Paraoxonase 1, B Vitamins Supplementation, and Mild Cognitive Impairment. - Perła-Kaján, Joanna; Włoczkowska, Olga; Zioła-Frankowska, Anetta; Frankowski, Marcin; David Smith, A; de Jager, Celeste A; Refsum, Helga; Jakubowski, Hieronim (J Alzheimers Dis, 2021)
BACKGROUND: Identification of modifiable risk factors that affect cognitive decline is important for the development of preventive and treatment strategies. Status of paraoxonase 1 (PON1), a high-density lipoprotein-associated enzyme, may play a role in the development of neurological diseases, including Alzheimer's disease. OBJECTIVE: We tested a hypothesis that PON1 status predicts cognition in individuals with mild cognitive impairment (MCI). METHODS: Individuals with MCI (n = 196, 76.8-years-old, 60% women) participating in a randomized, double-blind placebo-controlled trial (VITACOG) were assigned to receive a daily dose of folic acid (0.8 mg), vitamin B12 (0.5 mg) and B6 (20 mg) (n = 95) or placebo (n = 101) for 2 years. Cognition was analyzed by neuropsychological tests. Brain atrophy was quantified in a subset of participants (n = 168) by MRI. PON1 status, including PON1 Q192R genotype, was determined by quantifying enzymatic activity of PON1 using paraoxon and phenyl acetate as substrates. RESULTS: In the placebo group, baseline phenylacetate hydrolase (PhAcase) activity of PON1 (but not paraoxonase activity or PON1 Q192R genotype) was significantly associated with global cognition (Mini-Mental State Examination, MMSE; Telephone Inventory for Cognitive Status-modified, TICS-m), verbal episodic memory (Hopkins Verbal Learning Test-revised: Total Recall, HVLT-TR; Delayed Recall, HVLT-DR), and attention/processing speed (Trail Making A and Symbol Digits Modalities Test, SDMT) at the end of study. In addition to PhAcase, baseline iron and triglycerides predicted MMSE, baseline fatty acids predicted SDMT, baseline anti-N-Hcy-protein autoantibodies predicted TICS-m, SDMT, Trail Making A, while BDNF V66M genotype predicted HVLT-TR and HVLT-DR scores at the end of study. B-vitamins abrogated associations of PON1 and other variables with cognition. CONCLUSION: PON1 is a new factor associated with impaired cognition that can be ameliorated by B-vitamins in individuals with MCI.

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 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.

Plasma Total-Tau and Neurofilament Light Chain as Diagnostic Biomarkers of Alzheimer's Disease Dementia and Mild Cognitive Impairment in Adults with Down Syndrome. - Petersen, Melissa E; Rafii, Michael S; Zhang, Fan; Hall, James; Julovich, David; Ances, Beau M; Schupf, Nicole; Krinsky-McHale, Sharon J; Mapstone, Mark; Silverman, Wayne; Lott, Ira; Klunk, William; et al. (J Alzheimers Dis, 2021)
BACKGROUND: The need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD); however, the application of such biomarkers has been limited among the DS population. OBJECTIVE: This study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults. METHODS: Plasma samples were analyzed from n = 305 (n = 225 cognitively stable (CS); n = 44 MCI-DS; n = 36 DS-AD) participants enrolled in the Alzheimer's Biomarker Consortium -Down Syndrome. RESULTS: In distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS. CONCLUSION: Advanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs.

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

Preventing Delirium and Promoting Long-Term Brain Health: A Clinical Trial Design for the Perioperative Cognitive Enhancement (PROTECT) Trial. - Atkins, Kelly J; Scott, David; Silbert, Brendan; Pike, Kerryn E; Evered, Lis (J Alzheimers Dis, 2021)
BACKGROUND: Perioperative neurocognitive disorders (PND), including postoperative delirium (POD), are common in older adults and, for many, precipitate functional decline and/or dementia. OBJECTIVE: In this protocol, we describe a novel multidisciplinary, multicomponent perioperative intervention that seeks to prevent or reduce POD and associated cognitive decline. METHODS: We will conduct a prospective, single-blind, pragmatic, randomized-controlled trial to compare our tailored multi-disciplinary perioperative pathway against current standard of care practices. We will recruit a total of 692 elective surgical patients aged 65 years or more and randomize them in a 1:1 design. Our perioperative intervention targets delirium risk reduction strategies by emphasizing the importance of early mobilization, nutrition, hydration, cognitive orientation, sensory aids, and avoiding polypharmacy. To promote healthy behavior change, we will provide a tailored psychoeducation program both pre- and postoperatively, focusing on cardiovascular and psychosocial risks for cognitive and functional decline. RESULTS: Our primary outcome is the incidence of any PND (encapsulating POD and mild or major postoperative neurocognitive disorder) at three months postoperative. Secondary outcomes include any incidence of POD or neurocognitive disorder at 12 months. A specialized delirium screening instrument, the Confusion Assessment Method (3D-CAM), and a neuropsychological test battery, will inform our primary and secondary outcomes. CONCLUSION: Delirium is a common and debilitating postoperative complication that contributes to the cognitive and functional decline of older adults. By adopting a multicomponent, multidisciplinary approach to perioperative delirium prevention, we seek to reduce the burden of delirium and subsequent dementia in older adults.

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.

Relation of a Socioeconomic Index with Cognitive Function and Neuroimaging in Hypertensive Individuals. - Paradela, Regina Silva; Ferreira, Naomi Vidal; Nucci, Mariana Penteado; Cabella, Brenno; Martino, Luiza Menoni; Torres, Laura Aló; Costa, Danielle Irigoyen da; Consolim-Colombo, Fernanda Marciano; Suemoto, Claudia Kimie; Irigoyen, Maria Claudia (J Alzheimers Dis, 2021)
BACKGROUND: Socioeconomic factors are important contributors to brain health. However, data from developing countries (where social inequalities are the most prominent) are still scarce, particularly about hypertensive individuals. OBJECTIVE: To evaluate the relationship between socioeconomic index, cognitive function, and cortical brain volume, as well as determine whether white matter hyperintensities are mediators of the association of the socioeconomic index with cognitive function in hypertensive individuals. METHODS: We assessed 92 hypertensive participants (mean age = 58±8.6 years, 65.2%female). Cognitive evaluation and neuroimaging were performed and clinical and sociodemographic data were collected using questionnaires. A socioeconomic index was created using education, income, occupation (manual or non-manual work), and race. The associations of the socioeconomic index with cognitive performance and brain volume were investigated using linear regression models adjusted for age, sex, time of hypertension since diagnosis, and comorbidities. A causal mediation analysis was also conducted. RESULTS: Better socioeconomic status was associated with better visuospatial ability, executive function, and global cognition. We found associations between a better socioeconomic index and a higher parietal lobe volume. White matter hyperintensities were also not mediators in the relationship between the socioeconomic index and cognitive performance. CONCLUSION: Socioeconomic disadvantages are associated with worse cognitive performance and brain volume in individuals with hypertension.

Relationships Between Cognition and Neuropathological Tau in Alzheimer's Disease Assessed by 18F Flortaucipir PET. - Devous, Michael D; Fleisher, Adam S; Pontecorvo, Michael J; Lu, Ming; Siderowf, Andrew; Navitsky, Michael; Kennedy, Ian; Southekal, Sudeepti; Harris, Thomas S; Mintun, Mark A (J Alzheimers Dis, 2021)
BACKGROUND: Tau neurofibrillary tangle burden increases with Alzheimer's disease (AD) stage and correlates with degree of cognitive impairment. Tau PET imaging could facilitate understanding the relationship between tau pathology and cognitive impairment. OBJECTIVE: Evaluate the relationship between 18F flortaucipir uptake patterns and cognition across multiple cognitive domains. METHODS: We acquired flortaucipir PET scans in 84 amyloid-positive control, mild cognitive impairment (MCI), and AD subjects. Flortaucipir standardized uptake value ratio (SUVr) values were obtained from a neocortical volume of interest (VOI), a precuneus VOI, and VOIs defined by the correlation between flortaucipir SUVr images and domain-specific cognitive tests. Cognitive assessments included Mini-Mental State Exam (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), and a neuropsychological test battery (i.e., Wechsler Memory Scale-Revised Logical Memory (WMS-R), Trail Making Test, Boston Naming Test, Digit Symbol Substitution Test, Animal List Generation, WMS-R Digit Span, American National Adult Reading Test, Clock Drawing Test, Judgment of Line Orientation, and WMS-R Logical Memory II (Delayed Recall)) and the Functional Activities Questionnaire (FAQ). Correlation analyses compared regional and voxel-wise VOIs to cognitive scores. RESULTS: Subjects included 5 controls, 47 MCI, and 32 AD subjects. Significant correlations were seen between both flortaucipir and florbetapir SUVrs and MMSE, ADAS-Cog, and FAQ. Cognitive impairment was associated with increased flortaucipir uptake in regionally specific patterns consistent with the neuroanatomy underlying specific cognitive tests. CONCLUSION: Flortaucipir SUVr values demonstrated significant inverse correlations with cognitive scores in domain-specific patterns. Findings support the hypothesis that PET imaging of neuropathologic tau deposits may reflect underlying neurodegeneration in AD.

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.

Reliability of Telephone and Videoconference Methods of Cognitive Assessment in Older Adults with and without Dementia. - Hunter, Matthew B; Jenkins, Natalie; Dolan, Clare; Pullen, Hannah; Ritchie, Craig; Muniz-Terrera, Graciela (J Alzheimers Dis, 2021)
BACKGROUND: Telephone and videoconference administration of cognitive tests introduce additional sources of variance compared to in-person testing. Reviews of test-retest reliability have included mixed neurocognitive and psychiatric populations with limited consideration of methodological and statistical contributions. OBJECTIVE: We reviewed reliability estimates from comparison studies of older adults with and without dementia, considering test-retest analyses and study methods. METHODS: Medline, Embase, PsycINFO, and Web of Science were systematically searched from 1 January 2000 to 9 June 2020 for original articles comparing telephone or videoconference administered cognitive instruments to in-person administration in older adults with and without dementia or mild cognitive impairment. RESULTS: Of 4,125 articles, 23 were included: 11 telephone (N = 2 dementia cohorts) and 12 videoconference (N = 4 dementia cohorts). Telephone administered subtest scores trended in the same direction as in-person with comparable means. Person-level data were scarce. Data on dementia was only available for MMSE, with resulting subtle modality bias. MMSE, SMMSE, Letter Fluency, and HVLT-R in healthy to mild-moderate Alzheimer's disease were particularly reliable for videoconference administration. Other tests show promise but require more observations and comprehensive analyses. Most studies used high-speed stable videoconferencing hardware resulting in a lack of ecological validity for home administration. CONCLUSION: Remote administration is often consistent with in-person administration but variable and limited at the person/test level. Improved statistical design and inclusion of dementia related cohorts in telephone studies is recommended. Reliability evidence is stronger for videoconferencing but with limited applicability to home administration and severe dementia. Improved reporting of administrative procedures is recommended.
Keywords: Aged; Aged, 80 and over; Cognition; Cognitive Dysfunction; Dementia; Geriatric Assessment; Humans; Neuropsychological Tests; Remote Consultation; Reproducibility of Results; Telephone; Videoconferencing

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.

Selective Impairment of Long-Range Default Mode Network Functional Connectivity as a Biomarker for Preclinical Alzheimer's Disease in People with Down Syndrome. - DiProspero, Natalie D; Keator, David B; Phelan, Michael; van Erp, Theo G M; Doran, Eric; Powell, David K; Van Pelt, Kathryn L; Schmitt, Frederick A; Head, Elizabeth; Lott, Ira T; Yassa, Michael A (J Alzheimers Dis, 2021)
BACKGROUND: Down syndrome (DS) is associated with increased risk for Alzheimer's disease (AD). In neurotypical individuals, clinical AD is preceded by reduced resting state functional connectivity in the default mode network (DMN), but it is unknown whether changes in DMN connectivity predict clinical onset of AD in DS. OBJECTIVE: Does lower DMN functional connectivity predict clinical onset of AD and cognitive decline in people with DS? METHODS: Resting state functional MRI (rsfMRI), longitudinal neuropsychological, and clinical assessment data were collected on 15 nondemented people with DS (mean age = 51.66 years, SD = 5.34 years, range = 42-59 years) over four years, during which 4 transitioned to dementia. Amyloid-β (Aβ) PET data were acquired on 13 of the 15 participants. Resting state fMRI, neuropsychological, and clinical assessment data were also acquired on an independent, slightly younger unimpaired sample of 14 nondemented people with DS (mean age = 44.63 years, SD = 7.99 years, range = 38-61 years). RESULTS: Lower functional connectivity between long-range but not short-range DMN regions predicts AD diagnosis and cognitive decline in people with DS. Aβ accumulation in the inferior parietal cortex is associated with lower regional DMN functional connectivity. CONCLUSION: Reduction of long-range DMN connectivity is a potential biomarker for AD in people with DS that precedes and predicts clinical conversion.

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.

Sustained Hippocampal Neural Plasticity Questions the Reproducibility of an Amyloid-β-Induced Alzheimer's Disease Model. - Paulo, Sara L; Ribeiro-Rodrigues, Leonor; Rodrigues, Rui S; Mateus, Joana M; Fonseca-Gomes, João; Soares, Rita; Diógenes, Maria J; Solá, Susana; Sebastião, Ana M; Ribeiro, Filipa F; Xapelli, Sara (J Alzheimers Dis, 2021)
BACKGROUND: The use of Alzheimer's disease (AD) models obtained by intracerebral infusion of amyloid-β (Aβ) has been increasingly reported in recent years. Nonetheless, these models may present important challenges. OBJECTIVE: We have focused on canonical mechanisms of hippocampal-related neural plasticity to characterize a rat model obtained by an intracerebroventricular (icv) injection of soluble amyloid-β42 (Aβ42). METHODS: Animal behavior was evaluated in the elevated plus maze, Y-Maze spontaneous or forced alternation, Morris water maze, and open field, starting 2 weeks post-Aβ42 infusion. Hippocampal neurogenesis was assessed 3 weeks after Aβ42 injection. Aβ deposition, tropomyosin receptor kinase B levels, and neuroinflammation were appraised at 3 and 14 days post-Aβ42 administration. RESULTS: We found that immature neuronal dendritic morphology was abnormally enhanced, but proliferation and neuronal differentiation in the dentate gyrus was conserved one month after Aβ42 injection. Surprisingly, animal behavior did not reveal changes in cognitive performance nor in locomotor and anxious-related activity. Brain-derived neurotrophic factor related-signaling was also unchanged at 3 and 14 days post-Aβ icv injection. Likewise, astrocytic and microglial markers of neuroinflammation in the hippocampus were unaltered in these time points. CONCLUSION: Taken together, our data emphasize a high variability and lack of behavioral reproducibility associated with these Aβ injection-based models, as well as the need for its further optimization, aiming at addressing the gap between preclinical AD models and the human disorder.

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.

TAR DNA-Binding Protein 43 Is Associated with Rate of Memory and Functional and Global Cognitive Decline in the Decade Prior to Death. - Buciuc, Marina; Tosakulwong, Nirubol; Machulda, Mary M; Whitwell, Jennifer L; Weigand, Stephen D; Murray, Melissa E; Ross Reichard, R; Parisi, Joseph E; Dickson, Dennis W; Boeve, Bradley F; Knopman, David S; Petersen, Ronald C; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with memory impairment and overall cognitive decline. It is unclear how TDP-43 contributes to the rate of clinical decline. OBJECTIVE: To determine whether cross-sectional and longitudinal cognitive and functional decline are associated with anatomical distribution of TDP-43 in the brain. METHODS: Longitudinal clinical-neuropathologic autopsy cohort study of 385 initially cognitively normal/mildly impaired older adults prospectively followed until death. We investigated how TDP-43, amyloid-β (Aβ), tau neurofibrillary tangles (NFT), Lewy body disease (LBD), age, sex, and genetics are associated with clinical scores and rates of their longitudinal decline. RESULTS: Of 385 participants, 260 (68%) had no TDP-43, 32 (8%) TDP-43 limited to amygdala, and 93 (24%) TDP-43 in the hippocampus and beyond. Higher TDP-43 and Braak NFT stages independently were associated with faster decline in global cognition, functional performance measured by Clinical Dementia Rating scale, and naming and episodic memory, whereas older age was associated with slower rate of cognitive, psychiatric, and functional decline. Cross-sectionally the following associations were found: higher TDP-43 and Braak NFT - worse performance; higher Aβ burden - worse global cognition, more behavioral changes, the latter also with higher LBD; older age - worse naming, lower frequency of behavioral changes; female sex - more impaired naming and better preserved episodic memory. There were no genetic associations. CONCLUSION: The association of TDP-43 distribution with decline in cognitive and functional performance suggests that TDP-43 is playing a role in the clinical progression to dementia. Further characterization of clinical features associated with TDP-43 can facilitate establishment of antemortem diagnosis.

Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus. - Lukkarinen, Heikki; Tesseur, Ina; Pemberton, Darrel; van der Ark, Peter; Timmers, Maarten; Slemmon, Randy; Janssens, Luc; Streffer, Johannes; Van Nueten, Luc; Bottelbergs, Astrid; Rauramaa, Tuomas; Koivisto, Anne M; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant. OBJECTIVE: To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared. METHODS: L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs. RESULTS: All biomarkers but Aβ42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p <  0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ4. CONCLUSION: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.

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

Urban Air Pollution Nanoparticles from Los Angeles: Recently Decreased Neurotoxicity. - Zhang, Hongqiao; D'Agostino, Carla; Forman, Henry Jay; Cacciottolo, Mafalda; Thorwald, Max; Mack, William J; Liu, Qinghai; Shkirkova, Kristina; Lamorie-Foote, Krista; Sioutas, Constantinos; Pirhadi, Milad; Mack, Wendy Jean; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Air pollution is widely associated with accelerated cognitive decline at later ages and risk of Alzheimer's disease (AD). Correspondingly, rodent models demonstrate the neurotoxicity of ambient air pollution and its components. Our studies with nano-sized particulate matter (nPM) from urban Los Angeles collected since 2009 have shown pro-amyloidogenic and pro-inflammatory responses. However, recent batches of nPM have diminished induction of the glutamate receptor GluA1 subunit, Iba1, TNFα, Aβ42 peptide, and white matter damage. The same methods, materials, and mouse genotypes were used throughout. OBJECTIVE: Expand the nPM batch comparisons and evaluate archived brain samples to identify the earliest change in nPM potency. METHODS: Batches of nPM were analyzed by in vitro cell assays for NF-κB and Nrf2 induction for comparison with in vivo responses of mouse brain regions from mice exposed to these batches, analyzed by PCR and western blot. RESULTS: Five older nPM batches (2009-2017) and four recent nPM batches (2018, 2019) for NF-κB and Nrf2 induction showed declines in nPM potency after 2017 that paralleled declines of in vivo activity from independent exposures in different years. CONCLUSION: Transcription-based in vitro assays of nPM corresponded to the loss of in vivo potency for inflammatory and oxidative responses. These recent decreases of nPM neurotoxicity give a rationale for evaluating possible benefits to the risk of dementia and stroke in Los Angeles populations.

Visual Memory Deficits in Middle-Aged APOEɛ4 Homozygotes Detected Using Unsupervised Cognitive Assessments. - Lim, Yen Ying; Pase, Matthew P; Buckley, Rachel F; Yassi, Nawaf; Bransby, Lisa; Fowler, Christopher; Laws, Simon M; Masters, Colin L; Maruff, Paul (J Alzheimers Dis, 2021)
BACKGROUND: The apolipoprotein E (APOE) ɛ4 allele is associated with dose-response effects on cognitive dysfunction and dementia risk in older adults. However, its effects on cognition in middle-aged adults remains unclear. OBJECTIVE: We examined effects of ɛ4 heterozygosity and homozygosity on objective and subjective cognition in middle-aged adults enrolled in the Healthy Brain Project (HBP) and in older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. METHODS: HBP participants (1,000 non-carriers; 450 ɛ4 heterozygotes; 50 ɛ4 homozygotes) completed unsupervised assessments of the Cogstate Brief Battery (CBB), ratings of subjective cognitive function and provided a saliva sample. AIBL cognitively normal participants (650 non-carriers; 204 ɛ4 heterozygotes; 31 ɛ4 homozygotes) completed in-person assessments of the CBB, ratings of subjective cognitive function and provided a blood sample. RESULTS: Greater memory impairment was observed in middle-aged ɛ4 homozygotes compared with ɛ4 heterozygotes and non-carriers. When data from middle-aged (HBP) and older (AIBL) adults were pooled, the effect of ɛ4 homozygosity and memory impairment increased with age. In both middle-aged and older adults, ɛ4 heterozygotes did not differ from non-carriers on any measure of objective or subjective cognition. CONCLUSION: Memory impairment in ɛ4 homozygotes is evident in adults aged 50-60 years, and this can be detected through unsupervised cognitive assessments. The effect of ɛ4 homozygosity increases with older age. APOEɛ4 homozygosity has a negative impact on memory as early as midlife, but due to the subtle magnitude of effect, our findings support the necessity of online platforms in large cohorts to assess these complex relationships.

Vitamin D Levels, APOE Allele, and MRI Volumetry Assessed by NeuroQuant in Norwegian Adults with Cognitive Symptoms. - Soares, Jelena Z; Pettersen, Renate; Benth, Jūratė Š; Persson, Karin; Strobel, Carsten; Selbæk, Geir; Bogdanovic, Nenad (J Alzheimers Dis, 2021)
BACKGROUND: Allele ɛ4 of the apolipoprotein (APOE∈4) gene is the strongest known genetic risk factor for late-onset sporadic Alzheimer's disease. A possible relationship between vitamin D and APOE is not yet clear. OBJECTIVE: In this exploratory, cross-sectional study, we examined the association between serum levels of 25-hydroxyvitamin D [25(OH)D] and brain volumes and the associations of both serum levels of 25(OH)D and APOE polymorphism to brain volumes in 127 persons (mean age 66 years) with cognitive symptoms. METHODS: All subjects were examined with fully automated software for MRI volumetry, NeuroQuant. RESULTS: After adjustment for relevant covariates, higher serum 25(OH)D levels were associated with greater volumes of cortical gray matter on both left (p = 0.02) and right (p = 0.04) sides. When both 25(OH)D levels and APOE genotype were used as the main covariates, no significant associations were found between vitamin D level and brain volume in any of the 11 brain regions. In adjusted models, only homozygous but not heterozygous APOE∈4 allele carriers had significantly larger inferior lateral ventricles (p = 0.003) and smaller hippocampal volume (p = 0.035) than those without ɛ4. Homozygous APOE∈4 carriers also had significantly higher vitamin D levels (p = 0.009) compared to persons without the APOE∈4 allele. CONCLUSION: Higher vitamin D levels might have a preserving effect on cortical grey matter volume.

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.

Alzheimer's/Vascular Spectrum Dementia: Classification in Addition to Diagnosis. - Emrani, Sheina; Lamar, Melissa; Price, Catherine C; Wasserman, Victor; Matusz, Emily; Au, Rhoda; Swenson, Rodney; Nagele, Robert; Heilman, Kenneth M; Libon, David J (J Alzheimers Dis, 2020)
Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common types of dementia. Although the combination of these disorders, called 'mixed' dementia, is recognized, the prevailing clinical and research perspective continues to consider AD and VaD as independent disorders. A review of recent neuropathological and neuropsychological literature reveals that these two disorders frequently co-occur and so-called 'pure' AD or VaD is comparatively rare. In addition, recent research shows that vascular dysfunction not only potentiates AD pathology, but that pathological changes in AD may subsequently induce vascular disorders. On the basis of these data, we propose that the neurobiological underpinnings underlying AD/VaD dementia and their neuropsychological phenotypes are best understood as existing along a clinical/pathological continuum or spectrum. We further propose that in conjunction with current diagnostic criteria, statistical modeling techniques using neuropsychological test performance should be leveraged to construct a system to classify AD/VaD spectrum dementia in order to test hypotheses regarding how mechanisms related to AD and VaD pathology interact and influence each other.

APOE4 Status is Related to Differences in Memory-Related Brain Function in Asymptomatic Older Adults with Family History of Alzheimer's Disease: Baseline Analysis of the PREVENT-AD Task Functional MRI Dataset. - Rabipour, Sheida; Rajagopal, Sricharana; Yu, Elsa; Pasvanis, Stamatoula; Lafaille-Magnan, Marie-Elyse; Breitner, John; Rajah, M Natasha (J Alzheimers Dis, 2020)
BACKGROUND: Episodic memory decline is one of the earliest symptoms of late-onset Alzheimer's disease (AD). Older adults with the apolipoprotein E ɛ4 (+APOE4) genetic risk factor for AD may exhibit altered patterns of memory-related brain activity years prior to initial symptom onset. OBJECTIVE: Here we report the baseline episodic memory task functional MRI results from the PRe-symptomatic EValuation of Experimental or Novel Treatments for Alzheimer's Disease cohort in Montreal, Canada, in which 327 healthy older adults were scanned within 15 years of their parent's conversion to AD. METHODS: Volunteers were scanned as they encoded and retrieved object-location spatial source associations. The task was designed to discriminate between brain activity related to spatial source recollection and object-only (recognition) memory. We used multivariate partial least squares (PLS) to test the hypothesis that +APOE4 adults with family history of AD would exhibit altered patterns of brain activity in the recollection-related memory network, comprised of medial frontal, parietal, and medial temporal cortices, compared to APOE4 non-carriers (-APOE4). We also examined group differences in the correlation between event-related brain activity and memory performance. RESULTS: We found group similarities in memory performance and in task-related brain activity in the recollection network, but differences in brain activity-behavior correlations in ventral occipito-temporal, medial temporal, and medial prefrontal cortices during episodic encoding. CONCLUSION: These findings are consistent with previous literature on the influence of APOE4 on brain activity and provide new perspective on potential gene-based differences in brain-behavior relationships in people with first-degree family history of AD.

APOEɛ4-TOMM40L Haplotype Increases the Risk of Mild Cognitive Impairment Conversion to Alzheimer's Disease. - Cardoso, Remy; Lemos, Carolina; Oliveiros, Bárbara; Rosário Almeida, Maria; Baldeiras, Ines; Fragão Pereira, Cláudia; Santos, Ana; Duro, Diana; Vieira, Daniela; Santana, Isabel; Resende Oliveira, Catarina (J Alzheimers Dis, 2020)
BACKGROUND: Mild cognitive impairment (MCI) has been considered as a pre-dementia stage, although the factors leading to Alzheimer's disease (AD) conversion remain controversial. OBJECTIVE: Evaluate whether TOMM40 poly-T (TOMM40' 523) polymorphism is associated with the risk and conversion time from MCI to AD and secondly with AD cerebrospinal fluid (CSF) biomarkers, disentangling the APOE genotype. METHODS: 147 AD patients, 102 MCI patients, and 105 cognitively normal controls were genotyped for poly-T polymorphism. MCI patients were subdivided into two groups, the group of patients that converted to AD (MCI-AD) and the group of those that remained stable (MCI-S). RESULTS: TOMM40' 523 L allele was significantly more frequent in the MCI-AD group and having at least one L allele significantly increased the risk of conversion from MCI to AD (OR = 8.346, p <  0.001, 95% CI: 2.830 to 24.617). However, when adjusted for the presence of APOEɛ4 allele, both the L allele and ɛ4 allele lost significance in the model (p >  0.05). We then analyzed the APOEɛ4-TOMM40' 523 haplotype and observed that patients carrying this haplotype had significantly higher risk (OR = 5.83; 95% CI = 2.30-14.83) and mean lower times of conversion to AD (p = 0.003). This haplotype was also significantly associated with a biomarker profile compatible with AD (p = 0.007). CONCLUSION: This study shows that the APOEɛ4-TOMM40' 523 haplotype is associated with a higher risk and shorter times of conversion from MCI to AD, possibly driven by CSF biomarkers and mitochondrial dysfunction.

Association of Peripheral Insulin Resistance and Other Markers of Type 2 Diabetes Mellitus with Brain Amyloid Deposition in Healthy Individuals at Risk of Dementia. - Pekkala, Timo; Hall, Anette; Mangialasche, Francesca; Kemppainen, Nina; Mecocci, Patrizia; Ngandu, Tiia; Rinne, Juha O; Soininen, Hilkka; Tuomilehto, Jaakko; Kivipelto, Miia; Solomon, Alina (J Alzheimers Dis, 2020)
We explored the association of type 2 diabetes related blood markers with brain amyloid accumulation on PiB-PET scans in 41 participants from the FINGER PET sub-study. We built logistic regression models for brain amyloid status with12 plasma markers of glucose and lipid metabolism, controlled for diabetes and APOEɛ4 carrier status. Lower levels of insulin, insulin resistance index (HOMA-IR), C-peptide, and plasminogen activator (PAI-1) were associated with amyloid positive status, although the results were not significant after adjusting for multiple testing. None of the models found evidence for associations between amyloid status and fasting glucose or HbA1c.

Braak Stage, Cerebral Amyloid Angiopathy, and Cognitive Decline in Early Alzheimer's Disease. - Malek-Ahmadi, Michael; Perez, Sylvia E; Chen, Kewei; Mufson, Elliott J (J Alzheimers Dis, 2020)
The aim of this study was to determine the interaction between cerebral amyloid angiopathy (CAA) and Braak staging on cognition in the elderly. 141 [72 non-cognitively impaired (NCI), 33 mild cognitive impairment (MCI), 36 Alzheimer's disease (AD)] cases consisting of Braak stages 0-II and III from the Rush Religious Order Study cohort were used. The association between Braak stage and CAA status and cognition was evaluated using a series of regression models that adjusted for age at death, sex, education, APOEɛ4 status, and Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropathological diagnosis. Individuals with CAA were more likely to be classified as Braak stage III relative to those without CAA [OR = 2.33, 95% CI (1.06, 5.14), p = 0.04]. A significant interaction was found between Braak stage and CAA status on a global cognitive score (β= -0.58, SE = 0.25, p = 0.02). Episodic memory also showed a significant association between Braak stage and CAA (β= -0.75, SE = 0.35, p = 0.03). These data suggest that there is a significant interaction between tau pathology and cerebrovascular lesions on cognition within the AD clinical spectrum. These findings show that CAA plays a key role in the early stages of tau pathology and cognitive decline in AD.

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.

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

Combining Select Blood-Based Biomarkers with Neuropsychological Assessment to Detect Mild Cognitive Impairment among Mexican Americans. - Petersen, Melissa; Hall, James; Parsons, Thomas; Johnson, Leigh; O'Bryant, Sid (J Alzheimers Dis, 2020)
BACKGROUND: Recent work has supported use of blood-based biomarkers in detection of amnestic mild cognitive impairment (MCI). Inclusion of neuropsychological measures has shown promise in enhancing utility of biomarkers to detect disease. OBJECTIVE: The present study sought to develop cognitive-biomarker profiles for detection of MCI. METHODS: Data were analyzed on 463 participants (normal control n = 378; MCI n = 85) from HABLE. Random forest analyses determined proteomic profile of MCI. Separate linear regression analyses determined variance accounted for by select biomarkers per neuropsychological measure. When neuropsychological measure with the least shared variance was identified, it was then combined with select biomarkers to create a biomarker-cognitive profile. RESULTS: The biomarker-cognitive profile was 90% accurate in detecting MCI. Among amnestic MCI cases, the detection accuracy of the biomarker-cognitive profile was 92% and increased to 94% with demographic variables. CONCLUSION: The biomarker-cognitive profile for MCI was highly accurate in its detection with use of only five biomarkers.

Computational Modeling of Catecholamines Dysfunction in Alzheimer's Disease at Pre-Plaque Stage. - Caligiore, Daniele; Silvetti, Massimo; D'Amelio, Marcello; Puglisi-Allegra, Stefano; Baldassarre, Gianluca (J Alzheimers Dis, 2020)
BACKGROUND: Alzheimer's disease (AD) etiopathogenesis remains partially unexplained. The main conceptual framework used to study AD is the Amyloid Cascade Hypothesis, although the failure of recent clinical experimentation seems to reduce its potential in AD research. OBJECTIVE: A possible explanation for the failure of clinical trials is that they are set too late in AD progression. Recent studies suggest that the ventral tegmental area (VTA) degeneration could be one of the first events occurring in AD progression (pre-plaque stage). METHODS: Here we investigate this hypothesis through a computational model and computer simulations validated with behavioral and neural data from patients. RESULTS: We show that VTA degeneration might lead to system-level adjustments of catecholamine release, triggering a sequence of events leading to relevant clinical and pathological signs of AD. These changes consist first in a midfrontal-driven compensatory hyperactivation of both VTA and locus coeruleus (norepinephrine) followed, with the progression of the VTA impairment, by a downregulation of catecholamine release. These processes could then trigger the neural degeneration at the cortical and hippocampal levels, due to the chronic loss of the neuroprotective role of norepinephrine. CONCLUSION: Our novel hypothesis might contribute to the formulation of a wider system-level view of AD which might help to devise early diagnostic and therapeutic interventions.

The Contribution of Vascular Pathology Toward Cognitive Impairment in Older Individuals with Intermediate Braak Stage Tau Pathology. - Robinson, Andrew C; Roncaroli, Federico; Chew-Graham, Stephen; Davidson, Yvonne S; Minshull, James; Horan, Michael A; Payton, Antony; Pendleton, Neil; Mann, David M A (J Alzheimers Dis, 2020)
BACKGROUND: The pathological features of Alzheimer's disease (AD) are well described but little is known as to how both neurodegeneration and vascular changes might interact in causing cognitive impairment. OBJECTIVE: The present study aims to investigate relationships between vascular and AD pathology in cognitively healthy and cognitively impaired individuals with a particular emphasis on those at intermediate Braak tau stages. METHODS: We investigated the interplay between Braak tau stage and measures of vascular pathology as described by the vascular cognitive impairment neuropathology guidelines (VCING) in 185 brains from the Brains for Dementia Research programme and The University of Manchester Longitudinal Study of Cognition in Healthy Old Age. VCING asserts that at least one large (>10 mm) infarct, moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, and moderate/severe arteriosclerosis in occipital white matter accurately predicts the contribution of cerebrovascular pathology to cognitive impairment. RESULTS: We found that the extent of arteriosclerosis in the occipital white matter did not differ between cognitive groups at intermediate (III-IV) Braak stages whereas moderate/severe leptomeningeal occipital cerebral amyloid angiopathy was greater in cognitively impaired than normal individuals at Braak stage III-IV. This finding remained significant after controlling for effects of age, sex, CERAD score, Thal phase, presence/severity of primary age-related tauopathy, presence/severity of limbic-predominant age-related TDP43 encephalopathy and small vessel disease in basal ganglia. CONCLUSION: Interventions targeting cerebral amyloid angiopathy may contribute to delay the onset of cognitive impairment in individuals with intermediate Alzheimer's type pathology.

Death Rate Due to COVID-19 in Alzheimer's Disease and Frontotemporal Dementia. - Matías-Guiu, Jordi A; Pytel, Vanesa; Matías-Guiu, Jorge (J Alzheimers Dis, 2020)
We aimed to evaluate the frequency and mortality of COVID-19 in patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD). We conducted an observational case series. We enrolled 204 patients, 15.2% of whom were diagnosed with COVID-19, and 41.9% of patients with the infection died. Patients with AD were older than patients with FTD (80.36±8.77 versus 72.00±8.35 years old) and had a higher prevalence of arterial hypertension (55.8% versus 26.3%). COVID-19 occurred in 7.3% of patients living at home, but 72.0% of those living at care homes. Living in care facilities and diagnosis of AD were independently associated with a higher probability of death. We found that living in care homes is the most relevant factor for an increased risk of COVID-19 infection and death, with AD patients exhibiting a higher risk than those with FTD.
Keywords: Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Coronavirus Infections; COVID-19; Female; Frontotemporal Dementia; Humans; Hypertension; Independent Living; Male; Nursing Homes; Pandemics; Pneumonia, Viral; Prevalence; Risk Factors

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.

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

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.

Examining Cognitive Decline Across Black and White Participants in the Harvard Aging Brain Study. - Amariglio, Rebecca E; Buckley, Rachel F; Rabin, Jennifer S; Papp, Kathryn V; Quiroz, Yakeel T; Mormino, Elizabeth C; Sparks, Kathryn P; Johnson, Keith A; Rentz, Dorene M; Sperling, Reisa A (J Alzheimers Dis, 2020)
BACKGROUND: Black Americans are approximately twice as likely to develop dementia as compared to White Americans and the magnitude of this disparity is often attributed to a variety of factors that include psychosocial and vascular risk factors. However, less is known about the potential contribution of Alzheimer's disease pathological differences. OBJECTIVE: To examine potential differences incross-sectional and longitudinal cognitive performance in black and white participants who were clinically normal at baseline. METHODS: 296 participants (48 African-American/black participants) underwent MRI and amyloid PET at baseline. Linear mixed models were used to examine the main effects of race, years of education, reading ability, Framingham Heart Study cardiovascular risk score (FHS-CVD), white matter hyperintensities (WMH), and amyloid (Aβ) burden on the Preclinical Alzheimer Cognitive Composite-5 (PACC5). RESULTS: Lower levels of educationalattainment and reading ability were found for blacks compared to whites. By contrast, no differences in FHS-CVD, WMH, or Aβ were found by racial group. Baseline differences in PACC5 score were attenuated after adjusting for educationalfactors, vascular factors, and Aβ, but remained lower for blacks compared to whites (β= -0.24, p = 0.014). Further, blacks demonstrated a faster rate of PACC5 decline longitudinally compared to whites (β  = -0.055, p = 0.025) after adjusting for covariates. CONCLUSION: Accounting for educationalfactors, vascular factors, and Aβ burden diminished, but did not eliminate, racial differences in PACC5 performance longitudinally. Understanding potential differences in longitudinal cognitive outcomes by race may be important for upcoming secondary prevention trials.

Exploration of Plasma Lipids in Mild Cognitive Impairment due to Alzheimer's Disease. - Bergland, Anne Katrine; Proitsi, Petroula; Kirsebom, Bjørn-Eivind; Soennesyn, Hogne; Hye, Abdul; Larsen, Alf Inge; Xu, Jin; Legido-Quigley, Cristina; Rajendran, Lawrence; Fladby, Tormod; Aarsland, Dag (J Alzheimers Dis, 2020)
BACKGROUND: Lipids have important structural roles in cell membranes and changes to these membrane lipids may influence β- and γ-secretase activities and thus contribute to Alzheimer's disease (AD) pathology. OBJECTIVE: To explore baseline plasma lipid profiling in participants with mild cognitive impairment (MCI) with and without AD pathology. METHODS: We analyzed 261 plasma lipid profiles using reversed phase chromatography mass spectrometry in cerebrospinal fluid amyloid positive (Aβ+) or negative (Aβ-) participants with MCI as compared to controls. Additionally, we analyzed the potential associations of plasma lipid profiles with performance on neuropsychological tests at baseline and after two years. RESULTS: Sphingomyelin (SM) concentrations, particularly, SM(d43:2), were lower in MCI Aβ+ individuals compared to controls. Further, SM(d43:2) was also nominally reduced in MCI Aβ+ individuals compared to MCI Aβ-. No plasma lipids were associated with performance on neuropsychological tests at baseline or between the two time points after correction for multiple testing. CONCLUSION: Reduced plasma concentrations of SM were associated with AD.

Gait Disturbances are Associated with Increased Cognitive Impairment and Cerebrospinal Fluid Tau Levels in a Memory Clinic Cohort. - Muurling, Marijn; Rhodius-Meester, Hanneke F M; Pärkkä, Juha; van Gils, Mark; Frederiksen, Kristian S; Bruun, Marie; Hasselbalch, Steen G; Soininen, Hilkka; Herukka, Sanna-Kaisa; Hallikainen, Merja; Teunissen, Charlotte E; Visser, Pieter Jelle; et al. (J Alzheimers Dis, 2020)
BACKGROUND: Gait analysis with accelerometers is a relatively inexpensive and easy to use method to potentially support clinical diagnoses of Alzheimer's disease and other dementias. It is not clear, however, which gait features are most informative and how these measures relate to Alzheimer's disease pathology. OBJECTIVE: In this study, we tested if calculated features of gait 1) differ between cognitively normal subjects (CN), mild cognitive impairment (MCI) patients, and dementia patients, 2) are correlated with cerebrospinal fluid (CSF) biomarkers related to Alzheimer's disease, and 3) predict cognitive decline. METHODS: Gait was measured using tri-axial accelerometers attached to the fifth lumbar vertebra (L5) in 58 CN, 58 MCI, and 26 dementia participants, while performing a walk and dual task. Ten gait features were calculated from the vertical L5 accelerations, following principal component analysis clustered in four domains, namely pace, rhythm, time variability, and length variability. Cognitive decline over time was measured using MMSE, and CSF biomarkers were available in a sub-group. RESULTS: Linear mixed models showed that dementia patients had lower pace scores than MCI patients and CN subjects (p < 0.05). In addition, we found associations between the rhythm domain and CSF-tau, especially in the dual task. Gait was not associated with CSF Aβ42 levels and cognitive decline over time as measured with the MMSE. CONCLUSION: These findings suggest that gait-particularly measures related to pace and rhythm-are altered in dementia and have a direct link with measures of neurodegeneration.

Gene Ontology Curation of Neuroinflammation Biology Improves the Interpretation of Alzheimer's Disease Gene Expression Data. - Kramarz, Barbara; Huntley, Rachael P; Rodríguez-López, Milagros; Roncaglia, Paola; Saverimuttu, Shirin C C; Parkinson, Helen; Bandopadhyay, Rina; Martin, Maria-Jesus; Orchard, Sandra; Hooper, Nigel M; Brough, David; Lovering, Ruth C (J Alzheimers Dis, 2020)
BACKGROUND: Gene Ontology (GO) is a major bioinformatic resource used for analysis of large biomedical datasets, for example from genome-wide association studies, applied universally across biological fields, including Alzheimer's disease (AD) research. OBJECTIVE: We aim to demonstrate the applicability of GO for interpretation of AD datasets to improve the understanding of the underlying molecular disease mechanisms, including the involvement of inflammatory pathways and dysregulated microRNAs (miRs). METHODS: We have undertaken a systematic full article GO annotation approach focused on microglial proteins implicated in AD and the miRs regulating their expression. PANTHER was used for enrichment analysis of previously published AD data. Cytoscape was used for visualizing and analyzing miR-target interactions captured from published experimental evidence. RESULTS: We contributed 3,084 new annotations for 494 entities, i.e., on average six new annotations per entity. This included a total of 1,352 annotations for 40 prioritized microglial proteins implicated in AD and 66 miRs regulating their expression, yielding an average of twelve annotations per prioritized entity. The updated GO resource was then used to re-analyze previously published data. The re-analysis showed novel processes associated with AD-related genes, not identified in the original study, such as 'gliogenesis', 'regulation of neuron projection development', or 'response to cytokine', demonstrating enhanced applicability of GO for neuroscience research. CONCLUSIONS: This study highlights ongoing development of the neurobiological aspects of GO and demonstrates the value of biocuration activities in the area, thus helping to delineate the molecular bases of AD to aid the development of diagnostic tools and treatments.

The GSM BPN-15606 as a Potential Candidate for Preventative Therapy in Alzheimer's Disease. - Prikhodko, Olga; Rynearson, Kevin D; Sekhon, Travis; Mante, Mike M; Nguyen, Phuong D; Rissman, Robert A; Tanzi, Rudolph E; Wagner, Steven L (J Alzheimers Dis, 2020)
BACKGROUND: In the amyloid hypothesis of Alzheimer's disease (AD), the dysregulation of amyloid-β protein (Aβ) production and clearance leads to amyloid deposits, tau tangles, neuronal loss, and cognitive dysfunction. Thus far, therapies targeting the enzymes responsible for Aβ production have been found ineffective or having significant side effects. OBJECTIVE: To test whether a γ-secretase modulator, BPN-15606, is an effective disease-modifying or preventative treatment in the PSAPP mouse model of AD. METHODS: We treated pre-plaque (3-month-old) and post-plaque (6-month-old) PSAPP AD transgenic mice for 3 months and examined behavioral, biochemical, and pathological end points. RESULTS: BPN-15606 attenuated cognitive impairment and reduced amyloid plaque load, microgliosis, and astrogliosis associated with the AD phenotype of PSAPP mice when administered to pre-plaque (3-month-old) but was ineffective when administered to post-plaque (6-month-old) mice. No treatment-related toxicity was observed. CONCLUSION: BPN-15606 appears efficacious when administered prior to significant pathology.

Heavy Metals Exposure and Alzheimer's Disease and Related Dementias. - Bakulski, Kelly M; Seo, Young Ah; Hickman, Ruby C; Brandt, Daniel; Vadari, Harita S; Hu, Howard; Park, Sung Kyun (J Alzheimers Dis, 2020)
Alzheimer's disease and related dementias lack effective treatment or cures and are major public health challenges. Risk for Alzheimer's disease and related dementias is partially attributable to environmental factors. The heavy metals lead, cadmium, and manganese are widespread and persistent in our environments. Once persons are exposed to these metals, they are adept at entering cells and reaching the brain. Lead and cadmium are associated with numerous health outcomes even at low levels of exposure. Although manganese is an essential metal, deficiency or environmental exposure or high levels of the metal can be toxic. In cell and animal model systems, lead, cadmium, and manganese are well documented neurotoxicants that contribute to canonical Alzheimer's disease pathologies. Adult human epidemiologic studies have consistently shown lead, cadmium, and manganese are associated with impaired cognitive function and cognitive decline. No longitudinal human epidemiology study has assessed lead or manganese exposure on Alzheimer's disease specifically though two studies have reported a link between cadmium and Alzheimer's disease mortality. More longitudinal epidemiologic studies with high-quality time course exposure data and incident cases of Alzheimer's disease and related dementias are warranted to confirm and estimate the proportion of risk attributable to these exposures. Given the widespread and global exposure to lead, cadmium, and manganese, even small increases in the risks of Alzheimer's disease and related dementias would have a major population impact on the burden on disease. This article reviews the experimental and epidemiologic literature of the associations between lead, cadmium, and manganese on Alzheimer's disease and related dementias and makes recommendations of critical areas of future investment.

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.

The Impact of Amyloid-β or Tau on Cognitive Change in the Presence of Severe Cerebrovascular Disease. - Jang, Hyemin; Kim, Hee Jin; Sim Choe, Yeong; Kim, Soo-Jong; Park, Seongbeom; Kim, Yeshin; Woon Kim, Ko; Hyoung Lyoo, Chul; Cho, Hanna; Hoon Ryu, Young; Choi, Jae Yong; DeCarli, Charles; et al. (J Alzheimers Dis, 2020)
BACKGROUND: As Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) commonly coexist, the interaction between two has been of the considerable interest. OBJECTIVE: We determined whether the association of Aβ and tau with cognitive decline differs by the presence of significant CSVD. METHODS: We included 60 subcortical vascular cognitive impairment (SVCI) from Samsung Medical Center and 82 Alzheimer's disease-related cognitive impairment (ADCI) from ADNI, who underwent Aβ (florbetaben or florbetapir) and tau (flortaucipir, FTP) PET imaging. They were retrospectively assessed for 5.0±3.9 and 5.6±1.9 years with Clinical Dementia Rating-sum of boxes (CDR-SB)/Mini-Mental State Examination (MMSE). Mixed effects models were used to investigate the interaction between Aβ/tau and group on CDR-SB/MMSE changes. RESULTS: The frequency of Aβ positivity (45% versus 54.9%, p = 0.556) and mean global FTP SUVR (1.17±0.21 versus 1.16±0.17, p = 0.702) were not different between the two groups. We found a significant interaction effect of Aβ positivity and SVCI group on CDR-SB increase/MMSE decrease (p = 0.013/p <  0.001) change, and a significant interaction effect of global FTP uptake and SVCI group on CDR-SB increase/MMSE decrease (p <  0.001 and p = 0.030) change. Finally, the interaction effects of regional tau and group were prominent in the Braak III/IV (p = 0.001) and V/VI (p = 0.003) not in Braak I/II region (p = 0.398). CONCLUSION: The association between Aβ/tau and cognitive decline is stronger in SVCI than in ADCI. Therefore, our findings suggested that Aβ positivity or tau burden (particularly in the Braak III/IV or V/VI regions) and CSVD might synergistically affect cognitive decline.

Inflammation in Traumatic Brain Injury. - Postolache, Teodor T; Wadhawan, Abhishek; Can, Adem; Lowry, Christopher A; Woodbury, Margaret; Makkar, Hina; Hoisington, Andrew J; Scott, Alison J; Potocki, Eileen; Benros, Michael E; Stiller, John W (J Alzheimers Dis, 2020)
There is an increasing evidence that inflammation contributes to clinical and functional outcomes in traumatic brain injury (TBI). Many successful target-engaging, lesion-reducing, symptom-alleviating, and function-improving interventions in animal models of TBI have failed to show efficacy in clinical trials. Timing and immunological context are paramount for the direction, quality, and intensity of immune responses to TBI and the resulting neuroanatomical, clinical, and functional course. We present components of the immune system implicated in TBI, potential immune targets, and target-engaging interventions. The main objective of our article is to point toward modifiable molecular and cellular mechanisms that may modify the outcomes in TBI, and contribute to increasing the translational value of interventions that have been identified in animal models of TBI.

Metabolic Profiles Help Discriminate Mild Cognitive Impairment from Dementia Stage in Alzheimer's Disease. - Jääskeläinen, Olli; Hall, Anette; Tiainen, Mika; van Gils, Mark; Lötjönen, Jyrki; Kangas, Antti J; Helisalmi, Seppo; Pikkarainen, Maria; Hallikainen, Merja; Koivisto, Anne; Hartikainen, Päivi; Hiltunen, Mikko; et al. (J Alzheimers Dis, 2020)
Accurate differentiation between neurodegenerative diseases is developing quickly and has reached an effective level in disease recognition. However, there has been less focus on effectively distinguishing the prodromal state from later dementia stages due to a lack of suitable biomarkers. We utilized the Disease State Index (DSI) machine learning classifier to see how well quantified metabolomics data compares to clinically used cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD). The metabolic profiles were quantified for 498 serum and CSF samples using proton nuclear magnetic resonance spectroscopy. The patient cohorts in this study were dementia (with a clinical AD diagnosis) (N = 359), mild cognitive impairment (MCI) (N = 96), and control patients with subjective memory complaints (N = 43). DSI classification was conducted for MCI (N = 51) and dementia (N = 214) patients with low CSF amyloid-β levels indicating AD pathology and controls without such amyloid pathology (N = 36). We saw that the conventional CSF markers of AD were better at classifying controls from both dementia and MCI patients. However, quantified metabolic subclasses were more effective in classifying MCI from dementia. Our results show the consistent effectiveness of traditional CSF biomarkers in AD diagnostics. However, these markers are relatively ineffective in differentiating between MCI and the dementia stage, where the quantified metabolomics data provided significant benefit.

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.

A Narrative Review of Alzheimer's Disease Stigma. - Rosin, Eric R; Blasco, Drew; Pilozzi, Alexander R; Yang, Lawrence H; Huang, Xudong (J Alzheimers Dis, 2020)
As the most common form of senile dementia, Alzheimer's disease (AD) is accompanied by a great deal of uncertainty which can lead to fear and stigma for those identified with this devastating disease. As the AD definition evolves from a syndromal to a biological construct, and early diagnoses becomes more commonplace, more confusion and stigma may result. We conducted a narrative review of the literature on AD stigma to consolidate information on this body of research. From the perspective of several stigma theories, we identified relevant studies to inform our understanding of the way in which implementation of the new framework for a biological based AD diagnosis may have resulted in new and emerging stigma. Herein, we discuss the emergence of new AD stigma as our understanding of the definition of the disease changes. We further propose recommendations for future research to reduce the stigma associated with AD.

Neuroimaging in Vascular Cognitive Impairment and Dementia: A Systematic Review. - Frantellizzi, Viviana; Pani, Arianna; Ricci, Maria; Locuratolo, Nicoletta; Fattapposta, Francesco; De Vincentis, Giuseppe (J Alzheimers Dis, 2020)
Cerebrovascular diseases are well established causes of cognitive impairment. Different etiologic entities, such as vascular dementia (VaD), vascular cognitive impairment, subcortical (ischemic) VaD, and vascular cognitive disorder, are included in the umbrella definition of vascular cognitive impairment and dementia (VCID). Because of the variability of VCID clinical presentation, there is no agreement on criteria defining the neuropathological threshold of this disorder. In fact, VCID is characterized by cerebral hemodynamic alteration which ranges from decreased cerebral blood flow to small vessels disease and involves a multifactorial process that leads to demyelination and gliosis, including blood-brain barrier disruption, hypoxia, and hypoperfusion, oxidative stress, neuroinflammation and alteration on neurovascular unit coupling, cerebral microbleeds, or superficial siderosis. Numerous criteria for the definition of VaD have been described: the National Institute of Neurological Disorders and Stroke Association Internationale pour Recherche'-et-l'Enseignement en Neurosciences criteria, the State of California Alzheimer's Disease Diagnostic and Treatment Centers criteria, DSM-V criteria, the Diagnostic Criteria for Vascular Cognitive Disorders (a VASCOG Statement), and Vascular Impairment of Cognition Classification Consensus Study. Neuroimaging is fundamental for definition and diagnosis of VCID and should be used to assess the extent, location, and type of vascular lesions. MRI is the most sensible technique, especially if used according to standardized protocols, even if CT plays an important role in several conditions. Functional neuroimaging, in particular functional MRI and PET, may facilitate differential diagnosis among different forms of dementia. This systematic review aims to explore the state of the art and future perspective of non-invasive diagnostics of VCID.

New BACE1 Chimeric Peptide Inhibitors Selectively Prevent AβPPβ Cleavage Decreasing Amyloid-β Production and Accumulation in Alzheimer's Disease Models. - Resende, Rosa; Ferreira-Marques, Marisa; Moreira, Patrícia; Coimbra, Judite R M; Baptista, Salete J; Isidoro, Ciro; Salvador, Jorge A R; Dinis, Teresa C P; Pereira, Cláudia F; Santos, Armanda E (J Alzheimers Dis, 2020)
BACKGROUND: A disease-modifying therapy for Alzheimer's disease (AD) is still an unmet clinical need. The formation of amyloid-β (Aβ) requires the initial cleavage of the amyloid-β protein precursor (AβPP) by BACE1 (beta-site AβPP cleaving enzyme 1), which is a prime therapeutic target for AD. OBJECTIVE: We aimed to design and develop a selective BACE1 inhibitor suitable to AD treatment. METHODS: The new BACE1 inhibitors consist on a chimeric peptide including a sequence related to the human Swedish mutant form of AβPP (AβPPswe) conjugated with the TAT carrier that facilitates cell membrane permeation and the crossing of the blood-brain barrier. Additionally to the chimeric peptide in the L-form, we developed a D-retro in verso chimeric peptide. The latter strategy, never used with BACE1 inhibitors, is considered to favor a significantly higher half-life and lower immunogenicity. RESULTS: We found that both chimeric peptides inhibit recombinant BACE1 activity and decrease Aβ40/42 production in Neuro-2a (N2A) cells expressing AβPPswe without inducing cytotoxicity. The intraperitoneal administration of these peptides to 3xTg-AD mice decreased plasma and brain Aβ40/42 levels, as well as brain soluble AβPPβ production. Also, a reduction of insoluble Aβ was observed in the brain after chronic treatment. Noteworthy, the chimeric peptides selectively inhibited the AβPPβ cleavage relatively to the proteolysis of other BACE1 substrates such as close homologue of L1 (CHL1) and seizure-related gene 6 (SEZ6). CONCLUSIONS: Overall these new BACE1 chimeric peptideshold promising potential as a selective disease-modifying therapy for AD.

Normal Pressure Hydrocephalus in Down Syndrome: The Report of Two Cases. - Marano, Massimo; Pompucci, Angelo; Motolese, Francesco; Rossi, Mariagrazia; Coletta, Ernesto; Di Lazzaro, Vincenzo; Fasano, Alfonso; Petrella, Gianpaolo (J Alzheimers Dis, 2020)
Down syndrome (DS) is the most common cause of intellectual disability in infants and has a well-known relationship with the Alzheimer's disease. The association between DS and the other pathologies of senescence, such as normal pressure hydrocephalus (NPH), has been poorly investigated. This series included two DS patients with NPH. In both cases, NPH symptoms were initially misdiagnosed as DS associated senescence. Patients were treated with ventricular-peritoneal shunt, showing a sustained improvement (1 and 4 years of follow-up). To our knowledge, this is the first description of the occurrence of NPH in adult patients with DS and surgical outcomes.

Odor Identification Impairment and Change with Cholinesterase Inhibitor Treatment in Mild Cognitive Impairment. - Devanand, D P; Liu, Xinhua; Chunga, Richard E; Cohen, Hannah; Andrews, Howard; Schofield, Peter W; Stern, Yaakov; Huey, Edward D; Choi, Jongwoo; Pelton, Gregory H (J Alzheimers Dis, 2020)
BACKGROUND: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer's disease (AD) pathology, and short-term change in odor identification impairment with cholinesterase inhibitor (CheI) treatment may predict longer term cognitive outcomes. OBJECTIVE: In patients with mild cognitive impairment (MCI) treated prospectively with donepezil, a CheI, for 52 weeks, to determine if 1) acute decline in odor identification ability with anticholinergic challenge can predict cognitive improvement, and 2) change in odor identification over 8 weeks can predict cognitive improvement. METHODS: MCI was diagnosed clinically without AD biomarkers. At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and this dose was maintained for 52 weeks. Main outcomes were ADAS-Cog total score and Selective Reminding Test (SRT) total immediate recall score measured at baseline, 26 and 52 weeks. RESULTS: In 100 study participants, mean age 70.14 (SD 9.35) years, atropine-induced decrease in UPSIT score at baseline was not associated with change in ADAS-Cog or SRT scores over 52 weeks. Change in UPSIT score from 0 to 8 weeks did not show a significant association with change in the ADAS-Cog or SRT measures over 52 weeks. CONCLUSION: These negative findings in a relatively large sample of patients with MCI did not replicate results in much smaller samples. Change in odor identification with anticholinergic challenge, and over 8 weeks, may not be useful predictors of cognitive improvement with CheI in patients with MCI.

Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice. - Stojakovic, Andrea; Chang, Su-Youne; Nesbitt, Jarred; Pichurin, Nicholas P; Ostroot, Mark A; Aikawa, Tomonori; Kanekiyo, Takahisa; Trushina, Eugenia (J Alzheimers Dis, 2020)
BACKGROUND: Accumulation of hyperphosphorylated tau (pTau) protein is associated with synaptic dysfunction in Alzheimer's disease (AD). We previously demonstrated that neuroprotection in familial mouse models of AD could be achieved by targeting mitochondria complex I (MCI) and activating the adaptive stress response. Efficacy of this strategy on pTau-related pathology remained unknown. OBJECTIVE: To investigate the effect of specific MCI inhibitor tricyclic pyrone compound CP2 on levels of human pTau, memory function, long term potentiation (LTP), and energy homeostasis in 18-month-old 3xTg-AD mice and explore the potential mechanisms. METHODS: CP2 was administered to male and female 3xTg-AD mice from 3.5-18 months of age. Cognitive function was assessed using the Morris water maze. Glucose metabolism was measured in periphery using a glucose tolerance test and in the brain using fluorodeoxyglucose F18 positron-emission tomography (FDG-PET). LTP was evaluated using electrophysiology in the hippocampus. The expression of key proteins associated with neuroprotective mechanisms were assessed by western blotting. RESULTS: Chronic CP2 treatment restored synaptic activity in female 3xTg-AD mice; cognitive function, levels of synaptic proteins, glucose metabolism, and energy homeostasis were improved in male and female 3xTg-AD mice. Significant reduction of human pTau in the brain was associated with increased activity of protein phosphatase of type 2A (PP2A), and reduced activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β). CONCLUSION: CP2 treatment protected against synaptic dysfunction and memory impairment in symptomatic 3xTg-AD mice, and reduced levels of human pTau, indicating that targeting mitochondria with small molecule specific MCI inhibitors represents a promising strategy for treating AD.

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.

Potential Novel Role of COVID-19 in Alzheimer's Disease and Preventative Mitigation Strategies. - Naughton, Sean X; Raval, Urdhva; Pasinetti, Giulio M (J Alzheimers Dis, 2020)
There are a number of potential implications for the field of Alzheimer's disease (AD) stemming from the global spread of SARS-CoV-2. Neuroinflammation is known to be a prominent feature of neurodegeneration and plays a major role in AD pathology. Immune response and excessive inflammation in COVID-19 may also accelerate the progression of brain inflammatory neurodegeneration, and elderly individuals are more susceptible to severe outcomes after SARS-CoV-2 infection. Individuals with type 2 diabetes (T2D) are at an increased risk for AD as well as severe outcomes after SARS-CoV-2 infection. Genetic and socioeconomic factors influencing the rates of T2D, AD, and COVID-19 severity may create an exceptionally high-risk profile for certain demographics such as African Americans and Hispanic Americans. Type I interferon response plays an important role in both host response to viral infection, as well as AD pathology and may be a sensible therapeutic target in both AD and COVID-19.
Keywords: Aged; Alzheimer Disease; Betacoronavirus; Coronavirus Infections; COVID-19; Diabetes Mellitus, Type 2; Humans; Interferon Type I; Pandemics; Pneumonia, Viral; SARS-CoV-2; Synapses

Reduced Hippocampal Glutamate and Posterior Cingulate N-Acetyl Aspartate in Mild Cognitive Impairment and Alzheimer's Disease Is Associated with Episodic Memory Performance and White Matter Integrity in the Cingulum: A Pilot Study. - Wong, Dickson; Atiya, Samir; Fogarty, Jennifer; Montero-Odasso, Manuel; Pasternak, Stephen H; Brymer, Chris; Borrie, Michael J; Bartha, Robert (J Alzheimers Dis, 2020)
Identification of biological changes underlying the early symptoms of Alzheimer's disease (AD) will help to identify and stage individuals prior to symptom onset. The limbic system, which supports episodic memory and is impaired early in AD, is a primary target. In this study, brain metabolism and microstructure evaluated by high field (7 Tesla) proton magnetic resonance spectroscopy (1H-MRS) and diffusion tensor imaging (DTI) were evaluated in the limbic system of eight individuals with mild cognitive impairment (MCI), nine with AD, and sixteen normal elderly controls (NEC). Left hippocampal glutamate and posterior cingulate N-acetyl aspartate concentrations were reduced in MCI and AD compared to NEC. Differences in DTI metrics indicated volume and white matter loss along the cingulum in AD compared to NEC. Metabolic and microstructural changes were associated with episodic memory performance assessed using Craft Story 21 Recall and Benson Complex Figure Copy. The current study suggests that metabolite concentrations measured using 1H-MRS may provide insight into the underlying metabolic and microstructural processes of episodic memory impairment.

Revised Framingham Stroke Risk Profile: Association with Cognitive Status and MRI-Derived Volumetric Measures. - Pelcher, Isabelle; Puzo, Christian; Tripodis, Yorghos; Aparicio, Hugo J; Steinberg, Eric G; Phelps, Alyssa; Martin, Brett; Palmisano, Joseph N; Vassey, Elizabeth; Lindbergh, Cutter; McKee, Ann C; Stein, Thor D; et al. (J Alzheimers Dis, 2020)
BACKGROUND: The Framingham Stroke Risk Profile (FSRP) was created in 1991 to estimate 10-year risk of stroke. It was revised in 2017 (rFSRP) to reflect the modern data on vascular risk factors and stroke risk. OBJECTIVE: This study examined the association between the rFSRP and cognitive and brain aging outcomes among participants from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS). METHODS: Cross-sectional rFSRP was computed at baseline for 19,309 participants (mean age = 72.84, SD = 8.48) from the NACC-UDS [9,697 (50.2%) normal cognition, 4,705 (24.4%) MCI, 4,907 (25.4%) dementia]. Multivariable linear, logistic, or ordinal regressions examined the association between the rFSRP and diagnostic status, neuropsychological test performance, CDR® Sum of Boxes, as well as total brain volume (TBV), hippocampal volume (HCV), and log-transformed white matter hyperintensities (WMH) for an MRI subset (n = 1,196). Models controlled for age, sex, education, racial identity, APOEɛ4 status, and estimated intracranial volume for MRI models. RESULTS: The mean rFSRP probability was 10.42% (min = 0.50%, max = 95.71%). Higher rFSRP scores corresponded to greater CDR Sum of Boxes (β= 0.02, p = 0.028) and worse performance on: Trail Making Test A (β= 0.05, p <  0.001) and B (β= 0.057, p <  0.001), and Digit Symbol (β= -0.058, p <  0.001). Higher rFSRP scores were associated with increased odds for a greater volume of log-transformed WMH (OR = 1.02 per quartile, p = 0.015). No associations were observed for diagnosis, episodic memory or language test scores, HCV, or TBV. CONCLUSION: These results support the rFSRP as a useful metric to facilitate clinical research on the associations between cerebrovascular disease and cognitive and brain aging.

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.

Sleep-Wake Cycle in Alzheimer's Disease Is Associated with Tau Pathology and Orexin Dysregulation. - Liguori, Claudio; Spanetta, Matteo; Izzi, Francesca; Franchini, Flaminia; Nuccetelli, Marzia; Sancesario, Giulia Maria; Di Santo, Simona; Bernardini, Sergio; Mercuri, Nicola Biagio; Placidi, Fabio (J Alzheimers Dis, 2020)
BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. It is mainly characterized by a progressive deterioration of cognition, but sleep-wake cycle disturbances frequently occur. Irregular sleep-wake cycle, insomnia, and daytime napping usually occur in patients with AD in the course of the disease. OBJECTIVE: The aim of the present study was to verify the sleep-wake cycle in mild to moderate AD patients compared to controls, and to evaluate the relationship between the sleep-wake cycle impairment and the neuropsychological testing, CSF AD biomarkers, and CSF orexin concentrations. METHODS: Mild to moderate AD patients were enrolled and underwent 14-day actigraphic recording, sleep diary, neuropsychological testing, and CSF biomarkers analysis. All patients were compared to controls. RESULTS: Eighteen AD patients were compared to ten controls. AD patients showed the alteration of the sleep-wake cycle, featured by sleep dysregulation and daytime wake fragmentation, with respect to controls. Considering the correlation analysis, we documented the correlation between tau proteins and orexin CSF levels and sleep-wake cycle dysregulation. CONCLUSION: This study confirmed the dysregulation of sleep-wake cycle in AD patients, as reflected by the daytime wake fragmentation, irregular sleep-wake rhythm, and nocturnal sleep impairment. This sleep-wake cycle disorder correlates with AD neuropathological in vivo features and brain orexin activity. Hence, we suppose that a more marked AD pathology coupled with orexinergic system dysregulation may promote sleep-wake cycle impairment in AD patients.

Soluble TREM2 and Inflammatory Proteins in Alzheimer's Disease Cerebrospinal Fluid. - Rauchmann, Boris-Stephan; Sadlon, Angélique; Perneczky, Robert (J Alzheimers Dis, 2020)
The present study explores the associations of soluble TREM2, an important regulator of microglial activity linked to Alzheimer's disease (AD), with other known inflammatory proteins in cerebrospinal fluid (CSF). We studied 303 participants, including 89 controls, 135 mild cognitive impairment, and 79 AD dementia patients. Using established CSF biomarkers, subjects were classified according to the National Institute on Aging-Alzheimer's Association research framework, which groups markers into those of amyloid-β deposition (A), tau pathology (T), and neurodegeneration (N). TNFR1, TNFR2, TGF-β1, TGFβ2, IL-9, TNF-α, ICAM1, and VCAM1 showed significant concentration differences between the ATN groups, with higher concentrations in more advanced disease categories. sTREM2 was positively associated with the pro-inflammatory proteins TNF-α, TNFR1, TNFR2, ICAM1, VCAM1, and IP-10 and negatively with IL-21; also, positive associations with the anti-inflammatory proteins TGFβ1, IL-10, and IL-9 were found. Pathway enrichment analysis highlighted the involvement of sTREM2 in key functional clusters including immunoglobulin and cytokine production and cellular response to lipopolysaccharides, cytokines, and steroid hormones. Our work provides further evidence in support of TREM2 as amarker of neuroinflammatory response in AD.

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.

Ultra-High Field MRI in Alzheimer's Disease: Effective Transverse Relaxation Rate and Quantitative Susceptibility Mapping of Human Brain In Vivo and Ex Vivo Compared to Histology. - Tuzzi, Elisa; Balla, David Z; Loureiro, Joana R A; Neumann, Manuela; Laske, Christoph; Pohmann, Rolf; Preische, Oliver; Scheffler, Klaus; Hagberg, Gisela E (J Alzheimers Dis, 2020)
Alzheimer's disease (AD) is the most common cause of dementia worldwide. So far, diagnosis of AD is only unequivocally defined through postmortem histology. Amyloid plaques are a classical hallmark of AD and amyloid load is currently quantified by Positron Emission tomography (PET) in vivo. Ultra-high field magnetic resonance imaging (UHF-MRI) can potentially provide a non-invasive biomarker for AD by allowing imaging of pathological processes at a very-high spatial resolution. The first aim of this work was to reproduce the characteristic cortical pattern previously observed in vivo in AD patients using weighted-imaging at 7T. We extended these findings using quantitative susceptibility mapping (QSM) and quantification of the effective transverse relaxation rate (R2*) at 9.4T. The second aim was to investigate the origin of the contrast patterns observed in vivo in the cortex of AD patients at 9.4T by comparing quantitative UHF-MRI (9.4T and 14.1T) of postmortem samples with histology. We observed a distinctive cortical pattern in vivo in patients compared to healthy controls (HC), and these findings were confirmed ex vivo. Specifically, we found a close link between the signal changes detected by QSM in the AD sample at 14.1T and the distribution pattern of amyloid plaques in the histological sections of the same specimen. Our findings showed that QSM and R2* maps can distinguish AD from HC at UHF by detecting cortical alterations directly related to amyloid plaques in AD patients. Furthermore, we provided a method to quantify amyloid plaque load in AD patients at UHF non-invasively.

Use of Immersive Virtual Reality in the Assessment and Treatment of Alzheimer's Disease: A Systematic Review. - Clay, Felix; Howett, David; Fitzgerald, James; Fletcher, Paul; Chan, Dennis; Price, Annabel (J Alzheimers Dis, 2020)
BACKGROUND: Immersive virtual reality (iVR) allows seamless interaction with simulated environments and is becoming an established tool in clinical research. It is unclear whether iVR is acceptable to people with Alzheimer's disease (AD) dementia or useful in their care. We explore whether iVR is a viable research tool that may aid the detection and treatment of AD. OBJECTIVES: This review examines the use of iVR in people with AD or mild cognitive impairment (MCI). METHODS: Medline, PsycINFO, Embase, CINAHL, and Web of Science databases were searched from inception. PRISMA guidelines were used with studies selected by at least two researchers. RESULTS: Nine studies were eligible for inclusion. None reported any issues with iVR tolerability in participants with MCI and AD on assessment or treatment tasks. One study demonstrated capability for detecting prodromal AD and correlated with neuroanatomical substrates. Two studies showed iVR to have high accuracy in differentiating participants with AD from controls but were not hypothesis driven or with adequate controls measures. In a small validation study and two longitudinal case studies, iVR cognitive training was positively rated but did not demonstrate reliable benefit. CONCLUSION: iVR is emerging as a viable method of assessing older adults and people with AD. Strongest benefits were seen when closely integrated with theoretical models of neurodegeneration and existing screening methods. Further randomized controlled trials integrated with clinical populations are required. This will consolidate the power of iVR for assessment of MCI and clarify treatment efficacy beyond current applications in physical rehabilitation.

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.

18F-FDG Is a Superior Indicator of Cognitive Performance Compared to 18F-Florbetapir in Alzheimer's Disease and Mild Cognitive Impairment Evaluation: A Global Quantitative Analysis. - Khosravi, Mohsen; Peter, Jonah; Wintering, Nancy A; Serruya, Mijail; Shamchi, Sara Pourhassan; Werner, Thomas J; Alavi, Abass; Newberg, Andrew B (J Alzheimers Dis, 2019)
BACKGROUND: 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and 18F-florbetapir PET are approved neuroimaging biomarkers for the Alzheimer's disease (AD) and mild cognitive impairment (MCI). OBJECTIVES: This study aims to compare the efficacy of 18F-FDG and 18F-florbetapir PET at evaluating the cognitive performance of patients with AD, MCI, and normal controls (NCs). METHODS: 63 subjects (36 male/27 female, mean age = 68.3) including 19 AD, 23 MCI, and 21 NCs underwent 18F-FDG and 18F-florbetapir PET imaging. A global quantification approach was applied on supra-tentorial, frontal, parieto-occipital, temporal, and cerebellar brain regions by calculating the global SUVmean ratios (GSUVr) as the weighted average of all regional SUVmean. 18F-FDG and 18F-florbetapir GSUVr of each region were subsequently correlated with the Mini-Mental Status Examination (MMSE). RESULTS: Subjects were studied in five categories as NC, MCI patients, AD patients, MCI and AD patients grouped together (MCI/AD), and a group including all the subjects (NC/MCI/AD). Both 18F-FDG and 18F-florbetapir could successfully detect subjects with dementia (p <  0.001). Studied in all regions and groups, the correlation analysis of 18F-FDG GSUVr with MMSE scores was significant in more regions and groups compared to that of 18F-florbetapir. We also demonstrated that the correlation of 18F-FDG GSUVr with MMSE is stronger than that of 18F-florbetapir in the supra-tentorial and temporal regions. CONCLUSIONS: This study reveals how 18F-FDG-PET global quantification is a superior indicator of cognitive performance in AD and MCI patients compared to 18F-florbetapir PET. Accordingly, we still recommend 18F-FDG-PET over amyloid imaging in the evaluation for AD and MCI.

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.

Air Pollution and Dementia: A Systematic Review. - Peters, Ruth; Ee, Nicole; Peters, Jean; Booth, Andrew; Mudway, Ian; Anstey, Kaarin J (J Alzheimers Dis, 2019)
BACKGROUND: Both air pollution and dementia are current and growing global issues. There are plausible links between exposure to specific air pollutants and dementia. OBJECTIVE: To systematically review the evidence base with respect to the relationship between air pollution and later cognitive decline and dementia. METHODS: Medline, Embase, and PsychINFO® were searched from their inception to September 2018, for publications reporting on longitudinal studies of exposure to air pollution and incident dementia or cognitive decline in adults. Studies reporting on exposure to tobacco smoke including passive smoking or on occupational exposure to pollutants were excluded. Using standard Cochrane methodology, two readers identified relevant abstracts, read full text publications, and extracted data into structured tables from relevant papers, as defined by inclusion and exclusion criteria. Papers were also assessed for validity. CRD42018094299Results:From 3,720 records, 13 papers were found to be relevant, with studies from the USA, Canada, Taiwan, Sweden, and the UK. Study follow-up ranged from one to 15 years. Pollutants examined included particulate matter ≤2.5 μ (PM2.5), nitrogen dioxide (NO2), nitrous oxides (NOx), carbon monoxide (CO), and ozone. Studies varied in their methodology, population selection, assessment of exposure to pollution, and method of cognitive testing. Greater exposure to PM2.5, NO2/NOx, and CO were all associated with increased risk of dementia. The evidence for air pollutant exposure and cognitive decline was more equivocal. CONCLUSION: Evidence is emerging that greater exposure to airborne pollutants is associated with increased risk of dementia.

Anemia in Association with Cognitive Impairment: A Systematic Review and Meta-Analysis. - Kim, Hong-Bae; Park, Byoungjin; Shim, Jae-Yong (J Alzheimers Dis, 2019)
BACKGROUND: Prevalence of both anemia and cognitive impairment tends to increase with age. Individual studies have recently shown that anemia could be associated with cognitive impairment. OBJECTIVE: To investigate the association between anemia and cognitive impairment including dementia. METHODS: Two of the authors systematically searched PubMed, EMBASE, and the Cochrane library to retrieve observational studies reporting a relationship between anemia and cognitive impairment from 1964 to July 10, 2019. Case-control and cohort studies were included, and odds ratios (ORs) or relative risks (RRs) with 95% confidence intervals (CIs) for the risk of cognitive impairment were calculated using a random-effects model. RESULTS: In total, 16 observational studies including eight case-control studies and eight cohort studies were included in the final analysis. Anemia was significantly linked to cognitive impairment (OR or RR 1.51; 95% CI: 1.32-1.73) in a random-effects meta-analysis, albeit with medium heterogeneity (I2 = 47.8%). Meta-estimates of dementia from prospective population-based cohort studies were similar (RR 1.46; 95% CI: 1.22-1.76) without substantial heterogeneity (I2 = 23.2%). CONCLUSION: Our meta-analysis indicates that anemia is associated with cognitive impairment. Further prospective research is warranted to determine the cause-effect relationship of anemia with cognitive impairment and whether treatment of anemia might reduce the risk of dementia.

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.

Association between Adipokines and Biomarkers of Alzheimer's Disease: A Cross-Sectional Study. - Letra, Liliana; Matafome, Paulo; Rodrigues, Tiago; Duro, Diana; Lemos, Raquel; Baldeiras, Ines; Patrício, Miguel; Castelo-Branco, Miguel; Caetano, Gina; Seiça, Raquel; Santana, Isabel (J Alzheimers Dis, 2019)
BACKGROUND: Adipose tissue dysfunction has been implicated in the pathophysiology of Alzheimer's disease. However, the involvement of adipokines, particularly adiponectin, remains unclear. OBJECTIVE: To compare serum and cerebrospinal fluid (CSF) levels of adiponectin, leptin and leptin-to-adiponectin ratio in patients within the spectrum of Alzheimer's disease and evaluate their relationship with classical biomarkers and their value as markers of progression. METHODS: Amnestic mild cognitive impairment (MCI, n = 71) and Alzheimer's dementia (AD, n = 53) subjects were consecutively recruited for serum and CSF adiponectin and leptin determination using an analytically validated commercial enzyme-linked immunosorbent assay (ELISA). Correlations were explored using adjusted Spearman's correlation coefficients. A logistic regression model and ROC analysis were performed to evaluate the staging predictive value of adipokines. RESULTS: Serum adiponectin was 33% higher in AD when compared to MCI patients. Adiponectin CSF levels, similar in both groups, were positively correlated with Aβ42 and cognitive function, though only in women. The area under the ROC curve was 0.673 (95% CI:0.57-0.78) for serum adiponectin as predictor of dementia stage and the cut-off 10.85μg/ml maximized the sum of specificity (87%) and sensitivity (44%). CONCLUSION: Although longitudinal studies are required, we hypothesize that higher serum adiponectin in AD patients constitutes a strategy to compensate possible central signaling defects. In addition, adiponectin might be specifically assigned to neuroprotective functions in women and eventually involved in the female-biased incidence of Alzheimer's disease.

Cerebral Amyloid Angiopathy and Neuritic Plaque Pathology Correlate with Cognitive Decline in Elderly Non-Demented Individuals. - Malek-Ahmadi, Michael; Chen, Kewei; Perez, Sylvia E; Mufson, Elliott J (J Alzheimers Dis, 2019)
BACKGROUND: Cerebral amyloid angiopathy (CAA) is a vascular neuropathology commonly reported in non-cognitively impaired (NCI), mild cognitive impairment, and Alzheimer's disease (AD) brains. However, it is unknown whether similar findings are present in non-demented elderly subjects. OBJECTIVE: This study determined the association between CAA and cognition among elderly NCI subjects with varying levels of AD pathology. METHODS: Data from 182 cases that received a diagnosis of NCI at their first clinical assessment were obtained from the Rush Religious Orders study (RROS). A cognitive composite score was used to measure cognitive decline. CAA was dichotomized as present or absent. Cases were also dichotomized according to CERAD neuropathological diagnosis and Braak staging. A mixed model-repeated measures analysis assessed decline on the cognitive composite score. RESULTS: CAA, alone, was not associated with cognitive decline [-0.87 (95% CI: -3.33, 1.58), p = 0.49]. However, among those with CAA, the High CERAD group had significantly greater decline relative to the Low CERAD group [-4.08 (95% CI: -7.10, -1.06), p = 0.008]. The High and Low CERAD groups were not significantly different [-1.77 (95% CI: -6.14, 2.60), p = 0.43] in those without CAA. Composite score decline in the High and Low Braak groups with [-1.32 (95% CI: -4.40, 1.75), p = 0.40] or without [0.27 (95% CI: -4.01, 4.56), p = 0.90] CAA was not significantly different. CONCLUSION: The current data shows that an interaction between CAA and plaque load is associated with greater decline on a cognitive composite score used to test non-cognitively impaired elderly participants in AD prevention trials.

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.

Circulating and Extracellular Vesicles Levels of N-(1-Carboxymethyl)-L-Lysine (CML) Differentiate Early to Moderate Alzheimer's Disease. - Haddad, Mohamed; Perrotte, Morgane; Landri, Sarra; Lepage, Aurelie; Fülöp, Tamás; Ramassamy, Charles (J Alzheimers Dis, 2019)
BACKGROUND: Both advanced glycation end products (AGEs) N-(1-carboxymethyl)-L-lysine (CML) and pentosidine were found in the brain from Alzheimer's disease (AD) patients and were associated with the neuropathological hallmarks of AD. In AD patients, the circulating level of both AGEs remains unknown. Moreover, their levels in peripheral extracellular vesicles (EVs) and their association with AD remain to be determined. Finally, it is not known if neuronal cells can release AGEs via EVs and propagate AGEs. OBJECTIVE: To determine the levels of circulating CML and pentosidine during the progression of AD. Moreover, their levels in circulating EVs were determined and their association with the clinical cognitive scores were analyzed. Finally, we have studied the possibility that neuronal cells eliminate and transfer these AGEs through EVs. METHODS: CML and pentosidine levels were measured in serum and in circulating EVs. Released-EVs from SK-N-SH neuronal cells were isolated and CML levels were also determined. RESULTS: The levels of CML in albumin-free serum proteins were higher in the early stage of AD while the levels of pentosidine remained unchanged. In contrast, the levels of CML in the EVs were lower in the moderate stage of AD. Interestingly, the levels of CML in serum were negatively correlated with the clinical cognitive scores MMSE and MoCA. For the first time, we were able to demonstrate that CML was present in EVs released from neuronal cells in culture. CONCLUSION: Peripheral and circulating EVs levels of CML can differentiate early to moderate AD. In the brain, neuronal CML can propagate from cells-to-cells via EVs.

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.∥.

Clinico-Neuropathological Findings in the Oldest Old from the Georgia Centenarian Study. - Tanprasertsuk, Jirayu; Johnson, Elizabeth J; Johnson, Mary Ann; Poon, Leonard W; Nelson, Peter T; Davey, Adam; Martin, Peter; Barbey, Aron K; Barger, Kathryn; Wang, Xiang-Dong; Scott, Tammy M (J Alzheimers Dis, 2019)
BACKGROUND: Centenarian studies are important sources for understanding of factors that contribute to longevity and healthy aging. Clinico-neuropathological finding is a key in identifying pathology and factors contributing to age-related cognitive decline and dementia in the oldest old. OBJECTIVE: To characterize the cross-sectional relationship between neuropathologies and measures of premortem cognitive performance in centenarians. METHODS: Data were acquired from 49 centenarians (≥98 years) from the Georgia Centenarian Study. Cognitive assessment from the time point closest to mortality was used ( RESULTS: Wide ranges of AD-type neuropathological changes were observed in both non-demented and demented subjects. Neocortical NFT and Braak staging were related to clinical dementia rating. Neocortical NFT and NP, Braak and NIARI staging, cerebral and ventricular atrophy, HS, CAA, and TDP-43 proteinopathy were differentially associated with poor performance in multiple cognitive domains and activities of daily living. CONCLUSION: AD-type pathology was associated with severe dementia and poor cognition but was not the only variable that explained cognitive impairment, indicating the complexity and heterogeneity of pathophysiology of dementia in the oldest old.

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.

Education Moderates the Relation Between APOE ɛ4 and Memory in Nondemented Non-Hispanic Black Older Adults. - Vonk, Jet M J; Rentería, Miguel Arce; Medina, Valerie M; Pericak-Vance, Margaret A; Byrd, Goldie S; Haines, Jonathan; Brickman, Adam M; Manly, Jennifer J (J Alzheimers Dis, 2019)
BACKGROUND: The APOEɛ4 allele is a well-known risk factor for Alzheimer's disease (AD). Previous research argues that higher education helps to preserve cognition in older adults with AD pathology because of its key role in cognitive reserve and resilience. OBJECTIVE: To test if higher educational level buffers the effect of APOEɛ4 on cognition among older non-Hispanic Blacks. METHODS: Participants were 849 non-demented older non-Hispanic Blacks (38.3% APOEɛ4+), who underwent a comprehensive neuropsychological evaluation. Multiple linear regression models tested the relationship between APOEɛ4 status and twelve cognitive measures with education (up to high school and beyond high school) as a moderator. RESULTS: Education buffered the effects of the APOEɛ4 allele, such that there was no impact of APOEɛ4 status on word-list memory retention and working memory among participants with more than a high school degree. This pattern was not observed for ten other cognitive measures of verbal and visual episodic memory, semantic memory, executive function, and processing speed-although a similar trend was observed for switching ability in executive functioning. The buffering effect of education was stronger among women than men. CONCLUSION: Our findings suggest that genetic effects on late-life cognition may be modified by environmental factors such as educational attainment. These results are consistent with the framework of cognitive reserve such that engaging in cognitively enriching activities and acquiring skills and knowledge with more years of education may increase the capacity to maintain cognitive function despite high genetic risk for impairment.

The Effects of APOE4 on Mitochondrial Dynamics and Proteins in vivo. - Simonovitch, Shira; Schmukler, Eran; Masliah, Eliezer; Pinkas-Kramarski, Ronit; Michaelson, Daniel M (J Alzheimers Dis, 2019)
This study examined the effects of apolipoprotein E4 (APOE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), on proteins involved in mitochondrial dynamics and autophagy, in the hippocampus of targeted replacement mice. Immunohistochemical measurements revealed that the levels of the mitochondrial fusion-mediating protein, MFN1, were higher, whereas those of corresponding fission-regulating protein, DRP-1, were lower in the hippocampus of ApoE4 mice than in the corresponding ApoE3 mice, indicating that APOE4 is associated with increased mitochondrial fusion and decreased fission. A similar ApoE4-driven decrease in DRP-1 was also observed in AD brains. The levels of the mitochondrial proteins COX1 and Tom40, were higher in the ApoE4 mice, which is consistent with the increased fusion. Measurements of the levels of cleaved PINK1 and parkin, which mark and target mitochondria for mitophagic degradation, revealed lower levels of cleaved PINK1, suggesting reduced mitochondrial membrane potential, and higher levels of parkin in the hippocampus of ApoE4 compared with the ApoE3 mice, indicating altered mitophagy. The levels of the ubiquitin-binding scaffold protein, p62/SQSTM1, which directs selected cargo to the autophagosomes, were also higher in the ApoE4 mice. These findings suggest that APOE4 is associated with enhanced mitochondrial fusion and decreased fission. Additionally, the results indicate that the mitophagy/autophagy is reduced in ApoE4 mice, resulting in higher levels of proteins such as parkin and p62, which are normally degraded during this process. Taken together, these results suggest a novel mechanism that may underlie the pathological effects of APOE4 and indicate that use of APOE4 genotyping could pave the way for identification of novel APOE4-related therapeutic targets.

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.

Genome-Wide Methylation of Mild Cognitive Impairment in Mexican Americans Highlights Genes Involved in Synaptic Transport, Alzheimer's Disease-Precursor Phenotypes, and Metabolic Morbidities. - Pathak, Gita A; Silzer, Talisa K; Sun, Jie; Zhou, Zhengyang; Daniel, Ann A; Johnson, Leigh; O'Bryant, Sid; Phillips, Nicole R; Barber, Robert C (J Alzheimers Dis, 2019)
The Mexican American population is among the fastest growing aging population and has a younger onset of cognitive decline. This group is also heavily burdened with metabolic conditions such as hypertension, diabetes, and obesity. Unfortunately, limited research has been conducted in this group. Understanding methylation alterations, which are influenced by both genetic and lifestyle factors, is key to identifying and addressing the root cause for mild cognitive impairment, a clinical precursor for dementia. We conducted an epigenome-wide association study on a community-based Mexican American population using the Illumina EPIC array. Following rigorous quality control measures, we identified 10 CpG sites to be differentially methylated between normal controls and individuals with mild cognitive impairment annotated to PKIB, KLHL29, SEPT9, OR2C3, CPLX3, BCL2L2-PABPN1, and CCNY. We found four regions to be differentially methylated in TMEM232, SLC17A8, ALOX12, and SEPT8. Functional gene-set analysis identified four gene-sets, RIN3, SPEG, CTSG, and UBE2L3, as significant. The gene ontology and pathway analyses point to neuronal cell death, metabolic dysfunction, and inflammatory processes. We found 1,450 processes to be enriched using empirical Bayes gene-set enrichment. In conclusion, the functional overlap of differentially methylated genes associated with cognitive impairment in Mexican Americans implies cross-talk between metabolically-instigated systemic inflammation and disruption of synaptic vesicular transport.

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.

Highly Elevated Cerebrospinal Fluid Total Tau Level Reflects Higher Likelihood of Non-Amnestic Subtype of Alzheimer's Disease. - Pillai, Jagan A; Bonner-Jackson, Aaron; Bekris, Lynn M; Safar, Jiri; Bena, Jim; Leverenz, James B (J Alzheimers Dis, 2019)
BACKGROUND: Cerebrospinal fluid (CSF) levels of total tau (t-tau) protein are thought to reflect the intensity of the neuronal damage in neurodegeneration, including Alzheimer's disease (AD). The recent link of CSF t-tau to rapidly progressive AD raises the question among other AD clinical variants regarding CSF t-tau. We investigated the clinical phenotypes of AD patients with varying CSF t-tau levels. OBJECTIVE: We tested the hypothesis that highly elevated CSF t-tau level would have a higher likelihood of presenting with atypical non-amnestic variants of AD. METHODS: Retrospective comparative case study of 97 patients evaluated in a memory clinic with clinical presentation and CSF biomarkers consistent with AD. We compared the age, sex, education, APOEɛ4 status, Montreal Cognitive Assessment (MoCA) score, clinical phenotype, and MRI volumetric measures by CSF t-tau quartile at baseline. Multivariable logistic regression models were used to evaluate if CSF t-tau levels predict non-amnestic presentations controlling for covariates. RESULTS: Non-amnestic AD had a higher median CSF t-tau level compared to amnestic-AD (p = 0.014). Each 50 pg/ml increase in CSF t-tau was associated with an increase in the odds of having a non-amnestic presentation (7.4%) and aphasia (10.6 %) as the initial presenting symptom even after taking into account; age, sex, education, APOEɛ4, MoCA, and CSF Aβ42. Logopenic AD had higher t-tau and p-tau levels compared to other variants. CONCLUSIONS: Highly elevated CSF t-tau levels could indicate more cortical involvement presenting with early non-amnestic symptoms in atypical AD subtypes, particularly in the logopenic variant.

Impacts of Overweight and Obesity in Older Age on the Risk of Dementia: A Systematic Literature Review and a Meta-Analysis. - Danat, Isaac M; Clifford, Angela; Partridge, Martin; Zhou, Weiju; Bakre, Aishat T; Chen, Anthony; McFeeters, Danielle; Smith, Tina; Wan, Yuhui; Copeland, John; Anstey, Kaarin J; Chen, Ruoling (J Alzheimers Dis, 2019)
BACKGROUND: It is unclear whether overweight and obesity in older age reduces or increases the risk of incident dementia. OBJECTIVE: To assess the impacts of overweight and obesity in older age on incident dementia. METHODS: We searched cohort studies reporting body weight measured in older age and dementia through PubMed, Embase, Medline, PyschInfo, and Cochrane library until July 2016. Sixteen articles were identified for the review. We pooled data from them and a new unpublished study from China, to calculate relative risk (RR) of incident dementia in relation to body mass index (BMI) and waist circumference (WC). RESULTS: All 16 cohort studies were undertaken in high income countries, with follow-up periods ranging between 3 to 18 years. Thirteen studies showed an inverse association between BMI and dementia, and three studies demonstrated a positive association. Pooled RR of dementia in relation to continuous BMI from 14 studied populations, including the new Chinese data, was 0.97 (95% CI 0.95-1.00); in those followed up CONCLUSION: The current evidence did not support a paradox on beneficial impacts of overweight and obesity in older age on incident dementia. More studies with long term follow up are needed to clarify the association of body weight in older age with dementia risk.

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.

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.

Intraneuronal Tau Misfolding Induced by Extracellular Amyloid-β Oligomers. - Rudenko, Lauren K; Wallrabe, Horst; Periasamy, Ammasi; Siller, Karsten H; Svindrych, Zdenek; Seward, Matthew E; Best, Merci N; Bloom, George S (J Alzheimers Dis, 2019)
Abnormal folding and aggregation of the microtubule-associated protein, tau, is a hallmark of several neurodegenerative disorders, including Alzheimer's disease (AD). Although normal tau is an intrinsically disordered protein, it does exhibit tertiary structure whereby the N- and C-termini are often in close proximity to each other and to the contiguous microtubule-binding repeat domains that extend C-terminally from the middle of the protein. Unfolding of this paperclip-like conformation might precede formation of toxic tau oligomers and filaments, like those found in AD brain. While there are many ways to monitor tau aggregation, methods to monitor changes in tau folding are not well established. Using full length human 2N4R tau doubly labeled with the Förster resonance energy transfer (FRET) compatible fluorescent proteins, Venus and Teal, on the N- and C-termini, respectively (Venus-Tau-Teal), intensity and lifetime FRET measurements were able to distinguish folded from unfolded tau in living cells independently of tau-tau intermolecular interactions. When expression was restricted to low levels in which tau-tau aggregation was minimized, Venus-Tau-Teal was sensitive to microtubule binding, phosphorylation, and pathogenic oligomers. Of particular interest is our finding that amyloid-β oligomers (AβOs) trigger Venus-Tau-Teal unfolding in cultured mouse neurons. We thus provide direct experimental evidence that AβOs convert normally folded tau into a conformation thought to predominate in toxic tau aggregates. This finding provides further evidence for a mechanistic connection between Aβ and tau at seminal stages of AD pathogenesis.

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.

A Meta-Analysis of Alzheimer's Disease Brain Transcriptomic Data. - Patel, Hamel; Dobson, Richard J B; Newhouse, Stephen J (J Alzheimers Dis, 2019)
BACKGROUND: Microarray technologies have identified imbalances in the expression of specific genes and biological pathways in Alzheimer's disease (AD) brains. However, there is a lack of reproducibility across individual AD studies, and many related neurodegenerative and mental health disorders exhibit similar perturbations. OBJECTIVE: Meta-analyze publicly available transcriptomic data from multiple brain-related disorders to identify robust transcriptomic changes specific to AD brains. METHODS: Twenty-two AD, eight schizophrenia, five bipolar disorder, four Huntington's disease, two major depressive disorder, and one Parkinson's disease dataset totaling 2,667 samples and mapping to four different brain regions (temporal lobe, frontal lobe, parietal lobe, and cerebellum) were analyzed. Differential expression analysis was performed independently in each dataset, followed by meta-analysis using a combining p-value method known as Adaptively Weighted with One-sided Correction. RESULTS: Meta-analysis identified 323, 435, 1,023, and 828 differentially expressed genes specific to the AD temporal lobe, frontal lobe, parietal lobe, and cerebellum brain regions, respectively. Seven of these genes were consistently perturbed across all AD brain regions with SPCS1 gene expression pattern replicating in RNA-Seq data. A further nineteen genes were perturbed specifically in AD brain regions affected by both plaques and tangles, suggesting possible involvement in AD neuropathology. In addition, biological pathways involved in the "metabolism of proteins" and viral components were significantly enriched across AD brains. CONCLUSION: This study identified transcriptomic changes specific to AD brains, which could make a significant contribution toward the understanding of AD disease mechanisms and may also provide new therapeutic targets.

Midlife Insulin Resistance as a Predictor for Late-Life Cognitive Function and Cerebrovascular Lesions. - Toppala, Sini; Ekblad, Laura L; Lötjönen, Jyrki; Helin, Semi; Hurme, Saija; Johansson, Jarkko; Jula, Antti; Karrasch, Mira; Koikkalainen, Juha; Laine, Hanna; Parkkola, Riitta; Viitanen, Matti; et al. (J Alzheimers Dis, 2019)
BACKGROUND: Type 2 diabetes (T2DM) increases the risk for Alzheimer's disease (AD) but not for AD neuropathology. The association between T2DM and AD is assumed to be mediated through vascular mechanisms. However, insulin resistance (IR), the hallmark of T2DM, has been shown to associate with AD neuropathology and cognitive decline. OBJECTIVE: To evaluate if midlife IR predicts late-life cognitive performance and cerebrovascular lesions (white matter hyperintensities and total vascular burden), and whether cerebrovascular lesions and brain amyloid load are associated with cognitive functioning. METHODS: This exposure-to-control follow-up study examined 60 volunteers without dementia (mean age 70.9 years) with neurocognitive testing, brain 3T-MRI and amyloid-PET imaging. The volunteers were recruited from the Finnish Health 2000 survey (n = 6062) to attend follow-up examinations in 2014-2016 according to their insulin sensitivity in 2000 and their APOE genotype. The exposure group (n = 30) had IR in 2000 and the 30 controls had normal insulin sensitivity. There were 15 APOEɛ4 carriers per group. Statistical analyses were performed with multivariable linear models. RESULTS: At follow-up the IR+group performed worse on executive functions (p = 0.02) and processing speed (p = 0.007) than the IR- group. The groups did not differ in cerebrovascular lesions. No associations were found between cerebrovascular lesions and neurocognitive test scores. Brain amyloid deposition associated with slower processing speed. CONCLUSION: Midlife IR predicted poorer executive functions and slower processing speed, but not cerebrovascular lesions. Brain amyloid deposition was associated with slower processing speed. The association between midlife IR and late-life cognition might not be mediated through cerebrovascular lesions measured here.

Neuronal Exosome-Derived Human Tau is Toxic to Recipient Mouse Neurons in vivo. - Winston, Charisse N; Aulston, Brent; Rockenstein, Edward M; Adame, Anthony; Prikhodko, Olga; Dave, Kishan N; Mishra, Priyanka; Rissman, Robert A; Yuan, Shauna H (J Alzheimers Dis, 2019)
Progressive accumulation of aggregation-prone proteins, amyloid-β (Aβ) and hyperphosphorylated tau (p-tau), are the defining hallmarks of Alzheimer's disease (AD). The mechanisms by which Aβ and p-tau are transmitted throughout the diseased brain are not yet completely understood. Interest in exosome research has grown dramatically over the past few years, specifically due to their potential role as biomarkers for staging of neurodegenerative diseases, including AD. Despite their diagnostic utility, the pathogenic potential of exosomes has yet to be fully elucidated. In this study, we use a series of recombinant tau antibodies to characterize a new model of human tau in vivo. Exosome suspensions derived from neuronally-differentiated, human induced pluripotent stem cells that express the repeat domain of tau P301L and V337M mutations (NiPSCEs) were injected into the wild-type mouse brain and pathological changes were characterized by immunostaining at one- (1 m) and two-month (2 m) post-injection. We found that tau inclusions were present throughout the brain at 2 m post-injection, which were detectable using antibodies raised against full-length tau (K9JA) and misfolded tau (MC1). Furthermore, we found that phosphorylated tau immunoreactivity was elevated 1 m post-injection, which was surprisingly normalized after 2 m. Finally, we observed extensive degeneration of neuronal dendrites in both ipsilateral and contralateral hippocampi in NiPSCE treated mice. In summary, we demonstrate that exosomes are sufficient to cause long-distance propagation of tau pathology and neurodegeneration in vivo. These novel findings support an active role of exosomes in AD pathogenesis.

Putative Survival Advantages in Young Apolipoprotein ɛ4 Carriers are Associated with Increased Neural Stress. - Smith, Carr J; Ashford, J Wesson; Perfetti, Thomas A (J Alzheimers Dis, 2019)
Inheritance of a single copy of the apolipoprotein E (APOE) ɛ4 allele increases risk of Alzheimer's disease (AD) by 3-4-fold, with homozygosity associated with a 12-16-fold increase in risk, relative to ɛ3 allele homozygosity. There is a decreased risk associated with the APOE ɛ2 allele. The pathological consequence of APOE genotype has led to intense efforts to understand the mechanistic basis of the interplay between APOE status and loss of synapses. Numerous ɛ4 allele-related associations have been reported with the potential relevance of these associations to the pathogenesis of AD unknown at this time. In primarily young subjects, we have reviewed a representative body of literature on ɛ4 allele-associations related to the following: cardiovascular responses; impacts on reproduction and fetal development; co-morbidities; resistance to infectious disease; responses to head injury; biochemical differences possibly related to neural stress; and brain structure-function differences. In addition, the literature on the association between the ɛ4 allele and cognitive performance has been reviewed comprehensively. The weight-of-the-evidence supports the hypothesis that possession of the ancestral ɛ4 allele in youth is associated with improved fitness during fetal development, infancy, and youth relative to the more recently appearing ɛ3 allele, at the expense of decreased fitness in old age, which is substantially improved by the ɛ3 allele. However, possession of the ɛ4 allele is also associated with higher levels of synaptic macromolecular turnover, which likely stresses basic cellular neuroplasticity mechanisms. Clinical trials of potential AD therapeutics should consider APOE status as an enrollment criterion.

Self and Informant Memory Reports in FINGER: Associations with Two-Year Cognitive Change. - Vaskivuo, Laura; Hokkanen, Laura; Hänninen, Tuomo; Antikainen, Riitta; Bäckman, Lars; Laatikainen, Tiina; Paajanen, Teemu; Stigsdotter-Neely, Anna; Strandberg, Timo; Tuomilehto, Jaakko; Soininen, Hilkka; Kivipelto, Miia; et al. (J Alzheimers Dis, 2019)
BACKGROUND: Subjective memory complaints (SMCs) may be the first sign of cognitive decline in aging. OBJECTIVE: To examine whether SMCs reported by oneself and informant predict cognitive change over 2 years among at-risk elderly people, and to determine the relationship of different types of SMCs (prospective and retrospective memory complaints) and change in cognitive function. METHODS: This investigation is part of the FINGER project, which is a multicenter randomized controlled trial aiming at preventing cognitive decline in cognitively healthy older adults with increased risk of dementia. A subsample of 303 control-group participants (aged 60-80 years) and their informants (n = 261) rated the frequency of SMCs, using the Prospective and Retrospective Memory Questionnaire (PRMQ). Cognitive performance was measured at baseline and at 1- and 2-year follow-up visits using a neuropsychological test battery. RESULTS: Participants who reported more SMCs improved less in global cognition, executive function, and memory during the subsequent 2 years in the fully-adjusted analyses. Self-reported retrospective memory problems predicted less improvement in all cognitive domains, whereas prospective memory problems did not. Informant-reported memory problems were not linked to subsequent change in cognition. CONCLUSION: Our results indicate that self-reported SMCs, measured with PRMQ, predict future cognitive change in several cognitive domains. By contrast, reports by informants were not linked to changes in cognition. Among cognitively healthy at-risk elderly individuals, the persons themselves observe more easily problems relevant for their future cognitive trajectories than their informants.

Small Molecule Amyloid-β Protein Precursor Processing Modulators Lower Amyloid-β Peptide Levels via cKit Signaling. - Chen, Ci-Di; Zeldich, Ella; Khodr, Christina; Camara, Kaddy; Tung, Tze Yu; Lauder, Emma C; Mullen, Patrick; Polanco, Taryn J; Liu, Yen-Yu; Zeldich, Dean; Xia, Weiming; Van Nostrand, William E; et al. (J Alzheimers Dis, 2019)
Alzheimer's disease (AD) is characterized by the accumulation of neurotoxic amyloid-β (Aβ) peptides consisting of 39-43 amino acids, proteolytically derived fragments of the amyloid-β protein precursor (AβPP), and the accumulation of the hyperphosphorylated microtubule-associated protein tau. Inhibiting Aβ production may reduce neurodegeneration and cognitive dysfunction associated with AD. We have previously used an AβPP-firefly luciferase enzyme complementation assay to conduct a high throughput screen of a compound library for inhibitors of AβPP dimerization, and identified a compound that reduces Aβ levels. In the present study, we have identified an analog, compound Y10, which also reduced Aβ. Initial kinase profiling assays identified the receptor tyrosine kinase cKit as a putative Y10 target. To elucidate the precise mechanism involved, AβPP phosphorylation was examined by IP-western blotting. We found that Y10 inhibits cKit phosphorylation and increases AβPP phosphorylation mainly on tyrosine residue Y743, according to AβPP751 numbering. A known cKit inhibitor and siRNA specific to cKit were also found to increase AβPP phosphorylation and lower Aβ levels. We also investigated a cKit downstream signaling molecule, the Shp2 phosphatase, and found that known Shp2 inhibitors and siRNA specific to Shp2 also increase AβPP phosphorylation, suggesting that the cKit signaling pathway is also involved in AβPP phosphorylation and Aβ production. We further found that inhibitors of both cKit and Shp2 enhance AβPP surface localization. Thus, regulation of AβPP phosphorylation by small molecules should be considered as a novel therapeutic intervention for AD.

Stem Cell-Derived Neurons as Cellular Models of Sporadic Alzheimer's Disease. - Foveau, Bénédicte; Correia, Ana Sofia; Hébert, Sébastien S; Rainone, Sara; Potvin, Olivier; Kergoat, Marie-Jeanne; Belleville, Sylvie; Duchesne, Simon; LeBlanc, Andréa C (J Alzheimers Dis, 2019)
Alzheimer's disease (AD) occurs as either an autosomal dominant inherited disease or sporadically. While familial mutant genes can be expressed in cells or in animal models to assess dysregulated functions, sporadic AD cannot be replicated in models given our lack of understanding of causality. Furthermore, the study of sporadic forms of AD is difficult given the inaccessibility of brain tissues in living individuals and the manifestation of symptoms years after the onset of disease. Here, the objective was to assess if induced pluripotent stem cell-derived neurons from well-ascertained sporadic AD individuals could represent potential cellular models to determine the underlying molecular mechanisms of disease. We used cryopreserved peripheral blood mononuclear cells from three well-ascertained sporadic AD and three non-cognitively impaired (NCI) individuals of the CIMA-Q cohort to obtain iPSC-derived neurons. Microtubule associated protein 2 was decreased in AD neurons, whereas expression of AD-associated amyloid precursor protein, tau, and amyloid-β peptide was similar in AD and NCI individuals. RNA sequencing identified several upregulated and downregulated mRNAs in AD relative to NCI neurons. Of these, complement Factor H (CFH), signal regulatory protein beta1 (SIRPB1), and insulin like growth factor binding protein 5 (IGFBP5) were previously associated with AD. In addition, several transcription factors not previously associated with AD, but involved in neuronal proliferation and differentiation were differentially expressed. The results identify novel avenues for the study of the underlying causes of sporadic AD and support the establishment of additional lines to identify mechanisms of disease in sporadic AD individuals.

Subjective Cognitive Decline May Be a Stronger Predictor of Incident Dementia in Women than in Men. - Heser, Kathrin; Kleineidam, Luca; Wiese, Birgitt; Oey, Anke; Roehr, Susanne; Pabst, Alexander; Kaduszkiewicz, Hanna; van den Bussche, Hendrik; Brettschneider, Christian; König, Hans-Helmut; Weyerer, Siegfried; Werle, Jochen; et al. (J Alzheimers Dis, 2019)
BACKGROUND/OBJECTIVE: Subjective cognitive decline (SCD) has often been associated with an increased risk for subsequent dementia. However, sex-specific associations are understudied until now. METHODS: Cross-sectional and longitudinal associations over a follow-up period of up to 13 years were investigated in a sample of participants without objective cognitive impairment at baseline (n = 2,422, mean age = 79.63 years). Logistic regression and Cox proportional hazards models were conducted. RESULTS: Women less frequently reported SCD without worries (p <  0.001), but tended to report more often SCD with worries (p = 0.082) at baseline compared to men. In models adjusted for age, education, cognitive status, and depressive symptoms, SCD at baseline increased the risk for subsequent dementia (p <  0.001), and this effect was less pronounced in males (interaction sex×SCD: p = 0.022). Stratified analyses showed that SCD increased the risk for subsequent dementia in women (HR = 1.77, p <  0.001), but not in men (HR = 1.07, p = 0.682). Similar results were found in analyses with SCD without and with worries, except that SCD with worries also predicted subsequent Alzheimer's disease (AD) in men (p = 0.037). CONCLUSION: At baseline, men reported more SCD without worries and women tended to report more SCD with worries. SCD in women was more strongly associated with subsequent dementia. SCD without and with worries was related to incident dementia and AD in women, whereas in men only SCD with worries increased the risk for AD, but not for all-cause dementia.

Tau Biology, Tauopathy, Traumatic Brain Injury, and Diagnostic Challenges. - Castellani, Rudy J; Perry, George (J Alzheimers Dis, 2019)
There is considerable interest in the pathobiology of tau protein, given its potential role in neurodegenerative diseases and aging. Tau is an important microtubule associated protein, required for the assembly of tubulin into microtubules and maintaining structural integrity of axons. Tau has other diverse cellular functions involving signal transduction, cellular proliferation, developmental neurobiology, neuroplasticity, and synaptic activity. Alternative splicing results in tau isoforms with differing microtubule binding affinity, differing representation in pathological inclusions in certain disease states, and differing roles in developmental biology and homeostasis. Tau haplotypes confer differing susceptibility to neurodegeneration. Tau phosphorylation is a normal metabolic process, critical in controlling tau's binding to microtubules, and is ongoing within the brain at all times. Tau may be hyperphosphorylated, and may aggregate as detectable fibrillar deposits in tissues, in both aging and neurodegenerative disease. The hypothesis that p-tau is neurotoxic has prompted constructs related to isomers, low-n assembly intermediates or oligomers, and the "tau prion". Human postmortem studies have elucidated broad patterns of tauopathy, with tendencies for those patterns to differ as a function of disease phenotype. However, there is extensive overlap, not only between genuine neurodegenerative diseases, but also between aging and disease. Recent studies highlight uniqueness to pathological patterns, including a pattern attributed to repetitive head trauma, although clinical correlations have been elusive. The diagnostic process for tauopathies and neurodegenerative diseases in general is challenging in many respects, and may be particularly problematic for postmortem evaluation of former athletes and military service members.

Tracking Cognitive Performance in the General Population and in Patients with Mild Cognitive Impairment with a Self-Applied Computerized Test (Brain on Track). - Ruano, Luis; Severo, Milton; Sousa, Andreia; Ruano, Catarina; Branco, Mariana; Barreto, Rui; Moreira, Sandra; Araújo, Natália; Pinto, Paula; Pais, Joana; Lunet, Nuno; Cruz, Vítor Tedim (J Alzheimers Dis, 2019)
Repeated measurements could be helpful to identify patients with early cognitive decline. We compare the variation of cognitive performance over one year in patients with mild cognitive impairment (MCI) and healthy individuals using the Brain on Track self-applied computerized test (BoT). The study was initiated 30 patients with probable MCI and 377 controls from a population-based cohort, who performed the BoT test from home every three months for one year. The scores were compared using a linear mixed-effects model. All participants increased their scores in the first tests, after 120 days MCI patients started to decline, with a statistically significant higher rate. The area under the curve to detect MCI was 0.94. We identified a significant decline in cognitive performance over one year in patients with MCI using BoT and the test presented a high discriminative ability.

Transcriptome Changes in the Alzheimer's Disease Middle Temporal Gyrus: Importance of RNA Metabolism and Mitochondria-Associated Membrane Genes. - Piras, Ignazio S; Krate, Jonida; Delvaux, Elaine; Nolz, Jennifer; Mastroeni, Diego F; Persico, Antonio M; Jepsen, Wayne M; Beach, Thomas G; Huentelman, Matthew J; Coleman, Paul D (J Alzheimers Dis, 2019)
We used Illumina Human HT-12 v4 arrays to compare RNA expression of middle temporal gyrus (MTG; BA21) in Alzheimer's disease (AD = 97) and non-demented controls (ND = 98). A total of 938 transcripts were highly differentially expressed (adj p < 0.01; log2 FC ≥ |0.500|, with 411 overexpressed and 527 underexpressed in AD. Our results correlated with expression profiling in neurons from AD and ND obtained by laser capture microscopy in MTG from an independent dataset (log2 FC correlation: r = 0.504; p = 2.2e-16). Additionally, selected effects were validated by qPCR. ANOVA analysis yielded no difference between genders in response to AD, but some gender specific genes were detected (e.g., IL8 and AGRN in males, and HSPH1 and GRM1 in females). Several transcripts were associated with Braak staging (e.g., AEBP1 and DNALI1), antemortem MMSE (e.g., AEBP1 and GFAP), and tangle density (e.g., RNU1G2, and DNALI1). At the pathway level, we detected enrichment of synaptic vesicle processes and GABAergic transmission genes. Finally, applying the Weighted Correlation Network Analysis, we identified four expression modules enriched for neuronal and synaptic genes, mitochondria-associated membrane, chemical stimulus and olfactory receptor and non-coding RNA metabolism genes. Our results represent an extensive description of MTG mRNA profiling in a large sample of AD and ND. These data provide a list of genes associated with AD, and correlated to neurofibrillary tangles density. In addition, these data emphasize the importance of mitochondrial membranes and transcripts related to olfactory receptors in AD.

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.

Understanding the Amyloid Hypothesis in Alzheimer's Disease. - Paroni, Giulia; Bisceglia, Paola; Seripa, Davide (J Alzheimers Dis, 2019)
The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer's disease (IAD). However, despite the neuropathological overlapping with the non-inherited form (NIAD), AH waver in explaining NIAD. Thus, 30 years after its first statement several questions are still open, mainly regarding the role of amyloid plaques (AP) and apolipoprotein E (APOE). Accordingly, a pathogenetic model including the role of AP and APOE unifying IAD and NIAD pathogenesis is still missing. In the present understanding of the AH, we suggested that amyloid-β (Aβ) peptides production and AP formation is a physiological aging process resulting from a systemic age-related decrease in the efficiency of the proteins catabolism/clearance machinery. In this pathogenetic model Aβ peptides act as neurotoxic molecules, but only above a critical concentration [Aβ]c. A threshold mechanism triggers IAD/NIAD onset only when [Aβ]≥[Aβ]c. In this process, APOE modifies [Aβ]c threshold in an isoform-specific way. Consequently, all factors influencing Aβ anabolism, such as amyloid beta precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) gene mutations, and/or Aβ catabolism/clearance could contribute to exceed the threshold [Aβ]c, being characteristic of each individual. In this model, AP formation does not depend on [Aβ]c. The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be observed in healthy aging and why they are not the cause of AD. It is clear that further studies are needed to confirm our pathogenetic model. Nevertheless, our suggestion may be useful to better understand the pathogenesis of AD.

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.

ABC Transporters Are Key Players in Alzheimer's Disease. - Pereira, Cátia D; Martins, Filipa; Wiltfang, Jens; da Cruz E Silva, Odete A B; Rebelo, Sandra (J Alzheimers Dis, 2018)
Human ATP-binding cassette (ABC) transporters mediate a critical function in the cell, namely the transport of molecules across lipid membranes. Associated to their ubiquitous tissue distribution, they are key players in cellular homeostasis but also potential causative or contributing factors for many pathologies, including Alzheimer's disease (AD). In the central nervous system (CNS), numerous ABC transporters are present throughout the brain parenchyma and especially at the blood-brain barrier (BBB). AD is a neurodegenerative disorder mainly characterized by extracellular deposition of amyloid-β (Aβ) peptides and intracellular accumulation of hyperphosphorylated forms of tau protein. Besides being degraded via proteolytic and phagocytic processes mediated by brain parenchymal cells, a major mechanism for eliminating cerebral Aβ is through its transport across the BBB into the peripheral blood. In fact, many AD cases are associated with impaired Aβ clearance. Consistently, several studies have recently uncovered important roles for ABC transporters in AD pathophysiology. Hence, this review focuses on the relevance of ABC transporters in CNS homeostasis by highlighting AD as a strong example of the deleterious consequences that might result from the former's altered expression and/or activity in the brain. The potentiality of human ABC transporters as novel pharmacological targets for both the diagnosis and therapeutics of AD is emphasized.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; ATP-Binding Cassette Transporters; Blood-Brain Barrier; Humans

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.

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.

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.

Albuminuria and Microalbuminuria as Predictors of Cognitive Performance in a General Population: An 11-Year Follow-Up Study. - Ekblad, Laura L; Toppala, Sini; Johansson, Jouni K; Koskinen, Seppo; Sundvall, Jouko; Rinne, Juha O; Puukka, Pauli; Viitanen, Matti; Jula, Antti (J Alzheimers Dis, 2018)
Microalbuminuria, defined as urine albumin-to-creatinine ratio (UACR)>3.0 mg/mmol and ≤ 30 mg/mmol, is an early marker of endothelial damage of the renal glomeruli. Recent research suggests an association among microalbuminuria, albuminuria (UACR > 3.0 mg/mmol), and cognitive impairment. Previous studies on microalbuminuria, albuminuria, and cognition in the middle-aged have not provided repeated cognitive testing at different time-points. We hypothesized that albuminuria (micro- plus macroalbuminuria) and microalbuminuria would predict cognitive decline independently of previously reported risk factors for cognitive decline, including cardiovascular risk factors. In addition, we hypothesized that UACR levels even below the cut-off for microalbuminuria might be associated with cognitive functioning. These hypotheses were tested in the Finnish nationwide, population-based Health 2000 Survey (n = 5,921, mean age 52.6, 55.0% women), and its follow-up, Health 2011 (n = 3,687, mean age at baseline 49.3, 55.6% women). Linear regression analysis was used to determine the associations between measures of albuminuria and cognitive performance. Cognitive functions were assessed with verbal fluency, word-list learning, word-list delayed recall (at baseline and at follow-up), and with simple and visual choice reaction time tests (at baseline only). Here, we show that micro- plus macroalbuminuria associated with poorer word-list learning and a slower reaction time at baseline, with poorer word-list learning at follow-up, and with a steeper decline in word-list learning during 11 years after multivariate adjustments. Also, higher continuous UACR consistently associated with poorer verbal fluency at levels below microalbuminuria. These results suggest that UACR might have value in evaluating the risk for cognitive decline.
Keywords: Adult; Aged; Albuminuria; Cognition; Cognitive Dysfunction; Creatinine; Cross-Sectional Studies; Female; Finland; Follow-Up Studies; Humans; Kidney; Linear Models; Male; Middle Aged; Multivariate Analysis; Neuropsychological Tests; Risk Factors

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

Alzheimer-Like Pattern of Hypometabolism Emerges with Elevated Amyloid-β Burden in Down Syndrome. - Lao, Patrick J; Handen, Ben L; Betthauser, Tobey J; Mihaila, Iulia; Hartley, Sigan L; Cohen, Annie D; Tudorascu, Dana L; Bulova, Peter D; Lopresti, Brian J; Tumuluru, Rameshwari V; Murali, Dhanabalan; Mathis, Chester A; et al. (J Alzheimers Dis, 2018)
BACKGROUND: The Down syndrome (DS) population is genetically predisposed to amyloid-β protein precursor overproduction and Alzheimer's disease (AD). OBJECTIVE: The temporal ordering and spatial association between amyloid-β, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD. METHODS: Twenty-four adults (13 male, 11 female; 39±7 years) with DS underwent [11C]PiB, [18F]FDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest. RESULTS: Positive associations of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume. CONCLUSIONS: In adults with DS, early amyloid-β accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-β, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions.
Keywords: Adult; Alzheimer Disease; Amyloid beta-Peptides; Down Syndrome; Female; Fluorodeoxyglucose F18; Gray Matter; Humans; Linear Models; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; United States

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 Progression: Factors Influencing Cognitive Decline. - Ferrari, Camilla; Lombardi, Gemma; Polito, Cristina; Lucidi, Giulia; Bagnoli, Silvia; Piaceri, Irene; Nacmias, Benedetta; Berti, Valentina; Rizzuto, Debora; Fratiglioni, Laura; Sorbi, Sandro (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) patients present high variability in the rate of cognitive decline. Despite the wide knowledge on factors influencing dementia risk, little is known on what accounts for AD progression. Previous studies on this topic have mainly analyzed each factor separately without taking into account the interaction between genetic and non-genetic factors. OBJECTIVE: The aim of the present study is to evaluate the role of demographic, clinical, therapeutic, and genetic factors and their interaction on cognitive decline among newly diagnosed AD patients. METHODS: We retrospectively selected 160 AD patients diagnosed at the Neurology Unit of Careggi University Hospital of Florence. We evaluated the occurrence of rapid cognitive changes defined as the worsening of more than four points at the Mini-Mental State Examination after 2-year follow up period. RESULTS: Among the 160 AD patients, 50% presented rapid disease progression. Extrapyramidal signs at disease onset were predictors of worse outcome (OR 2.2), especially among Apolipoprotein E (APOE) ɛ4 allele carriers, while the presence of family history for dementia decreased the risk of rapid progression by about 50%. Higher educated ɛ4-carriers showed a slower AD progression. We identified the chronic use of aspirin as potential secondary preventative strategy for the non ɛ4-carriers. CONCLUSION: At dementia onset, some clinical and demographic data can be predictors of future progression. The outcomes of the present study support the already hypothesized interaction between genetic and non-genetic factors during disease course and suggest genetic-based approaches.
Keywords: Aged; Aged, 80 and over; Alleles; Alzheimer Disease; Apolipoprotein E4; Aspirin; Cognitive Dysfunction; Disease Progression; Female; Heterozygote; Humans; Italy; Male; Middle Aged; Neuropsychological Tests; Retrospective Studies; Secondary Prevention

Amyloid Accumulation and Cognitive Decline in Clinically Normal Older Individuals: Implications for Aging and Early Alzheimer's Disease. - Mormino, Elizabeth C; Papp, Kathryn V (J Alzheimers Dis, 2018)
The aberrant accumulation of the amyloid protein is a critical and early event in the Alzheimer's disease (AD) cascade. Given the early involvement of this pathological process, it is not surprising that many clinically normal (CN) older individuals demonstrate evidence of abnormal Aβ at postmortem examination and in vivo using either CSF or PET imaging. Converging evidence across multiple research groups suggests that the presence of abnormal Aβ among CN individuals is associated with elevated risk of future clinical impairment and cognitive decline. Amyloid positivity in conjunction with biomarkers of neuronal injury offers further insight into which CN are most at risk for short-term decline. Although in its infancy, tau PET has demonstrated early increases among Aβ+ that will likely be an important indicator of risk among CN. Overall, the detection of early Aβ among CN individuals has provided an important opportunity to understand the contributions of this pathology to age-related cognitive decline and to explore early intervention with disease modifying strategies.

Amyloid-Mediated Cholinergic Dysfunction in Motor Impairment Related to Alzheimer's Disease. - Schirinzi, Tommaso; Di Lorenzo, Francesco; Sancesario, Giulia Maria; Di Lazzaro, Giulia; Ponzo, Viviana; Pisani, Antonio; Mercuri, Nicola Biagio; Koch, Giacomo; Martorana, Alessandro (J Alzheimers Dis, 2018)
BACKGROUND: Although motor disturbances parallel the course of dementia, worsening both quality of life and social costs, the pathogenesis remains still unclear. OBJECTIVE: Through the combination of cerebrospinal fluid (CSF) biomarkers assessment and transcranial magnetic stimulation (TMS) protocols, here we provided a cross-sectional study to understand pathogenic mechanisms of Alzheimer's disease (AD)-related early motor disturbances. METHODS: The motor phenotype, as defined with Unified Parkinson's Disease Rating Scale (UPDRS) part 2-3, Rating Scale for Gait Evaluation in Cognitive Deterioration (RSEGCD) and Tinetti scale, together with CSF profile of amyloid-β 42 (Aβ42), total-tau, and phosphorylated-tau were determined in 37 AD patients and compared to 18 patients with vascular dementia (VaD). A TMS protocol of short afferent inhibition (SAI) was further applied on a subset of AD patients. Clinical, biochemical, and neurophysiological data were then compared and correlated in order to find significant associations. RESULTS: AD patients exhibited subtle locomotor impairment and slight extrapyramidal signs. Main motor features (UPDRS part 3, RSGECD, and Tinetti scale scores) correlate with Aβ42 levels but not with t-tau and p-tau. AD patients also presented SAI impairment directly related to UPDRS part 3 score and Aβ42 levels. Motor disturbances of VaD group did not differ statistically from AD and did not correlate with CSF biomarkers. CONCLUSIONS: The association of motor disturbances with low Aβ42 CSF levels and individual SAI suggests that amyloid-mediated degeneration of cholinergic system may account for early AD-related motor impairment, providing interesting insights either for frailty stratification of patients or personalized therapies.

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.

Antemortem-Postmortem Correlation of Florbetapir (18F) PET Amyloid Imaging with Quantitative Biochemical Measures of Aβ42 but not Aβ40. - Beach, Thomas G; Maarouf, Chera L; Intorcia, Anthony; Sue, Lucia I; Serrano, Geidy E; Lu, Ming; Joshi, Abhinay; Pontecorvo, Michael J; Roher, Alex E (J Alzheimers Dis, 2018)
Amyloid imaging demonstrates the in vivo presence of amyloid-β (Aβ) deposits in the aging human brain but it is still unknown which structural forms and modifications of Aβ are detected. In Alzheimer's disease, most amyloid deposits are predominantly composed of Aβ ending at amino acid residues Val40 or Ala42. It has been reported that Aβ40 is largely restricted to neuritic plaques while Aβ42 may be deposited in amyloid plaques of all types, and is often the sole component of diffuse plaques. The distinction is important as it is mainly the neuritic plaques that correlate with cognitive impairment while diffuse plaques may be the initial type of Aβ deposited. Whether PET amyloid ligands such as florbetapir-18F (Amyvid) are partially or wholly selective for brain deposits of Aβ40 or Aβ42 is currently unknown. We compared antemortem florbetapir PET cortical/cerebellar signal intensity (SUVr) of 55 subjects with postmortem biochemical (ELISA) measurements employing specific antibodies against Aβ40 and Aβ42. Spearman's univariable correlations were significant for both Aβ40 and Aβ42, but were much stronger for Aβ42. Multiple linear regression showed significance only for Aβ42. These results suggest that florbetapir binds only weakly, if at all, to Aβ40. This may be in part due to the higher likelihood for Aβ42 to be present in a β-pleated sheet tertiary structure, or to differences between Aβ40 and Aβ42 in β-pleated sheet tertiary or quaternary structure.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Aniline Compounds; Autopsy; Brain; Ethylene Glycols; Humans; Linear Models; Peptide Fragments; Plaque, Amyloid; Positron-Emission Tomography

An Aspartyl Cathepsin Targeted PET Agent: Application in an Alzheimer's Disease Mouse Model. - Snir, Jonatan A; Suchy, Mojmir; Bindseil, Geron A; Kovacs, Michael; Chronik, Blaine A; Hudson, Robert H E; Pasternak, Stephen H; Bartha, Robert (J Alzheimers Dis, 2018)
BACKGROUND: Early detection of Alzheimer's disease (AD) pathology is a serious challenge for both diagnosis and clinical trials. The aspartyl protease, Cathepsin D (CatD), is overexpressed in AD and could be a biomarker of disease. We have previously designed a unique contrast agent (CA) for dual-optical and magnetic resonance imaging of the activity of the CatD class of enzymes. OBJECTIVE: To compare the uptake and retention of a novel, more sensitive, and clinically-translatable 68Ga PET tracer targeting CatD activity in 5XFAD mice and non-Tg littermates. METHODS: The targeted CA consisted of an HIV-1 Tat cell penetrating peptide (CPP) conjugated to a specialized cleavage sequence targeting aspartyl cathepsins and a DOTA conjugate chelating 68Ga. PET images were acquired using a Siemens Inveon preclinical microPET in female Tg AD mice and non-Tg age matched female littermates (n = 5-8) following intravenous CA administration at 2, 6, and 9 months of age. Additionally, 18F fluorodeoxyglucose (FDG) PET imaging was performed at 10 months to measure glucose uptake. RESULTS: The Tg mice showed significantly higher relative uptake rate of the targeting CA in the forebrain relative to hindbrain at all ages compared to controls, consistent with histology. In contrast, no differences were seen in CA uptake in other organs. Additionally, the Tg mice did not show any differences in relative uptake of FDG at 10 months of age in the forebrain relative to the hindbrain compared to age matched non-Tg controls. CONCLUSIONS: Elevated aspartryl cathepsin activity was detected in vivo in the 5XFAD mouse model of AD using a novel targeted PET contrast agent.
Keywords: Alzheimer Disease; Animals; Brain; Cathepsin D; Contrast Media; Disease Models, Animal; Female; Fluorodeoxyglucose F18; Glucose; Mice; Mice, Transgenic; Positron-Emission Tomography

Assessing Mild Behavioral Impairment with the Mild Behavioral Impairment-Checklist in People with Mild Cognitive Impairment. - Mallo, Sabela C; Ismail, Zahinoor; Pereiro, Arturo X; Facal, David; Lojo-Seoane, Cristina; Campos-Magdaleno, María; Juncos-Rabadán, Onésimo (J Alzheimers Dis, 2018)
BACKGROUND: Neuropsychiatric symptoms (NPS) are non-cognitive, behavioral, or psychiatric symptoms, common in mild cognitive impairment (MCI) and associated with a higher risk of dementia. Mild behavioral impairment (MBI) is a validated diagnostic entity, that describes the emergence of later life NPS in pre-dementia states. The Mild Behavioral Impairment Checklist (MBI-C) is the first measure developed to assess MBI. OBJECTIVE: To estimate the prevalence of MBI in people with MCI and to study the score distribution, sensitivity, specificity, diagnostic utility of the MBI-C, and its correlations with neuropsychological tests. METHODS: One hundred eleven MCI participants were evaluated with the Questionnaire for Subjective Memory Complaints (QSMC), Mini-Mental State Examination, Cambridge Cognitive Assessment-Revised, Neuropsychiatric Inventory-Questionnaire (NPI-Q), Geriatric Depression Scale-15 items (GDS-15), Lawton and Brody Index, and the MBI-C, which was administered by phone to participants' informants. Descriptive, logistic regression, ROC curve, and bivariate correlations analyses were performed. RESULTS: MBI diagnosis prevalence was 14.2%. The total MBI-C score differentiated people with MBI at a cutoff-point of 6.5, optimizing sensitivity and specificity. MBI-C total score correlated positively with NPI-Q, QSMC, GDS-15, and Lawton and Brody Index. CONCLUSION: The total MBI-C score, obtained by phone administration, is sensitive for detecting MBI in people with MCI. The MBI-C scores indicated that MCI participants had subtle NPS that were correlated to their subjective memory complaints reported by informants, depressive symptoms, and negatively with Instrumental Activities of Daily Living. Further research should be done to clarify the predictive role of NPS in MCI for incident dementia.

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

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.

The Association between Social Engagement, Loneliness, and Risk of Dementia: A Systematic Review and Meta-Analysis. - Penninkilampi, Ross; Casey, Anne-Nicole; Singh, Maria Fiatarone; Brodaty, Henry (J Alzheimers Dis, 2018)
It has been reported that social engagement may be associated with dementia risk. We searched PubMed, EMBASE, PsycINFO, CINAHL, LILACS, Biomed Central, Scopus, and Web of Science from January 2012 - May 2017, supplemented by extraction from previous reviews. We included cohort and case-control studies examining the association between social engagement or loneliness and dementia risk, pooling data using a random-effects model. Registered: PROSPERO (CRD42017067074). We included 31 cohort and 2 case-control studies comprising 2,370,452 participants. Poor social engagement indices were associated with increased dementia risk, including having a poor social network (RR = 1.59, 95% CI 1.31-1.96; I2 = 0.00%) and poor social support (RR = 1.28, 95% CI 1.01-1.62; I2 = 55.51%). In long-term studies (≥10 years), good social engagement was modestly protective (RR = 0.88, 95% CI 0.80-0.96; I2 = 0.00%). Loneliness was non-significantly associated with increased risk (RR = 1.38, 95% CI 0.98-1.94; I2 = 45.32). Our findings encourage interventions targeting social isolation and disengagement for dementia prevention.

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 the New Variant Tyr424Asp at TBK1 Gene with Amyotrophic Lateral Sclerosis and Cognitive Decline. - Piaceri, Irene; Bessi, Valentina; Matà, Sabrina; Polito, Cristina; Tedde, Andrea; Berti, Valentina; Bagnoli, Silvia; Braccia, Arianna; Del Mastio, Monica; Pignone, Alberto Moggi; Pupi, Alberto; Sorbi, Sandro; et al. (J Alzheimers Dis, 2018)
A new risk gene associated with amyotrophic lateral sclerosis (ALS) has recently been identified: the Tank-binding kinase 1 (TBK1) gene. Up to now, 90 TBK1 variants have been described in ALS patients with or without frontotemporal dementia (FTD), thus making TBK1 the third or fourth most frequent genetic cause of ALS and FTD. A point mutation analysis in a cohort of 69 Italian ALS patients was performed in order to analyze the frequency of TBK1 mutations and the correlation with clinical phenotypes. The analysis identified the novel variant p.Tyr424Asp in a patient with a rapid progression of the disease. Our data supports the implication of TBK1 in ALS pathogenesis in Italy.
Keywords: Aged; Amyotrophic Lateral Sclerosis; Aspartic Acid; C9orf72 Protein; Cognitive Dysfunction; DNA Mutational Analysis; Female; Fluorodeoxyglucose F18; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Italy; Male; Mental Status and Dementia Tests; Middle Aged; Mutation; Neuropsychological Tests; Positron-Emission Tomography; Protein-Serine-Threonine Kinases; Tyrosine

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 between Use of Specific Analgesics and Concentrations of Amyloid-β 42 or Phospho-Tau in Regions of Human Cerebral Cortex. - Flanagan, Margaret E; Larson, Eric B; Walker, Rod L; Keene, C Dirk; Postupna, Nadia; Cholerton, Brenna; Sonnen, Joshua A; Dublin, Sascha; Crane, Paul K; Montine, Thomas J (J Alzheimers Dis, 2018)
Analgesics are commonly used by older adults, raising the question of whether their use might contribute to dementia risk and neuropathologic changes of Alzheimer's disease (AD). The Adult Changes in Thought (ACT) study is a population-based study of brain aging and incident dementia among people 65 years or older who are community dwelling and not demented at entry. Amyloid-β (Aβ)42 and phospho-tau were quantified using Histelide in regions of cerebral cortex from 420 brain autopsies. Total standard daily doses of prescription opioid and non-aspirin nonsteroidal anti-inflammatory drug (NSAID) exposure during a defined 10-year exposure window were identified using automated pharmacy dispensing data and used to classify people as having no/low, intermediate, or high exposure. People with high NSAID exposure had significantly greater Aβ42 concentration in middle frontal gyrus and superior and middle temporal gyri, but not inferior parietal lobule; no Aβ42 regional concentration was associated with prescription opioid usage. People with high opioid usage had significantly greater concentration of phospho-tau in middle frontal gyrus than people with little-to-no opioid usage. Consistent with our previous studies, findings suggest that high levels of NSAID use in older individuals may promote Aβ42 accumulation in cerebral cortex.
Keywords: Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Analgesics; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Autopsy; Cerebral Cortex; Female; Humans; Logistic Models; Male; Peptide Fragments; Prospective Studies; tau Proteins

Associations of Genetic Susceptibility to Alzheimer's Disease with Adiposity and Cardiometabolic Risk Factors among Children in a 2-Year Follow-up Study. - Haapala, Eero A; Paananen, Jussi; Hiltunen, Mikko; Lakka, Timo A (J Alzheimers Dis, 2018)
We investigated the associations of genetic risk score (GRS) for Alzheimer's disease and apolipoprotein E (APOE) ɛ variant with cardiometabolic risk factors during 2-year follow-up in children and whether body fat percentage (BF%) modify these associations. A population-based sample of 469 children (246 boys, 223 girls) at baseline and 398 children (201 boys, 197 girls) at 2-year follow-up participated in the study. Genotyping was performed using the Illumina Custom Infinium CardioMetabo BeadChip and the Illumina Infinium HumanCoreExome BeadChip. The GRS was calculated using information on nine independent gene variants available in our genomic data. We assessed BF%, waist circumference, insulin, glucose, triglycerides, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and systolic and diastolic blood pressure. We computed a cardiometabolic risk score and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). In boys, the GRS was not associated with cardiometabolic risk factors. In girls, GRS was directly associated with LDL cholesterol (β= 0.133, 95% CI = 0.002 to 0.262) at baseline and with a higher cardiometabolic risk score (β= 0.154, 95% CI = 0.015 to 0.294), glucose (β= 0.143, 95% CI = 0.003 to 0.284), and HOMA-IR (β= 0.141, 95% CI = 0.004 to 0.278) at 2-year follow-up. GRS was directly associated with a cardiometabolic risk score at baseline and 2-year follow-up among girls in the highest third of BF% at baseline, but not in other girls (p < 0.05 for interaction). Children with the APOEɛ3/3 genotype had higher LDL cholesterol at and 2-year follow-up than those with the APOEɛ2/3 genotype. In conclusion, GRS was associated with increased cardiometabolic risk in girls and especially those with higher BF%.

Atrophy in Distributed Networks Predicts Cognition in Alzheimer's Disease and Type 2 Diabetes. - Buss, Stephanie S; Padmanabhan, Jaya; Saxena, Sadhvi; Pascual-Leone, Alvaro; Fried, Peter J (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) and type 2 diabetes (T2DM) are common causes of cognitive decline among older adults and share strong epidemiological links. Distinct patterns of cortical atrophy are observed in AD and T2DM, but robust comparisons between structure-function relationships across these two disease states are lacking. OBJECTIVE: To compare how atrophy within distributed brain networks is related to cognition across the spectrum of cognitive aging. METHODS: The relationship between structural MRI changes and cognition was studied in 22 mild-to-moderate AD, 28 T2DM, and 27 healthy participants. Cortical thickness measurements were obtained from networks of interest (NOIs) matching the limbic, default, and frontoparietal resting-state networks. Composite cognitive scores capturing domains of global cognition, memory, and executive function were created. Associations between cognitive scores and the NOIs were assessed using linear regression, with age as a covariate. Within-network General Linear Model (GLM) analysis was run in Freesurfer 6.0 to visualize differences in patterns of cortical atrophy related to cognitive function in each group. A secondary analysis examined hemispheric differences in each group. RESULTS: Across all groups, cortical atrophy within the limbic NOI was significantly correlated with Global Cognition (p = 0.009) and Memory Composite (p = 0.002). Within-network GLM analysis and hemispheric analysis revealed qualitatively different patterns of atrophy contributing to cognitive dysfunction between AD and T2DM. CONCLUSION: Brain network atrophy is related to cognitive function across AD, T2DM, and healthy participants. Differences in cortical atrophy patterns were seen between AD and T2DM, highlighting neuropathological differences.

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.

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.

Bi-directional Association of Cerebrospinal Fluid Immune Markers with Stage of Alzheimer's Disease Pathogenesis. - Meyer, Pierre-François; Savard, Mélissa; Poirier, Judes; Labonte, Anne; Rosa-Neto, Pedro; Weitz, Tara M; Town, Terrence; Breitner, John (J Alzheimers Dis, 2018)
Immune mechanisms may be important in the pathogenesis of Alzheimer's disease (AD). Yet, studies comparing cerebrospinal fluid (CSF) and plasma immune marker levels of healthy and demented individuals have yielded conflicting results. We analyzed CSF from 101 members of the parental history-positive PREVENT-AD cohort of healthy aging adults, and 237 participants without dementia from the initial cohort of the Alzheimer's Disease Neuroimaging Initiative (ADNI-1). Following recent practice, we used the biomarkers total-tau and amyloid-β1-42 to allocate participants from each study into four stages of AD pathogenesis: Stage 0 (no abnormality), Stage 1 (reduced amyloid-β1-42), Stage 2 (reduced amyloid-β1-42 and increased total-tau), or "Suspected Non-Alzheimer Pathology" (elevated total-tau only). Investigating the PREVENT-AD participants' CSF assay results for 19 immune/inflammatory markers, we found six that showed a distinct bi-directional relationship with pathogenetic stage. Relative to Stage 0, these were diminished at Stage 1 but strongly increased at Stage 2. Among the ADNI participants (90 healthy controls and 147 with mild cognitive impairment), we found that 23 of 83 available CSF markers also showed this distinct pattern. These results support recent observations that immune activation may become apparent only after the onset of both amyloid and tau pathologies. Unexpectedly, they also suggest that immune marker activity may diminish along with earliest appearance of amyloid-β plaque pathology. These findings may explain discordant results from past studies, and suggest the importance of characterizing the extent of AD pathology when comparing clinical groups.

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 Factors Contributing to the Response to Cognitive Training in Mild Cognitive Impairment. - Peter, Jessica; Schumacher, Lena V; Landerer, Verena; Abdulkadir, Ahmed; Kaller, Christoph P; Lahr, Jacob; Klöppel, Stefan (J Alzheimers Dis, 2018)
In mild cognitive impairment (MCI), small benefits from cognitive training were observed for memory functions but there appears to be great variability in the response to treatment. Our study aimed to improve the characterization and selection of those participants who will benefit from cognitive intervention. We evaluated the predictive value of disease-specific biological factors for the outcome after cognitive training in MCI (n = 25) and also considered motivation of the participants. We compared the results of the cognitive intervention group with two independent control groups of MCI patients (local memory clinic, n = 20; ADNI cohort, n = 302). The primary outcome measure was episodic memory as measured by verbal delayed recall of a 10-word list. Episodic memory remained stable after treatment and slightly increased 6 months after the intervention. In contrast, in MCI patients who did not receive an intervention, episodic memory significantly decreased during the same time interval. A larger left entorhinal cortex predicted more improvement in episodic memory after treatment and so did higher levels of motivation. Adding disease-specific biological factors significantly improved the prediction of training-related change compared to a model based simply on age and baseline performance. Bootstrapping with resampling (n = 1000) verified the stability of our finding. Cognitive training might be particularly helpful in individuals with a bigger left entorhinal cortex as individuals who did not benefit from intervention showed 17% less volume in this area. When extended to alternative treatment options, stratification based on disease-specific biological factors is a useful step towards individualized medicine.
Keywords: Aged; Aged, 80 and over; Analysis of Variance; Apolipoproteins E; Biological Factors; Cognitive Behavioral Therapy; Cognitive Dysfunction; Entorhinal Cortex; Female; Follow-Up Studies; Functional Laterality; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Mental Recall; Middle Aged; Neuropsychological Tests; Reaction Time; Spatial Navigation; Treatment Outcome

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.

Blood Glucose Levels May Exacerbate Executive Function Deficits in Older Adults with Cognitive Impairment. - Pappas, Colleen; Small, Brent J; Andel, Ross; Laczó, Jan; Pařízková, Martina; Ondrej, Lerch; Hort, Jakub (J Alzheimers Dis, 2018)
BACKGROUND: Identifying protective factors that promote healthy cognitive aging is of importance due to the growing older adult population. Preventing chronic hyperglycemia may be one such way to preserve cognitive abilities, as high blood glucose levels have been associated with cognitive impairment and decline. OBJECTIVE: To evaluate the influence of blood glucose levels on cognition among older adults using common neuropsychological tests and a spatial navigation task. METHODS: The association between cognitive performance and blood glucose levels was assessed among 117 older adults classified as cognitively healthy, subjective cognitive decline, amnestic mild cognitive impairment, or Alzheimer's disease dementia from the Czech Brain Aging Study. Cognitive abilities were measured by tests of verbal memory, nonverbal memory, working memory, visuospatial skills, and executive function. A test of spatial navigation known as the Hidden Goal Task was also used. Blood glucose levels were measured by glycosylated hemoglobin A1c (HbA1c). Analyses were performed using multiple linear regression controlling for age, gender, education, depressive symptoms, diabetes, and cognitive status. RESULTS: A significant relationship was observed for HbA1c and executive function performance (beta = -2.46, SE = 0.92, p = 0.008). Following moderation analysis, this relationship was significant only among those with cognitive impairment (beta = -4.37, SE = 1.28, p = 0.001, 95% CI [-6.91, -1.83]). Associations between HbA1c and other cognitive domains were not significant (ps >  0.05). CONCLUSIONS: Higher HbA1c was associated with poorer executive function among persons with cognitive impairment, but not with performance on other cognitive domains. Maintaining proper glucoregulation may help preserve executive function performance among cognitively impaired older adults.

Blood Inflammatory Mediators and Cognitive Decline in Alzheimer's Disease: A Two Years Longitudinal Study. - Julian, Adrien; Rioux-Bilan, Agnès; Ragot, Stéphanie; Krolak-Salmon, Pierre; Berrut, Gilles; Dantoine, Thierry; Hommet, Caroline; Hanon, Olivier; Page, Guylène; Paccalin, Marc (J Alzheimers Dis, 2018)
Peripheral inflammatory processes are involved in Alzheimer's disease (AD). We aimed to determine whether plasma inflammatory mediator levels at diagnosis are associated with cognitive decline through a 2-year follow-up in AD patients. Patients (n = 109, mean age 79.44 (6.82) years) were included at diagnosis with MMSE scores between 16 and 25, with C-reactive protein <10 mg/L, and without any acute or chronic inflammation status. Plasma IL-1β, IL-6, TNF-α, and CCL5 were measured using Luminex X-MAP technology at baseline, and after one year and two years of follow-up. The mean values of IL-1β, IL-6, TNF-α, and CCL5 at diagnosis were 0.3, 1.94, 6.57, and 69,615.81 pg/mL, respectively. Mean cognitive decline in MMSE was 3.35 points. No correlation between plasmatic value of IL-1β, IL-6, TNF-α, or CCL5 at diagnosis and cognitive decline during the two years of follow-up was found. Cognitive decline in AD does not appear to be predictable by the tested inflammatory mediators.

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.

Cardiorespiratory Fitness and Cognitive Function are Positively Related Among Participants with Mild and Subjective Cognitive Impairment. - Stuckenschneider, Tim; Askew, Christopher David; Rüdiger, Stefanie; Polidori, Maria Cristina; Abeln, Vera; Vogt, Tobias; Krome, Andreas; Olde Rikkert, Marcel; Lawlor, Brian; Schneider, Stefan (J Alzheimers Dis, 2018)
BACKGROUND: By 2030, about 74 million people will be diagnosed with dementia, and many more will experience subjective (SCI) or mild cognitive impairment (MCI). As physical inactivity has been identified to be a strong modifiable risk factor for dementia, exercise and physical activity (PA) may be important parameters to predict the progression from MCI to dementia, but might also represent disease trajectory modifying strategies for SCI and MCI. OBJECTIVE: A better understanding of the relationship between activity, fitness, and cognitive function across the spectrum of MCI and SCI would provide an insight into the potential utility of PA and fitness as early markers, and treatment targets to prevent cognitive decline. METHODS: 121 participants were stratified into three groups, late MCI (LMCI), early MCI (EMCI), and SCI based on the Montreal Cognitive Assessment (MoCA). Cognitive function assessments also included the Trail Making Test A+B, and a verbal fluency test. PA levels were evaluated with an interviewer-administered questionnaire (LAPAQ) and an activity monitor. An incremental exercise test was performed to estimate cardiorespiratory fitness and to determine exercise capacity relative to population normative data. RESULTS: ANCOVA revealed that LMCI subjects had the lowest PA levels (LAPAQ, p = 0.018; activity monitor, p = 0.041), and the lowest exercise capacity in relation to normative values (p = 0.041). Moreover, a modest correlation between MoCA and cardiorespiratory fitness (r = 0.25; p < 0.05) was found. CONCLUSION: These findings suggest that during the earliest stages of cognitive impairment PA and exercise capacity might present a marker for the risk of further cognitive decline. This finding warrants further investigation using longitudinal cohort studies.

Cerebrospinal Fluid Biomarkers in Alzheimer's Disease: An Invaluable Tool for Clinical Diagnosis and Trial Enrichment. - Parnetti, Lucilla; Eusebi, Paolo (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting around 35 million people worldwide. Cerebrospinal fluid (CSF) biomarkers entered the diagnostic criteria as support for early diagnosis. The classical biochemical signature of AD includes total tau (T-tau), phosphorylated tau (P-tau), and the 42 amino acid peptide (Aβ42) of amyloid-β. Recent observations suggest that the use of CSF Aβ42:Aβ40 ratio rather than CSF Aβ42 alone could contribute to reduce inter-laboratory variation in Aβ values and increasing diagnostic performance of the CSF AD biomarkers in routine practice. However, research efforts aimed at enriching the CSF biomarker panel are ongoing. The CSF AD signature is also crucial for the design of clinical trials for AD, since it best guarantees AD pathology as the cause of cognitive impairment. Accordingly, CSF biomarkers have been now reported in the inclusion criteria of Phase I, Phase II, and Phase III clinical trials as enrichment strategy. So far, one of the most important reasons for the failure of AD clinical trials was the inclusion of participants with unlikely AD pathology. In order to implement the use of CSF biomarkers in AD routine diagnostic work-up and as accepted strategy for enriching trial populations, inter-laboratory variability should be minimized. Increasing efforts should also be devoted to promote data sharing practices, encouraging individual participant data meta-analyses.

Cerebrospinal Fluid Biomarkers in Patients with Frontotemporal Dementia Spectrum: A Single-Center Study. - Abu-Rumeileh, Samir; Mometto, Nicola; Bartoletti-Stella, Anna; Polischi, Barbara; Oppi, Federico; Poda, Roberto; Stanzani-Maserati, Michelangelo; Cortelli, Pietro; Liguori, Rocco; Capellari, Sabina; Parchi, Piero (J Alzheimers Dis, 2018)
Cerebrospinal fluid (CSF) neurofilament light chain protein (NfL) and Alzheimer's disease (AD) core biomarker levels have been evaluated in cohorts of patients with frontotemporal dementia spectrum (FTD), but the distribution of values across the different clinical syndromes and underlying proteinopathies, and the relative diagnostic accuracy appear discordant among studies. We measured CSF NfL, total (t)-tau, phosphorylated (p)-tau, and amyloid-β (Aβ)42 in healthy controls (n = 38) and subjects with a clinical, genetic, CSF biomarker-based, and/or neuropathological diagnosis of FTD (n = 141) or AD (n = 60). Sub-analyses were conducted in a proportion of subjects with definite and/or probable frontotemporal lobar degeneration with tau (FTLD-TAU) (n = 42) or TDP43 pathology (FTLD-TDP) (n = 36). Both FTD and AD groups showed significantly increased CSF NfL levels in comparison to controls (p < 0.001). CSF NfL levels were significantly higher in FTD patients than in AD (p < 0.001), reaching the highest values in amyotrophic lateral sclerosis associated with FTD. Patients with probable and definite FTLD-TDP had significantly higher NfL levels (p < 0.001) and lower p-tau/t-tau values (p < 0.001) in comparison with probable and definite FTLD-TAU cases. NfL showed good diagnostic accuracy in the distinction between FTD and controls (AUC 0.862±0.027) and yielded an accuracy (AUC 0.861±0.045) comparable to that of the p-tau/t-tau ratio (AUC 0.814±0.050), with 80.0% sensitivity and 81.0% specificity, in the discrimination between probable/definite FTLD-TAU and FTLD-TDP. Our data further validate CSF NfL as a surrogate biomarker of neurodegeneration and disease severity in patients with FTD spectrum. Moreover, they demonstrate a good diagnostic value for NfL and p-tau/t-tau ratio in the discrimination between FTLD-TAU and FTLD-TDP.

Cerebrospinal Fluid Orexin Levels and Nocturnal Sleep Disruption in Alzheimer's Disease Patients Showing Neuropsychiatric Symptoms. - Liguori, Claudio; Mercuri, Nicola Biagio; Nuccetelli, Marzia; Izzi, Francesca; Bernardini, Sergio; Placidi, Fabio (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. It is characterized by a progressive deterioration of cognition, frequently associated with neuropsychiatric symptoms (NPS). Among NPS, sleep disturbances often affect AD patients. Orexinergic system dysregulation has been associated with sleep impairment in AD patients. OBJECTIVE: The present study investigated CSF orexin levels in AD patients and their relationship with both NPS, measured by the neuropsychiatric inventory (NPI), and sleep, measured via polysomnography. METHODS: This is a secondary analysis of a previous study investigating CSF biomarkers, sleep impairment and cognitive decline in AD patients. AD patients completing the NPI were included in this analysis and distributed in two groups based on the presence (NPI score ≥4, AD/NPS+) or absence (NPI score <4, AD/NPS-) of NPS. RESULTS: Twenty-two AD patients constituted the AD/NPS+ group and 20 patients constituted the AD/NPS-group. We observed higher CSF orexin levels in AD/NPS+ than AD/NPS-patients. Moreover, AD/NPS+ showed a more fragmented and the reduction of REM sleep compared to AD/NPS-patients. Notably, higher NPI scores correlated with a more altered sleep structure, higher CSF orexin levels and lower MMSE scores. CONCLUSION: This study documented that AD patients showing NPS present a more fragmented sleep coupled with higher CSF orexin levels compared to AD patients not affected by NPS. This finding showing the increased orexinergic tone in AD patients affected by NPS suggests the possible influence of the orexinergic system dysregulation not only on sleep impairment but also on neurobehavioral disturbances.

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.

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.

Clinical Subtypes of Dementia with Lewy Bodies Based on the Initial Clinical Presentation. - Morenas-Rodriguez, Estrella; Sala, Isabel; Subirana, Andrea; Pascual-Goñi, Elba; Sánchez-Saudinós, Ma Belén; Alcolea, Daniel; Illán-Gala, Ignacio; Carmona-Iragui, María; Ribosa-Nogué, Roser; Camacho, Valle; Blesa, Rafael; Fortea, Juan; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Dementia with Lewy bodies (DLB) is a heterogeneous disease in which clinical presentation, symptoms, and evolution widely varies between patients. OBJECTIVE: To investigate the existence of clinical subtypes in DLB based on the initial clinical presentation. METHODS: 81 patients with a clinical diagnosis of probable DLB were consecutively included. All patients underwent a neurological evaluation including a structured questionnaire about neuropsychiatric symptoms and sleep, an assessment of motor impairment (Unified Parkinson Disease Rating Scale subscale III), and a formal neuropsychological evaluation. Onset of core symptoms (hallucinations, parkinsonism, and fluctuations) and dementia were systematically reviewed from medical records. We applied a K-means clustering method based on the initial clinical presentation. RESULTS: Cluster analysis yielded three different groups. Patients in cluster I (cognitive-predominant, n = 46) presented more frequently with cognitive symptoms (95.7%, n = 44, p < 0.001), and showed a longer duration from onset to DLB diagnosis (p < 0.001) than the other clusters. Patients in cluster II (neuropsychiatric-predominant, n = 22) were older at disease onset (78.1±5 versus 73.6±6.1 and 73.6±4.2 in clusters I and III, respectively, both p < 0.01), presented more frequently with psychotic symptoms (77.3%, n = 17), and had a shorter duration until the onset of hallucinations (p < 0.001). Patients in cluster III (parkinsonism-predominant, n = 13) showed a shorter time from onset to presence of parkinsonism (p < 0.001) and dementia (0.008). CONCLUSIONS: Three clinical subtypes of DLB can be defined when considering the differential initial presentations. The proposed subtypes have distinct clinical profiles and progression patterns.

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

A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer's Disease Neuropathology. - Alosco, Michael L; Sugarman, Michael A; Besser, Lilah M; Tripodis, Yorghos; Martin, Brett; Palmisano, Joseph N; Kowall, Neil W; Au, Rhoda; Mez, Jesse; DeCarli, Charles; Stein, Thor D; McKee, Ann C; et al. (J Alzheimers Dis, 2018)
BACKGROUND: White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) have been postulated to be a core feature of Alzheimer's disease. Clinicopathological studies are needed to elucidate and confirm this possibility. OBJECTIVE: This study examined: 1) the association between antemortem WMH and autopsy-confirmed Alzheimer's disease neuropathology (ADNP), 2) the relationship between WMH and dementia in participants with ADNP, and 3) the relationships among cerebrovascular disease, WMH, and ADNP. METHODS: The sample included 82 participants from the National Alzheimer's Coordinating Center's Data Sets who had quantitated volume of WMH from antemortem FLAIR MRI and available neuropathological data. The Clinical Dementia Rating (CDR) scale (from MRI visit) operationalized dementia status. ADNP+ was defined by moderate to frequent neuritic plaques and Braak stage III-VI at autopsy. Cerebrovascular disease neuropathology included infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy. RESULTS: 60/82 participants were ADNP+. Greater volume of WMH predicted increased odds for ADNP (p = 0.037). In ADNP+ participants, greater WMH corresponded with increased odds for dementia (CDR≥1; p = 0.038). WMH predicted cerebral amyloid angiopathy, microinfarcts, infarcts, and lacunes (ps < 0.04). ADNP+ participants were more likely to have moderate-severe arteriolosclerosis and cerebral amyloid angiopathy compared to ADNP-participants (ps < 0.04). CONCLUSIONS: This study found a direct association between total volume of WMH and increased odds for having ADNP. In patients with Alzheimer's disease, FLAIR MRI WMH may be able to provide key insight into disease severity and progression. The association between WMH and ADNP may be explained by underlying cerebrovascular disease.

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 Training Improves Ratio Processing and Decision Making in Patients with Mild Cognitive Impairment. - Burgio, Francesca; Delazer, Margarete; Meneghello, Francesca; Pertl, Marie-Theres; Semenza, Carlo; Zamarian, Laura (J Alzheimers Dis, 2018)
BACKGROUND: Patients with mild cognitive impairment (MCI) show lower decision making and ratio processing abilities as compared to healthy peers. OBJECTIVE: To evaluate whether cognitive training on number processing and/or executive functions improves performance on ratio processing and decision making under risk. METHODS: In a controlled cross-over study, patients with MCI (n = 23; mean MMSE 26.48, SD 2.43) underwent a week of numerical training followed by a week of executive-functions training (subgroup A), or vice versa (subgroup B). Before training (T1), patients performed experimental tasks of decision making (Game of Dice Task, GDT; Probability-Associated Gambling task, PAG-60 task) and of ratio processing as well as a neuropsychological background assessment. Experimental tasks were also administered after the first (T2) and the second (T3) training week. RESULTS: The numerical training and the training of executive functions had a differential effect on experimental tasks of ratio processing. Only the numerical training proved to be effective. The effects of the two training types on decision making under risk were less clear-cut. While no changes over time were observed in the GDT, performance on the PAG-60 task improved in both training subgroups. These improvements were apparent in one subgroup after a period of executive-functions training, in the other subgroup after both training weeks. That means, improvements are not attributable to one specific training type. CONCLUSION: Patients with MCI can profit from a cognitive training on number processing and executive functions. Improvements are reflected in higher ratio processing abilities and more advantageous decisions after training. These results are consistent with assumptions of current cognitive models.

Combining Cognitive, Genetic, and Structural Neuroimaging Markers to Identify Individuals with Increased Dementia Risk. - Payton, Nicola M; Kalpouzos, Grégoria; Rizzuto, Debora; Fratiglioni, Laura; Kivipelto, Miia; Bäckman, Lars; Laukka, Erika J (J Alzheimers Dis, 2018)
BACKGROUND: Cognitive and biological markers have shown varying degrees of success in identifying persons who will develop dementia. OBJECTIVE: To evaluate different combinations of cognitive and biological markers and identify prediction models with the highest accuracy for identifying persons with increased dementia risk. METHODS: Neuropsychological assessment, genetic testing (apolipoprotein E -APOE), and structural magnetic resonance imaging (MRI) were performed for 418 older individuals without dementia (60-97 years) from a population-based study (SNAC-K). Participants were followed for six years. RESULTS: Cognitive, genetic, and MRI markers were systematically combined to create prediction models for dementia at six years. The most predictive individual markers were perceptual speed or carrying at least one APOEɛ4 allele (AUC = 0.875). The most predictive model (AUC = 0.924) included variables from all three modalities (category fluency, general knowledge, any ɛ4 allele, hippocampal volume, white matter-hyperintensity volume). CONCLUSION: This study shows that combining markers within and between modalities leads to increased predictivity for future dementia. However, minor increases in predictive value should be weighed against the cost of additional tests in larger-scale screening.

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

Concordance Between Cerebrospinal Fluid Biomarkers with Alzheimer's Disease Pathology Between Three Independent Assay Platforms. - Doecke, James D; Rembach, Alan; Villemagne, Victor L; Varghese, Shiji; Rainey-Smith, Stephanie; Sarros, Shannon; Evered, Lisbeth A; Fowler, Christopher J; Pertile, Kelly K; Rumble, Rebecca L; Trounson, Brett; Taddei, Kevin; et al. (J Alzheimers Dis, 2018)
BACKGROUND: To enhance the accuracy of clinical diagnosis for Alzheimer's disease (AD), pre-mortem biomarkers have become increasingly important for diagnosis and for participant recruitment in disease-specific treatment trials. Cerebrospinal fluid (CSF) biomarkers provide a low-cost alternative to positron emission tomography (PET) imaging for in vivo quantification of different AD pathological hallmarks in the brains of affected subjects; however, consensus around the best platform, most informative biomarker and correlations across different methodologies are controversial. OBJECTIVE: Assessing levels of Aβ-amyloid and tau species determined using three different versions of immunoassays, the current study explored the ability of CSF biomarkers to predict PET Aβ-amyloid (32 Aβ-amyloid-and 45 Aβ-amyloid+), as well as concordance between CSF biomarker levels and PET Aβ-amyloid imaging. METHODS: Prediction and concordance analyses were performed using a sub-cohort of 77 individuals (48 healthy controls, 15 with mild cognitive impairment, and 14 with AD) from the Australian Imaging Biomarker and Lifestyle study of aging. RESULTS: Across all three platforms, the T-tau/Aβ42 ratio biomarker had modestly higher correlation with SUVR/BeCKeT (ρ= 0.69-0.8) as compared with Aβ42 alone (ρ= 0.66-0.75). Differences in CSF biomarker levels between the PET Aβ-amyloid-and Aβ-amyloid+ groups were strongest for the Aβ42/Aβ40 and T-tau/Aβ42 ratios (p < 0.0001); however, comparison of predictive models for PET Aβ-amyloid showed no difference between Aβ42 alone and the T-tau/Aβ42 ratio. CONCLUSION: This study confirms strong concordance between CSF biomarkers and PET Aβ-amyloid status is independent of immunoassay platform, supporting their utility as biomarkers in clinical practice for the diagnosis of AD and for participant enrichment in clinical trials.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognition Disorders; Female; Humans; Male; Mental Status Schedule; Peptide Fragments; Positron-Emission Tomography; ROC Curve; tau Proteins

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.

Contribution of Bilingualism to Cognitive Reserve of an Italian Literature Professor at High Risk for Alzheimer's Disease. - Lombardi, Gemma; Polito, Cristina; Berti, Valentina; Bagnoli, Silvia; Nacmias, Benedetta; Pupi, Alberto; Sorbi, Sandro (J Alzheimers Dis, 2018)
Bilingualism is an independent component of cognitive reserve that permits to delay dementia onset up to 5 years. We describe a case of a bilingual Italian man affected by mild cognitive impairment with high cognitive reserve that, despite the presence of multiple risk factors (ApoE ɛ4/ɛ4 genotype, older age, untreated Obstructive Sleep Apnea Syndrome, AD-like biomarker alterations) did not convert to Alzheimer's disease up to 5 years follow-up. The present case confirms the role of bilingualism as a strong protective factor for dementia, even in the occurrence of multiple risk factors.

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 of the Memory Circuit: Improving Cognition in Alzheimer's Disease. - Posporelis, Sotirios; David, Anthony S; Ashkan, Keyoumars; Shotbolt, Paul (J Alzheimers Dis, 2018)
Deep brain stimulation (DBS) is an effective invasive treatment for a wide range of neurological and psychiatric disorders. Neurosurgically implanted electrodes deliver stimulation of pre-programmed amplitude, frequency, and pulse width within deep brain structures; those settings can be adjusted at a later stage according to individual needs for optimal response. This results in variable effects dependent on the targeted region. An established treatment for movement disorders, the effectiveness of DBS in dementia remains under investigation. Translational studies have uncovered a pro-cognitive effect mediated by changes on cellular as well as network level. Several groups have attempted to examine the benefits of DBS in Alzheimer's disease; differences in inclusion criteria and methodology make generalization of results difficult. This review aims to summarize all completed and ongoing human studies of DBS in Alzheimer's disease. The results are classified by targeted anatomical structure. Future directions, as well as economical and ethical arguments, are explored in the final section.

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.

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.

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

Diagnosis of Mild Cognitive Impairment Due to Alzheimer's Disease with Transcranial Magnetic Stimulation. - Padovani, Alessandro; Benussi, Alberto; Cantoni, Valentina; Dell'Era, Valentina; Cotelli, Maria Sofia; Caratozzolo, Salvatore; Turrone, Rosanna; Rozzini, Luca; Alberici, Antonella; Altomare, Daniele; Depari, Alessandro; Flammini, Alessandra; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Considering the increasing evidence that disease-modifying treatments for Alzheimer's disease (AD) must be administered early in the disease course, the development of diagnostic tools capable of accurately identifying AD at early disease stages has become a crucial target. In this view, transcranial magnetic stimulation (TMS) has become an effective tool to discriminate between different forms of neurodegenerative dementia. OBJECTIVE: To determine whether a TMS multi-paradigm approach can be used to correctly identify mild cognitive impairment (MCI) due to AD (AD MCI). METHODS: A sample of 69 subjects with MCI were included and classified as AD MCI or MCI unlikely due to AD (non-AD MCI) based on 1) extensive neurological and neuropsychological evaluation, 2) MRI imaging, and 3) cerebrospinal fluid analysis or/and amyloid PET imaging. A paired-pulse TMS multi-paradigm approach assessing short interval intracortical inhibition-facilitation (SICI-ICF), dependent on GABAergic and glutamatergic intracortical circuits, respectively, and short latency afferent inhibition (SAI), dependent on cholinergic circuits, was performed. RESULTS: We observed a significant impairment of SAI and unimpaired SICI and ICF in AD MCI as compared to non-AD MCI. According to ROC curve analysis, the SICI-ICF / SAI index differentiated AD MCI from non-AD MCI with a specificity of 87.9% and a sensitivity of 94.4%. CONCLUSIONS: The assessment of intracortical connectivity with TMS could aid in the characterization of MCI subtypes, correctly identifying AD pathophysiology. TMS can be proposed as an adjunctive, non-invasive, inexpensive, and time-saving screening tool in MCI differential diagnosis.

Diagnostic Value of Diffusion Tensor Imaging and Positron Emission Tomography in Early Stages of Frontotemporal Dementia. - Krämer, Julia; Lueg, Gero; Schiffler, Patrick; Vrachimis, Alexis; Weckesser, Matthias; Wenning, Christian; Pawlowski, Matthias; Johnen, Andreas; Teuber, Anja; Wersching, Heike; Meuth, Sven G; Duning, Thomas (J Alzheimers Dis, 2018)
BACKGROUND: Due to suboptimal sensitivity and specificity of structural and molecular neuroimaging tools, the diagnosis of behavioral variant frontotemporal dementia (bvFTD) remains challenging. OBJECTIVE: Investigation of the sensitivity of diffusion tensor imaging (DTI) and fluorodeoxyglucose positron emission tomography (FDG-PET) to detect cerebral alterations in early stages of bvFTD despite inconspicuous conventional MRI. METHODS: Thirty patients with early stages of bvFTD underwent a detailed neuropsychological examination, cerebral 3T MRI with DTI analysis, and FDG-PET. After 12 months of follow-up, all patients finally fulfilled the diagnosis of bvFTD. Individual FDG-PET data analyses showed that 20 patients exhibited a "typical" pattern for bvFTD with bifrontal and/or temporal hypometabolism (bvFTD/PET+), and that 10 patients showed a "non-typical"/normal pattern (bvFTD/PET-). DTI data were compared with 42 healthy controls in an individual and voxel-based group analysis. To examine the clinical relevance of the findings, associations between pathologically altered voxels of DTI or FDG-PET results and behavioral symptoms were estimated by linear regression analyses. RESULTS: DTI voxel-based group analyses revealed microstructural degeneration in bifrontal and bitemporal areas in bvFTD/PET+ and bvFTD/PET- groups. However, when comparing the sensitivity of individual DTI data analysis with FDG-PET, DTI appeared to be less sensitive. Neuropsychological symptoms were considerably related to neurodegeneration within frontotemporal areas identified by DTI and FDG-PET. CONCLUSION: DTI seems to be an interesting tool for detection of functionally relevant neurodegenerative alterations in early stages of bvFTD, even in bvFTD/PET- patients. However, at a single subject level, it seems to be less sensitive than FDG-PET. Thus, improvement of individual DTI analysis is necessary.

Diet Supplementation with Hydroxytyrosol Ameliorates Brain Pathology and Restores Cognitive Functions in a Mouse Model of Amyloid-β Deposition. - Nardiello, Pamela; Pantano, Daniela; Lapucci, Andrea; Stefani, Massimo; Casamenti, Fiorella (J Alzheimers Dis, 2018)
Alzheimer's disease is the most common form of dementia affecting a large proportion of aged people. Plant polyphenols have been reported to be potentially useful in the prevention of AD due to their multiple pharmacological activities. The aim of the present study was to assess whether the previously reported neuroprotective and anti-inflammatory effects resulting from oleuropein aglycone administration were reproduced by diet supplementation with similar amounts of its metabolite hydoxytyrosol (HT). Four-month-old TgCRND8 and wild type mice were treated for 8 weeks with a low-fat diet (5%) supplemented with HT (50 mg/kg of diet). We found that HT supplementation significantly improved cognitive functions of TgCRND8 mice and significantly reduced Aβ42 and pE3-Aβ plaque area and number in the cortex; in the hippocampal areas of HT-fed TgCRND8 mice, we found a significant reduction in the pE3-Aβ plaque number together with a tendency toward a reduction in Aβ42 load and pE3-Aβ plaque area, associated with a marked reduction of TNF-α expression and astrocyte reaction. Macroautophagy induction and modulation of MAPKs signaling were found to underlie the beneficial effects of HT. Our findings indicate that HT administration reproduces substantially the beneficial effects on behavioral performance and neuropathology previously reported in TgCRND8 mice fed with oleuropein aglycone, resulting in comparable neuroprotection.

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.

Diffuse Amyloid-β Plaques, Neurofibrillary Tangles, and the Impact of APOE in Elderly Persons' Brains Lacking Neuritic Amyloid Plaques. - Abner, Erin L; Neltner, Janna H; Jicha, Gregory A; Patel, Ela; Anderson, Sonya L; Wilcock, Donna M; Van Eldik, Linda J; Nelson, Peter T (J Alzheimers Dis, 2018)
Data from a large autopsy series were analyzed to address questions pertinent to primary age-related tauopathy (PART) and Alzheimer's disease (AD): what factors are associated with increased severity of neurofibrillary degeneration in brains that lack neuritic amyloid plaques?; is there an association between Apolipoprotein E (APOE) alleles and PART pathologic severity independent of amyloid-β (Aβ) deposits?; and, how do the stains used to detect plaques and tangles impact the experimental results? Neuropathologic data were evaluated from elderly research volunteers whose brain autopsies were performed at University of Kentucky Alzheimer's Disease Center (UK-ADC; N = 145 subjects). All of the included subjects' brains lacked neuritic amyloid plaques according to the CERAD diagnostic criteria and the average final MMSE score before death was 26.8±4.6 stdev. The study incorporated evaluation of tissue with both silver histochemical stains and immunohistochemical stains to compare results; the immunohistochemical stains (Aβ and phospho-tau) were scanned and quantified using digital pathologic methods. Immunohistochemical stains provided important advantages over histochemical stains due to sensitivity and detectability via digital methods. When AD-type pathology was in its presumed earliest phases, neocortical parenchymal Aβ deposits were associated with increased medial temporal lobe neurofibrillary tangles. The observation supports the NIA-AA consensus recommendation for neuropathologic diagnoses, because even these "diffuse" Aβ deposits signal that AD pathobiologic mechanisms are occurring. Further, the data were most compatible with the hypothesis that the APOEɛ4 allele exerts its effect(s) via driving Aβ deposition, i.e., an "upstream" influence, rather than being associated directly with Aβ- independent PART pathology.

Dissecting the Role of 5-Lipoxygenase in the Homocysteine-Induced Alzheimer's Disease Pathology. - Di Meco, Antonio; Li, Jian-Guo; Praticò, Domenico (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) affects over 40 million patients around the world and poses a huge economic burden on society since no effective therapy is available yet. While the cause(s) for the most common sporadic form of the disease are still obscure, lifestyle and different environmental factors have emerged as modulators of AD susceptibility. Hyperhomocysteinemia (HHCY), a condition of high circulating levels of homocysteine, is an independent but modifiable risk factor for AD. Studies in AD mouse models have linked HHCY with memory impairment, amyloidosis, tau pathology, synaptic dysfunction, and neuroinflammation. However, the exact mechanism by which HHCY affects AD pathogenesis is unclear. The 5-lipoxygenase (5LO) is a protein upregulated in postmortem AD brains and plays a functional role in AD pathogenesis. Recently, in vitro and in vivo studies showed that HHCY effects on amyloid-β and tau pathology, synapse and memory impairments are dependent on the activation of the 5LO enzymatic pathway, since its genetic absence or pharmacological inhibition prevents them. HHCY induces 5LO gene upregulation by lowering the methylation of its promoter, which results in increased translation and transcription of its mRNA. Based on these findings, we propose that epigenetic modification of 5LO represents the missing biological link between HHCY and AD pathogenesis, and for this reason it represents a viable therapeutic target to prevent AD development in individuals bearing this risk factor.

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.

DJ-1 Suppresses Cytoplasmic TDP-43 Aggregation in Oxidative Stress-Induced Cell Injury. - Lei, Yang; Zhang, Zhi-Feng; Lei, Rui-Xue; Wang, Shu; Zhuang, Yang; Liu, An-Chun; Wu, Yan; Chen, Juan; Tang, Jun-Chun; Pan, Meng-Xian; Liu, Rui; Liao, Wei-Jing; et al. (J Alzheimers Dis, 2018)
DJ-1 (also called PARK7) is a multifunctional redox-sensitive protein that is protective against oxidative stress-induced cell death. TAR DNA-binding protein 43 (TDP-43) is a major protein component of pathological inclusions in amyotrophic lateral sclerosis and frontotemporal dementia. Reducing aberrant aggregation of TDP-43 is a potential approach to prevent cell death. To investigate whether DJ-1 might inhibit TDP-43 aggregation to exert a protective effect in oxidative stress-induced injury, we tested the protein level and subcellular localization of TDP-43 and DJ-1 in SH-SY5Y cells transfected with wild-type DJ-1, DJ-1 mutant (L166P) cDNA, or DJ-1 siRNA. We show that oxidative stress induced by paraquat leads to the formation of cytosolic TDP-43 aggregation in SH-SY5Y cells. DJ-1 overexpression decreases paraquat-induced cytoplasmic accumulation of TDP-43 in SH-SY5Y cells and protects against paraquat-induced cell death. Transfection of DJ-1 L166P mutant or DJ-1 siRNA leads to increased cytosolic aggregation of TDP-43 in paraquat-treated SH-SY5Y cells and promotes cell death. These data suggest that DJ-1 may protect against oxidative stress-induced cell death through the suppression of cytoplasmic TDP-43 aggregation.

DNA Hypomethylation in Blood Links B3GALT4 and ZADH2 to Alzheimer's Disease. - Madrid, Andy; Hogan, Kirk J; Papale, Ligia A; Clark, Lindsay R; Asthana, Sanjay; Johnson, Sterling C; Alisch, Reid S (J Alzheimers Dis, 2018)
Differentially methylated positions (DMPs) between persons with and without late-onset Alzheimer's disease (LOAD) were observed at 477 of 769,190 loci in a plurality of genes. Of these, 17 were shared with DMPs identified using clinical LOAD markers analyzed independently as continuous variables comprising Rey Auditory Verbal Learning Test scores, cerebrospinal fluid total tau (t-tau) and phosphorylated tau 181 (p-tau181) levels, and t-tau/Aβ1-42 (Aβ42), p-tau181/Aβ42, and Aβ42/Aβ1-40 (Aβ40) ratios. In patients with LOAD, 12 of the shared 17 DMPs were hypomethylated in B3GALT4 (Beta-1,3-galatcosyltransferase 4) (EC 2.4.1.62), and 5 were hypomethylated in ZADH2 (Prostaglandin reductase 3) (EC 1.3.1.48).

Does Fatty Acid Composition in Subcutaneous Adipose Tissue Differ between Patients with Alzheimer's Disease and Cohabiting Proxies? - Faxen-Irving, Gerd; Falahati, Farshad; Basun, Hans; Eriksdotter, Maria; Vedin, Inger; Wahlund, Lars-Olof; Schultzberg, Marianne; Hjorth, Erik; Palmblad, Jan; Cederholm, Tommy; Freund-Levi, Yvonne (J Alzheimers Dis, 2018)
Low tissue levels of the major marine ω3 fatty acids (FAs) DHA and EPA are found in Alzheimer's disease (AD). We investigated if healthy proxies to AD patients have higher levels of these ω3 FAs. We observed lower levels of EPA and DHA in subcutaneous adipose tissue biopsies from 64 AD patients compared with 16 cognitively healthy proxies. No significant difference was observed when pairwise comparisons were made between a subset of 16 AD patients and their co-habiting proxies. Larger studies are needed to replicate these findings and to determine if they could depend on FA intake or differences in metabolism.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Dietary Supplements; Fatty Acids, Omega-3; Female; Humans; Male; Regression Analysis; Subcutaneous Fat

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.

Dual-Task Gait and Alzheimer's Disease Genetic Risk in Cognitively Normal Adults: A Pilot Study. - Whitson, Heather E; Potter, Guy G; Feld, Jody A; Plassman, Brenda L; Reynolds, Kelly; Sloane, Richard; Welsh-Bohmer, Kathleen A (J Alzheimers Dis, 2018)
BACKGROUND: Dual-task paradigms, in which an individual performs tasks separately and then concurrently, often demonstrate that people with neurodegenerative disorders experience more dual-task interference, defined as worse performance in the dual-task condition compared to the single-task condition. OBJECTIVE: To examine how gait-cognition dual-task performance differs between cognitively normal older adults with and without an APOE ɛ4 allele. METHODS: Twenty-nine individuals ages 60 to 72 with normal cognition completed a dual-task protocol in which walking and cognitive tasks (executive function, memory) were performed separately and concurrently. Fourteen participants carried APOE ɛ4 alleles (ɛ3/ɛ4 or ɛ2/ɛ4); fifteen had APOE genotypes (ɛ2/ɛ2, ɛ2/ɛ3, or ɛ3/ɛ3) associated with lower risk of Alzheimer's disease (AD). RESULTS: The two risk groups did not differ by age, sex, race, education, or gait or cognitive measures under single-task conditions. Compared to low risk participants, APOE ɛ4 carriers tended to exhibit greater dual-task interference. Both the memory and executive function tasks resulted in dual-task interference on gait, but effect sizes for a group difference were larger when the cognitive task was executive function. In the dual-task protocol that combined walking and the executive function task, effect sizes for group difference in gait interference were larger (0.62- 0.70) than for cognitive interference (0.45- 0.47). DISCUSSION: Dual-task paradigms may reveal subtle changes in brain function in asymptomatic individuals at heightened risk of AD.

Dynamic Causal Modeling of Preclinical Autosomal-Dominant Alzheimer's Disease. - Penny, Will; Iglesias-Fuster, Jorge; Quiroz, Yakeel T; Lopera, Francisco Javier; Bobes, Maria A (J Alzheimers Dis, 2018)
Dynamic causal modeling (DCM) is a framework for making inferences about changes in brain connectivity using neuroimaging data. We fitted DCMs to high-density EEG data from subjects performing a semantic picture matching task. The subjects are carriers of the PSEN1 mutation, which leads to early onset Alzheimer's disease, but at the time of EEG acquisition in 1999, these subjects were cognitively unimpaired. We asked 1) what is the optimal model architecture for explaining the event-related potentials in this population, 2) which connections are different between this Presymptomatic Carrier (PreC) group and a Non-Carrier (NonC) group performing the same task, and 3) which network connections are predictive of subsequent Mini-Mental State Exam (MMSE) trajectories. We found 1) a model with hierarchical rather than lateral connections between hemispheres to be optimal, 2) that a pathway from right inferotemporal cortex (IT) to left medial temporal lobe (MTL) was preferentially activated by incongruent items for subjects in the PreC group but not the NonC group, and 3) that increased effective connectivity among left MTL, right IT, and right MTL was predictive of subsequent MMSE scores.

Early and Selective Activation and Subsequent Alterations to the Unfolded Protein Response in Down Syndrome Mouse Models. - Lanzillotta, Chiara; Tramutola, Antonella; Meier, Shelby; Schmitt, Frederick; Barone, Eugenio; Perluigi, Marzia; Di Domenico, Fabio; Abisambra, Jose F (J Alzheimers Dis, 2018)
Down syndrome (DS) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans, which results from the triplication of chromosome 21. DS individuals have an increased risk of developing Alzheimer's disease (AD)-like pathology and dementia by the age of 40 due to the triplication of several genes involved in the formation of amyloid plaques and tau tangles. Further, DS and AD are characterized by the aberrant accumulation of unfolded/misfolded proteins resulting from over-burdened protein quality control systems. The accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the unfolded protein response (UPR). Long-term activation of the UPR mediates neuronal dysfunction in AD. We hypothesized that the UPR is impacted in a mouse model of DS. To test this, we performed gene and protein expression analysis of ER stress markers in the Ts65Dn mouse model of DS at 3, 9, and 18 months. We identified activation of the PERK pathway in Ts65Dn DS mice at 3 months of age compared to euploid controls. We also determined that the early and overt UPR activation decreased with age, the UPR signal was significantly reduced by 18 months. Our data suggest that UPR activation in DS mouse models occurs early before consistent brain neurodegeneration and might be an essential contributor to dys-proteostasis.

Early Impairments of Hippocampal Neurogenesis in 5xFAD Mouse Model of Alzheimer's Disease Are Associated with Altered Expression of SOXB Transcription Factors. - Zaletel, Ivan; Schwirtlich, Marija; Perović, Milka; Jovanović, Mirna; Stevanović, Milena; Kanazir, Selma; Puškaš, Nela (J Alzheimers Dis, 2018)
Dysregulation of neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus has been related to cognitive deficits and memory loss in neurodegenerative diseases, such as Alzheimer's disease (AD). Members of the B group of SOX transcription factors play critical roles in regulating neurogenesis in the embryonic and adult nervous system, including maintaining the multipotency, renewal, and cell fate decision of neural stem/progenitor cells. The aim of the present study was to evaluate the expression patterns of selected SOXB proteins in the SGZ, of 8-week-old male and female 5xFAD mice, which represent a transgenic model of AD with a severe and very early development of amyloid pathology. Immunohistochemical analysis showed a significant decrease in the number of cells expressing SOX1, SOX2, and SOX21 transcription factors within the SGZ of 5xFAD mice in comparison to their non-transgenic counterparts which coincidences with reduced number of doublecortin immunoreactive immature neurons found in Tg males. Despite observed changes in expressional pattern of examined SOXB proteins, the proliferative capacity evaluated by the number of Ki-67 immunoreactive cells remained unaffected in transgenic mice of both genders. Based on our results, we suggest that SOXB proteins might be considered as new biomarkers for the detection of early impairments in adult neurogenesis in different animal models or/and new targets in human regenerative medicine.

Effect of Cilostazol on Incident Dementia in Elderly Men and Women with Ischemic Heart Disease. - Kim, Mi-Young; Noh, Yoojin; Son, Sang Joon; Shin, Sooyoung; Paik, Hee-Young; Lee, Sukhyang; Jung, Yi-Sook (J Alzheimers Dis, 2018)
BACKGROUND: Ischemic heart disease (IHD) is associated with cognitive decline and may contribute to an increased risk of dementia. OBJECTIVE: The goal of the present study was to investigate whether cilostazol use is associated with a lower risk of incident dementia in Asian patients with IHD, and whether these effects differed based on sex. METHODS: This retrospective cohort study was performed using the Korean National Insurance Claim Data of the Health Insurance Review and Assessment Service; the duration of the study was from January 1, 2007 to December 31, 2015. The study group comprised 66,225 patients with IHD, aged >65 years, who had received cilostazol. Age- and sex-matched IHD patients without cilostazol exposure were selected as the control group. The risk of dementia was compared between the cilostazol and control groups. RESULTS: Compared to the control group, total cilostazol users had a marginally significant lower risk of incident dementia. After stratification by sex, the reducing effect of cilostazol on incident dementia was significant in female participants, but not in male participants. Female patients who had cilostazol for over 2 years showed a clinically meaningful preventive effect (HR, 0.85; 95% CI, 0.82-0.88). CONCLUSIONS: This study suggested that cilostazol treatment may reduce the risk of incident dementia in Korean patients with IHD. Its beneficial effect was remarkably significant in female patients who received cilostazol for over a 2-year period.

Effect of Physical Activity on the Progression of Alzheimer's Disease: The Clinical Research Center for Dementia of South Korea Study. - Minn, Yang-Ki; Choi, Seong Hye; Suh, Young Ju; Jeong, Jee Hyang; Kim, Eun-Joo; Kim, Jong Hun; Park, Kyung Won; Park, Moon Ho; Youn, Young Chul; Yoon, Bora; Choi, Seok-Jin; Oh, Youn Kyung; et al. (J Alzheimers Dis, 2018)
BACKGROUND: There is a lack of research on the effects of physical activity (PA) on the progression of Alzheimer's disease (AD). OBJECTIVES: We investigated whether PA is associated with progression of dementia and mortality in AD. METHODS: In the present study, 934 patients with mild-to-moderate AD were included. PA was evaluated using a questionnaire written by the caregiver. The outcome measures were the Clinical Dementia Rating-Sum of Boxes (CDR-SB), Seoul-Instrumental Activities of Daily Living (S-IADL), Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI), a global composite score of neuropsychological subtests, and mortality. They were evaluated annually and received a maximum of three follow-up examinations. RESULTS: Between-group differences compared with the no PA group in the change of CDR-SB scores were -0.431 (95% CI = -0.824∼-0.039; p = 0.031) for the moderate PA group (150-750 minutes per week of moderate intensity PA), and -1.148 (-1.656∼-0.639; p < 0.001) for the high PA group (>750 minutes per week). As PA increased, there was a significant trend to slow the rate of increase in the CDR-SB, S-IADL, and CGA-NPI scores. The patients with ≥150 minutes per week for each of non-recreational and recreational PAs had a lower risk of mortality compared to those with <150 minutes per week for each of the PAs (hazard ratio 0.22, 95% CI = 0.05∼0.88; p = 0.033). CONCLUSION: More PA is associated with slower progression of dementia severity, functional decline, and abnormal behavior, and with a lower risk of mortality in AD.

Effectiveness of Anti-Dementia Drugs in Extremely Severe Alzheimer's Disease: A 12-Week, Multicenter, Randomized, Single-Blind Study. - Hong, Yun Jeong; Choi, Seong Hye; Jeong, Jee Hyang; Park, Kyung Won; Na, Hae Ri (J Alzheimers Dis, 2018)
BACKGROUND/OBJECTIVE: There is insufficient evidence to guide decisions concerning how long anti-dementia drug (ADD) regimens should be maintained in severe Alzheimer's disease (AD). We investigated whether patients with extremely severe AD who were already receiving donepezil or memantine benefited from continuing treatment. METHODS: In this randomized and rater-blinded trial, 65 AD patients with a Mini-Mental State Examination score from 0 to 5 and a score of 6c or worse on Functional Assessment Staging were randomly assigned to an ADD-continuation group (N = 30) or an ADD-discontinuation group (N = 35). The current use of donepezil or memantine was maintained for 12 weeks in the ADD-continuation group and was discontinued after baseline in the ADD-discontinuation group. Efficacy measures were obtained at baseline and 12 weeks. The primary efficacy variable was the change from baseline to the end of the study in Baylor Profound Mental State Examination (BPMSE) scores. RESULTS: The change in the BPMSE from baseline to the end of the study in the ADD-continuation group (a 0.4-point improvement) was not equivalent to that in the ADD-discontinuation group (a 0.5-point decline), as determined by two one-sided tests of equivalence. Study withdrawals due to adverse events (11.4% versus 6.7%) were more frequent in the ADD-discontinuation group than in the ADD-continuation group. CONCLUSION: Continued treatment with donepezil or memantine seems unequal and might be superior to withdrawal of the drugs in terms of the effects on global cognition in patients with extremely severe AD. Current Controlled Trials number: KCT0000874 (CRIS).

The Effects and Meanings of Receiving a Diagnosis of Mild Cognitive Impairment or Alzheimer's Disease When One Lives Alone. - Portacolone, Elena; Johnson, Julene K; Covinsky, Kenneth E; Halpern, Jodi; Rubinstein, Robert L (J Alzheimers Dis, 2018)
BACKGROUND: One third of older adults with cognitive impairment live alone and are at high risk for poor health outcomes. Little is known about how older adults who live alone experience the process of receiving a diagnosis of mild cognitive impairment (MCI) or Alzheimer's disease (AD). OBJECTIVE: The aim of this study was to understand the effects and meanings of receiving a diagnosis of MCI or AD on the lived experience of older adults living alone. METHODS: This is a qualitative study of adults age 65 and over living alone with cognitive impairment. Participants' lived experiences were elicited through ethnographic interviews and participant observation in their homes. Using a qualitative content analysis approach, interview transcripts and fieldnotes were analyzed to identify codes and themes. RESULTS: Twenty-nine older adults and 6 members of their social circles completed 114 ethnographic interviews. Core themes included: relief, distress, ambiguous recollections, and not knowing what to do. Participants sometimes felt uplifted and relieved by the diagnostic process. Some participants did not mention having received a diagnosis or had only partial recollections about it. Participants reported that, as time passed, they did not know what to do with regard to the treatment of their condition. Sometimes they also did not know how to prepare for a likely worsening of their condition, which they would experience while living alone. CONCLUSION: Findings suggest the need for more tailored care and follow-up as soon as MCI or AD is diagnosed in persons living alone.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cognitive Dysfunction; Emotions; Female; Health Services; Humans; Interviews as Topic; Male; Residence Characteristics; Single Person

Effects of a 3-Year Multi-Domain Intervention with or without Omega-3 Supplementation on Cognitive Functions in Older Subjects with Increased CAIDE Dementia Scores. - Chhetri, Jagadish K; de Souto Barreto, Philipe; Cantet, Christelle; Pothier, Kristell; Cesari, Matteo; Andrieu, Sandrine; Coley, Nicola; Vellas, Bruno (J Alzheimers Dis, 2018)
Findings from recent Alzheimer's disease prevention trials have shown subjects with increased dementia score based upon mid-life cardiovascular risk factors, to benefit from multi-domain intervention strategies to some extent. The effects of such interventions on cognitive functions remains yet to be well-established. This study is a secondary analysis of the MAPT study, 1,293 older subjects (mean age 75 years) with high CAIDE score (i.e., ≥6) were classified according to the four intervention groups: 1) multi-domain intervention plus placebo, 2) isolated supplementation with Omega-3 polyunsaturated fatty acid (n-3 PUFA), 3) combination of the two interventions, and 4) placebo alone. Linear mixed-model repeated-measures analyses were used to assess the cognitive changes according to various neuropsychological test scores between intervention groups compared to the placebo at 36 months from baseline. Compared to the placebo, group with multi-domain intervention in combination withn-3PUFA was found to show significant improvement in the delayed total recall test of the free and cued selective reminding test (FCSRT) (mean±standard error(SE) = 0.20±0.10) and MMSE orientation test (mean±SE = 0.15±0.06) at 36 months. Isolated multi-domain intervention group showed significant less decline in the MMSE orientation test (mean±SE = 0.12±0.06) compared to the placebo. There was significant less improvement (mean±SE = - 1.01±0.46) in the FCSRT free recall test in the n-3 PUFA intervention group compared to the placebo at 36 months. Our findings show high-risk subjects for dementia screened with CAIDE dementia score might benefit from multi-domain intervention strategies as in the MAPT study, particularly in the orientation and delayed recall domain.

Episodic Memory and Learning Dysfunction Over an 18-Month Period in Preclinical and Prodromal Alzheimer's Disease. - Baker, Jenalle E; Lim, Yen Ying; Jaeger, Judith; Ames, David; Lautenschlager, Nicola T; Robertson, Joanne; Pietrzak, Robert H; Snyder, Peter J; Villemagne, Victor L; Rowe, Christopher C; Masters, Colin L; Maruff, Paul (J Alzheimers Dis, 2018)
Recent meta-analyses suggest that episodic memory impairment associated with preclinical Alzheimer's disease (AD) equates to 0.15-0.24 standard deviations below that of cognitively healthy older adults. The current study aimed to characterize impairments in verbal acquisition and recall detectable at a single assessment, and investigate how verbal learning and episodic memory deteriorates in preclinical AD. A verbal list-learning task, the International Shopping List Test (ISLT), was administered multiple times over an 18-month period, to three groups of participants: amyloid-beta negative healthy older adults (Aβ- CN; n = 50); Aβ+ positive healthy older adults (preclinical AD; n = 25); and Aβ+ positive individuals diagnosed with mild cognitive impairment (prodromal AD; n = 22). At baseline, there was no significant difference between the preclinical AD and control groups rate of acquisition, or total and delayed recall, however all indices were impaired in prodromal AD. Performance on ISLT total score improved in the control group over the 18-month period, but showed a moderate magnitude decline in the preclinical AD group (Cohen's d = - 0.63, [- 1.12, - 0.14]) and the prodromal AD group (Cohen's d = - 0.36, [- 0.94, 0.22]). No significant impairment in acquisition associated with preclinical AD was seen at baseline. Individuals with preclinical AD showed a significantly different performance on the ISLT total score over an 18-month period, compared to those without abnormal Aβ. Individuals with prodromal AD showed substantial impairment on the ISLT at baseline and declined to a greater extent over time.

Executive Dysfunction Detected with the Frontal Assessment Battery in Alzheimer's Disease Versus Vascular Dementia. - D'Onofrio, Grazia; Panza, Francesco; Sancarlo, Daniele; Addante, Filomena; Solfrizzi, Vincenzo; Cantarini, Chiara; Mangiacotti, Antonio; Lauriola, Michele; Cascavilla, Leandro; Paris, Francesco; Lozupone, Madia; Daniele, Antonio; et al. (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) and vascular dementia (VaD) lead to progressive decline in executive function. We estimated the prevalence of executive dysfunction in AD and VaD patients, investigating cognitive, functional, and clinical correlates and also using a multidimensional approach based on a standardized comprehensive geriatric assessment (CGA). We included 215 patients (115 AD patients and 100 VaD patients) consecutively evaluated with a complete cognitive and affective assessment, a CGA, and the Frontal Assessment Battery (FAB) with six subtests investigating conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. The prevalence of dysexecutive syndrome screened with a FAB score <12 points was high in both AD (97 patients) and VaD (77 patients) (84.3% versus 77.0%, p = 0.171). AD patients were significantly younger, with higher grade of cognitive impairment and less severe comorbidity and polypharmacy than VaD patients. AD patients showed a significantly higher impairment in FAB total score and five FAB subtests (conceptualization, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy) than VaD patients. These findings were largely confirmed in a sub-analysis conducted subdividing the sample in mild and moderate-to-severe demented patients and suggesting that in moderate-to-severe AD there was higher impairment in FAB total score and four FAB subtests (conceptualization, sensitivity to interference, inhibitory control, and environmental autonomy). Executive dysfunction could be greater in AD patients with moderate-to-severe dementia compared to VaD patients, although our groups were also not matched for age, comorbidity or polypharmacy, which could also exert an effect.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cognitive Dysfunction; Comorbidity; Dementia, Vascular; Executive Function; Female; Frontal Lobe; Geriatric Assessment; Humans; Logistic Models; Male; Polypharmacy; Severity of Illness Index

Exercise Training on Locomotion in Patients with Alzheimer's Disease: A Feasibility Study. - Pedrinolla, Anna; Venturelli, Massimo; Fonte, Cristina; Munari, Daniele; Benetti, Maria Vittoria; Rudi, Doriana; Tamburin, Stefano; Muti, Ettore; Zanolla, Luisa; Smania, Nicola; Schena, Federico (J Alzheimers Dis, 2018)
BACKGROUND: Although current literature has shown that patients with Alzheimer's disease (AD) have worse locomotion compared with healthy counterparts, no studies have focused on the efficacy of exercise training in improving gait abnormalities including biomechanics and metabolic aspects, in this population. OBJECTIVE: To verify the effectiveness of exercise training (ET) on gait parameters (i.e., speed, step and stride length, single and double support, and energy cost of walking (Cw)) in patients with AD with respect to a standard cognitive treatment (CT). METHODS: In this study, we included a small portion of data belonging to a larger study (ClinicalTrials.gov number, NCT03034746). Patients with AD (Mini-Mental State Examination 22±5) were included in the study. Gait parameters and Cw were assessed at baseline and after 6 months (72 treatment sessions) of treatment. ET included 90 min of aerobic and strength training. CT included 90 min of cognitive stimuli. RESULTS: The 16 patients assigned to ET exhibited significant improvement of Cw (-0.9±0.1 J/kg·m-1), while differences in gait parameters were negligible. The effect on gait parameters were undetectable in the 18 patients assigned to CT (-0.2±0.5 J/kg·m-1). CONCLUSIONS: Data from this study showed that ET program seems effective in improving Cw in patients with AD. Interestingly, the positive effect of ET on Cw was not coupled with ameliorations of patient's gait parameters, suggesting that the gain of metabolic aspects of locomotion were the main factors responsible for this positive result.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Biomechanical Phenomena; Exercise Test; Exercise Therapy; Feasibility Studies; Female; Gait; Humans; Italy; Male; Single-Blind Method

Exploring the Profile of Incidental Memory in Patients with Amnestic Mild Cognitive Impairment and Mild Alzheimer's Disease. - Kontaxopoulou, Dionysia; Beratis, Ion N; Fragkiadaki, Stella; Pavlou, Dimosthenis; Andronas, Nikos; Yannis, George; Economou, Alexandra; Papanicolaou, Andrew C; Papageorgiou, Sokratis G (J Alzheimers Dis, 2018)
Incidental memory can be defined as the ability to acquire information unintentionally. The present study investigated incidental memory performance in amnestic mild cognitive impairment (aMCI) and mild Alzheimer's disease (AD) patients; additionally, hippocampal atrophy between groupswas examined. Twenty-nine aMCI patients (14 with hippocampal atrophy, measured by the Medial Temporal Lobe Atrophy scale), 15 mild AD patients, and 20 cognitively intact individuals underwent a detailed medical and neuropsychological assessment examining intentional memory, using the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test. Participants first took part in a driving simulator experiment, followed by an unexpected incidental memory questionnaire referring to elements related to the driving simulation. The mild AD group performed worse than the aMCI group and the control group both in incidental and intentional memory tasks, whereas the aMCI group differed significantly from the control group only in the intentional memory tasks. The incidental recognition memory task was the only measure that differed between aMCI patients with and without hippocampal atrophy. Moreover, incidental memory tasks were the only measures that correlated significantly with both left and right hippocampal atrophy. The current findings indicate that incidental memory testing may provide potentially useful information for detecting aMCI patients with greater hippocampal atrophy, who may be considered at higher risk of developing dementia due to AD.

Expression Profiling of Cytokine, Cholinergic Markers, and Amyloid-β Deposition in the APPSWE/PS1dE9 Mouse Model of Alzheimer's Disease Pathology. - Reale, Marcella; D'Angelo, Chiara; Costantini, Erica; Di Nicola, Marta; Yarla, Nagnedra Sastry; Kamal, Mohammad Amjad; Salvador, Nieves; Perry, George (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD), a neurodegenerative disease, is associated with dysfunction of the olfactory and the entorhinal cortex of the brain that control memory and cognitive functions and other daily activities. Pro-inflammatory cytokines, amyloid-β (Aβ), and the cholinergic system play vital roles in the pathophysiology of AD. However, the role of changes in cholinergic system components, Aβ accumulation, and cytokines in both the olfactory and entorhinal cortex is not known clearly. OBJECTIVE: The present study is aimed to evaluate the changes of cholinergic system components, Aβ accumulation, and cytokines in both the olfactory bulb (OB) and entorhinal cortex (EC) of young and aged APPSWE/PS1dE9 transgenic (Tg) mice. METHODS: We have explored the changes of cholinergic system components, Aβ accumulation, and expression profiling of cytokines in the OB and EC of aged APPswe transgenic mice and age-matched wild type mice using quantitative Real-Time PCR assays and immunohistochemistry techniques. RESULTS: In aged Tg mice, a significant increase of expression of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and chemokine MCP1 (p < 0.001, p < 0.001, and p = 0.001, respectively) and a significant reduction of nAChRα4 (p = 0.048) and AChE (p = 0.023) was observed when compared with age-matched wild type mice. Higher levels of AChE and BuChE are expressed in OB and EC of the APPSWE/PS1dE9 of Tg mice. Aβ accumulation was observed in OB and EC of the APPSWE/PS1dE9 of Tg mice. CONCLUSION: The study demonstrates the expression profiling of pro-inflammatory cytokines and cholinergic markers as well as Aβ accumulation in OB and EC of the APPSWE/PS1dE9 Tg mice. Moreover, the study also demonstrated that the APPSWE/PS1dE9 Tg mice can be useful as a mouse model to understand the role of pro-inflammatory cytokines and cholinergic markers in pathophysiology of AD.

The First Historically Reported Italian Family with FTD/ALS Teaches a Lesson on C9orf72 RE: Clinical Heterogeneity and Oligogenic Inheritance. - Giannoccaro, Maria Pia; Bartoletti-Stella, Anna; Piras, Silvia; Casalena, Alfonsina; Oppi, Federico; Ambrosetto, Giovanni; Montagna, Pasquale; Liguori, Rocco; Parchi, Piero; Capellari, Sabina (J Alzheimers Dis, 2018)
BACKGROUND: In 1969, Dazzi and Finizio reported the second observation of frontotemporal dementia (FTD) - amyotrophic lateral sclerosis (ALS) association in a large Italian kindred affected by an autosomal dominant form of ALS with high penetrance, frequent bulbar onset, and frequent cognitive decline. OBJECTIVE: To expand the original characterization of this family and report the link with the C9orf72 repeat expansion (RE). METHODS: We followed or reviewed the medical records of thirteen patients belonging to the original family and performed genetic analyses in four individuals. RESULTS: Eight patients presented with ALS, four with FTD, and one with schizophrenia. The C9orf72 RE was found in three patients but not in the healthy survivor. Additionally, we found a novel possible pathogenic variant in the ITM2B gene in one patient with a complex phenotype, associating movement disorders, psychiatric and cognitive features, deafness, and optic atrophy. The neuropathological examination of this patient did not show the classical features of ITM2B mutation related dementias suggesting that the putative pathogenic mechanism does not involve cellular mislocalization of the protein or the formation of amyloid plaques. CONCLUSION: We showed that the original Italian pedigree described with FTD/ALS carries the C9orf72 RE. Moreover, the finding of an additional mutation in another dementia causing gene in a patient with a more complex phenotype suggests a possible role of genetic modifiers in the disease. Together with other reports showing the coexistence of mutations in multiple ALS/FTD causative genes in the same family, our study supports an oligogenic etiology of ALS/FTD.
Keywords: Adult; Amyotrophic Lateral Sclerosis; C9orf72 Protein; Cerebral Cortex; DNA Repeat Expansion; Female; Frontotemporal Dementia; Genetic Testing; Humans; Male; Membrane Glycoproteins; Middle Aged; Multifactorial Inheritance; Mutation; Pedigree

Forgetting Rate on the Recency Portion of a Word List Differentiates Mild to Moderate Alzheimer's Disease from Other Forms of Dementi. - Turchetta, Chiara Stella; Perri, Roberta; Fadda, Lucia; Caruso, Giulia; De Simone, Maria Stefania; Caltagirone, Carlo; Carlesimo, Giovanni Augusto (J Alzheimers Dis, 2018)
Patients with Alzheimer's disease (AD) demonstrate a disproportionately larger forgetting rate in episodic memory tasks. Previous studies documented that, in comparison with healthy controls, the increased forgetting manifested by AD patients in word list recall tasks is confined to the recency portion of the list with normal forgetting rates on the primacy and mid-list portions. In this study we compared the primacy, mid-list, and recency ratios, obtained by dividing the immediate and delayed recall of words in position 1-4, 5-11, and 12-15 of a 15-word list, in different groups of demented patients, i.e., AD, frontal variant of frontotemporal dementia (fvFTD), Lewy body disease (LBD), subcortical ischemic vascular dementia (SIVD), and a group of normal controls (NC). The aim was to investigate whether the above reported forgetting pattern would differentiate AD performance from that of other dementia groups. Results of the statistical analysis showed that only the recency ratio differentiated AD from patients in the other dementia groups. Consistently, hierarchical logistic regression analyses demonstrated that the recency ratio discriminated between AD patients and individuals affected by other forms of dementia. In particular, the discrimination power was high in differentiating AD from fvFTD patients but was less accurate in differentiating AD from LBD and SIVD patients. We assume that the increased forgetting in AD patients is due to a deficit in memory consolidation mechanisms (specific to AD) that prevent the terminal items in a list from being transferred from a temporary short-term memory store to a stable long-term memory store.

Frequency of Cardiovascular Genetic Risk Factors in a Calabrian Population and Their Effects on Dementia. - Maletta, Raffaele; Smirne, Nicoletta; Bernardi, Livia; Anfossi, Maria; Gallo, Maura; Conidi, Maria Elena; Colao, Rosanna; Puccio, Gianfranco; Curcio, Sabrina A M; Laganà, Valentina; Frangipane, Francesca; Cupidi, Chiara; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Several genetic variants playing a key role in cholesterol levels, blood pressure, and vascular dysfunction influence the risk of Alzheimer's disease (AD) and vascular dementia (VaD). The many meta-analysis studies carried out on large numbers of samples in different populations have not provided clear results to date, because a trans-ethnic shift of risk genotypes in different populations is often observed. OBJECTIVES: To determine genotypes allele frequencies of the polymorphisms most frequently identified to be correlated with cardio-cerebrovascular disease and AD in a Southern Italy population and to investigate their possible association with dementia. METHODS: The genotype and allele frequencies of 13 cardio-cerebrovascular risk polymorphisms were assessed and their possible association with dementia was investigated in a case-control study, including 221 consecutive unrelated subjects diagnosed with dementia (120 subjects affected by AD, 55 by frontotemporal dementia, and 33 by vascular dementia) and 218 matched controls of Calabrian origin. RESULTS: Carriers of at least one APOEɛ4 allele resulted to be at higher risk of AD [OR(95% CI) = 2.721(1.477-5.011)] and VaD [OR(95% CI) = 6.205(2.356-16.342)] compared to non-carriers. Individuals with the IV genotype of the CETP polymorphism were more likely to have AD [OR(95% CI) = 2.427(1.364-4.319)] and VaD [OR(95% CI) = 3.649(1.455-9.152)] compared to subjects with the II-VV genotypes. CONCLUSION: CETP I405V polymorphism is likely a risk factor for AD and VaD in our cohort, independent of APOEɛ4 status. Unmodifiable genetic risk factors should be taken into account to promote a healthy lifestyle to prevent dementia.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoprotein E4; Case-Control Studies; Cholesterol Ester Transfer Proteins; Cohort Studies; Dementia, Vascular; Female; Frontotemporal Dementia; Gene Frequency; Humans; Italy; Male; Middle Aged; Polymorphism, Genetic; Risk Factors

From Subjective Cognitive Decline to Alzheimer's Disease: The Predictive Role of Neuropsychological Assessment, Personality Traits, and Cognitive Reserve. A 7-Year Follow-Up Study. - Bessi, Valentina; Mazzeo, Salvatore; Padiglioni, Sonia; Piccini, Carolina; Nacmias, Benedetta; Sorbi, Sandro; Bracco, Laura (J Alzheimers Dis, 2018)
The aim of this study was to evaluate the accuracy of neuropsychological assessment in predicting conversion from subjective cognitive decline (SCD) and mild cognitive impairment (MCI) to Alzheimer's disease (AD) and the effect of personality traits and cognitive reserve in progression from SCD to MCI. As part of a longitudinal, clinical-neuropsychological-genetic survey on SCD and MCI, 284 patients referred to our hospital between 1990 and 2017 were included. All patients underwent clinical-extensive neuropsychological evaluation and Apolipoprotein E genotyping; personality traits were assessed in a subgroup. Each patient underwent clinical-neuropsychological follow-up. Subjects with a follow-up shorter than two years were excluded. A total of 212 subjects were, after exclusions, considered: 26 out of 109 SCD subjects progressed to MCI (SCD-p), 15 converted to AD (SCD-c), and 68 remained stable (SCD-s). Of 103 MCI subjects, 39 converted to AD (MCI-c) and 64 remained stable (MCI-s). At baseline, SCD-c performed significantly worse than SCD-s in tests assessing long-term verbal memory. MCI-c showed worse performance on neuropsychological tests for short- and long-term verbal memory and for ecological evaluation of memory (RBMT). These tests provided good accuracy in distinguishing MCI-c and MCI-s. Emotional stability was significantly lower in SCD-s than in SCD-p while higher intellectual activities were associated with a lower risk of conversion to MCI. Our results suggest that memory neuropsychological tests may represent a reliable tool to estimate the risk of progression to AD. Personality and lifestyle factors could provide useful information to identify SCD subjects who may develop an objective cognitive impairment.

Frontal Cortex Epigenetic Dysregulation During the Progression of Alzheimer's Disease. - Mahady, Laura; Nadeem, Muhammad; Malek-Ahmadi, Michael; Chen, Kewei; Perez, Sylvia E; Mufson, Elliott J (J Alzheimers Dis, 2018)
Although the frontal cortex plays an important role in cognitive function and undergoes neuronal dysfunction in Alzheimer's disease (AD), the factors driving these cellular alterations remain unknown. Recent studies suggest that alterations in epigenetic regulation play a pivotal role in this process in AD. We evaluated frontal cortex histone deacetylase (HDAC) and sirtuin (SIRT) levels in tissue obtained from subjects with a premortem diagnosis of no-cognitive impairment (NCI), mild cognitive impairment (MCI), mild to moderate AD (mAD), and severe AD (sAD) using quantitative western blotting. Immunoblots revealed significant increases in HDAC1 and HDAC3 in MCI and mAD, followed by a decrease in sAD compared to NCI. HDAC2 levels remained stable across clinical groups. HDAC4 was significantly increased in MCI and mAD, but not in sAD compared to NCI. HDAC6 significantly increased during disease progression, while SIRT1 decreased in MCI, mAD, and sAD compared to NCI. HDAC1 levels negatively correlated with perceptual speed, while SIRT1 positively correlated with perceptual speed, episodic memory, global cognitive score, and Mini-Mental State Examination. HDAC1 positively, while SIRT1 negatively correlated with cortical neurofibrillary tangle counts. These findings suggest that dysregulation of epigenetic proteins contribute to neuronal dysfunction and cognitive decline in the early stage of AD.

Gamma Band Neural Stimulation in Humans and the Promise of a New Modality to Prevent and Treat Alzheimer's Disease. - McDermott, Barry; Porter, Emily; Hughes, Diarmaid; McGinley, Brian; Lang, Mark; O'Halloran, Martin; Jones, Marggie (J Alzheimers Dis, 2018)
Existing treatments for Alzheimer's disease (AD) have questionable efficacy with a need for research into new and more effective therapies to both treat and possibly prevent the condition. This review examines a novel therapeutic modality that shows promise for treating AD based on modulating neuronal activity in the gamma frequency band through external brain stimulation. The gamma frequency band is roughly defined as being between 30 Hz-100 Hz, with the 40 Hz point being of particular significance. The epidemiology, diagnostics, existing pathological models, and related current treatment targets are initially briefly reviewed. Next, the concept of external simulation triggering brain activity in the gamma band with potential demonstration of benefit in AD is introduced with reference to a recent important study using a mouse model of the disease. The review then presents a selection of relevant studies that describe the neurophysiology involved in brain stimulation by external sources, followed by studies involving application of the modality to clinical scenarios. A table summarizing the results of clinical studies applied to AD patients is also reported and may aid future development of the modality. The use of a therapy based on modulation of gamma neuronal activity represents a novel non-invasive, non-pharmacological approach to AD. Although use in clinical scenarios is still a relatively recent area of research, the technique shows good signs of efficacy and may represent an important option for treating AD in the future.