on average 5.5 years after first diagnosis. Although the ability of the registers to detect dementia cases was moderate, the ability to detect non-dementia cases was almost perfect (99%). When registers indicate that there is a dementia diagnosis, there are very few instances in which the clinicians determined the person was not demented. Indeed, PPVs were close to 90%. However, misclassification between dementia subtype diagnoses is quite common, especially in NPR. CONCLUSIONS: Although the overall sensitivity is low, the specificity and the positive predictive value are very high. This suggests that hospital and death registers can be used to identify dementia cases in the community, but at the cost of missing a large proportion of the cases.
Keywords: Aged; Aged, 80 and over; Cause of Death; Dementia; Female; Humans; Incidence; Longitudinal Studies; Male; Middle Aged; Registries; Sensitivity and Specificity; Sweden; Twin Studies as Topic

Differences Between Women and Men in Incidence Rates of Dementia and Alzheimer's Disease. - Beam, Christopher R; Kaneshiro, Cody; Jang, Jung Yun; Reynolds, Chandra A; Pedersen, Nancy L; Gatz, Margaret (J Alzheimers Dis, 2018)
In the following brief report, we examined gender differences in incidence rates of any dementia, Alzheimer's disease (AD) alone, and non-Alzheimer's dementia alone in 16,926 women and men in the Swedish Twin Registry aged 65+. Dementia diagnoses were based on clinical workup and national health registry linkage. Incidence rates of any dementia and AD were greater in women than men, with any dementia rates diverging after age 85 and AD rates diverging around 80. This pattern is consistent with women's survival to older ages compared to men. These findings are similar to incidence rates reported in other Swedish samples.

Differences in Synaptic Dysfunction Between rTg4510 and APP/PS1 Mouse Models of Alzheimer's Disease. - Gelman, Simon; Palma, Jonathan; Tombaugh, Geoffrey; Ghavami, Afshin (J Alzheimers Dis, 2018)
Genetically modified mice have provided insights into the progression and pathology of Alzheimer's disease (AD). Here, we have examined two mouse models of AD: the rTg4510 mouse, which overexpresses mutant human Tau gene, and the APP/PS1 mouse, which overexpresses mutant human genes for amyloid precursor protein and presenilin 1. Both models exhibit deficits in hippocampal function, but comparative analyses of these deficits are sparse. We used extracellular field potential recordings in hippocampal slices to study basal synaptic transmission (BST), paired-pulse facilitation (PPF), and long-term potentiation (LTP) at the Schaffer collateral-CA1 pyramidal cell synapses in both models. We found that 6-7, but not 2-3-month-old rTg4510 mice exhibited reduced pre-synaptic activation (fiber volley (FV) amplitude, ∼50%) and field excitatory post-synaptic potential (fEPSP) slope (∼40%) compared to wild-type controls. In contrast to previous reports, BST, when controlled for FV amplitude, was not altered in rTg4510. APP/PS1 mice (2-3 mo and 8-10 mo) had unchanged FV amplitude compared to wild-type controls, while fEPSP slope was reduced by ∼34% in older mice, indicating a deficit in BST. PPF was unchanged in 8-10-month-old APP/PS1 mice, but was reduced in 6-7-month-old rTg4510 mice. LTP was reduced only in older rTg4510 and APP/PS1 mice. Our data suggest that BST deficits appear earlier in APP/PS1 than in rTg4510, which exhibited no BST deficits at the ages tested. However, FV and synaptic plasticity deficits developed earlier in rTg4510. These findings highlight fundamental differences in the progression of synaptic pathology in two genetically distinct models of AD.
Keywords: Age Factors; Alzheimer Disease; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Biophysics; Disease Models, Animal; Electric Stimulation; Excitatory Postsynaptic Potentials; Hippocampus; Humans; Mice; Mice, Transgenic; Mutation; Presenilin-1; Synapses; Synaptic Transmission; tau Proteins

Different Abnormalities of Cortical Neural Synchronization Mechanisms in Patients with Mild Cognitive Impairment due to Alzheimer's and Chronic Kidney Diseases: An EEG Study. - Lizio, Roberta; Babiloni, Claudio; Del Percio, Claudio; Losurdo, Antonia; Vernò, Lucia; De Tommaso, Marina; Montemurno, Anna; Dalfino, Giuseppe; Cirillo, Pietro; Soricelli, Andrea; Ferri, Raffaele; Noce, Giuseppe; et al. (J Alzheimers Dis, 2018)
This study tested whether resting state alpha rhythms (8-13 Hz) may characterize mild cognitive impairment due to Alzheimer's disease (ADMCI) compared with MCI due to chronic kidney disease (CKDMCI). Clinical and resting state eyes-closed electroencephalographic (rsEEG) rhythms from 40 ADMCI, 29 CKDMCI, and 45 cognitively normal elderly (Nold) subjects were available in a national archive. Age, gender, and education were matched in the three groups, and Mini-Mental State Evaluation (MMSE) score was paired in the ADMCI and CKDMCI groups. Delta (<4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), beta 2 (20-30 Hz), and gamma (30-40 Hz) cortical sources were estimated by eLORETA freeware and classified across individuals by area under the receiver operating characteristic curve (AUROCC). Compared with Nold group, posterior alpha 1 source activities were more reduced in ADMCI than CKDMCI group. In contrast, widespread delta source activities were greater in CKDMCI than ADMCI group. These source activities correlated with the MMSE score and correctly classified between Nold and all MCI individuals (AUROCC = 0.8-0.85) and between ADMCI and CKDMCI subjects (AUROCC = 0.75). These results suggest that early AD affects cortical neural synchronization at alpha frequencies underpinning brain arousal and low vigilance in the quiet wakefulness. In contrast, CKD may principally affect cortical neural synchronization at the delta frequencies. Future prospective cross-validation studies will have to test these candidate rsEEG markers for clinical applications and drug discovery.

Different Cognitive Frailty Models and Health- and Cognitive-related Outcomes in Older Age: From Epidemiology to Prevention. - Panza, Francesco; Lozupone, Madia; Solfrizzi, Vincenzo; Sardone, Rodolfo; Dibello, Vittorio; Di Lena, Luca; D'Urso, Francesca; Stallone, Roberta; Petruzzi, Massimo; Giannelli, Gianluigi; Quaranta, Nicola; Bellomo, Antonello; et al. (J Alzheimers Dis, 2018)
Frailty, a critical intermediate status of the aging process that is at increased risk for negative health-related events, includes physical, cognitive, and psychosocial domains or phenotypes. Cognitive frailty is a condition recently defined by operationalized criteria describing coexisting physical frailty and mild cognitive impairment (MCI), with two proposed subtypes: potentially reversible cognitive frailty (physical frailty/MCI) and reversible cognitive frailty (physical frailty/pre-MCI subjective cognitive decline). In the present article, we reviewed the framework for the definition, different models, and the current epidemiology of cognitive frailty, also describing neurobiological mechanisms, and exploring the possible prevention of the cognitive frailty progression. Several studies suggested a relevant heterogeneity with prevalence estimates ranging 1.0-22.0% (10.7-22.0% in clinical-based settings and 1.0-4.4% in population-based settings). Cross-sectional and longitudinal population-based studies showed that different cognitive frailty models may be associated with increased risk of functional disability, worsened quality of life, hospitalization, mortality, incidence of dementia, vascular dementia, and neurocognitive disorders. The operationalization of clinical constructs based on cognitive impairment related to physical causes (physical frailty, motor function decline, or other physical factors) appears to be interesting for dementia secondary prevention given the increased risk for progression to dementia of these clinical entities. Multidomain interventions have the potential to be effective in preventing cognitive frailty. In the near future, we need to establish more reliable clinical and research criteria, using different operational definitions for frailty and cognitive impairment, and useful clinical, biological, and imaging markers to implement intervention programs targeted to improve frailty, so preventing also late-life cognitive disorders.

Differential Effect of APOE ɛ4 Status and Elevated Pulse Pressure on Functional Decline in Cognitively Normal Older Adults. - Werhane, Madeleine L; Thomas, Kelsey R; Edmonds, Emily C; Bangen, Katherine J; Tran, My; Clark, Alexandra L; Nation, Daniel A; Gilbert, Paul E; Bondi, Mark W; Delano-Wood, Lisa (J Alzheimers Dis, 2018)
BACKGROUND/OBJECTIVE: The APOE ɛ4 allele and increased vascular risk have both been independently linked to cognitive impairment and dementia. Since few studies have characterized how these risk factors affect everyday functioning, we investigated the relationship between APOE ɛ4 genotype and elevated pulse pressure (PP) on functional change in cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: 738 normally aging participants underwent APOE genotyping, and baseline PP was calculated from blood pressure indices. The Functional Activities Questionnaire (FAQ) was completed by participants' informant at baseline and 6, 12, 24, 36, and 48-month follow-up visits. Multiple linear regression and multilevel modeling were used to examine the effects of PP and APOE ɛ4 genotype on cross-sectional and longitudinal FAQ scores, respectively. RESULTS: Adjusting for demographic and clinical covariates, results showed that both APOE ɛ4 status and elevated PP predicted greater functional difficulty trajectories across four years of follow-up. Interestingly, however, elevated PP was associated with greater functional decline over time in ɛ4 non-carriers versus carriers. CONCLUSION: Results show that, although APOE ɛ4 status is the prominent predictor of functional difficulty for ɛ4 carriers, an effect of arterial stiffening on functional difficulty was observed in non-carriers. Future studies are needed in order to clarify the etiology of the association between PP and different brain aging processes, and further explore its utility as a marker of dementia risk. The present study underscores the importance of targeting modifiable risk factors such as elevated PP to prevent or slow functional decline and pathological brain aging.

Differentiating between Alzheimer's Disease and Vascular Cognitive Impairment: Is the "Memory Versus Executive Function" Contrast Still Relevant? - Andriuta, Daniela; Roussel, Martine; Barbay, Mélanie; Despretz-Wannepain, Sandrine; Godefroy, Olivier (J Alzheimers Dis, 2018)
BACKGROUND: The contrast between memory versus executive function impairments is commonly used to differentiate between neurocognitive disorders (NCDs) due to Alzheimer's disease (AD) and vascular cognitive impairment (VCI). We reconsidered this question because of the current use of AD biomarkers and the recent revision of the criteria for AD, VCI, and dysexecutive syndrome. OBJECTIVE: To establish and compare the neuropsychological profiles in AD (i.e., with positive CSF biomarkers) and in VCI. METHODS: We included 62 patients with mild or major NCDs due to pure AD (with positive CSF biomarker assays), and 174 patients (from the GRECogVASC cohort) with pure VCI. The neuropsychological profiles were compared after stratification for disease severity (mild or major NCD). We defined a memory-executive function index (the mean z score for the third free recall and the delayed free recall in the Free and Cued Selective Reminding Test minus the mean z score for category fluency and the completion time in the Trail Making Test part B) and determined its diagnostic accuracy. RESULTS: Compared with VCI patients, patients with AD had significantly greater memory impairments (p = 0.001). Executive function was impaired to a similar extent in the two groups (p = 0.11). Behavioral executive disorders were more prominent in the AD group (p = 0.001). Although the two groups differed significant with regard to the memory-executive function index (p < 0.001), the latter's diagnostic accuracy was only moderate (sensitivity: 63%, specificity: 87%). CONCLUSION: Although the contrast between memory and executive function impairments was supported at the group level it does not reliably discriminate between AD and VCI at the individual level.

Distinct Cognitive and Brain Morphological Features in Healthy Subjects Unaware of Informant-Reported Cognitive Decline. - Sánchez-Benavides, Gonzalo; Grau-Rivera, Oriol; Cacciaglia, Raffaele; Suárez-Calvet, Marc; Falcon, Carles; Minguillon, Carolina; Gramunt, Nina; Sala-Vila, Aleix; Gispert, Juan Domingo; Molinuevo, José Luis (J Alzheimers Dis, 2018)
BACKGROUND: Subtle cognitive decline preceding cognitive impairment can be self-perceived, referred to as subjective cognitive decline (SCD), or go unrecognized. OBJECTIVE: To study the clinical, cognitive, and structural neuroimaging characteristics of psychometrically normal subjects without self-awareness of cognitive decline (unaware decliners, UD) and to compare them with SCD participants and controls. METHODS: 2,640 participants from the ALFA cohort, 1,899 controls, 173 UD (decline reported by the informant only), and 568 SCD underwent clinical and cognitive explorations. A subset of 530 underwent structural MRI (379 Controls; 43 UD; 108 SCD). Linear models adjusting for confounders (age, sex, education, and mood state) were used to assess group differences on cognition and voxel-wise grey matter (GM) volumes. RESULTS: 6.6% were UD while 21.5% SCD. No differences in anxiety and depression were observed between controls and UD, while SCD did (p < 0.01). UD showed lower performance in the Memory Binding Test free recall (p < 0.005) than controls, but no differences compared to SCD. Right medial frontal and insular increments of GM volumes were observed in UD with respect to controls. Informant report of decline in UD and SCD was associated with lower left hippocampal GM volume but related to memory performance only in UD (rho = 0.46, p = 0.002). CONCLUSIONS: UD had worse memory performance than controls which correlated with hippocampal GM volume and presented brain volume increments in self-appraisal areas (medial frontal and insula). Individuals unaware of cognitive decline may represent a distinct group at risk for cognitive impairment and support the usefulness of informant-reported cognitive decline.

Distinct Neuroanatomical Correlates of Neuropsychiatric Symptoms in the Three Main Forms of Genetic Frontotemporal Dementia in the GENFI Cohort. - Sellami, Leila; Bocchetta, Martina; Masellis, Mario; Cash, David M; Dick, Katrina M; van Swieten, John; Borroni, Barbara; Galimberti, Daniela; Tartaglia, Maria Carmela; Rowe, James B; Graff, Caroline; Tagliavini, Fabrizio; et al. (J Alzheimers Dis, 2018)
BACKGROUND: The overlap between frontotemporal dementia (FTD) and primary psychiatric disorders has been brought to light by reports of prominent neuropsychiatric symptoms (NPS) in FTD-related genetic mutations, particularly among C9orf72 and GRN carriers. It has been recently demonstrated that early neuroanatomical changes in genetic FTD may be different across the major disease-causing mutations. OBJECTIVE: We aimed to identify whether NPS could be driven by distinct structural correlates. METHODS: One hundred and sixty-seven mutation carriers (75 GRN, 60 C9orf72, and 32 MAPT) were included from the Genetic FTD Initiative (GENFI) study, a large international cohort of genetic FTD. Neuropsychiatric symptoms including delusions, hallucinations (visual, auditory, and tactile), depression, and anxiety were investigated using a structured interview. Voxel-based morphometry was performed to identify neuroanatomical correlates of NPS. RESULTS: Psychotic symptoms correlated mainly with grey matter (GM) atrophy in the anterior insula, left thalamus, cerebellum, and cortical regions including frontal, parietal, and occipital lobes in GRN mutations carriers. GM atrophy in posterior structures of the default-mode network was associated with anxiety in the GRN group. Delusions in C9orf72 expansion carriers were mainly associated with left frontal cortical atrophy. Cerebellar atrophy was found to be correlated only with anxiety in C9orf72 carriers. NPS in the MAPT group were mainly associated with volume loss in the temporal lobe. CONCLUSION: Neuroanatomical correlates of NPS appear to be distinct across the main forms of genetic FTD. Overall, our findings support overlapping brain structural changes between FTD and primary psychiatric disorders.

Distinct White Matter Changes Associated with Cerebrospinal Fluid Amyloid-β1-42 and Hypertension. - Al-Janabi, Omar M; Brown, Christopher A; Bahrani, Ahmed A; Abner, Erin L; Barber, Justin M; Gold, Brian T; Goldstein, Larry B; Murphy, Ronan R; Nelson, Peter T; Johnson, Nathan F; Shaw, Leslie M; Smith, Charles D; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) pathology and hypertension (HTN) are risk factors for development of white matter (WM) alterations and might be independently associated with these alterations in older adults. OBJECTIVE: To evaluate the independent and synergistic effects of HTN and AD pathology on WM alterations. METHODS: Clinical measures of cerebrovascular disease risk were collected from 62 participants in University of Kentucky Alzheimer's Disease Center studies who also had cerebrospinal fluid (CSF) sampling and MRI brain scans. CSF Aβ1-42 levels were measured as a marker of AD, and fluid-attenuated inversion recovery imaging and diffusion tensor imaging were obtained to assess WM macro- and microstructural properties. Linear regression analyses were used to assess the relationships among WM alterations, cerebrovascular disease risk, and AD pathology. Voxelwise analyses were performed to examine spatial patterns of WM alteration associated with each pathology. RESULTS: HTN and CSF Aβ1-42 levels were each associated with white matter hyperintensities (WMH). Also, CSF Aβ1-42 levels were associated with alterations in normal appearing white matter fractional anisotropy (NAWM-FA), whereas HTN was marginally associated with alterations in NAWM-FA. Linear regression analyses demonstrated significant main effects of HTN and CSF Aβ1-42 on WMH volume, but no significant HTN×CSF Aβ1-42 interaction. Furthermore, voxelwise analyses showed unique patterns of WM alteration associated with hypertension and CSF Aβ1-42. CONCLUSION: Associations of HTN and lower CSF Aβ1-42 with WM alteration were statistically and spatially distinct, suggesting independent rather than synergistic effects. Considering such spatial distributions may improve diagnostic accuracy to address each underlying pathology.

Distribution of Cerebrospinal Fluid Biomarker Profiles in Patients Explored for Cognitive Disorders. - Paquet, Claire; Bouaziz-Amar, Elodie; Cognat, Emmanuel; Volpe-Gillot, Lisette; Haddad, Victor; Mahieux, Florence; Dekimeche, Siham; Defontaines, Benedicte; Chabriat, Hugues; Belin, Catherine; Texeira, Antonio; Goutagny, Stephane; et al. (J Alzheimers Dis, 2018)
BACKGROUND: CSF Alzheimer's disease (AD) biomarkers allow classifying individuals based on their levels of amyloid and neurodegeneration pathologies. OBJECTIVE: To investigate the distribution of AD biomarker profiles from patients suffering from cognitive disorders. METHODS: We analyzed 3001 patients with cognitive disorders and referred by 18 French memory clinics located in and around Paris. Patients were classified as normal, amyloidosis (A+/N-), amyloidosis and neurodegeneration (A+/N+) or suspected non-AD pathophysiology (SNAP), according to their CSF levels of biomarkers. Analysis were performed for the overall population and stratified by gender, age quintiles, and Mini-Mental State Examination (MMSE) score quintiles. Results were compared to previous findings in cohorts of healthy elderly adults. RESULTS: 37% of the sample were classified as A+/N+, 22% were classified A+/N-, and 15% as SNAP. The A+/N+ profile was associated with female gender, advanced age, and lower MMSE score, while the A+/N-profile was observed more frequently in men and the distribution was stable across age and MMSE. The SNAP profile showed no association with gender or age, was less frequent in patients with lower MMSE, and had a lower repartition than the one previously reported in asymptomatic populations. CONCLUSIONS: While A+/N+ patients had the clinical characteristics typically observed in AD, A+/N-patients had a different epidemiological pattern (higher frequency in men, no association with advanced age or lower MMSE). The SNAP profile was less frequent than previously reported in the general elderly population, suggesting that this profile is not a frequent cause of memory impairment in this population.

The Distribution of Urinary Alzheimer-Associated Neuronal Thread Protein and Its Association with Common Chronic Diseases in the General Population. - Jin, He; Guan, Shaochen; Wang, Rong; Fang, Xianghua; Liu, Hongjun; Wu, Yanchuan; Zhang, Yanlei; Liu, Chunxiao (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer-associated neuronal thread protein (AD7c-NTP) has been found to be a biomarker for Alzheimer's disease (AD). OBJECTIVE: The aim of the present study was to investigate the distribution of Alzheimer-associated neuronal thread protein and its relationship to common chronic diseases in the general population. METHODS: Urine samples of 1,805 participants were collected from four districts (Xi Cheng, Fang Shan, Tong Zhou, and Yan Qing) in Beijing. The assessment in this study included a questionnaire that captured participants' demographic information, use of medication and histories of disease, neurological examinations, psychometric evaluations, physical and clinical examinations, and laboratory tests. RESULTS: Urine AD7c-NTP level was increased among the population over 60 years old and females exhibited higher levels than males. These results controlled for other demographic factors such as education levels, employment status, body mass index and current residence. The urine AD7c-NTP levels exhibited no association with non-neurological diseases (0.3346±0.4482 ng/ml), such as hypertension (0.3445±0.4187), stroke (0.3652±0.4010), diabetes (0.3319±0.4371), dyslipidemia (0.3440±0.4314), renal insufficiency (0.3223±0.3909), cancer (0.5055±1.0006), chronic lung disease (0.2911±0.2852), chronic liver disease (0.5579±0.6726), severe depression symptoms (0.5186±0.7040), and mild depression symptoms (0.3669±0.3811). CONCLUSIONS: Cut-off values for urine AD7c-NTP levels for different age groups and genders should be established. AD7c-NTP levels proved relatively stable in the body and were not impacted by demographic factors or common chronic diseases.

Dual Time-Point [18F]Florbetaben PET Delivers Dual Biomarker Information in Mild Cognitive Impairment and Alzheimer's Disease. - Florek, Lisa; Tiepolt, Solveig; Schroeter, Matthias L; Berrouschot, Jörg; Saur, Dorothee; Hesse, Swen; Jochimsen, Thies; Luthardt, Julia; Sattler, Bernhard; Patt, Marianne; Hoffmann, Karl-Titus; Villringer, Arno; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Current research diagnostic criteria for Alzheimer's disease (AD) and mild cognitive impairment (MCI) due to AD include biomarkers to supplement clinical testing. Recently, we demonstrated that dual time-point [18F]FBB PET is able to deliver both blood flow and amyloid-β (Aβ) load surrogates. OBJECTIVE: The aim of this study was to investigate whether these surrogates can be utilized as AD biomarkers. METHODS: 112 subjects (41 with MCI, 50 with probable/possible AD, 21 with other dementias) underwent dual time-point [18F]FBB PET. Data were visually and relative quantitatively (Herholz scores for the early and composite SUVRs for the late PET data) analyzed. RESULTS: In the early images AD-typical patterns were present in 42% /27% /33% of probable/possible AD/MCI/other dementia cases. In late [18F]FBB PET, 42% /29% /38% of probable/possible AD/ MCI/other dementia cases were Aβ-positive. 17% of the MCIs were categorized as "MCI due to AD-high likelihood", 44% of the probable ADs as "probable AD with high evidence of AD pathophysiological process" and 28% of the possible ADs as "possible AD with evidence of AD pathophysiological process". 27% of all subjects showed a positive diagnostic and progression biomarker. Herholz scores were lower (0.85±0.05 versus 0.88±0.04, p = 0.015) for probable/possible AD versus MCI. Composite late phase SUVRs were significantly higher (1.65±0.23 versus 1.15±0.17, p < 0.005) in Aβ-positive versus Aβ-negative patients. Herholz and MMSE scores were positively correlated (R = 0.30 p = 0.006). CONCLUSION: Dual time-point [18F]FBB PET provides dual biomarker information which enables to categorize MCI and AD dementia patients according to established diagnostic criteria. Thus, dual time-point [18F]FBB PET has great potential to supplement diagnostic dementia workups.