Characteristics of Cognitively Normal Mexican-Americans with Cognitive Complaints. - Hall, James R; Wiechmann, April; Johnson, Leigh A; Edwards, Melissa; O'Bryant, Sid E (J Alzheimers Dis, 2018)
BACKGROUND: Subjective cognitive complaints in cognitively normal adults have been linked to later cognitive decline and dementia. Research on the characteristics of this group has been conducted on a variety of clinical and community-based populations. The current study focuses on the rapidly expanding population of Mexican-American elders. OBJECTIVE: The objective of the study is the determination of characteristics of cognitively normal Mexican-Americans with cognitive complaints. METHODS: Data on 319 cognitively normal participants in a large-scale community-based study of elderly Mexican-Americans (HABLE) were analyzed comparing those with cognitive complaints with those without on clinical characteristics, affective status, neuropsychological functioning, and proteomic markers. RESULTS: Those expressing concern about cognitive decline scored lower on the MMSE, were more likely to have significantly more affective symptoms, higher levels of diabetic markers, poorer performance on attention and executive functioning, and a different pattern of inflammatory markers. CONCLUSION: Although longitudinal research is needed to determine the impact of these differences on later cognition, possible targets for early intervention with Mexican-Americans were identified.
Keywords: Aged; Biomarkers; Cognition; Cognitive Dysfunction; Executive Function; Female; Humans; Male; Mexican Americans; Middle Aged; Neuropsychological Tests; Risk Factors; Texas

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

Circulating, Cell-Free Micro-RNA Profiles Reflect Discordant Development of Dementia in Monozygotic Twins. - Mengel-From, Jonas; Rønne, Mette E; Carlsen, Anting L; Skogstrand, Kristin; Larsen, Lisbeth A; Tan, Qihua; Christiansen, Lene; Christensen, Kaare; Heegaard, Niels H H (J Alzheimers Dis, 2018)
We aim to examine if circulating micro-RNA and cytokine levels associate with dementia diagnosis and cognitive scores. To test our hypothesis, we use plasma donated from 48 monozygotic twin pairs in 1997 and 46 micro-RNAs and 10 cytokines were quantified using microfluidic RT-qPCR and multiplex solid-phase immunoassays, respectively. Micro-RNA and cytokine profiling were examined for associations with dementia diagnoses in a longitudinal registry study or with cognitive scores at baseline. Thirty-six micro-RNAs and all cytokines were detected consistently. Micro-RNA profiles associate with diagnoses and cognitive scores at statistically significant levels while cytokine only showed trends pointing at chronic inflammation in twins having or developing dementia. The most notable findings were decreased miR-106a and miR-210, and increased miR-106b expression in twins with a dementia diagnosis. This pioneering evaluation of micro-RNA and cytokine and dementia diagnosis suggests micro-RNA targets in vasculogenesis, lipoprotein transport, and amyloid precursor protein genes.

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

Class-Specific Incidence of All-Cause Dementia and Alzheimer's Disease: A Latent Class Approach. - Zammit, Andrea R; Hall, Charles B; Katz, Mindy J; Muniz-Terrera, Graciela; Ezzati, Ali; Bennett, David A; Lipton, Richard B (J Alzheimers Dis, 2018)
Identifying preclinical Alzheimer's disease (AD) is an important step toward developing approaches to early treatment and dementia prevention. We applied latent class analysis (LCA) to 10 baseline neuropsychological assessments for 1,345 participants from Einstein Aging Study. Time-to-event models for all-cause dementia and AD were run examining events in 4-year intervals. Five classes were identified: Mixed-Domain Impairment (n = 107), Memory-Specific Impairment (n = 457), Average (n = 539), Frontal Impairment (n = 118), and Superior Cognition (n = 124). Compared to the Average class, the Mixed-Domain Impairment and Memory-Specific Impairment classes were at higher risk of incident all-cause dementia and AD in the first 4 years from baseline, while the Frontal Impairment class was associated with higher risk between 4 and 8 years of follow-up. LCA identified classes which differ in cross-sectional cognitive patterns and in risk of dementia over specific follow-up intervals.

Clinical Experience with Cerebrospinal Fluid Aβ42, Total and Phosphorylated Tau in the Evaluation of 1,016 Individuals for Suspected Dementia. - Tariciotti, Leonardo; Casadei, Matthew; Honig, Lawrence S; Teich, Andrew F; McKhann Ii, Guy M; Tosto, Giuseppe; Mayeux, Richard (J Alzheimers Dis, 2018)
BACKGROUND: Elevated total tau (tTau), 181-phosphorylated phosphorylated tau (pTau), and low amyloid-β42 (Aβ42) in cerebrospinal fluid (CSF) represent a diagnostic biomarker for Alzheimer's disease (AD). OBJECTIVE: The goal was to determine the overall accuracy of CSF Aβ42, tTau, pTau, and the Aβ42/total tau index (ATI) in a non-research, clinical setting for the diagnosis of AD. METHODS: From medical records in 1,016 patients that had CSF studies for dementia over a 12-year period (2005 to 2017), we calculated the sensitivity and specificity of CSF Aβ42, tTau, and pTau and the ATI in relation to the final clinical diagnosis. RESULTS: Compared with non-demented patients and patients with other dementias or mild cognitive impairment (MCI), the sensitivity and specificity of the recommended ATI and pTau cut-offs (ATI < 1.0 and pTau >61 pg/ml) for the diagnosis of AD were 0.88 and 0.72, respectively. Similar results were obtained comparing AD with non-demented patients only (0.88, 0.82) and AD with other types of dementia (0.81, 0.77). A subgroup of patients with presumed normal pressure hydrocephalus (n = 154) were biopsied at the time of shunt placement. Using the pathological manifestations of AD as the standard, the sensitivity was 0.83 while the specificity was 0.72. CONCLUSIONS: In a non-research setting, CSF biomarkers for AD showed a high sensitivity in accordance with previous studies, but modest specificity differentiating AD from other types of dementia or MCI. This study of unselected patients provides a valid and realistic assessment of the diagnostic accuracy of these CSF biomarkers in clinical practice.

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.

Cognitive Decline in Preclinical Alzheimer's Disease: Amyloid-Beta versus Tauopathy. - Huber, Colin M; Yee, Connor; May, Taylor; Dhanala, Apoorva; Mitchell, Cassie S (J Alzheimers Dis, 2018)
We perform a large-scale meta-analysis of 51 peer-reviewed 3xTg-AD mouse publications to compare Alzheimer's disease (AD) quantitative clinical outcome measures, including amyloid-β (Aβ), total tau, and phosphorylated tau (pTau), with cognitive performance in Morris water maze (MWM) and Novel Object Recognition (NOR). "High" levels of Aβ (Aβ40, Aβ42) showed significant but weak trends with cognitive decline (MWM: slope = 0.336, R2 = 0.149, n = 259, p < 0.001; NOR: slope = 0.156, R2 = 0.064, n = 116, p < 0.05); only soluble Aβ or directly measured Aβ meaningfully contribute. Tau expression in 3xTg-AD mice was within 10-20% of wild type and not associated with cognitive decline. In contrast, increased pTau is directly and significantly correlated with cognitive decline in MWM (slope = 0.408, R2 = 0.275, n = 371, p < < 0.01) and NOR (slope = 0.319, R2 = 0.176, n = 113, p < 0.05). While a variety of pTau epitopes (AT8, AT270, AT180, PHF-1) were examined, AT8 correlated most strongly with cognition (slope = 0.586, R2 = 0.521, n = 185, p < < 0.001). Multiple linear regression confirmed pTau is a stronger predictor of MWM performance than Aβ. Despite pTau's lower physical concentration than Aβ, pTau levels more directly and quantitatively correlate with 3xTg-AD cognitive decline. pTau's contribution to neurofibrillary tangles well after Aβ levels plateau makes pTau a viable treatment target even in late-stage clinical AD. Principal component analysis, which included hyperphosphorylation induced by kinases (pGSK3β, GSK3β, CDK5), identified phosphorylated ser9 GSK3β as the primary contributor to MWM variance. In summary, meta-analysis of cognitive decline in preclinical AD finds tauopathy more impactful than Aβ. Nonetheless, complex AD interactions dictate successful therapeutics harness synergy between Aβ and pTau, possibly through the GSK3 pathway.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cognitive Dysfunction; Disease Models, Animal; Maze Learning; Mice; Reaction Time; Recognition (Psychology); tau Proteins

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.

Comprehensive Characterization of the Pyroglutamate Amyloid-β Induced Motor Neurodegenerative Phenotype of TBA2.1 Mice. - Dunkelmann, Tina; Schemmert, Sarah; Honold, Dominik; Teichmann, Kerstin; Butzküven, Elke; Demuth, Hans-Ulrich; Shah, Nadim Joni; Langen, Karl-Josef; Kutzsche, Janine; Willbold, Dieter; Willuweit, Antje (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is the most common neurodegenerative disorder and is being intensively investigated using a broad variety of animal models. Many of these models express mutant versions of human amyloid-β protein precursor (AβPP) that are associated with amyloid-β protein (Aβ)-induced early onset familial AD. Most of these models, however, do not develop bold neurodegenerative pathology and the respective phenotypes. Nevertheless, this may well be essential for their suitability to identify therapeutically active compounds that have the potential for a curative or at least disease-modifying therapy in humans. In this study, the new transgenic mouse model TBA2.1 was explored in detail to increase knowledge about the neurodegenerative process induced by the presence of pyroglutamate modified human Aβ3-42 (pEAβ3-42). Analysis of the sensorimotor phenotype, motor coordination, Aβ pathology, neurodegeneration, and gliosis revealed formation and progression of severe pathology and phenotypes including massive neuronal loss in homozygous TBA2.1 mice within a few months. In contrast, the start of a slight phenotype was observed only after 21 months in heterozygous mice. These data highlight the role of pEAβ3-42 in the disease development and progression of AD. Based on the findings of this study, homozygous TBA2.1 mice can be utilized to gain deeper understanding in the underlying mechanisms of pEAβ3-42 and might be suitable as an animal model for treatment studies targeting toxic Aβ species, complementary to the well described transgenic AβPP mouse models.

Is Computerized Working Memory Training Effective in Healthy Older Adults? Evidence from a Multi-Site, Randomized Controlled Trial. - Simon, Sharon S; Tusch, Erich S; Feng, Nicole C; Håkansson, Krister; Mohammed, Abdul H; Daffner, Kirk R (J Alzheimers Dis, 2018)
BACKGROUND: Developing effective interventions to attenuate age-related cognitive decline and prevent or delay the onset of dementia are major public health goals. Computerized cognitive training (CCT) has been marketed increasingly to older adults, but its efficacy remains unclear. Working memory (WM), a key determinant of higher order cognitive abilities, is susceptible to age-related decline and a relevant target for CCT in elders. OBJECTIVE: To evaluate the efficacy of CCT focused on WM compared to an active control condition in healthy older adults. METHODS: Eighty-two cognitively normal adults from two sites (USA and Sweden) were randomly assigned to Cogmed Adaptive or Non-Adaptive (active control) CCT groups. Training was performed in participants' homes, five days per week over five weeks. Changes in the performance of the Cogmed trained tasks, and in five neuropsychological tests (Trail Making Test Part A and Part B, Digit Symbol, Controlled Oral Word Association Test and Semantic Fluency) were used as outcome measures. RESULTS: The groups were comparable at baseline. The Adaptive group showed robust gains in the trained tasks, and there was a time-by-group interaction for the Digit Symbol test, with significant improvement only after Adaptive training. In addition, the magnitude of the intervention effect was similar at both sites. CONCLUSION: Home-based CCT Adaptive WM training appears more effective than Non-Adaptive training in older adults from different cultural backgrounds. We present evidence of improvement in trained tasks and on a demanding untrained task dependent upon WM and processing speed. The benefits over the active control group suggest that the Adaptive CCT gains were linked to providing a continuously challenging level of WM difficulty.

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.

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

A Decade of Blood Biomarkers for Alzheimer's Disease Research: An Evolving Field, Improving Study Designs, and the Challenge of Replication. - Shi, Liu; Baird, Alison L; Westwood, Sarah; Hye, Abdul; Dobson, Richard; Thambisetty, Madhav; Lovestone, Simon (J Alzheimers Dis, 2018)
Blood-based biomarkers represent a less invasive and potentially cheaper approach for aiding Alzheimer's disease (AD) detection compared with cerebrospinal fluid and some neuroimaging biomarkers. Acknowledging that many in the field have made great progress, here we review some of the work that our group has pursued to identify and validate blood-based proteomic biomarkers through both case control and AD pathology endophenotype-based approaches. Our focus is primarily to identify a minimally invasive and hopefully cost-effective blood-based biomarker to reduce screen failure in clinical trials where participants have prodromal or even pre-clinical disease. We summarize some of the key findings and approaches taken in these biomarker studies, while addressing the main challenges, including that of limited replication in the field, and discuss opportunities for biomarker development.

Decreased Event-Related Beta Synchronization During Memory Maintenance Marks Early Cognitive Decline in Mild Cognitive Impairment. - Fodor, Zsuzsanna; Sirály, Enikő; Horváth, András; Salacz, Pál; Hidasi, Zoltán; Csibri, Éva; Szabó, Ádám; Csukly, Gábor (J Alzheimers Dis, 2018)
Mild cognitive impairment (MCI) refers to a measurable deficit in cognition in the absence of dementia or impairment in activities of daily living. Working memory impairment is among the earliest signs of MCI. Oscillatory analysis of working memory might be a potential tool for identifying patients at increased risk of developing dementia. Our study aimed to assess the temporospatial pattern of spectral differences during working memory maintenance between MCI patients and healthy controls and to compare the sources of oscillatory activity between the two groups. Event-related spectral perturbation of 17 MCI patients and 21 healthy control participants was studied with 128-channel EEG during the Sternberg working memory task. Source localization was performed by using the eLORETA software. Among the participants, 13 MCI and 15 control participants underwent a structural brain MRI examination. Event-related synchronization (ERS) in the alpha and beta frequency band was significantly lower in MCI patients compared to healthy control participants during retention. Both study groups showed significant memory load-related enhancement in both frequency band. In the MCI group, source localization revealed significantly attenuated beta oscillatory activity in the inferior and middle temporal gyrus, in the fusiform gyrus, and in the cuneus. Beta ERS correlated significantly with the size of the hippocampus, entorhinal cortex, and parahippocampal gyrus. During the retention period, MCI is characterized by decreased alpha and beta ERS compared to controls indicating early impairment in neural networks serving working memory maintenance. The assessment of electrophysiological changes in the beta frequency range may provide a useful diagnostic tool for the early detection of cognitive impairment.

Decreased Parietal Beta Power as a Sign of Disease Progression in Patients with Mild Cognitive Impairment. - Musaeus, Christian Sandøe; Nielsen, Malene Schjønning; Østerbye, Natascha Nellum; Høgh, Peter (J Alzheimers Dis, 2018)
BACKGROUND: Electroencephalography (EEG) power has previously been used to compare mild cognitive impairment (MCI) patients who progress to Alzheimer's disease (pMCI) with patients with MCI who remain stable (sMCI) by using beta power. However, the beta band is very broad and smaller frequency bands may improve accuracy. OBJECTIVE: In the present study, we wanted to investigate whether it was possible to find any differences between pMCI and sMCI using relative power and whether these differences were correlated to cognitive function or neuropathology markers. METHODS: 17 patients with AD, 27 patients with MCI, and 38 older healthy controls were recruited from two memory clinics and followed for three years. EEGs were recorded at baseline for all participants and relative power was calculated. All participants underwent adjusted batteries of standardized cognitive tests and lumbar puncture. RESULTS: We found that pMCI showed decreased baseline relative power in the parietal electrodes in the beta1 band (13-17.99 Hz). At 2-year follow-up, we found changes in all baseline beta bands but most pronounced in the beta1 band. In addition, we found that qEEG parietal power was correlated with amyloid-β42 and anterograde memory. CONCLUSION: These findings suggests that relative power in the parietal electrodes in the beta1 band may be a better way to discriminate between pMCI and sMCI at the time of diagnosis than the broad beta band. Similar findings have also been found with resting state fMRI. In addition, we found that anterograde memory was correlated to qEEG parietal beta1 power.

Decreased Prefrontal Activation during Matrix Reasoning in Predementia Progranulin Mutation Carriers. - Alexander, Courtney; Zeithamova, Dagmar; Hsiung, Ging-Yuek R; Mackenzie, Ian R; Jacova, Claudia (J Alzheimers Dis, 2018)
We tested the potential of task-based functional neuroimaging as a biomarker of emerging prefrontal brain changes in progranulin (GRN) mutations carriers. Five GRN mutation carriers free of frontotemporal dementia (FTD) and 11 non-carriers from families with FTD-GRN underwent functional MRI while solving matrix-reasoning problems. Mutation carriers displayed slower responses for more difficult problems and lower lateral prefrontal activation across all problems. Overall task-evoked posterior ventrolateral prefrontal activation predicted mutation status with 100% sensitivity and 91% specificity. Volumetric differences did not account for activation differences. Prefrontal activation may have utility as a biomarker in GRN mutation.
Keywords: Adult; Biomarkers; Female; Frontotemporal Dementia; Functional Neuroimaging; Heterozygote; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Mutation; Prefrontal Cortex; Progranulins

Dementia Care Competence Among Care Professionals and Reduced Challenging Behavior of Home-Dwelling Persons with Dementia: A Pre- and Post-Intervention Data Analysis. - Nakanishi, Miharu; Hirooka, Kayo; Imai, Yasuaki; Inoue, Shintaro; Yukari, Yukio; Katayama, Chie; Miyamoto, Yuki; Shindo, Yumi; Ueno, Hideki; Toya, Junichiro; Takano, Yosuke; Nishida, Atsushi (J Alzheimers Dis, 2018)
BACKGROUND: We developed a psychosocial dementia care program to help care managers and professional caregivers manage challenging behavior in home-dwelling persons with dementia in Japan. The program consists of a web-based tool for ongoing monitoring and assessment for challenging behavior, and multi-agency discussion meetings. Results of a cluster-randomized controlled trial indicate a reduction in challenging behavior through this program. OBJECTIVES: The present study aimed to identify a key component of the developed program that is associated with a reduction in challenging behavior. METHODS: We used consecutive data of the intervention and examined the association between challenging behavior in home-dwelling persons with dementia, professionals' competence, and the frequency of revision of action plans. Challenging behavior was assessed using the total score of the Neuropsychiatric Inventory. A baseline and follow-up questionnaire was completed by care professionals using a Japanese version of the Sense of Competence in Dementia Care Staff scale. RESULTS: A total of 86 care professionals completed a 6-month intervention with 219 persons with dementia. The 86 care professionals significantly improved in their dementia care competence. Challenging behavior was significantly reduced among the 219 persons with dementia at follow-up regardless of the level of professionals' competence or the frequency of revision of action plans. Less pain was significantly related to the lower levels of challenging behavior. CONCLUSION: The ongoing multi-agency discussion meetings, with a focus on challenging behavior, may have been the key component in the psychosocial dementia care program. Pain management should be emphasized in action plans for challenging behavior.

Dementia Research: Populations, Progress, Problems, and Predictions. - Hunter, Sally; Smailagic, Nadja; Brayne, Carol (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is a clinicopathologically defined syndrome leading to cognitive impairment. Following the recent failures of amyloid-based randomized controlled trials to change the course of AD, there are growing calls for a re-evaluation of basic AD research. Epidemiology offers one approach to integrating the available evidence. Here we examine relationships between evidence from population-based, clinicopathological studies of brain aging and a range of hypotheses from all areas of AD research. We identify various problems, including a lack of systematic approach to measurement of clinical and neuropathological factors associated with dementia in experimental and clinical settings, poor understanding of the strengths and weaknesses of different observational and experimental designs, a lack of clarity in relation to disease definitions from the clinical, neuropathological, and molecular perspectives, inadequate characterization of brain aging in the human population, difficulties in translation between laboratory-based and population-based evidence bases, and a lack of communication between different sections of the dementia research community. Population studies highlight complexity and predict that therapeutic approaches based on single disease features will not be successful. Better characterization of brain aging in the human population is urgently required to select biomarkers and therapeutic targets that are meaningful to human disease. The generation of detailed and reliable evidence must be addressed before progress toward therapeutic interventions can be made.

Depression and Alzheimer's Disease Biomarkers Predict Driving Decline. - Babulal, Ganesh M; Chen, Suzie; Williams, Monique M; Trani, Jean-Francois; Bakhshi, Parul; Chao, Grace L; Stout, Sarah H; Fagan, Anne M; Benzinger, Tammie L S; Holtzman, David M; Morris, John C; Roe, Catherine M (J Alzheimers Dis, 2018)
BACKGROUND: Symptomatic Alzheimer's disease (AD) and depression independently increase crash risk. Additionally, depression is both a risk factor for and a consequence of AD. OBJECTIVE: To examine whether a depression diagnosis, antidepressant use, and preclinical AD are associated with driving decline among cognitively normal older adults. METHODS: Cognitively normal participants, age ≥65, were enrolled. Cox proportional hazards models evaluated whether a depression diagnosis, depressive symptoms (Geriatric Depression Scale), antidepressant use, cerebrospinal fluid (amyloid-β42 [Aβ42], tau, phosphorylated tau181 [ptau181]), and amyloid imaging biomarkers (Pittsburgh Compound B and Florbetapir) were associated with time to receiving a rating of marginal/fail on a road test. Age was adjusted for in all models. RESULTS: Data were available from 131 participants with age ranging from 65.4 to 88.2 years and mean follow up of 2.4 years (SD = 1.0). A depression diagnosis was associated with a faster time to receiving a marginal/fail rating on a road test and antidepressant use (p = 0.024, HR = 2.62). Depression diagnosis and CSF and amyloid PET imaging biomarkers were associated with driving performance on the road test (p≤0.05, HR = 2.51-3.15). In the CSF ptau181 model, depression diagnosis (p = 0.031, HR = 2.51) and antidepressant use (p = 0.037, HR = 2.50) were statistically significant predictors. There were no interaction effects between depression diagnosis, antidepressant use, and biomarker groups. Depressive symptomology was not a statistically significant predictor of driving performance. CONCLUSIONS: While, as previously shown, preclinical AD alone predicts a faster time to receiving a marginal/fail rating, these results suggest that also having a diagnosis of depression accelerates the onset of driving problems in cognitively normal older adults.

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

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

The Diagnostic and Prognostic Value of a Dual-Tasking Paradigm in a Memory Clinic. - Nielsen, Malene Schjnning; Simonsen, Anja Hviid; Siersma, Volkert; Hasselbalch, Steen Gregers; Hoegh, Peter (J Alzheimers Dis, 2018)
BACKGROUND: Daily living requires the ability to perform dual-tasking. As cognitive skills decrease in dementia, performing a cognitive and motor task simultaneously become increasingly challenging and subtle gait abnormalities may even be present in pre-dementia stages. Therefore, a dual-tasking paradigm, such as the Timed Up and Go-Dual Task (TUG-DT), may be useful in the diagnostic assessment of mild cognitive impairment (MCI). OBJECTIVE: To investigate the diagnostic and prognostic ability of a dual-tasking paradigm in patients with MCI or mild Alzheimer's disease (AD) and to evaluate the association between the dual-tasking paradigm and cerebrospinal fluid (CSF) AD biomarkers. METHODS: The study is a prospective cohort study conducted in a clinical setting in two memory clinics. Eighty-six patients were included (28 MCI, 17 AD, 41 healthy controls (HC)). The ability to perform dual-tasking was evaluated by the TUG-DT. Patients underwent a standardized diagnostic assessment and were evaluated to determine progression yearly. RESULTS: ROC curve analysis illustrated a high discriminative ability of the dual-tasking paradigm in separating MCI patients from HC (AUC: 0.78, AUC: 0.82) and a moderate discriminative ability in separating MCI from AD (AUC: 0.73, AUC: 0.55). Performance discriminated clearly between all groups (p < 0.01). Logistic regression analyses revealed a low prognostic value of the dual-tasking paradigm for progression and rate of cognitive decline. A moderately strong correlation between the dual-tasking paradigm and CSF AD biomarkers was observed. CONCLUSION: In our study, we found that patients with MCI and mild AD have increasing difficulties in dual-tasking compared to healthy elderly. Hence, the dual-tasking paradigm may be a potential complement in the diagnostic assessment in a typical clinical setting.
Keywords: Aged; Alzheimer Disease; Biomarkers; Case-Control Studies; Cognitive Dysfunction; Disease Progression; Female; Humans; Logistic Models; Male; Memory; Middle Aged; Neuropsychological Tests; Prognosis; Prospective Studies; ROC Curve

Diaphanous 1 (DIAPH1) is Highly Expressed in the Aged Human Medial Temporal Cortex and Upregulated in Myeloid Cells During Alzheimer's Disease. - Derk, Julia; Bermudez Hernandez, Keria; Rodriguez, Moises; He, Meilun; Koh, Hyunwook; Abedini, Andisheh; Li, Huilin; Fenyö, David; Schmidt, Ann Marie (J Alzheimers Dis, 2018)
BACKGROUND: The receptor for advanced glycation end products (RAGE) is linked to cellular stress and inflammation during Alzheimer's disease (AD). RAGE signals through Diaphanous-1 (DIAPH1); however, the expression of DIAPH1 in the healthy and AD human brain has yet to be methodically addressed. OBJECTIVE: To delineate the cell- and disease-state specific expression of DIAPH1 in the human medial temporal cortex during healthy aging and AD. METHODS: We used semi-quantitative immunohistochemistry in the human medial temporal cortex paired with widefield and confocal microscopy and automated analyses to determine colocalization and relative expression of DIAPH1 with key cell markers and molecules in the brains of subjects with AD versus age-matched controls. RESULTS: We report robust colocalization of DIAPH1 with myeloid cells and increased expression during AD, which strongly correlated to increased neutral lipids and morphology of inflamed myeloid cells. DIAPH1 moderately colocalized with markers of endothelial cells, astrocytes, neurons, and oligodendrocytes. DISCUSSION: Our findings localize DIAPH1 particularly to myeloid cells in the CNS, especially in AD in the locations of lipid droplet accumulation, thereby implicating RAGE-DIAPH1 signaling in dysregulated lipid metabolism and morphological changes of inflamed myeloid cells in this disorder.

Diosgenin Attenuates Lipopolysaccharide-Induced Parkinson's Disease by Inhibiting the TLR/NF-κB Pathway. - Li, Bingyu; Xu, Pengli; Wu, Shuyan; Jiang, Zhixian; Huang, Zhijian; Li, Qian; Chen, Danhong (J Alzheimers Dis, 2018)
BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of dopaminergic neurons in the substantia nigra. Diosgenin is a natural steroid saponin which was shown to play a beneficial role in Alzheimer's disease. OBJECTIVE: This study sought to investigate the potential effect of diosgenin on a rat model of PD. METHODS: Sprague Dawley rats were subjected to intra-striatal injection of lipopolysaccharide (LPS) and treated with diosgenin. Stepping, Whisker, and Cylinder tests were carried out to determine the motor function, and the expression of tyrosine hydroxylase was detected by immunohistochemistry. The levels of multiple proinflammatory cytokines, oxidative stress related factors and proteins involved in Toll-like receptor (TLR)/nuclear factor kappa B (NF-κB) pathway were measured. The synergistic effect of environment enrichment on diosgenin was also investigated. RESULTS: Intra-striatal injection of LPS caused motor deficits in rats, induced inflammatory response and oxidative stress response, and activated the TLR/NF-κB pathway both in vivo and in vitro. Diosgenin could attenuate the LPS-induced alterations. Enriched environment enhanced the effect of diosgenin to ameliorate the LPS-induced motor deficits in rats and decreased the protein levels of TLR2, TLR4, and nuclear NF-κB in diosgenin treated PD rats. CONCLUSION: Diosgenin had a beneficial effect in LPS-induced rat PD models, by suppressing the TLR/NF-κB signaling pathway. Environmental enrichment could play a synergistic effect with diosgenin, by enhancing the inhibitory effect of diosgenin on the TLR/ NF-κB signaling pathway.

Dipeptidyl-Peptidase Activity of Meprin β Links N-truncation of Aβ with Glutaminyl Cyclase-Catalyzed pGlu-Aβ Formation. - Schlenzig, Dagmar; Cynis, Holger; Hartlage-Rübsamen, Maike; Zeitschel, Ulrike; Menge, Katja; Fothe, Anja; Ramsbeck, Daniel; Spahn, Claudia; Wermann, Michael; Roßner, Steffen; Buchholz, Mirko; Schilling, Stephan; et al. (J Alzheimers Dis, 2018)
The formation of amyloid-β (Aβ) peptides is causally involved in the development of Alzheimer's disease (AD). A significant proportion of deposited Aβ is N-terminally truncated and modified at the N-terminus by a pGlu-residue (pGlu-Aβ). These forms show enhanced neurotoxicity compared to full-length Aβ. Although the truncation may occur by aminopeptidases after formation of Aβ, recently discovered processing pathways of amyloid-β protein precursor (AβPP) by proteases such as meprin β may also be involved. Here, we assessed a role of meprin β in forming Aβ3-40/42, which is the precursor of pGlu-Aβ3-40/42 generated by glutaminyl cyclase (QC). Similar to QC, meprin β mRNA is significantly upregulated in postmortem brain from AD patients. A histochemical analysis supports the presence of meprin β in neurons and astrocytes in the vicinity of pGlu-Aβ containing deposits. Cleavage of AβPP-derived peptides by meprin β in vitro results in peptides Aβ1-x, Aβ2-x, and Aβ3-x. The formation of N-truncated Aβ by meprin β was also corroborated in cell culture. A subset of the generated peptides was converted into pGlu-Aβ3-40 by an addition of glutaminyl cyclase, supporting the preceding formation of Aβ3-40. Further analysis of the meprin β cleavage revealed a yet unknown dipeptidyl-peptidase-like activity specific for the N-terminus of Aβ1-x. Thus, our data suggest that meprin β contributes to the formation of N-truncated Aβ by endopeptidase and exopeptidase activity to generate the substrate for QC-catalyzed pGlu-Aβ formation.

Distinct Patterns of Rich Club Organization in Alzheimer's Disease and Subcortical Vascular Dementia: A White Matter Network Study. - Lee, Wha Jin; Han, Cheol E; Aganj, Iman; Seo, Sang Won; Seong, Joon-Kyung (J Alzheimers Dis, 2018)
Recent advances in neuroimaging technology have shown that rich club organization in human brain networks plays a crucial role in global communication and cognitive functionality. In this study, we investigated rich club organization within white matter structural brain networks in two common types of dementia, Alzheimer's disease (AD) and subcortical vascular dementia (SVaD). We recruited 30 AD patients ([11C] Pittsburgh compound-B (PiB) PET positive), 39 SVaD patients (PiB negative), and 72 age-, gender-, and education-matched cognitively normal (CN) subjects. Rich club organization was significantly disrupted in both dementia patient groups, which exhibited higher rich club coefficients than the CN group. Rich club organization in the patient groups was primarily disrupted over the left frontal and left middle temporal areas when compared to the CN group. The number of rich club nodes was significantly reduced in the dementia groups, which was more severe in SVaD (p = 0.0107, permutation-based t-test). Although rich club organization was disrupted both in the patient groups, its disruption pattern is different between them. The rich-club connections normalized by degree-and-strength preserved random networks were significantly increased in the dementia groups with SVaD more severely, and feeder connections were reduced more significantly than in AD. Furthermore, SVaD patients exhibited more sporadic disruption in white matter connectivity than AD patients, with local connections showing a more significant degree of deterioration. Combined with the distinct disruption in rich club nodes, these findings may imply a differing role for rich club organization in AD and SVaD, due to different pathological mechanisms.

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.

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.

Early and Persistent O-GlcNAc Protein Modification in the Streptozotocin Model of Alzheimer's Disease. - Dos Santos, João Paulo Almeida; Vizuete, Adriana; Hansen, Fernanda; Biasibetti, Regina; Gonçalves, Carlos-Alberto (J Alzheimers Dis, 2018)
O-GlcNAc transferase (OGT), an enzyme highly expressed in brain tissue, catalyzes the addition of N-acetyl-glucosamine (GlcNAc) to hydroxyl residues of serine and threonine of proteins. Brain protein O-GlcNAcylation is diminished in Alzheimer's disease (AD), and OGT targets include proteins of the insulin-signaling pathway (e.g., insulin receptor susbtrate-1, IRS-1). We hypothesized that ICV streptozotocin (STZ) also affects O-GlcNAc protein modification. We investigated hippocampal metabolic changes in Wistar rats, particularly OGT levels and insulin resistance, as well as related astroglial activities, immediately after ICV STZ administration (first week) and later on (fourth week). We found an early (at one week) and persistent (at fourth week) decrease in OGT in the ICV STZ model of AD, characterized by a spatial cognitive deficit. Consistent with this observation, we observed a decrease in protein O-GlnNAc modification at both times. Increased phosphorylation at serine-307 of IRS-1, which is related to insulin resistance, was observed on the fourth week. The decrease in OGT and consequent protein O-GlnNAc modifications appear to precede the decrease in glucose uptake and increment of the glyoxalase system observed in the hippocampus. Changes in glial fibrillary acidic protein and S100B in the hippocampus, as well as the alterations in cerebrospinal fluid S100B, confirm the astrogliosis. Moreover, decreases in glutamine synthetase and glutathione content suggest astroglial dysfunction, which are likely implicated in the neurodegenerative cascade triggered in this model. Together, these data contribute to the understanding of neurochemical changes in the ICV STZ model of sporadic AD, and may explain the decreases in protein O-GlcNAc levels and insulin resistance observed in AD.
Keywords: Alzheimer Disease; Analysis of Variance; Animals; Antibiotics, Antineoplastic; Brain; Disease Models, Animal; Glial Fibrillary Acidic Protein; Glucose; Glutathione; Insulin Receptor Substrate Proteins; Lactoylglutathione Lyase; Male; Maze Learning; N-Acetylglucosaminyltransferases; Rats; Rats, Wistar; S100 Calcium Binding Protein beta Subunit; Streptozocin; Time Factors

Early Detection of Alzheimer's Disease Based on the Patient's Creative Drawing Process: First Results with a Novel Neuropsychological Testing Method. - Heymann, Petra; Gienger, Regine; Hett, Andreas; Müller, Stephan; Laske, Christoph; Robens, Sibylle; Ostermann, Thomas; Elbing, Ulrich (J Alzheimers Dis, 2018)
Based on the knowledge of art therapy, we developed a new neuropsychological drawing test in order to identify individuals with mild cognitive impairment (MCI) as well as dementia patients and healthy controls (HC). By observing a variety of drawing characteristics of 92 participants with a mean age of 67.7, art therapy and dementia experts discriminate HC from MCI, early dementia of the Alzheimer-type (eDAT), and moderate dementia of the Alzheimer-type (mDAT) by the process analysis of tree drawings on a digitizing tablet. The art therapist's average categorical rating of healthy and MCI or demented individuals matched the clinical diagnosis by 88%. In a first small study, we analyzed interrater reliability, sensitivity, specificity, negative and positive predicted values of our tree drawing test (TDT) in comparison with the clock drawing test (CDT). Similar values of moderate interrater reliability were found for the TDT (0.56) as well as for the CDT (0.54). A significant high sensitivity of 0.9 within this binary impairment scale (HC versus impaired or demented) can be demonstrated. Substantial values for the specificity (0.67) could be obtained that however remain under a perfect value of the CDT (1.0). Considering 31 individuals that received the clinical diagnosis "impaired or demented" the TDT shows a higher recognition rate for the MCI group than the CDT. Furthermore in 8 of 12 borderline cases of clinical diagnosis, the outcome of the TDT diagnosis was consistent with the final clinical result.

Early Emotional Attention is Impacted in Alzheimer's Disease: An Eye-Tracking Study. - Bourgin, Jessica; Guyader, Nathalie; Chauvin, Alan; Juphard, Alexandra; Sauvée, Mathilde; Moreaud, Olivier; Silvert, Laetitia; Hot, Pascal (J Alzheimers Dis, 2018)
Emotional deficits have been repetitively reported in Alzheimer's disease (AD) without clearly identifying how emotional processing is impaired in this pathology. This paper describes an investigation of early emotional processing, as measured by the effects of emotional visual stimuli on a saccadic task involving both pro (PS) and anti (AS) saccades. Sixteen patients with AD and 25 age-matched healthy controls were eye-tracked while they had to quickly move their gaze toward a positive, negative, or neutral image presented on a computer screen (in the PS condition) or away from the image (in the AS condition). The age-matched controls made more AS mistakes for negative stimuli than for other stimuli, and triggered PSs toward negative stimuli more quickly than toward other stimuli. In contrast, patients with AD showed no difference with regard to the emotional category in any of the tasks. The present study is the first to highlight a lack of early emotional attention in patients with AD. These results should be taken into account in the care provided to patients with AD, since this early impairment might seriously degrade their overall emotional functioning.

Early Intervention with a Multi-Ingredient Dietary Supplement Improves Mood and Spatial Memory in a Triple Transgenic Mouse Model of Alzheimer's Disease. - Hutton, Craig P; Lemon, Jennifer A; Sakic, Boris; Rollo, C David; Boreham, Douglas R; Fahnestock, Margaret; Wojtowicz, J Martin; Becker, Suzanna (J Alzheimers Dis, 2018)
The increasing global burden of Alzheimer's disease (AD) and failure of conventional treatments to stop neurodegeneration necessitates an alternative approach. Evidence of inflammation, mitochondrial dysfunction, and oxidative stress prior to the accumulation of amyloid-β in the prodromal stage of AD (mild cognitive impairment; MCI) suggests that early interventions which counteract these features, such as dietary supplements, may ameliorate the onset of MCI-like behavioral symptoms. We administered a polyphenol-containing multiple ingredient dietary supplement (MDS), or vehicle, to both sexes of triple transgenic (3xTg-AD) mice and wildtype mice for 2 months from 2-4 months of age. We hypothesized that the MDS would preserve spatial learning, which is known to be impaired in untreated 3xTg-AD mice by 4 months of age. Behavioral phenotyping of animals was done at 1-2 and 3-4 months of age using a comprehensive battery of tests. As previously reported in males, both sexes of 3xTg-AD mice exhibited increased anxiety-like behavior at 1-2 months of age, prior to deficits in learning and memory, which did not appear until 3-4 months of age. The MDS did not reduce this anxiety or prevent impairments in novel object recognition (both sexes) or on the water maze probe trial (females only). Strikingly, the MDS specifically prevented 3xTg-AD mice (both sexes) from developing impairments (exhibited by untreated 3xTg-AD controls) in working memory and spatial learning. The MDS also increased sucrose preference, an indicator of hedonic tone. These data show that the MDS can prevent some, but not all, psychopathology in an AD model.

Economic Burden, Mortality, and Institutionalization in Patients Newly Diagnosed with Alzheimer's Disease. - Black, Christopher M; Fillit, Howard; Xie, Lin; Hu, Xiaohan; Kariburyo, M Furaha; Ambegaonkar, Baishali M; Baser, Onur; Yuce, Huseyin; Khandker, Rezaul K (J Alzheimers Dis, 2018)
BACKGROUND: Current information is scarce regarding comorbid conditions, treatment, survival, institutionalization, and health care utilization for Alzheimer's disease (AD) patients. OBJECTIVES: Compare all-cause mortality, rate of institutionalization, and economic burden between treated and untreated newly-diagnosed AD patients. METHODS: Patients aged 65-100 years with ≥1 primary or ≥2 secondary AD diagnoses (ICD-9-CM:331.0] with continuous medical and pharmacy benefits for ≥12 months pre-index and ≥6 months post-index date (first AD diagnosis date) were identified from Medicare fee-for-service claims 01JAN2011-30JUN2014. Patients with AD treatment claims or AD/AD-related dementia diagnosis during the pre-index period were excluded. Patients were assigned to treated and untreated cohorts based on AD treatment received post-index date. Total 8,995 newly-diagnosed AD patients were identified; 4,037 (44.8%) were assigned to the treated cohort. Time-to-death and institutionalization were assessed using Cox regression. To compare health care costs and utilizations, 1 : 1 propensity score matching (PSM) was used. RESULTS: Untreated patients were older (83.85 versus 81.44 years; p < 0.0001), with more severe comorbidities (mean Charlson comorbidity index: 3.54 versus 3.22; p < 0.0001). After covariate adjustment, treated patients were less likely to die (hazard ratio[HR] = 0.69; p < 0.0001) and were associated with 20% lower risk of institutionalization (HR = 0.801; p = 0.0003). After PSM, treated AD patients were less likely to have hospice visits (3.25% versus 9.45%; p < 0.0001), and incurred lower annual all-cause costs ($25,828 versus $30,110; p = 0.0162). CONCLUSION: After controlling for comorbidities, treated AD patients have better survival, lower institutionalization, and sometimes fewer resource utilizations, suggesting that treatment and improved care management could be beneficial for newly-diagnosed AD patients from economic and clinical perspectives.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cohort Studies; Comorbidity; Cost of Illness; Female; Humans; Institutionalization; Male; Neuropsychological Tests

EEG Theta Power Is an Early Marker of Cognitive Decline in Dementia due to Alzheimer's Disease. - Musaeus, Christian Sandøe; Engedal, Knut; Høgh, Peter; Jelic, Vesna; Mørup, Morten; Naik, Mala; Oeksengaard, Anne-Rita; Snaedal, Jon; Wahlund, Lars-Olof; Waldemar, Gunhild; Andersen, Birgitte Bo (J Alzheimers Dis, 2018)
BACKGROUND: Quantitative EEG (qEEG) power could potentially be used as a diagnostic tool for Alzheimer's disease (AD) and may further our understanding of the pathophysiology. However, the early qEEG power changes of AD are not well understood. OBJECTIVE: To investigate the early changes in qEEG power and the possible correlation with memory function and cerebrospinal fluid biomarkers. In addition, whether qEEG power could discriminate between AD, mild cognitive impairment (MCI), and older healthy controls (HC) at the individual level. METHODS: Standard EEGs from 138 HC, 117 MCI, and 117 AD patients were included from six Nordic memory clinics. All EEGs were recorded consecutively before the diagnosis and were not used for the consensus diagnosis. Absolute and relative power was calculated for both eyes closed and open condition. RESULTS: At group level using relative power, we found significant increases globally in the theta band and decreases in high frequency power in the temporal regions for eyes closed for AD and, to a lesser extent, for MCI compared to HC. Relative theta power was significantly correlated with multiple neuropsychological measures and had the largest correlation coefficient with total tau. At the individual level, the classification rate for AD and HC was 72.9% for relative power with eyes closed. CONCLUSION: Our findings suggest that the increase in relative theta power may be the first change in patients with dementia due to AD. At the individual level, we found a moderate classification rate for AD and HC when using EEGs alone.

The Effect of Chronic Cerebral Hypoperfusion on Amyloid-β Metabolism in a Transgenic Mouse Model of Alzheimer's Disease (PS1V97L). - Yang, Heyun; Hou, Tingting; Wang, Wei; Luo, Yumin; Yan, Feng; Jia, Jianping (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) and cerebrovascular disease often coexist. However, it is difficult to determine how chronic cerebral hypoperfusion affects the metabolism of amyloid-β peptides (Aβ) in a living patient with AD. Thus, we developed an animal model of this condition, using transgenic mice (PS1V97L) and right common carotid artery ligation to create chronic cerebral hypoperfusion. The metabolic processes associated with amyloid-β peptide (Aβ) were observed and evaluated in this PS1V97L plus hypoperfusion model. Compared with control mice, the model revealed significantly upregulated expression of Aβ (including Aβ oligomers), with decreased α-secretase activity and expression and increased β-secretase activity and expression. Furthermore, the model revealed increased mRNA and protein expression of the receptor for advanced glycation end products (RAGE) and decreased mRNA and protein expression of low-density lipoprotein receptor-related protein 1 (LRP-1); both these are Aβ transporters. Moreover, the model revealed decreased activity and expression of neprilysin, which is a peripheral Aβ degrading enzyme. These findings suggest that hypoperfusion may magnify the effect of AD on Aβ metabolism by aggravating its abnormal production, transport, and clearance.

Effect of Fluvoxamine on Amyloid-β Peptide Generation and Memory. - Kim, Woojin Scott; Fu, YuHong; Dobson-Stone, Carol; Hsiao, Jen-Hsiang T; Shang, Kani; Hallupp, Marianne; Schofield, Peter R; Garner, Brett; Karl, Tim; Kwok, John B J (J Alzheimers Dis, 2018)
Alzheimer's disease is characterized by abnormal amyloid-β (Aβ) peptide accumulation beginning decades before symptom onset. An effective prophylactic treatment aimed at arresting the amyloidogenic pathway would therefore need to be initiated prior to the occurrence of Aβ pathology. The SIGMAR1 gene encodes a molecular chaperone that modulates processing of the amyloid-β protein precursor (AβPP). Fluvoxamine is a selective serotonin reuptake inhibitor and a potent SIGMAR1 agonist. We therefore hypothesized that fluvoxamine treatment would reduce Aβ production and improve cognition. We firstly investigated the impact of SIGMAR1 on AβPP processing, and found that overexpression and knockdown of SIGMAR1 significantly affected γ-secretase activity in SK-N-MC neuronal cells. We then tested the impact of fluvoxamine on Aβ production in an amyloidogenic cell model, and found that fluvoxamine significantly reduced Aβ production by inhibiting γ-secretase activity. Finally, we assessed the efficacy of long-term treatment (i.e., ∼8 months) of 10 mg/kg/day fluvoxamine in the J20 amyloidogenic mouse model; the treatment was initiated prior to the occurrence of predicted Aβ pathology. Physical examination of the animals revealed no overt pathology or change in weight. We conducted a series of behavioral tests to assess learning and memory, and found that the fluvoxamine treatment significantly improved memory function as measured by novel object recognition task. Two other tests revealed no significant change in memory function. In conclusion, fluvoxamine has a clear impact on γ-secretase activity and AβPP processing to generate Aβ, and may have a protective effect on cognition in the J20 mice.

Effectiveness of a Personalized Brain-Computer Interface System for Cognitive Training in Healthy Elderly: A Randomized Controlled Trial. - Yeo, Si Ning; Lee, Tih Shih; Sng, Wei Theng; Heo, Min Quan; Bautista, Dianne; Cheung, Yin Bun; Zhang, Hai Hong; Wang, Chuanchu; Chin, Zheng Yang; Feng, Lei; Zhou, Juan; Chong, Mei Sian; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Cognitive training has been demonstrated to improve cognitive performance in older adults. To date, no study has explored personalized training that targets the brain activity of each individual. OBJECTIVE: This is the first large-scale trial that examines the usefulness of personalized neurofeedback cognitive training. METHODS: We conducted a randomized-controlled trial with participants who were 60-80 years old, with Clinical Dementia Rating (CDR) score of 0-0.5, Mini-Mental State Examination (MMSE) score of 24 and above, and with no neuropsychiatric diagnosis. Participants were randomly assigned to the Intervention or Waitlist-Control group. The training system, BRAINMEM, has attention, working memory, and delayed recall game components. The intervention schedule comprised 24 sessions over eight weeks and three monthly booster sessions. The primary outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score after the 24-session training. RESULTS: There were no significant between-subjects differences in overall cognitive performance post-intervention. However, a sex moderation effect (p = 0.014) was present. Men in the intervention group performed better than those in the waitlist group (mean difference, +4.03 (95% CI 0.1 to 8.0), p = 0.046. Among females, however, both waitlist-control and intervention participants improved from baseline, although the between-group difference in improvement did not reach significance. BRAINMEM also received positive appraisal and intervention adherence from the participants. CONCLUSION: A personalized neurofeedback intervention is potentially feasible for use in cognitive training for older males. The sex moderation effect warrants further investigation and highlights the importance of taking sex into account during cognitive training.

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 Exergaming in People with Dementia: Results of a Systematic Literature Review. - van Santen, Joeke; Dröes, Rose-Marie; Holstege, Marije; Henkemans, Olivier Blanson; van Rijn, Annelies; de Vries, Ralph; van Straten, Annemieke; Meiland, Franka (J Alzheimers Dis, 2018)
BACKGROUND: Physical exercise benefits functioning, health, and well-being. However, people living with dementia in particular hardly engage in exercise. Exergaming (exercise and gaming) is an innovative, fun, and relatively safe way of exercising in a virtual reality or gaming environment. It may help people living with dementia overcome barriers they can experience regarding regular exercise activities. OBJECTIVE: This systematic literature review aims to provide an overview of the cost-effectiveness of exergaming and its effects on physical, cognitive, emotional, and social functioning, as well as the quality of life in people living with dementia. METHODS: PubMed, Embase, Cinahl, PsycINFO, the Cochrane Library, and the Web of Science Core Collection were searched. Selection of studies was carried out by at least two independent researchers. RESULTS: Three studies were found to be eligible and were included in this review. Two of these showed some statistically significant effects of exergaming on physical, cognitive, and emotional functioning in people living with dementia, although based on a very small sample. No articles were found about the cost-effectiveness of exergaming. CONCLUSIONS: Only a few controlled studies have been conducted into the effectiveness of exergaming, and these show very little significant benefits. More well-designed studies are necessary to examine the effects of exergaming.

Effects of Meditation and Music-Listening on Blood Biomarkers of Cellular Aging and Alzheimer's Disease in Adults with Subjective Cognitive Decline: An Exploratory Randomized Clinical Trial. - Innes, Kim E; Selfe, Terry Kit; Brundage, Kathleen; Montgomery, Caitlin; Wen, Sijin; Kandati, Sahiti; Bowles, Hannah; Khalsa, Dharma Singh; Huysmans, Zenzi (J Alzheimers Dis, 2018)
BACKGROUND: Telomere length (TL), telomerase activity (TA), and plasma amyloid-β (Aβ) levels have emerged as possible predictors of cognitive decline and dementia. OBJECTIVE: To assess the: 1) effects of two 12-week relaxation programs on TL, TA, and Aβ levels in adults with subjective cognitive decline; and 2) relationship of biomarker changes to those in cognitive function, psychosocial status, and quality of life (QOL). METHODS: Participants were randomized to a 12-week Kirtan Kriya meditation (KK) or music listening (ML) program and asked to practice 12 minutes/day. Plasma Aβ(38/40/42) and peripheral blood mononuclear cell TL and TA were measured at baseline and 3 months. Cognition, stress, sleep, mood, and QOL were assessed at baseline, 3 months, and 6 months. RESULTS: Baseline blood samples were available for 53 participants (25 KK, 28 ML). The KK group showed significantly greater increases in Aβ40 than the ML group. TA rose in both groups, although increases were significant only among those with higher practice adherence and lower baseline TA. Changes in both TL and TA varied by their baseline values, with greater increases among participants with values ≤50th percentile (ps-interaction <0.006). Both groups improved in cognitive and psychosocial status (ps ≤0.05), with improvements in stress, mood, and QOL greater in the KK group. Rising Aβ levels were correlated with gains in cognitive function, mood, sleep, and QOL at both 3 and 6 months, associations that were particularly pronounced in the KK group. Increases in TL and TA were also correlated with improvements in certain cognitive and psychosocial measures. CONCLUSION: Practice of simple mind-body therapies may alter plasma Aβ levels, TL, and TA. Biomarker increases were associated with improvements in cognitive function, sleep, mood, and QOL, suggesting potential functional relationships.

Effects of Physical Exercise on Alzheimer's Disease Biomarkers: A Systematic Review of Intervention Studies. - Frederiksen, Kristian Steen; Gjerum, Le; Waldemar, Gunhild; Hasselbalch, Steen Gregers (J Alzheimers Dis, 2018)
Physical exercise may be an important adjunct to pharmacological treatment of Alzheimer's disease (AD). Animal studies indicate that exercise may be disease modifying through several mechanisms including reduction of AD pathology. We carried out a systematic review of intervention studies of physical exercise with hippocampal volume (on MRI), amyloid-β, total tau, phosphorylated tau in cerebrospinal fluid (CSF), 18F-FDG-PET or amyloid PET as outcome measures in healthy subjects, patients with subjective memory complaints, mild cognitive impairment, or AD. We identified a total of 8 studies of which 6 investigated the effects of exercise on hippocampal volume in healthy subjects and 1 on CSF biomarkers and 1 on hippocampal volume in AD, and none investigating the remaining outcome measures or patient groups. Methodological quality of identified studies was generally low. One study found a detrimental effect on hippocampal volume and one found a positive effect, whereas the remaining studies did not find an effect of exercise on outcome measures. The present systematic study identified a relatively small number of studies, which did not support an effect of exercise on hippocampal volume. Methodological issues such small to moderate sample sizes and inadequate ramdomization procedures further limits conclusions. Our findings highlight the difficulties in conducting high quality studies of exercise and further studies are needed before definite conclusions may be reached.
Keywords: Alzheimer Disease; Biomarkers; Exercise; Hippocampus; Humans; Outcome Assessment (Health Care); Physical Therapy Modalities

Elevation of Plasma Amyloid-β Level is More Significant in Early Stage of Cognitive Impairment: A Population-Based Cross-Sectional Study. - Wang, Jin; Qiao, Fan; Shang, Suhang; Li, Pei; Chen, Chen; Dang, Liangjun; Jiang, Yu; Huo, Kang; Deng, Meiying; Wang, Jingyi; Qu, Qiumin (J Alzheimers Dis, 2018)
BACKGROUND: Aggregation and deposition of amyloid-β (Aβ) in the brain is the main pathological change of Alzheimer's disease (AD). Decreased Aβ42 in the cerebrospinal fluid has been confirmed as a biomarker of AD; however, the relationship between plasma Aβ and cognitive impairment is currently unclear. OBJECTIVE: The aim was to explore the relationship between plasma Aβ and cognitive impairment in a cross-sectional study. METHODS: A total of 1,314 subjects (age above 40) from a village in the suburbs of Xi'an, China were enrolled between October 8, 2014 and March 30, 2015. A validated Chinese version of the Mini-Mental State Examination and neuropsychological battery were used to assess cognition. Levels of plasma Aβ42 and Aβ40 were tested using commercial enzyme-linked immunosorbent assay. Relationship of plasma Aβ and cognitive impairment was analyzed using logistic regression analysis. RESULTS: Of the enrolled subjects, 1,180 (89.80%) had normal cognition, 85 (6.47%) had possible cognitive impairment and 49 (3.73%) had probable cognitive impairment. Logistic regression analysis showed that the Aβ42/Aβ40 ratio (OR = 4.042, 95% CI: 1.248-11.098, p = 0.012) and plasma Aβ42 (OR = 1.036, 95% CI: 1.003-1.071, p = 0.031) was higher in the possible cognitive impairment than that in the normal cognition group. Furthermore, the plasma Aβ42/Aβ40 ratio was higher in the possible cognitive impairment group than that in the probable cognitive impairment group (OR = 0.029, 95% CI: 0.002-0.450, p = 0.011). CONCLUSIONS: Levels of plasma Aβ42 and Aβ42/Aβ40 ratio were elevated in patients with possible cognitive impairment, indicating that plasma Aβ42 and Aβ42/Aβ40 ratio increases may be more pronounced in early stage of cognitive impairment.

Endogenous Murine Amyloid-β Peptide Assembles into Aggregates in the Aged C57BL/6J Mouse Suggesting These Animals as a Model to Study Pathogenesis of Amyloid-β Plaque Formation. - Ahlemeyer, Barbara; Halupczok, Sascha; Rodenberg-Frank, Elke; Valerius, Klaus-Peter; Baumgart-Vogt, Eveline (J Alzheimers Dis, 2018)
Amyloid-β peptide (Aβ), paired helical filament-tau (PHF-tau), and α-synuclein are in the focus of neuroscience research because they aggregate in brains of patients with Alzheimer's and Parkinson's diseases. For this purpose, transgenic mouse models were used containing the human genes for AβPP/presenilin/tau or α-synuclein with the most frequent mutations. This is not ideal because most patients develop sporadic forms of the diseases with no causative single gene defect and furthermore the aggregation of human proteins in man is not necessarily the same in rodents. We hypothesized that for such cases the aged mouse could be an alternative model and analyzed the distribution of endogenous Aβ, PHF-tau, and α-synuclein in mouse brains at different ages. Whereas Aβ was below detectable levels at birth, it was present at high levels in the 15-month-old mouse. Aβ was found in the cytosol and lysosomes of neurons of the temporal cortex, cingulate area, pons, and cerebellum as well as extracellularly in the periventricular zone. Contrary to Aβ, mouse brain was devoid of PHF-tau-positive neurofibrillary tangles. α-Synuclein was detectable in the newborn mouse with highest levels in the marginal zone of the lateral cortex and average levels in the hippocampus, pons, and cerebellum. Brain-area specific differences in the α-synuclein level persisted up to 15 months of age, but increased 3-fold in all areas over time. α-Synuclein resided in the neuropil, but not in intracellular aggregates even in the aged mouse. We suggest the aged mouse as a model to study Aβ plaque formation.
Keywords: Age Factors; Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Disease Models, Animal; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurofibrillary Tangles; Neurons; Plaque, Amyloid; tau Proteins

Epitomic Characterization of the Specificity of the Anti-Amyloid Aβ Monoclonal Antibodies 6E10 and 4G8. - Baghallab, Ibtisam; Reyes-Ruiz, Jorge Mauricio; Abulnaja, Khalid; Huwait, Etimad; Glabe, Charles (J Alzheimers Dis, 2018)
The monoclonal antibodies 6E10 and 4G8 are among the first anti-amyloid monoclonal antibodies against Aβ and the most widely used antibodies in Alzheimer's disease research. Although the epitopes for 6E10 and 4G8 have been reported to correspond to residues 1-16 and 17-24, a more recent high-resolution mapping approach indicates that 6E10 maps to residues 4-10 while 4G8 maps to residues 18-23. To characterize the binding specificity of both antibodies in greater detail, we used immunoselection of random sequences from phage display library followed by deep sequencing and analysis of resulting patterns from thousands of immunoselected sequences. We found that the minimum sequence required for 6E10 binding is R-x-D with over half (53%) of the immunoselected sequences conforming to this pattern. The vast majority of these sequences contain an H at position x (R-H-D), corresponding to residues 5-7 of the Aβ target sequences, but Y is also permitted at this position in a minority of sequences. For 4G8 we found that the most frequent pattern is F-x-A contained in approximately 30% of the sequences, followed by F-A, L-x(3)-A, L-x-F, and F-F each accounting for approximately 18% of the sequences. The F-x-A motif also occurs in islet amyloid poly peptide which may explain why 4G8 also recognizes amyloid fibrils of this peptide. Immunoselection of random sequences and deep sequencing may also be a facile and efficient means of determining residues critical for antibody binding and validating the specificity of monoclonal antibodies and polyclonal antisera.

Erythromyeloid-Derived TREM2: A Major Determinant of Alzheimer's Disease Pathology in Down Syndrome. - Raha-Chowdhury, Ruma; Henderson, James W; Raha, Animesh Alexander; Stott, Simon R W; Vuono, Romina; Foscarin, Simona; Wilson, Liam; Annus, Tiina; Fincham, Robert; Allinson, Kieren; Devalia, Vinod; Friedland, Robert P; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Down syndrome (DS; trisomy 21) individuals have a spectrum of hematopoietic and neuronal dysfunctions and by the time they reach the age of 40 years, almost all develop Alzheimer's disease (AD) neuropathology which includes senile plaques and neurofibrillary tangles. Inflammation and innate immunity are key players in AD and DS. Triggering receptor expressed in myeloid cells-2 (TREM2) variants have been identified as risk factors for AD and other neurodegenerative diseases. OBJECTIVE: To investigate the effects of TREM2 and the AD-associated R47H mutation on brain pathology and hematopoietic state in AD and DS. METHODS: We analyzed peripheral blood, bone marrow, and brain tissue from DS, AD, and age-matched control subjects by immunohistochemistry and western blotting. TREM2-related phagocytosis was investigated using a human myeloid cell line. RESULTS: TREM2 protein levels in brain and sera declined with age and disease progression in DS. We observed soluble TREM2 in brain parenchyma that may be carried by a subset of microglia, macrophages, or exosomes. Two DS cases had the AD-associated TREM2-R47H mutation, which manifested a morphologically extreme phenotype of megakaryocytes and erythrocytes in addition to impaired trafficking of TREM2 to the erythroid membrane. TREM2 was shown to be involved in phagocytosis of red blood cells. TREM2 was seen in early and late endosomes. Silencing TREM2 using siRNA in THP1 cells resulted in significant cell death. CONCLUSION: We provide evidence that peripheral TREM2 originating from erythromyeloid cells significantly determines AD neuropathology in DS subjects. Understanding the molecular signaling pathways mediated by TREM2 may reveal novel therapeutic targets.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cell Line; Disease Progression; Down Syndrome; Exosomes; Female; Humans; Immunity, Innate; Macrophages; Male; Membrane Glycoproteins; Microglia; Middle Aged; Phagocytosis; Polymorphism, Single Nucleotide; Receptors, Immunologic

Evolvability of Amyloidogenic Proteins in Human Brain. - Hashimoto, Makoto; Ho, Gilbert; Sugama, Shuei; Takamatsu, Yoshiki; Shimizu, Yuka; Takenouchi, Takato; Waragai, Masaaki; Masliah, Eliezer (J Alzheimers Dis, 2018)
Currently, the physiological roles of amyloidogenic proteins (APs) in human brain, such as amyloid-β and α-synuclein, are elusive. Given that many APs arose by gene duplication and have been resistant against the pressures of natural selection, APs may be associated with some functions that are advantageous for survival of offspring. Nonetheless, evolvability is the sole physiological quality of APs that has been characterized in microorganisms such as yeast. Since yeast and human brain may share similar strategies in coping with diverse range of critical environmental stresses, the objective of this paper was to discuss the potential role of evolvability of APs in aging-associated neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Given the heterogeneity of APs in terms of structure and cytotoxicity, it is argued that APs might be involved in preconditioning against diverse stresses in human brain. It is further speculated that these stress-related APs, most likely protofibrillar forms, might be transmitted to offspring via the germline, conferring preconditioning against forthcoming stresses. Thus, APs might represent a vehicle for the inheritance of the acquired characteristics against environmental stresses. Curiously, such a characteristic of APs is reminiscent of Charles Darwin's 'gemmules', imagined molecules of heritability described in his pangenesis theory. We propose that evolvability might be a physiological function of APs during the reproductive stage and neurodegenerative diseases could be a by-product effect manifested later in aging. Collectively, our evolvability hypothesis may play a complementary role in the pathophysiology of APs with the conventional amyloid cascade hypothesis.

Exposure to Strong Anticholinergic Medications and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort. - Gray, Shelly L; Anderson, Melissa L; Hanlon, Joseph T; Dublin, Sascha; Walker, Rod L; Hubbard, Rebecca A; Yu, Onchee; Montine, Thomas J; Crane, Paul K; Sonnen, Josh A; Keene, C Dirk; Larson, Eric B (J Alzheimers Dis, 2018)
BACKGROUND: Anticholinergic medication exposure has been associated with increased risk for dementia. No study has examined the association between anticholinergic medication use and neuropathologic lesions in a community-based sample. OBJECTIVE: To examine the relationship between anticholinergic exposure and dementia-related neuropathologic changes. METHODS: Within a community-based autopsy cohort (N = 420), we ascertained use of anticholinergic medications over a 10-year period from automated pharmacy data and calculated total standardized daily doses (TSDD). We used modified Poisson regression to calculate adjusted relative risks (RRs) and 95% confidence intervals (CIs) for the association between anticholinergic exposure and dementia-associated neuropathology. Inverse probability weighting was used to account for selection into the autopsy cohort. RESULTS: Heavy anticholinergic exposure (≥1,096 TSDD) was not associated with greater neuropathologic changes of Alzheimer's disease; the adjusted RRs for heavy use of anticholinergics (≥1,096 TSDD) compared to no use were 1.22 (95% CI 0.81-1.88) for neuritic plaque scores and 0.89 (0.47-1.66) for extent of neurofibrillary degeneration. Moderate (91-1,095 TSDD) and heavy use of anticholinergics was associated with a significantly lower cerebral microinfarct burden compared with no use with adjusted RRs of 0.44 (0.21-0.89) and 0.24 (0.09-0.62), respectively. Anticholinergic exposure was not associated with macroscopic infarcts or atherosclerosis. CONCLUSIONS: Use of anticholinergic medications is not associated with Alzheimer's disease-related neuropathologic changes but is associated with lower cerebral microinfarct burden. Further research into biological mechanisms underlying the anticholinergic-dementia link is warranteds.

FDDNP-PET Tau Brain Protein Binding Patterns in Military Personnel with Suspected Chronic Traumatic Encephalopathy1. - Chen, Stephen T; Siddarth, Prabha; Merrill, David A; Martinez, Jacqueline; D Emerson, Natacha; Liu, Jie; Wong, Koon-Pong; Satyamurthy, Nagichettiar; Giza, Christopher C; Huang, Sung-Cheng; Fitzsimmons, Robert P; Bailes, Julian; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Our group has shown that in vivo tau brain binding patterns from FDDNP-PET scans in retired professional football players with suspected chronic traumatic encephalopathy differ from those of tau and amyloid aggregate binding observed in Alzheimer's disease (AD) patients and cognitively-intact controls. OBJECTIVE: To compare these findings with those from military personnel with histories of mild traumatic brain injury(mTBI). METHODS: FDDNP-PET brain scans were compared among 7 military personnel and 15 retired players with mTBI histories and cognitive and/or mood symptoms, 24 AD patients, and 28 cognitively-intact controls. Nonparametric ANCOVAs with Tukey-Kramer adjusted post-hoc comparisons were used to test for significant differences in regional FDDNP binding among subject groups. RESULTS: FDDNP brain binding was higher in military personnel compared to controls in the amygdala, midbrain, medial thalamus, pons, frontal and anterior and posterior cingulate regions (p < 0.01-0.0001). Binding patterns in the military personnel were similar to those of the players except for the amygdala and striatum (binding higher in players; p = 0.02-0.003). Compared with the AD group, the military personnel showed higher binding in the midbrain (p = 0.0008) and pons (p = 0.002) and lower binding in the medial temporal, lateral temporal, and parietal regions (all p = 0.02). CONCLUSION: This first study of in vivo tau and amyloid brain signals in military personnel with histories of mTBI shows binding patterns similar to those of retired football players and distinct from the binding patterns in AD and normal aging, suggesting the potential value of FDDNP-PET for early detection and treatment monitoring in varied at-risk populations.

Gait in Mild Alzheimer's Disease: Feasibility of Multi-Center Measurement in the Clinic and Home with Body-Worn Sensors: A Pilot Study. - Mc Ardle, Ríona; Morris, Rosie; Hickey, Aodhán; Del Din, Silvia; Koychev, Ivan; Gunn, Roger N; Lawson, Jennifer; Zamboni, Giovanna; Ridha, Basil; Sahakian, Barbara J; Rowe, James B; Thomas, Alan; et al. (J Alzheimers Dis, 2018)
Gait is emerging as a potential diagnostic tool for cognitive decline. The 'Deep and Frequent Phenotyping for Experimental Medicine in Dementia Study' (D&FP) is a multicenter feasibility study embedded in the United Kingdom Dementia Platform designed to determine participant acceptability and feasibility of extensive and repeated phenotyping to determine the optimal combination of biomarkers to detect disease progression and identify early risk of Alzheimer's disease (AD). Gait is included as a clinical biomarker. The tools to quantify gait in the clinic and home, and suitability for multi-center application have not been examined. Six centers from the National Institute for Health Research Translational Research Collaboration in Dementia initiative recruited 20 individuals with early onset AD. Participants wore a single wearable (tri-axial accelerometer) and completed both clinic-based and free-living gait assessment. A series of macro (behavioral) and micro (spatiotemporal) characteristics were derived from the resultant data using previously validated algorithms. Results indicate good participant acceptability, and potential for use of body-worn sensors in both the clinic and the home. Recommendations for future studies have been provided. Gait has been demonstrated to be a feasible and suitable measure, and future research should examine its suitability as a biomarker in 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.

Genotyping of the Alzheimer's Disease Genome-Wide Association Study Index Single Nucleotide Polymorphisms in the Brains for Dementia Research Cohort. - Brookes, Keeley J; McConnell, George; Williams, Kirsty; Chaudhury, Sultan; Madhan, Gaganjit; Patel, Tulsi; Turley, Christopher; Guetta-Baranes, Tamar; Bras, Jose; Guerreiro, Rita; Hardy, John; Francis, Paul T; et al. (J Alzheimers Dis, 2018)
The Brains for Dementia Research project is a recently established longitudinal cohort which aims to provide brain tissue for research purposes from neuropathologically defined samples. Here we present the findings from our analysis on the 19 established GWAS index SNPs for Alzheimer's disease, in order to demonstrate if the BDR sample also displays association to these variants. A highly significant association of the APOEɛ4 allele was identified (p = 3.99×10-12). Association tests for the 19 GWAS SNPs found that although no SNPs survive multiple testing, nominal significant findings were detected and concordance with the Lambert et al. GWAS meta-analysis was observed.

Ginkgo biloba Extract EGb 761 and Its Specific Components Elicit Protective Protein Clearance Through the Autophagy-Lysosomal Pathway in Tau-Transgenic Mice and Cultured Neurons. - Qin, Yiren; Zhang, Yu; Tomic, Inge; Hao, Wenlin; Menger, Michael D; Liu, Chunfeng; Fassbender, Klaus; Liu, Yang (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is a neurodegenerative disease pathologically characterized by extracellular amyloid-β (Aβ) deposits and intracellular neurofibrillary tangles (NFT) in many brain regions. NFT are primarily composed of hyperphosphorylated tau protein (p-Tau). Aβ and p-Tau are two major pathogenic molecules with tau acting downstream to Aβ to induce neuronal degeneration. In this study, we investigated whether Ginkgo biloba extract EGb 761 reduces cerebral p-Tau level and prevents AD pathogenesis. Human P301S tau mutant-transgenic mice were fed with EGb 761, added to the regular diet for 2 or 5 months. We observed that treatment with EGb 761 for 5 months significantly improved the cognitive function of mice, attenuated the loss of synaptophysin and recovered the phosphorylation of CREB in the mouse brain. Treatment with EGb 761 for 5 but not 2 months also decreased p-Tau protein amount and shifted microglial pro-inflammatory to anti-inflammatory activation in the brain. As potential therapeutic mechanisms, we demonstrated that treatment with EGb 761, especially the components of ginkgolide A, bilobalide, and flavonoids, but not with purified ginkgolide B or C, increased autophagic activity and degradation of p-Tau in lysosomes of neurons. Inhibiting ATG5 function or treating cells with Bafilomycin B1 abolished EGb 761-enhanced degradation of p-Tau in cultured neurons. Additionally, we observed that 5- instead of 2-month-treatment with EGb 761 inhibited the activity of p38-MAPK and GSK-3β. Therefore, long-term treatment with Ginkgo biloba extract EGb 761, a clinically available and well-tolerated herbal medication, ameliorates AD pathology through mechanisms against multiple AD pathogenic processes.

Glucagon-Like Peptide-2 Receptor is Involved in Spatial Cognitive Dysfunction in Rats After Chronic Cerebral Hypoperfusion. - Xie, Yan-Chun; Yao, Zhao-Hui; Yao, Xiao-Li; Pan, Jian-Zhen; Zhang, Shao-Feng; Zhang, Yong; Hu, Ji-Chang (J Alzheimers Dis, 2018)
Chronic cerebral hypoperfusion (CCH) affects the aging population and especially patients with neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. CCH is closely related to the cognitive dysfunction in these diseases. Glucagon-like peptide-2 receptor (GLP2R) mRNA and protein are highly expressed in the gut and in hippocampal neurons. This receptor is involved in the regulation of food intake and the control of energy balance and glucose homeostasis. The present study employed behavioral techniques, electrophysiology, western blotting, immunohistochemistry, quantitative real time polymerase chain reaction (qRT-PCR), and Golgi staining to investigate whether the expression of GLP2R changes after CCH and whether GLP2R is involved in cognitive impairment caused by CCH. Our findings show that CCH significantly decreased hippocampal GLP2R mRNA and protein levels. GLP2R upregulation could prevent CCH-induced cognitive impairment. It also improved the CCH-induced impairment of long-term potentiation and long-term depression. Additionally, GLP2R modulated after CCH the AKT-mTOR-p70S6K pathway in the hippocampus. Moreover, an upregulation of the GLP2R increased the neurogenesis in the dentate gyrus, neuronal activity, and density of dendritic spines and mushroom spines in hippocampal neurons. Our findings reveal the involvement of GLP2R via a modulation of the AKT-mTOR-p70S6K pathway in the mechanisms underlying CCH-induced impairments of spatial learning and memory. We suggest that the GLP2R and the AKT-mTOR-p70S6K pathway in the hippocampus are promising targets to treat cognition deficits in CCH.

Hedonic Assessment of Odors: A Comparison of Two Sensory Scales for Use with Alzheimer's Disease Patients and Elderly Individuals. - Atanasova, Boriana; Mondon, Karl; Dreyfuss, Lise; Beaufils, Emilie; Desmidt, Thomas; Hommet, Caroline; El-Hage, Wissam; Belzung, Catherine (J Alzheimers Dis, 2018)
BACKGROUND: Several clinical studies concerning the olfactory function of patients with cognitive impairment have used sensory scales to investigate hedonic perception. However, no study has focused on the choice of the most appropriate sensory hedonic scale for the individuals with neurodegenerative disorders or other psychiatric diseases involving cognitive deficits. OBJECTIVE: The aim of this study was to investigate the ability of patients with Alzheimer's disease (AD) to use two hedonic scales (category scale and linear scale) and compare their discriminatory capacity, repeatability, and ease of use. This should allow us to identify the most appropriate hedonic scale for patients with AD. METHODS: We recruited 18 patients with mild to moderate AD, and 20 healthy volunteers matched for gender, age, smoking status, and educational level. The participants underwent a clinical assessment and hedonic evaluation of three odorants (pleasant, unpleasant, and neutral), using a five-point category scale and a 10-cm linear scale with a marked mid-point. RESULTS: AD patients were able to use hedonic scales as well as paired healthy elderly subjects. The linear scale performed slightly better in terms of ease of use for both patients and healthy controls and discriminatory capacity for AD patients. The results for AD patients and controls with both scales were repeatable. CONCLUSION: The linear scale may be more appropriate for AD patients pending further studies involving a larger population of patients, using several odorants.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cognitive Dysfunction; Female; Humans; Linear Models; Male; Olfaction Disorders; Olfactory Perception; Severity of Illness Index; Smell

Heme Oxygenase 1 Induces Tau Oligomer Formation and Synapse Aberrations in Hippocampal Neurons. - Si, Zizhen; Wang, Xidi; Zhang, Zhujun; Wang, Jinxin; Li, Jihong; Li, Jing; Li, Ling; Li, Yuanxin; Peng, Yahui; Sun, Chongran; Hui, Yang; Gao, Xu (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by behavioral changes and cognitive decline. Recent evidence suggests that it is the soluble forms of tau oligomers (Tau-O) and Aβ oligomers (oAβ) rather than the well-studied insoluble protein aggregates that possess the neurotoxicity, infectivity, and amplification underlying disease progression. Heme oxygenase 1 (HO-1), an inducible enzyme upregulated in the cortex and hippocampus of AD brains, was reported to damage neural structures and disrupt brain function, suggesting possible contributions to Tau-O-mediated neurodegeneration. In this study, we focused on the effects of HO-1 on Tau-O formation. In hippocampus of HO-1-overexpressing transgenic mice and neural 2a (N2a) cells, Tau-O was co-localized with HO-1 as visualized by immunofluorescence staining. Furthermore, primary cultured hippocampal neurons from HO-1 transgenic mice showed elevated Tau-O and concomitant reductions in spine density and length as well as dendritic length, diameter, and arborization. Blocking Tau-O formation by isoprenaline reversed these HO-1-induced morphological changes. These results indicated that HO-1 contributes to Tau-O formation and ensuing synaptic damage. Thus, HO-1 is a promising target for AD drug development.

Higher Blood Vitamin C Levels are Associated with Reduction of Apolipoprotein E E4-related Risks of Cognitive Decline in Women: The Nakajima Study. - Noguchi-Shinohara, Moeko; Abe, Chiemi; Yuki-Nozaki, Sohshi; Dohmoto, Chiaki; Mori, Ayaka; Hayashi, Koji; Shibata, Syutaro; Ikeda, Yoshihisa; Sakai, Kenji; Iwasa, Kazuo; Yokogawa, Masami; Ishimiya, Mai; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Antioxidants like vitamins C and E may minimize the risk for Alzheimer's disease. OBJECTIVE: We examined whether vitamins C and E modify the apolipoprotein E (APOE) E4-related risks for developing cognitive decline. METHODS: We conducted a population-based prospective study including Japanese residents aged 65 years from Nakajima, Japan. The participants received an evaluation of cognitive function and underwent blood tests including tests for vitamins C and E levels and APOE phenotypes. The APOE E4-by-gender-by-vitamin C or E interactions on developing cognitive decline were analyzed. RESULTS: Of 606 participants with normal cognitive function determined using a baseline survey (2007-2008), 349 completed the follow up survey between 2014 and 2016. In women with APOE E4, significantly reduced risk for cognitive decline was observed for the highest blood vitamin C concentration tertile [multivariate OR 0.10 (95% CI 0.01-0.93)] compared with the lowest tertile. In men without APOE E4, significantly reduced risk for cognitive decline was observed for the highest blood vitamin E concentration tertile [multivariate OR 0.19 (0.05-0.74)] as compared with the lowest tertile. CONCLUSION: Our results demonstrate significant beneficial effects of vitamins C and E in reducing the risk of cognitive decline in women with APOE E4 and men without APOE E4, respectively.

Hippocampal Stratum Radiatum, Lacunosum, and Moleculare Sparing in Mild Cognitive Impairment. - Su, Li; Hayes, Lawrence; Soteriades, Soteris; Williams, Guy; Brain, Susannah A E; Firbank, Michael J; Longoni, Giulia; Arnold, Robert J; Rowe, James B; O'Brien, John T (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is associated with atrophy in entorhinal cortex (ERC), the hippocampus, and its subfields Cornu Ammonis 1 (CA1) and subiculum, which predict conversion from mild cognitive impairment (MCI) to clinical AD. The stratum radiatum, lacunosum, and moleculare (SRLM) are also important gateways involving ERC and CA1, which are affected by early AD pathology. OBJECTIVE: To assess whether the SRLM is affected in MCI and AD. METHODS: In this proof-of-concept study, 27 controls, 13 subjects with AD, and 22 with MCI underwent 3T MRI. T1 maps were used for whole-hippocampal volumetry, T2 maps were segmented for hippocampal subfield areas, entorhinal cortex and subiculum thickness, and evaluated for SRLM integrity. RESULTS: Significant CA1 atrophy and subiculum thinning were found in both AD and MCI compared to similarly aged controls. However, SRLM integrity was only significantly reduced in AD but not in MCI compared to controls. There were no significant differences in other hippocampal subfields (CA2, CA3/dentate gyrus) or ERC thickness between the groups. Finally, CA1 and CA3/DG areas and SRLM clarity were correlated with clinical and cognitive measurements of disease severity. CONCLUSION: Although this study was cross sectional, it suggests a progression of specific subfield changes from MCI to established AD that is associated with the reduced integrity of SRLM, which may reflect more widespread hippocampal involvement as the disease progresses and the relative preservation of SRLM in MCI. These results provide new MRI biomarkers for disease staging and understanding of the neurobiology in AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Atrophy; Cognitive Dysfunction; Disease Progression; Entorhinal Cortex; Female; Hippocampus; Humans; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Male; Middle Aged; Reproducibility of Results

Homocysteine and Cerebral Atrophy: The Epidemiology of Dementia in Singapore Study. - Tan, Bryce; Venketasubramanian, Narayanaswamy; Vrooman, Henri; Cheng, Ching-Yu; Wong, Tien Yin; Ikram, Mohammad Kamran; Chen, Christopher; Hilal, Saima (J Alzheimers Dis, 2018)
BACKGROUND: Plasma homocysteine levels are increasingly studied as a potential risk factor for dementia. Elevated homocysteine levels have been linked with gray and white matter volume reduction among individuals with mild cognitive impairment and Alzheimer's disease. However, the effects of homocysteine on brain changes in preclinical stages of dementia remain unexplored. OBJECTIVE: To examine the association of elevated homocysteine levels with markers of neurodegeneration, i.e., white and gray matter volume in an elderly population. METHODS: The study included 768 participants (mean age: 69.6±6.5 years, 51.3% women) from the Epidemiology of Dementia In Singapore study. Participants underwent a brain MRI scan and blood tests. Serum homocysteine was measured using competitive immunoassay. Cortical thickness and subcortical structural volume were quantified using FreeSurfer whereas white matter volume was quantified using a previous validated method. RESULTS: Higher homocysteine levels were significantly associated with decreased global white matter volume [mean difference (β) in volume (ml) per micromole per liter (μmol/l) increase in homocysteine levels: - 0.555, 95% Confidence Interval (CI): - 0.873; - 0.237], decreased parietal cortical thickness [β in thickness (μm) per μmol/l increase in homocysteine levels:- 1.429, 95% CI: - 2.781; - 0.077], and smaller volumes of the thalamus [β: - 0.017, 95% CI: - 0.026; - 0.008], brainstem [β: - 0.037, 95% CI: - 0.058; - 0.016], and accumbens [β: - 0.004, 95% CI: - 0.006; - 0.002]. CONCLUSION: Higher homocysteine levels were associated with cerebral atrophy. Further studies are required to assess whether lowering plasma homocysteine levels may prevent neurodegenerative changes or delay progression of clinical symptoms before the development of dementia.
Keywords: Aged; Atrophy; Biomarkers; Dementia; Female; Homocysteine; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Organ Size; Risk Factors; Singapore; White Matter

Homocysteine and Dementia: An International Consensus Statement. - Smith, A David; Refsum, Helga; Bottiglieri, Teodoro; Fenech, Michael; Hooshmand, Babak; McCaddon, Andrew; Miller, Joshua W; Rosenberg, Irwin H; Obeid, Rima (J Alzheimers Dis, 2018)
Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may lower the risk factor level. One such risk factor is a raised concentration of the biomarker plasma total homocysteine, which reflects the functional status of three B vitamins (folate, vitamins B12, B6). A group of experts reviewed literature evidence from the last 20 years. We here present a Consensus Statement, based on the Bradford Hill criteria, and conclude that elevated plasma total homocysteine is a modifiable risk factor for development of cognitive decline, dementia, and Alzheimer's disease in older persons. In a variety of clinical studies, the relative risk of dementia in elderly people for moderately raised homocysteine (within the normal range) ranges from 1.15 to 2.5, and the Population Attributable risk ranges from 4.3 to 31%. Intervention trials in elderly with cognitive impairment show that homocysteine-lowering treatment with B vitamins markedly slows the rate of whole and regional brain atrophy and also slows cognitive decline. The findings are consistent with moderately raised plasma total homocysteine (>11 μmol/L), which is common in the elderly, being one of the causes of age-related cognitive decline and dementia. Thus, the public health significance of raised tHcy in the elderly should not be underestimated, since it is easy, inexpensive, and safe to treat with B vitamins. Further trials are needed to see whether B vitamin treatment will slow, or prevent, conversion to dementia in people at risk of cognitive decline or dementia.
Keywords: Cognition; Cognitive Dysfunction; Consensus; Dementia; Dietary Supplements; Homocysteine; Humans; Meta-Analysis as Topic; Review Literature as Topic; Risk Factors; Vitamin B Complex

Honokiol Alleviates Cognitive Deficits of Alzheimer's Disease (PS1V97L) Transgenic Mice by Activating Mitochondrial SIRT3. - Li, Haitao; Jia, Jianping; Wang, Wei; Hou, Tingting; Tian, Yuanruhua; Wu, Qiaoqi; Xu, Lingzhi; Wei, Yiping; Wang, Xiu (J Alzheimers Dis, 2018)
Accumulating evidence has demonstrated that mitochondrial dysfunction is a prominent early event in the progression of Alzheimer's disease (AD). Whether protecting mitochondrial function can reduce amyloid-β oligomer (AβO)-induced neurotoxicity in PS1V97L transgenic mice remains unknown. In this study, we examined the possible protective effects of honokiol (HKL) on mitochondrial dysfunction induced by AβOs in neurons, and cognitive function in AD PS1V97Ltransgenic mice. We determined that HKL increased mitochondrial sirtuin 3 (SIRT3) expression levels and activity, which in turn markedly improved ATP production and weakened mitochondrial reactive oxygen species production. We demonstrated that the enhanced energy metabolism and attenuated oxidative stress of HKL restores AβO-mediated mitochondrial dysfunction in vitro and in vivo. Consequently, memory deficits in the PS1V97L transgenic mice were rescued by HKL in the early stages. These results suggest that HKL has therapeutic potential for delaying the onset of AD symptoms by alleviating mitochondrial impairment and increasing hyperactivation of SIRT3 in the pathogenesis of preclinical AD.

Hospitalization after Oral Antibiotic Initiation in Finnish Community Dwellers with and without Alzheimer's Disease: Retrospective Register-Based Cohort Study. - Järvinen, Heli; Taipale, Heidi; Koponen, Marjaana; Tanskanen, Antti; Tiihonen, Jari; Tolppanen, Anna-Maija; Hartikainen, Sirpa (J Alzheimers Dis, 2018)
BACKGROUND: Persons with Alzheimer's disease (AD) are frequently hospitalized from infection-related causes. There are no previous studies investigating hospitalization associated with antibiotic initiation in persons with AD. OBJECTIVE: To investigate the frequency and risk of hospitalization associated with oral antibiotic initiation among community dwellers with and without AD. METHODS: We performed a retrospective register-based study utilizing register-based Medication Use and Alzheimer's disease (MEDALZ) cohort. It includes all community dwellers diagnosed with AD during 2005-2011 in Finland and their matched comparison persons without AD. Antibiotic use was initiated by 34,785 persons with and 36,428 without AD. Drug use data were collected from Prescription Register and comorbidities from Special Reimbursement and Hospital Care Registers. Infection diagnoses were collected from the Hospital Care Register. Factors associated with hospitalization were estimated utilizing logistic regression models. RESULTS: Risk of hospitalization following antibiotic initiation was higher among antibiotic initiators with AD than without AD (adjusted odds ratio, aOR, 1.37, 95% Cl 1.28-1.46).Strongest association with hospitalization was found for oral glucocorticoid use, aOR 1.41 (1.25-1.59); epilepsy, aOR 1.33 (1.10-1.63); and active cancer, aOR 1.30 (1.14-1.49). Among initiators of cephalexin, pivmecillinam, amoxicillin/amoxicillin, and enzyme inhibitor and doxycycline, persons with AD were more frequently hospitalized than persons without AD. A quarter of hospitalized antibiotic initiators had infection diagnosis in their hospital care records. CONCLUSIONS: Persons with AD initiating an antibiotic had a higher risk for hospitalization than antibiotic initiators without AD. Further research is needed to determine whether infection-related hospitalization could be reduced.

How Does Utilization of Health Care Services Change in People with Dementia Served by Dementia Care Networks? Results of the Longitudinal, Observational DemNet-D-Study. - Thyrian, Jochen René; Michalowsky, Bernhard; Hertel, Johannes; Wübbeler, Markus; Gräske, Johannes; Holle, Bernhard; Schäfer-Walkmann, Susanne; Wolf-Ostermann, Karin; Hoffmann, Wolfgang (J Alzheimers Dis, 2018)
BACKGROUND: There is no common definition for the Dementia Care Network (DCN). They are heterogeneous and there is no general, longitudinal evidence for the effects of DCN. OBJECTIVE: We describe changes in utilization of health services by people served by dementia care networks in Germany and factors associated with those changes over time. METHODS: Primary data was assessed in 560 people with dementia (PwD) and their caregivers supported by DCN in Germany; sociodemographic and clinical variables, utilization of services; DCN were characterized according to governance. The design: observational study with face-to-face interviews at two time points over a period of one year. Data was assessed via semi-structured interviews at the participants' homes. RESULTS: Utilization of health services in this study is consistently higher than reported for the general population and does not significantly change over time. The strongest predictor of utilization of any service after one year was the use of this service at baseline (OR from 3.23 to 44.16). Higher activities of daily functioning increased the chances to utilize specialist physicians (OR = 1.32; 95% -CI: 1.08-1.63) or occupational therapy (OR = 1.24; 95% -CI: 1.02-1.50) significantly. Being a female decreased chances to utilize specialist physicians (OR = 0.57; 95% -CI: 0.37-0.87) and increased the chances to utilize no services (OR = 2.08; 95% -CI: 1.29-3.33). CONCLUSION: While health care acknowledges the importance and benefits of dementia care networks (i.e., in Germany, the results were considered in new German legislation (SGB XI)), further research is needed to define this kind of service delivery to facilitate comparison as well as promote evidence-based implementation.

HSV-1-Specific IgG Subclasses Distribution and Serum Neutralizing Activity in Alzheimer's Disease and in Mild Cognitive Impairment. - Agostini, Simone; Mancuso, Roberta; Hernis, Ambra; Costa, Andrea Saul; Nemni, Raffaello; Clerici, Mario (J Alzheimers Dis, 2018)
Human Herpes Simplex Virus type 1 (HSV-1) infection is suggested to play a role in the development of Alzheimer's disease (AD). Immunoglobulin G (IgG) neutralize HSV-1 activity, but the virus can evade IgG-mediated immune responses by expressing receptor that efficiently binds the Fc portion of all IgG subclasses with the exception of IgG3. We analyzed HSV-1-specific IgG subclasses and IgG-mediated serum neutralization activity against HSV-1 in individuals with a diagnosis of either AD or mild cognitive impairment (MCI), comparing the results with those obtained in age-matched healthy controls (HC). 186 individuals were enrolled in the study: 67 AD, 58 MCI, and 61 HC. HSV-1 IgG titers and subclasses, neutralizing antibody (NAb) titers, and complement C3 concentration-critical component of antibody-mediated effector activity-were measured in sera by ELISA; IgG neutralizing activity was performed on HSV-1 infected Vero cells. Results showed that, whereas HSV-1-specific IgG1, IgG2, and IgG4 titers as well as complement C3 serum concentration were comparable in all groups of individuals, IgG3 were more frequently detected in MCI (89%) compared to AD (75%; p < 0.05) and HC (68%; p = 0.003), whereas the titer is similar among the three groups (AD: 0.66±0.21 OD; MCI: 0.68±0.24 OD; HC: 0.72±0.28 OD). Notably, HSV-1 specific neutralizing ability of AD sera was reduced even in the presence of high quantity of IgG3. As IgG3 plays a key role in counteracting the ability of HSV-1 to evade immune responses, these data reinforce the hypothesis of a pathogenetic role of HSV-1 in AD.

The Impact of Hospitalization on Readmission, Institutionalization, and Mortality of People with Dementia: A Systematic Review and Meta-Analysis. - Lehmann, Jana; Michalowsky, Bernhard; Kaczynski, Anika; Thyrian, Jochen René; Schenk, Nele Sophie; Esser, Alexander; Zwingmann, Ina; Hoffmann, Wolfgang (J Alzheimers Dis, 2018)
BACKGROUND: People with dementia (PwD) are at a high risk of hospitalization. Hospitals are often not adequately equipped for PwD and discharges often come unexpected. Therefore, PwD are at a risk of adverse outcomes. However, information about those outcomes is rare but crucial for the development of preventive strategies. OBJECTIVES: To conduct a quantitative systematic review and meta-analyses on the impact of a hospitalization on readmission, institutionalization, and mortality in PwD. To identify factors associated with these outcomes. METHODS: PubMed, CENTRAL, and ScienceDirect were searched for studies including terms for dementia, hospital, readmission, institutionalization, and mortality. Relevant were assessed by a quality criteria sheet. Results were summarized in a table. Meta-analysis was conducted with Review Manager 5.3. RESULTS: The search yielded 1,108 studies; 20 fulfilled the inclusion criteria and 10 studies were eligible for meta-analyses. The incidence and relative risk (RR) of mortality (RR 1.74 CI95 % 1.50, 2.05) and institutionalization (RR: 2.16 CI95 % 1.31, 3.56) of PwD was significantly higher when compared to people without dementia. Results according to readmission rate were inconsistent. Factors significantly associated with the examined adverse outcomes were severity of dementia, number of medications, and deficits in daily living activities. CONCLUSION: Hospitalization of PwD lead to adverse outcomes. An improvement in the identification of and care for PwD in the acute setting as well as in after care in the community setting, especially in the interface between both settings, is required to prevent adverse outcomes in hospitalized PwD.

Impact of Mild Cognitive Impairment on Mortality and Cause of Death in the Elderly. - Bae, Jong Bin; Han, Ji Won; Kwak, Kyung Phil; Kim, Bong Jo; Kim, Shin Gyeom; Kim, Jeong Lan; Kim, Tae Hui; Ryu, Seung-Ho; Moon, Seok Woo; Park, Joon Hyuk; Youn, Jong Chul; Lee, Dong Young; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Mild cognitive impairment (MCI) is a cognitive state that lies on the continuum between normal aging and dementia, and the prevalence of MCI is higher than dementia. However, the risk for mortality of people with MCI has been far less studied than that of people with dementia, and the population attributable risk percent (PAR%) of death attributable to MCI has not been estimated yet. OBJECTIVE: To investigate the impact of MCI on mortality and the cause of death in the elderly, and to estimate the PAR% of deaths attributable to MCI. METHODS: Data came from 7,315 elderly subjects aged ≥60 years without dementia from two cohort studies with diagnostic assessments of MCI at baseline. Deaths among participants were confirmed through the nationwide mortality database of Statistics Korea. RESULTS: MCI increased the risk of mortality in a multivariate Cox proportional model adjusting for age, sex, education, smoking, alcohol drinking, chronic illness, depression, vascular components, and cohort (hazard ratio = 1.59, 95% confidence interval 1.30, 1.94). PAR% of death attributable to MCI was 10.7% for age 65-74 years, 16.0% for age 75-84 years, and 24.2% for age ≥85 years. In the elderly with MCI, mortality risks from cerebrovascular disease, respiratory disease, and external causes were higher than in the cognitively normal elderly. CONCLUSIONS: Our results suggest that the mortality risk of MCI in Asian countries may be comparable to that in Western countries, and MCI can contribute to the death of the elderly as much as dementia.

Impact of Osteoporosis on the Risk of Dementia in Almost 60,000 Patients Followed in General Practices in Germany. - Kostev, Karel; Hadji, Peyman; Jacob, Louis (J Alzheimers Dis, 2018)
BACKGROUND: There has been in recent decades a growing interest in the relationship between osteoporosis and cognitive decline. OBJECTIVE: The goal of this study was to analyze the impact of osteoporosis on the risk of dementia in patients followed for up to 20 years in general practices in Germany. METHODS: This study included patients who received an initial diagnosis of osteoporosis and were followed by 1,215 general practitioners in Germany between January 1993 and December 2012 (index date). Controls were matched (1:1) to osteoporosis patients using propensity scores based on age, gender, index year, comorbidities, and co-therapies. Kaplan-Meier curves were performed to study the development of dementia separately in men and women with or without osteoporosis within 20 years of the index date. Cox proportional regression models were used to estimate the relationship between osteoporosis and dementia in men and women. RESULTS: The present study included 29,983 cases and 29,983 controls. After 20 years of follow-up, 20.5% of women with osteoporosis and 16.4% of controls had been diagnosed with dementia (log-rank p-value <0.001). At the end of the follow-up period, dementia was found in 22.0% of men previously diagnosed with osteoporosis and 14.9% of men without this chronic condition (log-rank p-value <0.001). Osteoporosis was associated with a 1.2-fold increase in the risk of being diagnosed with dementia in women and a 1.3-fold increase in the risk of being diagnosed with dementia in men. CONCLUSIONS: There was a positive association between osteoporosis and dementia in patients followed in general practices in Germany.

Impact of Total Knee Arthroplasty with General Anesthesia on Brain Networks: Cognitive Efficiency and Ventricular Volume Predict Functional Connectivity Decline in Older Adults. - Huang, Haiqing; Tanner, Jared; Parvataneni, Hari; Rice, Mark; Horgas, Ann; Ding, Mingzhou; Price, Catherine (J Alzheimers Dis, 2018)
Using resting state functional magnetic resonance imaging (RS-fMRI), we explored: 1) pre- to post-operative changes in functional connectivity in default mode, salience, and central executive networks after total knee arthroplasty (TKA) with general anesthesia, and 2) the contribution of cognitive/brain reserve metrics these resting state functional declines. Individuals age 60 and older electing unilateral total knee arthroplasty (TKA; n = 48) and non-surgery peers with osteoarthritis (n = 45) completed baseline cognitive testing and baseline and post-surgery (post-baseline, 48-h post-surgery) brain MRI. We acquired cognitive and brain estimates for premorbid (vocabulary, reading, education, intracranial volume) and current (working memory, processing speed, declarative memory, ventricular volume) reserve. Functional network analyses corrected for pain severity and pain medication. The surgery group declined in every functional network of interest (p < 0.001). Relative to non-surgery peers, 23% of surgery participants declined in at least one network and 15% of the total TKA sample declined across all networks. Larger preoperative ventricular volume and lower scores on preoperative metrics of processing speed and working memory predicted default mode network connectivity decline. Premorbid cognitive and premorbid brain reserve did not predict decline. Within 48 hours after surgery, at least one fourth of the older adult sample showed significant functional network decline. Metrics of current brain status (ventricular volume), working memory, and processing speed predicted the severity of default mode network connectivity decline. These findings demonstrate the relevance of preoperative cognition and brain integrity on acute postoperative functional network change.

Impact of Untimely Access to Formal Care on Costs and Quality of Life in Community Dwelling People with Dementia. - Janssen, Niels; Handels, Ron L; Sköldunger, Anders; Woods, Bob; Jelley, Hannah; Edwards, Rhiannon Tudor; Orrell, Martin; Selbæk, Geir; Røsvik, Janne; Gonçalves-Pereira, Manuel; Marques, Maria J; Zanetti, Orazio; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Access to formal care is not always timely and a better understanding on the impact of untimely access is needed. OBJECTIVE: To examine, from a societal perspective, the impact of untimely access to formal care in terms of total costs and quality of life over one year in community dwelling people with dementia. METHODS: Within the Actifcare study, needs, resource use, and quality of life were observed for one year in a cohort of 451 community dwelling people with dementia in 8 European countries. Untimely access to care was operationalized as having at least one unmet need for care identified by the Camberwell Assessment of Need for the Elderly (CANE) instrument. Two regression models were built for both total costs and quality of life measured by the EQ-5D-5L, one using sum of unmet needs and one using a predefined selection of need items. RESULTS: Unmet needs were not associated with higher total costs but they were associated with a lower quality of life of people with dementia. Of all CANE items, only an unmet need for "company" was significantly related to lower total costs. CONCLUSION: Total costs did not seem to differ between participants with unmet and met needs. Only few associations between specific unmet needs and costs and quality of life were found. Furthermore, quality of life of people with dementia decreases when multiple unmet needs are experienced, indicating that assessing and meeting needs is important to improve quality of life.

In Vitro Potency and Preclinical Pharmacokinetic Comparison of All-D-Enantiomeric Peptides Developed for the Treatment of Alzheimer's Disease. - Schartmann, Elena; Schemmert, Sarah; Niemietz, Nicole; Honold, Dominik; Ziehm, Tamar; Tusche, Markus; Elfgen, Anne; Gering, Ian; Brener, Oleksandr; Shah, Nadim Joni; Langen, Karl-Josef; Kutzsche, Janine; et al. (J Alzheimers Dis, 2018)
Diffusible amyloid-β (Aβ) oligomers are currently presumed to be the most cytotoxic Aβ assembly and held responsible to trigger the pathogenesis of Alzheimer's disease (AD). Thus, Aβ oligomers are a prominent target in AD drug development. Previously, we reported on our solely D-enantiomeric peptide D3 and its derivatives as AD drug candidates. Here, we compare one of the most promising D3 derivatives, ANK6, with its tandem version (tANK6), and its head-to-tail cyclized isoform (cANK6r). In vitro tests investigating the D-peptides' potencies to inhibit Aβ aggregation, eliminate Aβ oligomers, and reduce Aβ-induced cytotoxicity revealed that all three D-peptides efficiently target Aβ. Subsequent preclinical pharmacokinetic studies of the three all-D-peptides in wildtype mice showed promising blood-brain barrier permeability with cANK6r yielding the highest levels in brain. The peptides' potencies to lower Aβ toxicity and their remarkable brain/plasma ratios make them promising AD drug candidates.

In Vivo Visualization of Tau Accumulation, Microglial Activation, and Brain Atrophy in a Mouse Model of Tauopathy rTg4510. - Ishikawa, Ai; Tokunaga, Masaki; Maeda, Jun; Minamihisamatsu, Takeharu; Shimojo, Masafumi; Takuwa, Hiroyuki; Ono, Maiko; Ni, Ruiqing; Hirano, Shigeki; Kuwabara, Satoshi; Ji, Bin; Zhang, Ming-Rong; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Tau imaging using PET is a promising tool for the diagnosis and evaluation of tau-related neurodegenerative disorders, but the relationship among PET-detectable tau, neuroinflammation, and neurodegeneration is not yet fully understood. OBJECTIVE: We aimed to elucidate sequential changes in tau accumulation, neuroinflammation, and brain atrophy by PET and MRI in a tauopathy mouse model. METHODS: rTg4510 transgenic (tg) mice expressing P301L mutated tau and non-tg mice were examined with brain MRI and PET imaging (analyzed numbers: tg = 17, non-tg = 13; age 2.5∼14 months). As PET probes, [11C]PBB3 (Pyridinyl-Butadienyl-Benzothiazole 3) and [11C]AC-5216 were used to visualize tau pathology and 18-kDa translocator protein (TSPO) neuroinflammation. Tau pathology and microglia activation were subsequently analyzed by histochemistry. RESULTS: PET studies revealed age-dependent increases in [11C]PBB3 and [11C]AC-5216 signals, which were correlated with age-dependent volume reduction in the forebrain on MRI. However, the increase in [11C]PBB3 signals reached a plateau at age 7 months, and therefore its significant correlation with [11C]AC-5216 disappeared after age 7 months. In contrast, [11C]AC-5216 showed a strong correlation with both age and volume reduction until age 14 months. Histochemical analyses confirmed the relevance of pathological tau accumulation and elevated TSPO immunoreactivity in putative microglia. CONCLUSION: Our results showed that tau accumulation is associated with neuroinflammation and brain atrophy in a tauopathy mouse model. The time-course of the [11C]PBB3- and TSPO-PET finding suggests that tau deposition triggers progressive neuroinflammation, and the sequential changes can be evaluated in vivo in mouse brains.
Keywords: Animals; Atrophy; Benzothiazoles; Brain; Disease Models, Animal; Female; Magnetic Resonance Imaging; Male; Mice; Mice, Transgenic; Microglia; Positron-Emission Tomography; Receptors, GABA; tau Proteins; Tauopathies

Incidence and Prevalence of Antiepileptic Medication Use in Community-Dwelling Persons with and without Alzheimer's Disease. - Sarycheva, Tatyana; Taipale, Heidi; Lavikainen, Piia; Tiihonen, Jari; Tanskanen, Antti; Hartikainen, Sirpa; Tolppanen, Anna-Maija (J Alzheimers Dis, 2018)
BACKGROUND: Although antiepileptic drugs (AEDs) have a potential for adverse drug reactions in older populations, little is known about their use in relation to Alzheimer's disease (AD) diagnosis. OBJECTIVES: In this study, we investigated the incidence and prevalence of AED use in relation to AD diagnosis. METHODS: The MEDALZ-study includes all Finnish persons who received clinically verified AD diagnoses (n = 70,718) during 2005-2011 and a matched comparison cohort without AD (n = 70,718). AD diagnoses were identified from the Special Reimbursement Register. We used the Prescription Register to identify dispensed AEDs. Incident AED users were identified with a one-year washout period 9-10 years before AD diagnosis, and incidence rates per 100 person-years were calculated for each six-month period from nine years before to five years after AD diagnosis. Prevalence was assessed as proportion using AEDs during each six-month time period for incident use. RESULTS: Persons with AD were more likely to use AEDs during the study period (4.3%) than persons without AD (3.2%). The incidence and prevalence of AED use was higher among persons with AD and increased around the time of AD diagnosis. Epilepsy diagnoses did not explain these differences. Persons with AD were more likely to use older AEDs. CONCLUSION: Our study highlights the need to balance effective symptom control with the possible risks of treatment.

Increased Albumin Oxidation in Cerebrospinal Fluid and Plasma from Alzheimer's Disease Patients. - Costa, Montserrat; Horrillo, Raquel; Ortiz, Ana María; Pérez, Alba; Mestre, Anna; Ruiz, Agustin; Boada, Merce; Grancha, Salvador (J Alzheimers Dis, 2018)
BACKGROUND: Oxidative stress in the brain and peripheral systems is considered a major player in Alzheimer's disease (AD). Albumin is the main transporter and the main extracellular antioxidant in the human body. OBJECTIVE: Here we explore for the first time the oxidation status of cerebrospinal fluid (CSF) and plasma albumin in AD in comparison to healthy subjects. METHODS: Plasma and CSF samples were obtained from mild-moderate AD patients and control healthy age-matched donors. Albumin redox state forms (reduced: HMA; reversibly oxidized: HNA1; irreversibly oxidized: HNA2) were determined by HPLC. Albumin post-translational modifications (PTM) analysis was performed by mass spectrometry. RESULTS: HPLC showed less HMA in AD plasma than in controls (54.1% versus 65.2% ; p < 0.0001), mainly at expense of HNA1 (42.8% versus 32.5% ; p < 0.0001). In AD CSF, HMA was drastically decreased compared to controls (9.6% versus 77.4% ; p < 0.0001), while HNA2 was increased (52.8% versus 7.4% ; p < 0.0001). In AD patients but not in healthy controls, CSF albumin was much more irreversibly oxidized than in plasma (close to 20-fold increase in HNA2). PTM analysis showed that AD CSF albumin samples behave as a differentiated cluster, thus confirming the albumin oxidative pattern observed by HPLC. CONCLUSION: CSF albumin oxidation in AD patients was dramatically increased comparing to healthy controls, while in plasma this increase was smaller. CSF albumin in AD patients was much more oxidized than in plasma, but this effect was not observed in healthy controls. These results suggest that albumin oxidation, especially in CSF, and its role in AD deserves further investigation.

Increased Prevalence of Obesity/Type 2 Diabetes and Lower Levels of Lithium in Rural Texas Counties May Explain Greater Alzheimer's Disease Risk. - Baranowski, Bradley J; Hayward, Grant C; Fajardo, Val A; MacPherson, Rebecca E K (J Alzheimers Dis, 2018)
BACKGROUND/OBJECTIVE: To compare Alzheimer's disease (AD) mortality rates and coinciding risk factors in rural and urban Texas populations. METHODS: 155 Texas counties were divided into 73 rural and 82 urban areas using the U.S. Census Bureau definition of rurality. Changes in age-adjusted AD mortality across these counties were calculated using a 7-year aggregation model from 2000-2006 and 2009-2015. Data pertaining to gender, race, education, obesity, diabetes, physical inactivity, and lithium concentrations in tap water were also collected from readily available databases. RESULTS: Change in age-adjusted AD mortality was higher in rural counties (9.5±1.4) versus urban (5.9±1.1) over the time period examined. Similarly, obesity (30.2±0.2% ), diabetes (11.0±0.1% ), and physical inactivity (29.4±0.2% ) levels were significantly higher in rural populations compared to urban (29.1±0.2%, 9.7±0.1%, and 26.7±0.3, respectively). In contrast, the percent of population with some college education (40.1±0.7% ) was lower compared to urban (29.4±0.2% and 44.4±0.9%, respectively). Lithium concentrations in tap water was significantly lower in rural counties compared to urban (63.3±8.2 and 33.4±4.7μg/L, respectively). No significant differences were observed among females and however, we did find significant differences in the percent of African American and Hispanics. Correlational analysis uncovered a negative association between education status and AD mortality over time (r = -0.17). Further analysis controlling for physical inactivity, education, and trace lithium concentrations results in a loss of statistical significance. CONCLUSIONS: AD mortality rates are higher in rural counties when compared to urban counties, and this may be linked to greater physical inactivity, obesity, and diabetes, as well as lower trace lithium levels in tap water.

Increased Serum Acylated Ghrelin Levels in Patients with Mild Cognitive Impairment. - Cao, Xi; Zhu, Min; He, Yan; Chu, Wenzheng; Du, Yifeng; Du, Heng (J Alzheimers Dis, 2018)
Ghrelin is a stomach-derived circulating hormone. In addition to its function as an orexigenic stimulant, the role of ghrelin in the consolidation of learning and memory has been implicated in recent years. However, the status of circulating acylated ghrelin (AG, that is, the functional form of ghrelin) in the symptomatic predementia stage of Alzheimer's disease (AD) has rarely been investigated. In the current study, we examined the serum levels of acylated and total ghrelin in 22 patients with mild cognitive impairment (MCI) and 30 cognitively normal controls. We have found that patients with MCI had significantly increased serum AG levels, which were inversely associated with defected short- and long-term memory as well as language skills. Of note, the levels of total circulating ghrelin were similar between the two groups. Intriguingly, serum AG but not total ghrelin was associated with AD risk factors including the age, hypertension, and hyperlipidemia. Therefore, circulating AG may serve as a potential early systemic biomarker for AD-related cognitive impairments. Nevertheless, the simplest interpretation of the results is that the levels of circulating AG are associated with cognitive impairments in patients with MCI, thereby forming the groundwork for our future studies on the systemic mechanisms of AD pertaining to the ghrelin system.
Keywords: Aged; Alzheimer Disease; Biomarkers; Case-Control Studies; Cognitive Dysfunction; Female; Ghrelin; Humans; Male; Middle Aged; Risk Factors

Increasing Diagnostic Accuracy of Mild Cognitive Impairment due to Alzheimer's Disease by User-Independent, Web-Based Whole-Brain Volumetry. - Hedderich, Dennis M; Spiro, Judith E; Goldhardt, Oliver; Kaesmacher, Johannes; Wiestler, Benedikt; Yakushev, Igor; Zimmer, Claus; Boeckh-Behrens, Tobias; Grimmer, Timo (J Alzheimers Dis, 2018)
BACKGROUND: Volumetric quantification of structural MRI has been shown to increase the diagnostic accuracy of patients with mild cognitive impairment (MCI); however, its implementation in clinical routine is usually technically difficult and time-consuming. OBJECTIVE: The purpose of this study was to investigate whether volumetric information obtained from the free and easy-to-use online tool volBrain can improve correct identification of MCI patients with Alzheimer's disease (AD) compared to visual reading. METHODS: The study cohort consisted of 27 patients with MCI due to AD (AD positive) as determined by biomarker information and 26 cognitively normal controls (CN). Three blinded readers, 2 radiologists and 1 clinical dementia expert, assessed the patients' MRI regarding brain atrophy and probability of underlying AD two times, without and with supporting volumetric information from volBrain. To assess diagnostic accuracy of volBrain measures alone, a simple sum score based on basic volumetric measures was developed and tested. RESULTS: Correct patient classification by readers 1, 2, and 3 without a volumetric report was 73.6%, 77.4%, and 83.0%. With a volumetric report, correct classification increased for the radiological readers to 77.4% and 81.1%, respectively and decreased to 77.4% for reader 3. Usage of the volumetric report alone yielded the highest diagnostic accuracy of 84.9%. Diagnostic confidence increased significantly for radiological readers. CONCLUSION: Volumetric information from volBrain increases the radiologist's diagnostic performance and confidence in identifying MCI patients with AD. We propose that such tools may be implemented in the routine diagnostic work-up of patients with suspected AD.

An Inducible Alpha-Synuclein Expressing Neuronal Cell Line Model for Parkinson's Disease1. - Vasquez, Velmarini; Mitra, Joy; Perry, George; Rao, K S; Hegde, Muralidhar L (J Alzheimers Dis, 2018)
Altered expression of α-synuclein is linked to Parkinson's disease (PD). A major challenge to explore how the increased α-synuclein affect neurotoxicity is the lack of a suitable human neuronal cell model that mimics this scenario. Its expression in neural precursors affects their differentiation process, in addition to the neuronal adaptability and variability in maintaining a constant level of expression across passages. Here, we describe an SH-SY5Y line harboring Tet-ON SNCA cDNA cassette that allows for induction of controlled α-synuclein expression after neuronal differentiation, which can be an important tool for PD research.

Induction of Amyloid-β42 Production by Fipronil and Other Pyrazole Insecticides. - Cam, Morgane; Durieu, Emilie; Bodin, Marion; Manousopoulou, Antigoni; Koslowski, Svenja; Vasylieva, Natalia; Barnych, Bogdan; Hammock, Bruce D; Bohl, Bettina; Koch, Philipp; Omori, Chiori; Yamamoto, Kazuo; et al. (J Alzheimers Dis, 2018)
Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer's disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations of AβPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown. We hypothesize that the 'human chemical exposome' contains products able to favor the production of Aβ42/Aβ43 over Aβ40 and shorter Aβs. To detect such products, we screened a library of 3500 + compounds in a cell-based assay for enhanced Aβ42/Aβ43 production. Nine pyrazole insecticides were found to induce a β- and γ-secretase-dependent, 3-10-fold increase in the production of extracellular Aβ42 in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of Aβs cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase toward Aβ42/Aβ43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aβ42/Aβ43 in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Aβ42/Aβ43 peptides, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.

Inhibition of Histone Acetylation by ANP32A Induces Memory Deficits. - Chai, Gao-Shang; Feng, Qiong; Ma, Rong-Hong; Qian, Xiao-Hang; Luo, Dan-Ju; Wang, Zhi-Hao; Hu, Yu; Sun, Dong-Sheng; Zhang, Jun-Fei; Li, Xiao; Li, Xiao-Guang; Ke, Dan; et al. (J Alzheimers Dis, 2018)
There is accumulating evidence that decreased histone acetylation is involved in normal aging and neurodegenerative diseases. Recently, we found that ANP32A, a key component of INHAT (inhibitor of acetyltransferases) that suppresses histone acetylation, increased in aged and cognitively impaired C57 mice and expressing wild-type human full length tau (htau) transgenic mice. Downregulating ANP32A restored cognitive function and synaptic plasticity through upregulation of the expressions of synaptic-related proteins via increasing histone acetylation. However, there is no direct evidence that ANP32A can induce neurodegeneration and memory deficits. In the present study, we overexpressed ANP32A in the hippocampal CA3 region of C57 mice and found that ANP32A overexpression induced cognitive abilities and synaptic plasticity deficits, with decreased synaptic-related protein expression and histone acetylation. Combined with our recent studies, our findings reveal that upregulated ANP32A induced-suppressing histone acetylation may underlie the cognitive decline in neurodegenerative disease, and suppression of ANP32A may represent a promising therapeutic approach for neurodegenerative diseases including Alzheimer's disease.

Interaction between Cytomegalovirus and Herpes Simplex Virus Type 1 Associated with the Risk of Alzheimer's Disease Development. - Lövheim, Hugo; Olsson, Jan; Weidung, Bodil; Johansson, Anders; Eriksson, Sture; Hallmans, Göran; Elgh, Fredrik (J Alzheimers Dis, 2018)
BACKGROUND: Several environmental factors, including infectious agents, have been suggested to cause Alzheimer's disease (AD). Cytomegalovirus (CMV) has been associated with AD in several recent studies. OBJECTIVE: To investigate whether carriage of CMV, alone or in combination with Herpes simplex virus (HSV), increased the risk of developing AD. METHODS: Plasma samples from 360 AD cases (75.3% women, mean age 61.2 years), taken an average of 9.6 years before AD diagnosis, and 360 age-, sex-, cohort-, and sampling date matched dementia-free controls were analyzed to detect anti-CMV (immunoglobulin [Ig] G and IgM), group-specific anti-HSV (IgG and IgM), and specific anti-HSV1 and HSV2 IgG antibodies by enzyme-linked immunosorbent assays. AD cases and dementia-free controls were compared using conditional logistic regression analyses. RESULTS: The presence of anti-CMV IgG antibodies did not increase the risk of AD (odds ratio [OR], 0.857; p = 0.497). Among AD cases, an association between CMV and HSV1 carriage was detected (OR 7.145, p < 0.001); in a conditional logistic regression model, the interaction between CMV and HSV1 was associated with AD development (OR 5.662; p = 0.007). CONCLUSION: The present findings do not support a direct relationship between CMV infection and the development of AD; however, an interaction between CMV and HSV1 was found to be associated significantly with AD development. These findings suggest that CMV infection facilitates the development of HSV1-associated AD, possibly via its effects on the immune system.
Keywords: Aged; Alzheimer Disease; Antibodies, Viral; Case-Control Studies; Cytomegalovirus; Cytomegalovirus Infections; Enzyme-Linked Immunosorbent Assay; Female; Herpes Simplex; Herpesvirus 1, Human; Humans; Immunoglobulin G; Immunoglobulin M; Logistic Models; Male; Middle Aged

Interrelationship between the Levels of C9orf72 and Amyloid-β Protein Precursor and Amyloid-β in Human Cells and Brain Samples. - Leskelä, Stina; Takalo, Mari; Marttinen, Mikael; Huber, Nadine; Paananen, Jussi; Mitra, Vikram; Rauramaa, Tuomas; Mäkinen, Petra; Leinonen, Ville; Soininen, Hilkka; Pike, Ian; Remes, Anne M; et al. (J Alzheimers Dis, 2018)
A subset of C9orf72 repeat expansion-carrying frontotemporal dementia patients display an Alzheimer-like decrease in cerebrospinal fluid amyloid-β (Aβ) biomarker levels. We report that downregulation of C9orf72 in non-neuronal human cells overexpressing amyloid-β protein precursor (AβPP) resulted in increased levels of secreted AβPP fragments and Aβ, while levels of AβPP or its C-terminal fragments (CTFs) remained unchanged. In neuronal cells, AβPP and C83 CTF levels were decreased upon C9orf72 knockdown, but those of secreted AβPP fragments or Aβ remained unchanged. C9orf72 protein levels significantly increased in human brain with advancing neurofibrillary pathology and positively correlated with brain Aβ42 levels. Our data suggest that altered C9orf72 levels may lead to cell-type specific alterations in AβPP processing, but warrant further studies to clarify the underlying mechanisms.

Intracranial Transplantation of Pancreatic Islets Attenuates Cognitive and Peripheral Metabolic Dysfunctions in a Rat Model of Sporadic Alzheimer's Disease. - Bloch, Konstantin; Gil-Ad, Irit; Vanichkin, Alexey; Hornfeld, Shay Henry; Taler, Michal; Dar, Shira; Azarov, Dmitry; Vardi, Pnina; Weizman, Abraham (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is often associated with brain insulin resistance and peripheral metabolic dysfunctions. Recently, we developed a model of sporadic AD associated with obesity-related peripheral metabolic abnormalities in Lewis rats using intracerebroventricular administration of streptozotocin (icv-STZ). OBJECTIVE: We aimed to assess the effect of intracranially grafted pancreatic islets on cognitive and peripheral metabolic dysfunctions in the icv-STZ Lewis rats. METHODS: AD-like dementia associated with obesity was induced in inbred Lewis rats using a single icv-STZ. Two months after icv-STZ, syngeneic islets (100 islets per recipient) were implanted in the cranial subarachnoid cavity of icv-STZ rats. Morris water maze and marble burying tests were used for studying cognitive and behavioral functions. Central and peripheral metabolic alterations were assessed by histological and biochemical assays. RESULTS: The icv-STZ induced increases in food intake, body weight, and blood levels of insulin and leptin without alteration of glucose homeostasis. Grafted islets reduced body weight gain, food consumption, peripheral insulin resistance, and hyperleptinemia. Biochemical and histological analysis of the brain revealed viable grafted islets expressing insulin and glucagon. The grafted islets did not affect expression of brain insulin receptors and peripheral glucose homeostasis. Two months after islet transplantation, cognitive and behavioral functioning in transplanted rats were significantly better than the sham-operated icv-STZ rats. No significant differences in the locomotor activity between transplanted and non-transplanted icv-STZ rats were found. CONCLUSIONS: Intracranial islet transplantation attenuates cognitive decline and peripheral metabolic dysfunctions providing a novel therapeutic approach for sporadic AD associated with peripheral metabolic dysfunctions.

Involvement of Activation of Asparaginyl Endopeptidase in Tau Hyperphosphorylation in Repetitive Mild Traumatic Brain Injury. - Hu, Wen; Tung, Yunn Chyn; Zhang, Yanchong; Liu, Fei; Iqbal, Khalid (J Alzheimers Dis, 2018)
Traumatic brain injury (TBI) is an established risk factor for the development of neurodegeneration and dementia late in life. Repetitive mild TBI (r-mTBI) is directly associated with chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder characterized by focal perivascular to widespread Alzheimer-type neurofibrillary pathology of hyperphosphorylated tau. Studies in animal models have shown hyperphosphorylation of tau after TBI. However, the molecular mechanisms by which TBI leads to tau pathology are not understood. In this study, we employed western blots and immunohistochemistry to test, in triple-transgenic mouse model of Alzheimer's disease (3xTg-AD), the effect of r-mTBI on tau hyperphosphorylation and activation of asparaginyl endopeptidase (AEP), a cysteine proteinase which is known to be involved in tau hyperphosphorylation. We found that the level of active AEP was increased and correlated with the level of tau hyperphosphorylation following r-mTBI, and that fimbria showed increased immunoreactivity to phospho-tau. In addition, inhibitor 2 of protein phosphatase 2A (I2PP2A) was translocated from neuronal nucleus to the cytoplasm and colocalized with hyperphosphorylated tau. These data suggest the involvement of AEP-I2PP2A-PP2A-ptau pathway in tau pathology in TBI.

The Level of Plasma Amyloid-β40 Is Correlated with Peripheral Transport Proteins in Cognitively Normal Adults: A Population-Based Cross-Sectional Study. - Gao, Ling; Jiang, Yu; Wei, Shan; Shang, Suhang; Li, Pei; Chen, Chen; Dang, Liangjun; Wang, Jin; Huo, Kang; Deng, Meiying; Wang, Jingyi; Zhang, Rong; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Transport proteins, soluble low-density lipoprotein receptor-related protein-1 (sLRP1), and soluble receptor of advanced glycation end products (sRAGE), play an important role in the clearance of plasma amyloid-β (Aβ). However, their relationship is not clear. OBJECTIVE: The aim was to explore the relationship between plasma levels of sLRP1, sRAGE, and Aβ in a cross-sectional study. METHODS: A total of 1,185 cognitively normal participants (age above 40) from a village in the suburbs of Xi'an, China were enrolled from October 8, 2014 to March 30, 2015. Plasma Aβ40, Aβ42, sLRP1, and sRAGE were tested using a commercial ELISA. Apolipoprotein E (APOE) genotyping was conducted using PCR and sequencing. The relationship between plasma levels of sLRP1, sRAGE, and Aβ was analyzed using Pearson's correlation analysis and multiple linear regression. RESULTS: In the total population, Log sLRP1 and Log sRAGE were positively correlated with plasma Aβ40 (r= 0.103, p < 0.001; r= 0.064, p = 0.027, respectively), but neither were associated with plasma Aβ42. After multivariable adjustment in the regression model, Log sLRP1 and Log sRAGE were still positively related with plasma Aβ40 (β= 2.969, p < 0.001; β= 1.936, p = 0.017, respectively) but not Aβ42. Furthermore, the positive correlations between transport proteins and plasma Aβ40 remained significant only in APOEɛ4 non-carriers after Pearson's analysis and multiple regression analysis after stratification by gene status. CONCLUSION: The concentrations of plasma sLRP1 and sRAGE had a significant impact on the level of plasma Aβ40 in cognitively normal adults, especially in APOEɛ4 non-carriers. However, the mechanism by which the transport proteins are involved in peripheral Aβ clearance and the relationship between transporters and amyloid burden in the brain needs further validation.

Lipid Metabolism and Survival Across the Frontotemporal Dementia-Amyotrophic Lateral Sclerosis Spectrum: Relationships to Eating Behavior and Cognition. - Ahmed, Rebekah M; Highton-Williamson, Elizabeth; Caga, Jashelle; Thornton, Nicolette; Ramsey, Eleanor; Zoing, Margaret; Kim, Woojin Scott; Halliday, Glenda M; Piguet, Olivier; Hodges, John R; Farooqi, I Sadaf; Kiernan, Matthew C (J Alzheimers Dis, 2018)
BACKGROUND: Patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) exhibit changes in eating behavior that could potentially affect lipid levels. OBJECTIVE: This study aimed to document changes in lipid metabolism across the ALS-FTD spectrum to identify potential relationships to eating behavior (including fat intake), cognitive change, body mass index (BMI), and effect on survival. METHODS: One hundred and twenty-eight participants were recruited: 37 ALS patients, 15 ALS patients with cognitive and behavioral change (ALS-Plus), 13 ALS-FTD, 31 behavioral variant FTD, and 32 healthy controls. Fasting total cholesterol, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL) and triglyceride levels were measured and correlated to eating behavior (caloric, fat intake), cognitive change, and BMI; effect on survival was examined using cox regression analyses. RESULTS: There was a spectrum of lipid changes from ALS to FTD with increased triglyceride (p < 0.001), total cholesterol/HDL ratio (p < 0.001), and lower HDL levels (p = 0.001) in all patient groups compared to controls. While there was no increase in total cholesterol levels, a higher cholesterol level was found to correlate with 3.25 times improved survival (p = 0.008). Triglyceride and HDL cholesterol levels correlated to fat intake, BMI, and measures of cognition and disease duration. CONCLUSION: A spectrum of changes in lipid metabolism has been identified in ALS-FTD, with total cholesterol levels found to potentially impact on survival. These changes were mediated by changes in fat intake, and BMI, and may also be mediated by the neurodegenerative process, offering the potential to modify these factors to slow disease progression and improve survival.
Keywords: Adult; Aged; Amyotrophic Lateral Sclerosis; Australia; Body Mass Index; Case-Control Studies; Cholesterol; Cholesterol, HDL; Cognition; Energy Intake; Feeding Behavior; Female; Frontotemporal Dementia; Humans; Lipid Metabolism; Male; Middle Aged; Neuropsychological Tests; Survival Analysis

Longitudinal Neuroimaging Analysis in Mild-Moderate Alzheimer's Disease Patients Treated with Plasma Exchange with 5% Human Albumin. - Cuberas-Borrós, Gemma; Roca, Isabel; Boada, Merce; Tárraga, Lluís; Hernandez, Isabel; Buendia, Mar; Rubio, Lourdes; Torres, Gustavo; Bittini, Ángel; Guzmán-de-Villoria, Juan A; Pujadas, Francesc; Torres, Mireia; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Recently, modifications of Aβ1-42 levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer's disease (AD) treated with plasma exchange (PE) with albumin replacement. OBJECTIVE: To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial. METHODS: Patients received between 3 and 18 PE with albumin (Albutein® 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using an automated software (NeuroGam®) and brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline. RESULTS: 42 patients were recruited (39 evaluable; 37 analyzed: 18 PE-treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls. CONCLUSIONS: Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Plasma Exchange; Serum Albumin, Human; Time Factors; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

Long-Term Follow Up of Patients with Mild-to-Moderate Alzheimer's Disease Treated with Bapineuzumab in a Phase III, Open-Label, Extension Study. - Salloway, Stephen P; Sperling, Reisa; Fox, Nick C; Sabbagh, Marwan N; Honig, Lawrence S; Porsteinsson, Anton P; Rofael, Hany; Ketter, Nzeera; Wang, Daniel; Liu, Enchi; Carr, Stephen; Black, Ronald S; et al. (J Alzheimers Dis, 2018)
BACKGROUND: A 3-year extension of two Phase III parent studies of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer's disease dementia (apolipoprotein (APOE) ɛ4 carriers and noncarriers) is summarized. OBJECTIVES: The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of bapineuzumab. METHODS: A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received bapineuzumab or placebo in the parent studies. RESULTS: A total of 1,462 (688 were APOEɛ4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups. CONCLUSIONS: Infusion of bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies.

Loss in PKC Epsilon Causes Downregulation of MnSOD and BDNF Expression in Neurons of Alzheimer's Disease Hippocampus. - Sen, Abhik; Nelson, Thomas J; Alkon, Daniel L; Hongpaisan, Jarin (J Alzheimers Dis, 2018)
Oxidative stress and amyloid-β (Aβ) oligomers have been implicated in Alzheimer's disease (AD). The growth and maintenance of neuronal networks are influenced by brain derived neurotrophic factor (BDNF) expression, which is promoted by protein kinase C epsilon (PKCɛ). We investigated the reciprocal interaction among oxidative stress, Aβ, and PKCɛ levels and subsequent PKCɛ-dependent MnSOD and BDNF expression in hippocampal pyramidal neurons. Reduced levels of PKCɛ, MnSOD, and BDNF and an increased level of Aβ were also found in hippocampal neurons from autopsy-confirmed AD patients. In cultured human primary hippocampal neurons, spherical aggregation of Aβ (amylospheroids) decreased PKCɛ and MnSOD. Treatment with t-butyl hydroperoxide (TBHP) increased superoxide, the oxidative DNA/RNA damage marker, 8-OHG, and Aβ levels, but reduced PKCɛ, MnSOD, BDNF, and cultured neuron density. These changes were reversed with the PKCɛ activators, bryostatin and DCPLA-ME. PKCɛ knockdown suppressed PKCɛ, MnSOD, and BDNF but increased Aβ. In cultured neurons, the increase in reactive oxygen species (ROS) associated with reduced PKCɛ during neurodegeneration was inhibited by the SOD mimetic MnTMPyP and the ROS scavenger NAc, indicating that strong oxidative stress suppresses PKCɛ level. Reduction of PKCɛ and MnSOD was prevented with the PKCɛ activator bryostatin in 5-6-month-old Tg2576 AD transgenic mice. In conclusion, oxidative stress and Aβ decrease PKCɛ expression. Reciprocally, a depression of PKCɛ reduces BDNF and MnSOD, resulting in oxidative stress. These changes can be prevented with the PKCɛ-specific activators.

Low Accuracy of Brief Cognitive Tests in Tracking Longitudinal Cognitive Decline in an Asian Elderly Cohort. - Phua, April Ka Sin; Hiu, Shaun Kuan Wei; Goh, Win King; Ikram, Mohammad Kamran; Venketasubramanian, Narayanaswamy; Tan, Boon Yeow; Chen, Christopher Li-Hsian; Xu, Xin (J Alzheimers Dis, 2018)
BACKGROUND: Researchers have questioned the utility of brief cognitive tests such as the Mini-Mental Status Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in serial administration and suggested that brief cognitive tests may not accurately track changes in Global Cognition. OBJECTIVE: To examine the accuracy of longitudinal changes on brief cognitive tests in reflecting progression in Global Cognition measured using comprehensive neuropsychological assessments. METHODS: Two hundred and seven participants were assessed with the MMSE, MoCA, and a validated comprehensive neuropsychological battery. Global z-scores on the battery were derived and used to assess overall and significant (≥0.5 standard deviation) decline on Global Cognition. Different patterns of decline on MMSE/MoCA were classified. Accuracy was examined using receiver operating characteristic curve, and sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were reported. RESULTS: The overall ability of MMSE/MoCA change scores to discriminate participants who did and did not decline on Global Cognition was fair-to-moderate (AUC [95% CI] = 0.71 [0.64-0.78] & 0.73 [0.66-0.80] for overall decline; 0.78 [0.70-0.85] & 0.80 [0.73-0.86] for significant decline, respectively). Changes in MMSE/MoCA had low accuracy in identifying significant Global Cognitive Decline (PPV = 0.41 & 0.46, respectively) but high accuracy in ruling out significant decline and identifying cognitively stable participants (NPV = 0.89 & 0.88, respectively). CONCLUSION: There is limited utility in brief cognitive tests for tracking cognitive decline. Instead, they should be used for identifying participants who remain cognitively stable on follow up. These results accentuate the importance of acknowledging the limitations of brief cognitive tests when assessing cognitive change.

Low Prevalence of Cancer in Patients with Frontotemporal Lobar Degeneration. - Katisko, Kasper; Haapasalo, Annakaisa; Koivisto, Anne; Krüger, Johanna; Hartikainen, Päivi; Korhonen, Ville; Helisalmi, Seppo; Herukka, Sanna-Kaisa; Remes, Anne M; Solje, Eino (J Alzheimers Dis, 2018)
Several studies have reported reduced risk of cancer in patients with Alzheimer's disease (AD) or Parkinson's disease. The relationship between cancer and frontotemporal lobar degeneration (FTLD) has not been previously reported. Here, our aim was to evaluate the occurrence of cancer in Finnish FTLD patients with a high proportion of C9ORF72 repeat expansion carriers in comparison to age- and sex-matched group of AD patients and control subjects classified as not cognitively impaired (NCI). The prevalence of cancer was 9.7% in FTLD, 18.7% in AD, and 17.4% in NCI (FTLD versus AD p = 0.012, FTLD versus NCI p = 0.029) groups. No differences were observed between C9ORF72 repeat expansion carriers and non-carriers inside the FTLD group. To our knowledge, this is the first study showing significantly lower prevalence of cancer in FTLD patients compared to patients with AD or NCI subjects. Our data suggest an inverse association between neurodegeneration and cancer and that FTLD-specific mechanisms may underlie the especially strong inverse association observed in this study.
Keywords: Aged; Alzheimer Disease; C9orf72 Protein; DNA Repeat Expansion; Female; Finland; Frontotemporal Lobar Degeneration; Heterozygote; Humans; Male; Middle Aged; Neoplasms; Prevalence

Mental States in Moving Shapes: Distinct Cortical and Subcortical Contributions to Theory of Mind Impairments in Dementia. - Synn, Artemis; Mothakunnel, Annu; Kumfor, Fiona; Chen, Yu; Piguet, Olivier; Hodges, John R; Irish, Muireann (J Alzheimers Dis, 2018)
Impaired capacity for Theory of Mind (ToM) represents one of the hallmark features of the behavioral variant of frontotemporal dementia (bvFTD) and is suggested to underpin an array of socioemotional disturbances characteristic of this disorder. In contrast, while social processing typically remains intact in Alzheimer's disease (AD), the cognitive loading of socioemotional tasks may adversely impact mentalizing performance in AD. Here, we employed the Frith-Happé animations as a dynamic on-line assessment of mentalizing capacity with reduced incidental task demands in 18 bvFTD, 18 AD, and 25 age-matched Controls. Participants viewed silent animations in which geometric shapes interact in Random, Goal-Directed, and ToM conditions. An exclusive deficit in ToM classification was observed in bvFTD relative to Controls, while AD patients were impaired in the accurate classification of both Random and ToM trials. Correlation analyses revealed robust associations between ToM deficits and carer ratings of affective empathy disruption in bvFTD, and with episodic memory dysfunction in AD. Voxel-based morphometry analyses further identified dissociable neural correlates contingent on patient group. A distributed network of medial prefrontal, frontoinsular, striatal, lateral temporal, and parietal regions were implicated in the bvFTD group, whereas the right hippocampus correlated with task performance in AD. Notably, subregions of the cerebellum, including lobules I-IV and V, bilaterally were implicated in task performance irrespective of patient group. Our findings reveal new insights into the mechanisms potentially mediating ToM disruption in dementia syndromes, and suggest that the cerebellum may play a more prominent role in social cognition than previously appreciated.
Keywords: Aged; Alzheimer Disease; Brain; Case-Control Studies; Female; Frontotemporal Dementia; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Memory, Episodic; Mentalization; Middle Aged; Neuropsychological Tests; Task Performance and Analysis; Theory of Mind

Metabolomics Analyses of Saliva Detect Novel Biomarkers of Alzheimer's Disease. - Huan, Tao; Tran, Tran; Zheng, Jiamin; Sapkota, Shraddha; MacDonald, Stuart W; Camicioli, Richard; Dixon, Roger A; Li, Liang (J Alzheimers Dis, 2018)
Using a non-invasive biofluid (saliva), we apply a powerful metabolomics workflow for unbiased biomarker discovery in Alzheimer's disease (AD). We profile and differentiate Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and AD groups. The workflow involves differential chemical isotope labeling liquid chromatography mass spectrometry using dansylation derivatization for in-depth profiling of the amine/phenol submetabolome. The total sample (N = 109) was divided in to the Discovery Phase (DP) (n = 82; 35 CN, 25 MCI, 22 AD) and a provisional Validation Phase (VP) (n = 27; 10 CN, 10 MCI, 7 AD). In DP we detected 6,230 metabolites. Pairwise analyses confirmed biomarkers for AD versus CN (63), AD versus MCI (47), and MCI versus CN (2). We then determined the top discriminating biomarkers and diagnostic panels. A 3-metabolite panel distinguished AD from CN and MCI (DP and VP: Area Under the Curve [AUC] = 1.000). The MCI and CN groups were best discriminated with a 2-metabolite panel (DP: AUC = 0.779; VP: AUC = 0.889). In addition, using positively confirmed metabolites, we were able to distinguish AD from CN and MCI with good diagnostic performance (AUC > 0.8). Saliva is a promising biofluid for both unbiased and targeted AD biomarker discovery and mechanism detection. Given its wide availability and convenient accessibility, saliva is a biofluid that can promote diversification of global AD biomarker research.

Methylenetetrahydrofolate Reductase Deficiency Deregulates Regional Brain Amyloid-β Protein Precursor Expression and Phosphorylation Levels. - Hoffman, Alexander; Taleski, Goce; Qian, Helena; Wasek, Brandi; Arning, Erland; Bottiglieri, Teodoro; Sontag, Jean-Marie; Sontag, Estelle (J Alzheimers Dis, 2018)
Deregulation of the amyloid-β protein precursor (AβPP) plays a critical role in the neurodegenerative cascade of Alzheimer's disease (AD). Significantly, common functional polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene are a risk factor for the development of late-onset AD. Reduced MTHFR activity is associated with alterations in folate and homocysteine metabolism. Here, we first show that in young MTHFR knockout mice, mild and severe MTHFR deficiency markedly increase cortical and hippocampal AβPP phosphorylation at the regulatory Thr668 site. However, the hippocampus is especially vulnerable to the effects of aging and mild MTHFR deficiency. Notably, the effects of severe MTHFR deficiency in young mice are recapitulated by prolonged dietary folate deficiency in old mice, which leads to regional brain accumulation of cystathionine due to impaired methylation of homocysteine. The incremental AβPP phosphorylation at Thr668 mediated by severe genetic-or diet-induced impairment of the folate cycle correlates with enhanced accumulation of demethylated protein phosphatase 2A (PP2A), and activation of glycogen synthase kinase-3β (GSK-3β). Lastly, we show that severe disturbances in folate metabolism can also affect AβPP expression levels in a brain region specific manner. Together our findings identify a novel link between genetic MTHFR deficiency, activation of GSK-3β, demethylation of PP2A, and enhanced phosphorylation of AβPP at Thr668, which is known to critically influence neuronal AβPP function and pathological amyloidogenic processing. Deregulation of AβPP provides a novel mechanism by which common human MTHFR polymorphisms may interact with dietary folate deficiency to alter neuronal homeostasis and increase the risk for sporadic AD.

Microglial Activation During Pathogenesis of Tauopathy in rTg4510 Mice: Implications for the Early Diagnosis of Tauopathy. - Sahara, Naruhiko; Maeda, Jun; Ishikawa, Ai; Tokunaga, Masaki; Suhara, Tetsuya; Higuchi, Makoto (J Alzheimers Dis, 2018)
Tauopathy is characterized by the fibrillar tau accumulation in neurons and glial cells. In order to advance our understanding of the causative mechanisms of tauopathy, neuroinflammation, which has been suggested to play important roles in disease progression, will require particular attention. Neuroinflammation is characterized predominantly by microglial activation. At present, it is still under debate whether microglial activation is a cause or a result of neurodegeneration. To search for a temporal relationship between neurodegeneration and neuroinflammation, our group demonstrated that in vivo imaging (e.g., tau-PET, TSPO-PET, and volumetric MRI) of tauopathy mice strongly supports the evidence of microglial activation along with both pathological tau accumulation and brain atrophy. Both in vivo imaging and histochemical analysis confirmed that microglial TSPO accumulation was the late event during the pathogenesis of tauopathy. On the other hand, it is known that purinergic receptor P2Y12 as a marker of homeostatic microglia cells was reduced at an early stage of disease progression. In this review, we will introduce a phenotypic change of microglia in a mouse model of tauopathy and propose novel approaches to the establishment of imaging biomarkers, thereby targeting the early diagnosis of tauopathy.

microRNA 221 Targets ADAM10 mRNA and is Downregulated in Alzheimer's Disease. - Manzine, Patricia R; Pelucchi, Silvia; Horst, Maria A; Vale, Francisco A C; Pavarini, Sofia C I; Audano, Matteo; Mitro, Nico; Di Luca, Monica; Marcello, Elena; Cominetti, Márcia R (J Alzheimers Dis, 2018)
ADAM10 is the α-secretase that cleaves amyloid-β protein precursor in the non-amyloidogenic pathway in Alzheimer's disease (AD) and is known to be regulated by different microRNAs (miRNAs), which are post-transcriptional regulators related to several biological and pathological processes, including AD. Here we proposed to explore and validate miRNAs that have direct or indirect relations to the AD pathophysiology and ADAM10 gene. Approximately 700 miRNAs were analyzed and 21 differentially expressed miRNAs were validated in a sample of 21 AD subjects and 17 cognitively healthy matched controls. SH-SY5Y cells were transfected with miR-144-5p, miR-221, and miR-374 mimics and inhibitors, and ADAM10 protein levels were evaluated. miR-144-5p, miR-221, and miR-374 were downregulated in AD. The overexpression of miR-221 in SH-SY5Y cells resulted in ADAM10 reduction and its inhibition in ADAM10 increased. These findings show that miR-221 can be a new potential therapeutic target for increasing ADAM10 levels in AD. In addition, these results can contribute to the better understanding of ADAM10 post-transcriptional regulation.
Keywords: ADAM10 Protein; Aged; Aged, 80 and over; Alzheimer Disease; Cell Line, Tumor; Cohort Studies; Down-Regulation; Female; Humans; Male; MicroRNAs; Middle Aged; Neuroblastoma; Psychiatric Status Rating Scales; RNA, Messenger; ROC Curve; Transfection

Midlife Physical Activity, Psychological Distress, and Dementia Risk: The HUNT Study. - Zotcheva, Ekaterina; Bergh, Sverre; Selbæk, Geir; Krokstad, Steinar; Håberg, Asta Kristine; Strand, Bjørn Heine; Ernstsen, Linda (J Alzheimers Dis, 2018)
BACKGROUND: Physical activity (PA) is associated with a decreased dementia risk, whereas psychological distress (distress) is linked to an increased dementia risk. OBJECTIVE: We investigated independent and joint associations of midlife moderate-to-vigorous PA (MVPA) and distress with incident dementia. METHODS: Our study comprised 28,916 participants aged 30-60 years from the Nord-Trøndelag Health Study (HUNT1, 1984-1986). Data on MVPA and distress from HUNT1 was linked to the Health and Memory Study in Nord-Trøndelag for dementia case identification. Participants were followed from 1995 until 2011. We used adjusted Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI). RESULTS: In fully adjusted analyses, MVPA was associated with a reduced dementia risk (HR 0.81, 95% CI 0.62-1.06), compared to no MVPA. Distress was associated with an increased dementia risk (HR 1.30, 95% CI 0.99-1.70). Compared to distressed participants not taking part in MVPA, non-distressed no-MVPA participants had a reduced dementia risk (HR 0.72, 95% CI 0.54-0.96). The same applied to distressed MVPA participants (HR 0.50, 95% CI 0.22-1.14), and non-distressed MVPA participants (HR 0.63, 95% CI 0.44-0.90). Our results indicated an additive interaction between MVPA and distress on dementia risk. CONCLUSION: Our results suggest that midlife MVPA reduces risk of incident dementia among both distressed and non-distressed individuals.

Modeling Prion-Like Processing of Tau Protein in Alzheimer's Disease for Pharmaceutical Development. - Wischik, Claude M; Schelter, Björn O; Wischik, Damon J; Storey, John M D; Harrington, Charles R (J Alzheimers Dis, 2018)
Following our discovery of a fragment from the repeat domain of tau protein as a structural constituent of the PHF-core in Alzheimer's disease (AD), we developed an assay that captured several key features of the aggregation process. Tau-tau binding through the core tau fragment could be blocked by the same diaminophenothiazines found to dissolve proteolytically stable PHFs isolated from AD brain. We found that the PHF-core tau fragment is inherently capable of auto-catalytic self-propagation in vitro, or "prion-like processing", that has now been demonstrated for several neurodegenerative disorders. Here we review the findings that led to the first clinical trials to test tau aggregation inhibitor therapy in AD as a way to block this cascade. Although further trials are still needed, the results to date suggest that a treatment targeting the prion-like processing of tau protein may have a role in both prevention and treatment of AD.

Moringa Oleifera Alleviates Homocysteine-Induced Alzheimer's Disease-Like Pathology and Cognitive Impairments. - Mahaman, Yacoubou Abdoul Razak; Huang, Fang; Wu, Mengjuan; Wang, Yuman; Wei, Zhen; Bao, Jian; Salissou, Maibouge Tanko Mahamane; Ke, Dan; Wang, Qun; Liu, Rong; Wang, Jian-Zhi; Zhang, Bin; et al. (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is multifactorial with unclear etiopathology. Due to the complexity of AD, many attempted single therapy treatments, like Aβ immunization, have generally failed. Therefore, there is a need for drugs with multiple benefits. Naturally occurring phytochemicals with neuroprotective, anti-amyloidogenic, antioxidative, and anti-inflammatory properties could be a possible way out. In this study, the effect of Moringa oleifera (MO), a naturally occurring plant with high antioxidative, anti-inflammatory, and neuroprotective effects, was evaluated on hyperhomocysteinemia (HHcy) induced AD-like pathology in rats. Homocysteine (Hcy) injection for 14 days was used to induce AD-like pathology. Simultaneous MO extract gavage followed the injection as a preventive treatment or, after injection completion, MO gavage was performed for another 14 days as a curative treatment. MO was found to not only prevent but also rescue the oxidative stress and cognitive impairments induced by Hcy treatment. Moreover, MO recovered the decreased synaptic proteins PSD93, PSD95, Synapsin 1 and Synaptophysin, and improved neurodegeneration. Interestingly, MO decreased the Hyc-induced tau hyperphosphorylation at different sites including S-199, T-231, S-396, and S-404, and at the same time decreased Aβ production through downregulation of BACE1. These effects in HHcy rats were accompanied by a decrease in calpain activity under MO treatment, supporting that calpain activation might be involved in AD pathogenesis in HHcy rats. Taken together, our data, for the first time, provided evidence that MO alleviates tau hyperphosphorylation and Aβ pathology in a HHcy AD rat model. This and previous other studies support MO as a good candidate for, and could provide new insights into, the treatment of AD and other tauopathies.

Morphological and Pathological Characteristics of Brain in Diabetic Encephalopathy. - Chen, Rui; Shi, Jiangwei; Yin, Qingsheng; Li, Xiaojin; Sheng, Yanyuan; Han, Juan; Zhuang, Pengwei; Zhang, Yanjun (J Alzheimers Dis, 2018)
Diabetes mellitus is a metabolic disease often accompanied by a series of complications, such as diabetic nephropathy, retinopathy, and diabetic foot. The survival time of diabetics has been significantly prolonged due to advancements in medicine. However, the prolonged survival time for diabetics can increase the prevalence of diabetic central nervous system disease. Diabetic encephalopathy (DE) has become one of the main complications of the disease, and the main clinical manifestation of DE is cognitive dysfunction. However, the typical morphological and pathological characteristics of the brain in DE are rarely systematically reported. Thus, this phenomenon severely restricts the diagnosis and treatment of DE. This article presents a description of the pathology characteristics of DE, including atrophy of the brain (gray matter, white matter, and hippocampus), changes in cerebrovascular morphology and function, impairment of synaptic plasticity, and dysfunction of neuroglia. In addition, abnormalities in the glymphatic clearance system of the brain are closely related to the progression of DE. A review of typical brain morphological and pathological characteristics would aid in the diagnosis and treatment of DE.

Multicenter Resting State Functional Connectivity in Prodromal and Dementia Stages of Alzheimer's Disease. - Teipel, Stefan J; Metzger, Coraline D; Brosseron, Frederic; Buerger, Katharina; Brueggen, Katharina; Catak, Cihan; Diesing, Dominik; Dobisch, Laura; Fliebach, Klaus; Franke, Christiana; Heneka, Michael T; Kilimann, Ingo; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Alterations of intrinsic networks from resting state fMRI (rs-fMRI) have been suggested as functional biomarkers of Alzheimer's disease (AD). OBJECTIVE: To determine the diagnostic accuracy of multicenter rs-fMRI for prodromal and preclinical stages of AD. METHODS: We determined rs-fMRI functional connectivity based on Pearson's correlation coefficients and amplitude of low-frequency fluctuation in people with subjective cognitive decline, people with mild cognitive impairment, and people with AD dementia compared with healthy controls. We used data of 247 participants of the prospective DELCODE study, a longitudinal multicenter observational study, imposing a unified fMRI acquisition protocol across sites. We determined cross-validated discrimination accuracy based on penalized logistic regression to account for multicollinearity of predictors. RESULTS: Resting state functional connectivity reached significant cross-validated group discrimination only for the comparison of AD dementia cases with healthy controls, but not for the other diagnostic groups. AD dementia cases showed alterations in a large range of intrinsic resting state networks, including the default mode and salience networks, but also executive and language networks. When groups were stratified according to their CSF amyloid status that was available in a subset of cases, diagnostic accuracy was increased for amyloid positive mild cognitive impairment cases compared with amyloid negative controls, but still inferior to the accuracy of hippocampus volume. CONCLUSION: Even when following a strictly harmonized data acquisition protocol and rigorous scan quality control, widely used connectivity measures of multicenter rs-fMRI do not reach levels of diagnostic accuracy sufficient for a useful biomarker in prodromal stages of AD.

Mutation Screening of the CHCHD2 Gene for Alzheimer's Disease and Frontotemporal Dementia in Chinese Mainland Population. - Che, Xiang-Qian; Zhao, Qian-Hua; Huang, Yue; Li, Xia; Ren, Ru-Jing; Chen, Sheng-Di; Guo, Qi-Hao; Wang, Gang (J Alzheimers Dis, 2018)
As an important multifunctional protein involved in regulation of mitochondrial metabolism, CHCHD2 was identified as a causative gene for Parkinson's disease (PD), yet the relationship between CHCHD2 and neurodegenerative dementia is not well understood. We directly sequenced the entire coding region of CHCHD2 gene in 150 AD patients, 84 FTD patients, and 417 controls. Four rare putative pathogenic variants of CHCHD2, including rs142444896 (c.5C>T, p.P2L), rs752705344 (c.15C>G, p.S5R), rs145190179 (c.94G>A, p.A32T), and rs182992574 (c.255T>A, p.S85R) were identified from a cohort composed of 150 AD and 84 FTD patients. These results suggest that CH CHD2 gene play an important role in other neurodegenerative disorders from our dementia study in China.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Asian Continental Ancestry Group; Case-Control Studies; China; Female; Frontotemporal Dementia; Genetic Association Studies; Humans; Male; Middle Aged; Mitochondrial Proteins; Mutation; Transcription Factors

Negative Prospective Memory in Alzheimer's Disease: "Do Not Perform That Action". - El Haj, Mohamad; Coello, Yann; Kapogiannis, Dimitrios; Gallouj, Karim; Antoine, Pascal (J Alzheimers Dis, 2018)
Relatively to "standard" prospective memory, i.e., remembering to perform a future action, little is known about negative prospective memory, i.e., remembering not to perform a future action. This study investigated the latter ability in Alzheimer's disease (AD). AD participants and healthy older adults were asked to click on the keyboard or not to click on it when a cue word was encountered. Results showed more omissions (i.e., forgetting to click the keyboard when the instruction was to do so) in AD participants than in healthy older adults, suggesting a prospective memory deficit. Interestingly, more commissions (i.e., clicking the keyboard when the instruction was not to do so) were also observed in AD participants than in healthy older adults. Similar levels of commissions and omissions were observed in AD participants and in healthy older adults. Also, commissions and omissions were correlated with performance on an inhibition assessment task. Our findings reveal that AD is characterized by not only difficulty in the retrieval of recent information, but also difficulty to inhibit no-longer appropriate stimulus-response associations previously learned, suggesting a specific deficit of negative prospective memory in AD.
Keywords: Aged; Alzheimer Disease; Case-Control Studies; Female; Humans; Inhibition (Psychology); Male; Memory Disorders; Memory, Episodic; Mental Recall; Neuropsychological Tests

Neuroanatomical Comparison of the "Word" and "Picture" Versions of the Free and Cued Selective Reminding Test in Alzheimer's Disease. - Slachevsky, Andrea; Barraza, Paulo; Hornberger, Michael; Muñoz-Neira, Carlos; Flanagan, Emma; Henriquez, Fernando; Bravo, Eduardo; Farías, Mauricio; Delgado, Carolina (J Alzheimers Dis, 2018)
Episodic memory tests with cued recall, such as the Free and Cued Selective Reminding Test (FCSRT), allow for the delineation of hippocampal and prefrontal atrophy contributions to memory performance in Alzheimer's disease (AD). Both Word and Picture versions of the test exist but show different profiles, with the Picture version usually scoring higher across different cohorts. One possible explanation for this divergent performance between the different modality versions of the test might be that they rely on different sets of neural correlates. The current study explores this by contrasting the neural correlates of the Word and Picture versions of the FCSRT with voxel-based morphometry (VBM) in AD and healthy subjects. We predicted that the Picture version would be associated with different cortical regions than the Word version, which might be more hippocampal-centric. When comparing 35 AD patients and 34 controls, AD patients exhibited impairments on both versions of the FCSRT and both groups performed higher in the Picture version. A region of interest analysis based on prior work revealed significant correlations between free recall of either version with atrophy of the temporal pole and hippocampal regions. Thus, contrary to expectations, performance on both the Word and the Picture version of the FCSRT is associated with largely overlapping networks. Free recall is associated with hippocampal volume and might be properly considered as an indicator of hippocampal structural integrity.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Case-Control Studies; Cues; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Memory, Episodic; Mental Recall; Middle Aged; Neuropsychological Tests; Photic Stimulation

New Beginnings in Alzheimer's Disease: The Most Prevalent Tauopathy. - Hernández, Félix; Llorens-Martín, María; Bolós, Marta; Pérez, Mar; Cuadros, Raquel; Pallas-Bazarra, Noemí; Zabala, Juan C; Avila, Jesús (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is characterized by the presence of two aberrant structures: namely senile plaques, composed of amyloid-β peptide (Aβ), and neurofibrillary tangles, composed of tau protein. In this regard, Aβ and tau protein have been widely studied in research efforts aiming to find a therapy for AD. Aβ and tau pathologies do not always overlap. The precursor of Aβ is expressed in peripheral tissues and in the central nervous system (CNS), whereas tau is mainly a neuronal protein. Since AD is a disease of the CNS, it has been proposed that Aβ may initiate the disease process, with tau being the executor. In this review, we will focus on future studies of tau pathology, although we will comment on new beginnings for AD, as other molecules other than Aβ and tau may be involved in the onset of dementia.

Non-Phosphorylated Tau in Cerebrospinal Fluid is a Marker of Alzheimer's Disease Continuum in Young Urbanites Exposed to Air Pollution. - Calderón-Garcidueñas, Lilian; Mukherjee, Partha S; Waniek, Katharina; Holzer, Max; Chao, Chih-Kai; Thompson, Charles; Ruiz-Ramos, Rubén; Calderón-Garcidueñas, Ana; Franco-Lira, Maricela; Reynoso-Robles, Rafael; González-Maciel, Angelica; Lachmann, Ingolf (J Alzheimers Dis, 2018)
Long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above USEPA standards is associated with Alzheimer's disease (AD) risk. Metropolitan Mexico City (MMC) children exhibit subcortical pretangles in infancy and cortical tau pre-tangles, NFTs, and amyloid phases 1-2 by the 2nd decade. Given their AD continuum, we measured in 507 normal cerebrospinal fluid (CSF) samples (MMC 354, controls 153, 12.82±6.73 y), a high affinity monoclonal non-phosphorylated tau antibody (non-P-Tau), as a potential biomarker of AD and axonal damage. In 81 samples, we also measured total tau (T-Tau), tau phosphorylated at threonine 181 (P-Tau), amyloid-β1-42, BDNF, and vitamin D. We documented by electron microscopy myelinated axonal size and the pathology associated with combustion-derived nanoparticles (CDNPs) in anterior cingulate cortex white matter in 6 young residents (16.25±3.34 y). Non-P-Tau showed a strong increase with age significantly faster among MMC versus controls (p = 0.0055). Aβ1 - 42 and BDNF concentrations were lower in MMC children (p = 0.002 and 0.03, respectively). Anterior cingulate cortex showed a significant decrease (p = <0.0001) in the average axonal size and CDNPs were associated with organelle pathology. Significant age increases in non-P-Tau support tau changes early in a population with axonal pathology and evolving AD hallmarks in the first two decades of life. Non-P-Tau is an early biomarker of axonal damage and potentially valuable to monitor progressive longitudinal changes along with AD multianalyte classical CSF markers. Neuroprotection of young urbanites with PM2.5 and CDNPs exposures ought to be a public health priority to halt the development of AD in the first two decades of life.

The Novel DA-CH3 Dual Incretin Restores Endoplasmic Reticulum Stress and Autophagy Impairments to Attenuate Alzheimer-Like Pathology and Cognitive Decrements in the APPSWE/PS1ΔE9 Mouse Model. - Panagaki, Theodora; Gengler, Simon; Holscher, Christian (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) afflicts more than 46.8 million people worldwide, with a newly diagnosed case every 3 seconds and no remission in the disease progression. The discovery of disease-modifying drugs is now on the summit of the neuropharmacological research priorities. The long-lasting derivatives of the insulinotropic incretin hormones-glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)-have repeatedly been shown to cross the blood-brain barrier and counteract an array of deleterious effects across a range of experimental models of neuronal degeneration. Clinical trials for the efficacy of GLP-1 agonists in Alzheimer's and Parkinson's diseases have revealed beneficial effects of these anti-diabetic agents in halting neuronal degeneration progression. Herein, we examine whether the chronic treatment with the novel dual GLP-1/GIP receptor agonist DA-CH3 can restore the cognitive decline and AD-like cerebral pathology of the APPSWE/PS1ΔE9 mouse model at the age of 10 months old. We report that once-a-daily, eight-week intraperitoneal administration of 25 nmol/kg of the novel DA-CH3 dual-incretin analog rescues the spatial acquisition and memory impairments of this murine model that corresponds to the attenuation of the excessive plaque deposition, gliosis and synaptic damage in the APPSWE/PS1ΔE9 brain. The amelioration of the AD-related pathology reflects the resolution of the endoplasmic-reticulum stress and derailed autophagy that both lay downstream of the rectified Akt signaling. Collectively, our findings endorse the beneficial effects of the incretin-based therapeutic approaches for the neurotrophic support of the AD brain and for the first time associate the incretin-induced neuroprotection with the proteostasis machinery in vivo.

Novel Lipidized Analog of Prolactin-Releasing Peptide Improves Memory Impairment and Attenuates Hyperphosphorylation of Tau Protein in a Mouse Model of Tauopathy. - Popelová, Andrea; Pražienková, Veronika; Neprašová, Barbora; Kasperová, Barbora Judita; Hrubá, Lucie; Holubová, Martina; Zemenová, Jana; Blum, David; Železná, Blanka; Galas, Marie-Christine; Kuneš, Jaroslav; Maletínská, Lenka (J Alzheimers Dis, 2018)
Obesity and type 2 diabetes mellitus (T2DM) were characterized as risk factors for Alzheimer's disease (AD) development. Subsequently, T2DM drugs, such as liraglutide, were proven to be neuroprotective compounds attenuating levels of amyloid deposits, and tau hyperphosphorylation, both hallmarks of AD. The central anorexigenic effects of liraglutide inspired us to examine the potential neuroprotective effects of palm11-PrRP31, a strong anorexigenic analog with glucose-lowering properties, in THY-Tau22 mice overexpressing mutated human tau, a model of AD-like tau pathology. Seven-month-old THY-Tau22 mice were subcutaneously infused with palm11-PrRP31 for 2 months. Spatial memory was tested before and after the treatment, using a Y-maze. At the end of the treatment, mice were sacrificed by decapitation and hippocampi were dissected and analyzed by immunoblotting with specific antibodies. Treatment with palm11-PrRP31 resulted in significantly improved spatial memory. In the hippocampi of palm11-PrRP31-treated THY-Tau22 mice, tau protein phosphorylation was attenuated at Thr231, Ser396, and Ser404, the epitopes linked to AD progression. The mechanism of this attenuation remains unclear, since the activation of those kinases most implicated in tau hyperphosphorylation, such as GSK-3β, JNK, or MAPK/ERK1/2, remained unchanged by palm11-PrRP31 treatment. Furthermore, we observed a significant increase in the amount of postsynaptic density protein PSD95, and a non-significant increase of synaptophysin, both markers of increased synaptic plasticity, which could also result in improved spatial memory of THY-Tau22 mice treated with palm11-PrRP31. Palm11-PrRP31 seems to be a potential tool for the attenuation of neurodegenerative disorders in the brain. However, the exact mechanism of its action must be elucidated.

Nutritional Intervention to Prevent Alzheimer's Disease: Potential Benefits of Xanthophyll Carotenoids and Omega-3 Fatty Acids Combined. - Nolan, John M; Mulcahy, Riona; Power, Rebecca; Moran, Rachel; Howard, Alan N (J Alzheimers Dis, 2018)
BACKGROUND: A growing body of scientific evidence suggests that enrichment of certain nutritional compounds in the brain may reduce the risk of Alzheimer's disease (AD). OBJECTIVE: To investigate the impact of supplemental xanthophyll carotenoids plus omega-3 fatty acids on disease progression in patients with AD. METHODS: Three trial experiments were performed. In Trials 1 and 2 (performed on patients with AD over an 18-month period), 12 patients (AD status at baseline: 4 mild and 8 moderate) were supplemented with a xanthophyll carotenoid only formulation (Formulation 1; lutein:meso-zeaxanthin:zeaxanthin 10:10:2 mg/day) and 13 patients (AD status at baseline: 2 mild, 10 moderate, and 1 severe) were supplemented with a xanthophyll carotenoid and fish oil combination (Formulation 2; lutein:meso-zeaxanthin:zeaxanthin 10:10:2 mg/day plus 1 g/day of fish oil containing 430 mg docohexaenoic acid [DHA] and 90 mg eicopentaenoic acid [EPA]), respectively. In Trial 3, 15 subjects free of AD (the control group) were supplemented for 6 months with Formulation 1. Blood xanthophyll carotenoid response was measured in all trials by HPLC. Omega-3 fatty acids were profiled by direct infusion mass spectrometry. RESULTS: Xanthophyll carotenoid concentration increases were significantly greater for Formulation 2 compared to Formulation 1 (p < 0.05), and progression of AD was less for this group (p = 0.003), with carers reporting functional benefits in memory, sight, and mood. CONCLUSION: This preliminary report suggests positive outcomes for patients with AD who consumed a combination of xanthophyll carotenoids plus fish oil, but further study is required to confirm this important observation.

Observational Study of Clinical and Functional Progression Based on Initial Brain MRI Characteristics in Patients with Alzheimer's Disease. - Choi, Hojin; Yang, YoungSoon; Han, Hyun Jeong; Jeong, Jee Hyang; Park, Mee Young; Kim, Yong Bum; Jo, Kwang Deog; Choi, Jin-Yong; Kang, Kyung-Hun; Kang, Heeyoung; Kwon, Do-Young; Yoo, Bong-Goo; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Magnetic resonance imaging (MRI) is a useful tool to predict the diagnosis and progression of Alzheimer's disease (AD), especially for primary physicians. However, the correlation between baseline MRI findings and AD progression has not been fully established. OBJECTIVE: To investigate the correlation between hippocampal atrophy (HA) and white matter hyperintensities (WMH) on initial brain MRI images and the degree of cognitive decline and functional changes over 1 year. METHODS: In this prospective, 12-month observational study, dementia outpatients were recruited from 29 centers across South Korea. Baseline assessments of HA and WMH on baseline brain MRI were derived as well as cognitive function, dementia severity, activities of daily living, and acetylcholinesterase inhibitor (AChEI) use. Follow-up assessments were conducted at 6 and 12 months. RESULTS: Among 899 enrolled dementia patients, 748 were diagnosed with AD of whom 654 (87%) were taking AChEIs. Baseline WMH showed significant correlations with age, current alcohol consumption, and Clinical Dementia Rating score; baseline HA was correlated with age, family history, physical exercise, and the results of cognitive assessments. Among the AChEI group, changes in the Korean version of the Instrumental Activities of Daily Living (K-IADL) were correlated with the severity of HA on baseline brain MRI, but not with the baseline severity of WMH. In the no AChEI group, changes in K-IADL were correlated with the severity of WMH and HA at baseline. CONCLUSION: Baseline MRI findings could be a useful tool for predicting future clinical outcomes by primary physicians, especially in relation to patients' functional status.

Olfactory Function is Associated with Cognitive Performance: Results of the Heinz Nixdorf Recall Study. - Tebrügge, Sarah; Winkler, Angela; Gerards, Diana; Weimar, Christian; Moebus, Susanne; Jöckel, Karl-Heinz; Erbel, Raimund; Jokisch, Martha (J Alzheimers Dis, 2018)
BACKGROUND: There is strong evidence for an association of olfactory dysfunction and neurodegenerative diseases. Studies on the association of olfaction and cognition in the general population are rare. OBJECTIVE: To evaluate gender- and age-specific associations of olfactory function and cognitive performance in a well characterized population-based study sample. METHODS: At the third examination of the Heinz Nixdorf Recall study (n = 3,087), 2,640 participants (48% men; 68.2±7.2 years) underwent Sniffin' Sticks Screening Test measuring olfactory function on a scale of 0-12 points. Olfactory function was rated as anosmic, hyposmic, or normosmic (≤6, 7-10 or ≥11 points, respectively). All participants performed eight validated cognitive subtests. Age- (55-64 years, 65-74 years, 75-86 years) and gender-stratified multivariate analysis of covariance was used to evaluate group differences in cognitive performance. RESULTS: Women showed better olfactory function than men (p < 0.001). For middle-aged participants, olfactory groups differed in almost all cognitive subtests. The analyses revealed no gender effects, although associations were slightly greater for women than for men. Anosmics showed the worst cognitive performance and normosmics showed the best cognitive performance. In the young- and old-aged groups, a quantitative association was found for anosmics in all subtests and for normosmics and hyposmics in almost all subtests. CONCLUSION: This is the first study reporting on age-specific associations of olfactory function and cognitive performance in the general population. The association found in middle-aged participants (65-74 years) may serve as a marker to improve identification of persons at high risk for cognitive decline and dementia.

Parietal Involvement in the Semantic Variant of Primary Progressive Aphasia with Alzheimer's Disease Cerebrospinal Fluid Profile. - Bera, Géraldine; Migliaccio, Raffaella; Michelin, Thibaut; Lamari, Foudil; Ferrieux, Sophie; Nogues, Marie; Bertin, Hugo; Habert, Marie Odile; Dubois, Bruno; Teichmann, Marc; Kas, Aurélie (J Alzheimers Dis, 2018)
Semantic variant of primary progressive aphasia (svPPA) is typically associated with non-Alzheimer's disease (AD) pathology. However, some anatomopathological studies have found AD lesions in those patients. We compared brain perfusion SPECT of 18 svPPA patients with cerebrospinal fluid (CSF) biomarkers indicative of non-AD pathology (svPPA-nonAD) and three svPPA patients with CSF biomarkers indicative of underlying AD (svPPA-AD). All svPPA patients had severe left temporopolar hypoperfusion. SvPPA-nonAD had additional anterior cingulate and mediofrontal hypoperfusion, whereas svPPA-AD had greater left parietal and posterior cingulate involvement. Parietal damage in svPPA constitutes a biomarker for underlying Alzheimer pathology thus refining the classification of this PPA variant.

Pathological Correlates of Cognitive Impairment in The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. - Robinson, Andrew C; Davidson, Yvonne S; Horan, Michael A; Pendleton, Neil; Mann, David M A (J Alzheimers Dis, 2018)
The neuropathological changes responsible for cognitive impairment and dementia remain incompletely understood. Longitudinal studies with a brain donation end point allow the opportunity to examine relationships between cognitive status and neuropathology. We report on the first 97 participants coming to autopsy with sufficient clinical information from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. This study began in 1983 and recruited 6,542 healthy individuals between 1983 and 1994, 312 of whom consented to brain donation. Alzheimer-type pathology was common throughout the cohort and generally correlated well with cognitive status. However, there was some overlap between cognitive status and measures of Alzheimer pathology with 26% of cognitively intact participants reaching either CERAD B or C, 11% reaching Thal phase 4 or 5, and 29% reaching Braak stage III- VI. Cerebral amyloid angiopathy(CAA), α-synuclein, and TDP-43 pathology was less common, but when present correlated well with cognitive status. Possession of APOEɛ4 allele(s) was associated with more severe Alzheimer-type and CAA pathology and earlier death, whereas possession of APOEɛ2 allele(s) had no effect on pathology but was more common in cognitively intact individuals. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort is pathologically representative when compared with similar studies. Cognitive impairment in life correlates strongly with all pathologies examined and the APOE status of an individual can affect pathology severity and longevity.

Patients with Dementia in Primary Care: Who Is Referred to a Neurologist/Psychiatrist and What Patient-Oriented Factors Are Associated with the Visit? - Strohmaier, Urs; Keller, Felix; Kilimann, Ingo; Michalowsky, Bernhard; Wucherer, Diana; Zwingmann, Ina; Teipel, Stefan; Hoffmann, Wolfgang; Thyrian, Jochen René (J Alzheimers Dis, 2018)
BACKGROUND: The current guidelines imply that basic medical diagnostics for dementia should be provided by general practitioners in cooperation with other specialists such as neurologists and psychiatrists. OBJECTIVES: The aims of this paper were to 1) compare the dementia patients of general practice residents whose care is co-managed by neurology/psychiatry residents with those whose care is not; 2) identify the patient variables associated with the utilization of neurological and psychiatric specialists; and 3) describe the frequency of imaging used for dementia patients in primary care. METHODS: The analyses utilized data from 485 individuals who screened positive for dementia in primary care (PWD). Clinical variables and the utilization of specialists were assessed via medical records and face-to-face interviews. The factors associated with the utilization of specialists were assessed using multivariate linear regression and included age, sex, relationship status, cognitive impairment, depression, activities of daily living, and formal diagnosis of dementia. RESULTS: Our results show that 89 out of 485 study participants (18.4%) were referred to specialists 12 months prior to assessment. Of these 89 individuals, 14.6% (n = 13) did not receive imaging diagnostics, while 39.3% (n = 35) received brain imaging by CT scan and 46.1% (n = 41) by MRI. PWD referred to specialists differed from those not referred, in age, relationship status, and the presence of a formal diagnosis. Our multivariate analysis revealed that younger age (OR = 0.95; 95% -confidence interval 0.90-0.99; p = 0.04) and higher functional impairment (OR = 1.15; 95% -confidence interval 1.02-1.30; p = 0.02) were associated with a visit to a specialist. DISCUSSION: Only 1 out of every 4 to 5 individuals who have screened positive for dementia have visited a specialist in psychiatry or neurology. While in general, women utilized specialists less often than men, younger and more functionally impaired patients were more likely to be sent to a specialist by their treating general practitioner. Almost 90% of the patients sent to a specialist received cranial neuroimaging, suggesting high adherence to diagnostic guidelines in specialized care.

Patterns of Physical Activity and Sedentary Behavior for Older Adults with Alzheimer's Disease, Mild Cognitive Impairment, and Cognitively Normal in Hong Kong. - Lu, Zhihui; Harris, Tamara B; Shiroma, Eric J; Leung, Jason; Kwok, Timothy (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia, and mild cognitive impairment (MCI) is a transitional phase between healthy cognition and dementia. Physical activity (PA) has protective effects on cognitive decline. However, few studies have examined how PA and sedentary behavior is structured throughout the day in older adults across varied cognitive status in Hong Kong. OBJECTIVE: This study aimed to compare patterns of PA and sedentary behavior among individuals with AD, MCI, or normal cognition living in Hong Kong. METHODS: Participants in the MrOs and MsOs Hong Kong cohort study and the Hong Kong AD biomarker study (n = 810) wore a wrist-worn accelerometer for 7 days in free-living environment. Patterns of PA in wake time and in-bed time, and detailed analysis of sedentary bouts were compared between groups using analysis of covariance adjusting for covariates. RESULTS: Participants with MCI and low MoCA only did not differ from their cognitively normal peers in PA and sedentary behavior. Nevertheless, when comparing to the others, participants with AD exhibited significantly lower average daily counts per minute during the day (p < 0.05), and tended to start their activity later in the morning. AD participants spent a larger proportion of time in sedentary behavior (p < 0.05) and had more sedentary bouts≥30 minutes (p < 0.05). CONCLUSIONS: The pattern of PA and sedentary behavior was different between individuals with AD and the others. Cognitive status may alter the purpose and type of PA intervention for AD individuals.

Phenomenological Characteristics of Future Thinking in Alzheimer's Disease. - Moustafa, Ahmed A; El Haj, Mohamad (J Alzheimers Dis, 2018)
This study investigates phenomenological reliving of future thinking in Alzheimer's disease (AD) patients and matched controls. All participants were asked to imagine in detail a future event, and afterward, were asked to rate phenomenological characteristics of their future thinking. As compared to controls, AD participants showed poor rating for reliving, travel in time, visual imagery, auditory imagery, language, and spatiotemporal specificity. However, no significant differences were observed between both groups in emotion and importance of future thinking. Results also showed lower rating for visual imagery relative to remaining phenomenological features in AD participants compared to controls; conversely, these participants showed higher ratings for emotion and importance of future thinking. AD seems to compromise some phenomenological characteristics of future thinking, especially, visual imagery; however, other phenomenological characteristics, such as emotion, seem to be relatively preserved in these populations. By highlighting the phenomenological experience of future thinking in AD, our paper opens a unique window into the conscious experience of the future in AD patients.

Physical Fitness and Aortic Stiffness Explain the Reduced Cognitive Performance Associated with Increasing Age in Older People. - Kennedy, Greg; Meyer, Denny; Hardman, Roy J; Macpherson, Helen; Scholey, Andrew B; Pipingas, Andrew (J Alzheimers Dis, 2018)
BACKGROUND: Greater physical fitness is associated with reduced rates of cognitive decline in older people; however, the mechanisms by which this occurs are still unclear. One potential mechanism is aortic stiffness, with increased stiffness resulting in higher pulsatile pressures reaching the brain and possibly causing progressive micro-damage. There is limited evidence that those who regularly exercise may have lower aortic stiffness. OBJECTIVE: To investigate whether greater fitness and lower aortic stiffness predict better cognitive performance in older people and, if so, whether aortic stiffness mediates the relationship between fitness and cognition. METHODS: Residents of independent living facilities, aged 60-90, participated in the study (N = 102). Primary measures included a computerized cognitive assessment battery, pulse wave velocity analysis to measure aortic stiffness, and the Six-Minute Walk test to assess fitness. Based on hierarchical regression analyses, structural equation modelling was used to test the mediation hypothesis. RESULTS: Both fitness and aortic stiffness independently predicted Spatial Working Memory (SWM) performance, however no mediating relationship was found. Additionally, the derived structural equation model shows that, in conjunction with BMI and sex, fitness and aortic stiffness explain 33% of the overall variation in SWM, with age no longer directly predicting any variation. CONCLUSIONS: Greater fitness and lower aortic stiffness both independently predict better SWM in older people. The strong effect of age on cognitive performance is totally mediated by fitness and aortic stiffness. This suggests that addressing both physical fitness and aortic stiffness may be important to reduce the rate of age associated cognitive decline.

The Positive Effects of Viewing Gardens for Persons with Dementia. - Goto, Seiko; Shen, Xuting; Sun, Minkai; Hamano, Yutaka; Herrup, Karl (J Alzheimers Dis, 2018)
Dementia is highly prevalent among the worldwide elderly population. Only a small number of the currently marketed drugs are effective in controlling its symptoms, and none has any effect on its progression. Further, as the condition advances, even these pharmaceuticals lose their efficiency, and new research into interventions that might improve the life quality of patients at the end stage of dementia and their families is increasingly rare. In our previous studies, we explored the benefits of exposure to nature, in the form of a Japanese garden, for persons with advanced dementia. In the current work, we extended our observations to two new locations and a new set of subjects with a different ethnic composition with the goal of identifying interventions that might improve their quality of life. We found that, even in these new settings, garden observation not only relieved physiological stress, it improved qualitative measures such as verbalization and memory retrieval. We present data that viewing the garden is a holistic experience rather a solely visual stimulus. Our new data further support the conclusion that garden observation is worth including in the care planning schedule of advanced dementia patients. Its low cost and easy availability make it an economical adjunct to current pharmacological methods that has the potential to improve the quality of life of people with dementia.

Potential Factors Associated with Cognitive Improvement of Individuals Diagnosed with Mild Cognitive Impairment or Dementia in Longitudinal Studies. - Hadjichrysanthou, Christoforos; McRae-McKee, Kevin; Evans, Stephanie; De Wolf, Frank; Anderson, Roy M (J Alzheimers Dis, 2018)
Despite the progressive nature of Alzheimer's disease and other dementias, it is observed that many individuals that are diagnosed with mild cognitive impairment (MCI) in one clinical assessment, may return back to normal cognition (CN) in a subsequent assessment. Less frequently, such 'back-transitions' are also observed in people that had already been diagnosed with later stages of dementia. In this study, an analysis was performed on two longitudinal cohort datasets provided by 1) the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 2) the National Alzheimer's Coordinating Centre (NACC). The focus is on the observed improvement of individuals' clinical condition recorded in these datasets to explore potential associations with different factors. It is shown that, in both datasets, transitions from MCI to CN are significantly associated with younger age, better cognitive function, and the absence of ApoE ɛ4 alleles. Better cognitive function and in some cases the absence of ApoE ɛ4 alleles are also significantly associated with transitions from types of dementia to less severe clinical states. The effect of gender and education is not clear-cut in these datasets, although highly educated people who reach MCI tend to be more likely to show an improvement in their clinical state. The potential effect of other factors such as changes in symptoms of depression is also discussed. Although improved clinical outcomes can be associated with many factors, better diagnostic tools are required to provide insight into whether such improvements are a result of misdiagnosis, and if they are not, whether they are linked to improvements in the underlying neuropathological condition.

Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer's Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial. - Wilcock, Gordon K; Gauthier, Serge; Frisoni, Giovanni B; Jia, Jianping; Hardlund, Jiri H; Moebius, Hans J; Bentham, Peter; Kook, Karin A; Schelter, Bjoern O; Wischik, Damon J; Davis, Charles S; Staff, Roger T; et al. (J Alzheimers Dis, 2018)
BACKGROUND: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. OBJECTIVES: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD. METHODS: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error. RESULTS: The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy. CONCLUSIONS: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Cohort Studies; Double-Blind Method; Female; Humans; International Cooperation; Male; Mental Status and Dementia Tests; Methylene Blue; Middle Aged; Treatment Outcome

A Precision Medicine Model for Targeted NSAID Therapy in Alzheimer's Disease. - O'Bryant, Sid E; Zhang, Fan; Johnson, Leigh A; Hall, James; Edwards, Melissa; Grammas, Paula; Oh, Esther; Lyketsos, Constantine G; Rissman, Robert A (J Alzheimers Dis, 2018)
BACKGROUND: To date, the therapeutic paradigm for Alzheimer's disease (AD) has focused on a single intervention for all patients. However, a large literature in oncology supports the therapeutic benefits of a precision medicine approach to therapy. Here we test a precision-medicine approach to AD therapy. OBJECTIVE: To determine if a baseline, blood-based proteomic companion diagnostic predicts response to NSAID therapy. METHODS: Proteomic assays of plasma from a multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to rofecoxib (25 mg once daily), naproxen (220 mg twice-daily) or placebo. RESULTS: 474 participants with mild-to-moderate AD were screened with 351 enrolled into the trial. Using support vector machine (SVM) analyses, 89% of the subjects randomized to either NSAID treatment arms were correctly classified using a general NSAID companion diagnostic. Drug-specific companion diagnostics yielded 98% theragnostic accuracy in the rofecoxib arm and 97% accuracy in the naproxen arm. CONCLUSION: Inflammatory-based companion diagnostics have significant potential to identify select patients with AD who have a high likelihood of responding to NSAID therapy. This work provides empirical support for a precision medicine model approach to treating AD.

Predicting and Tracking Short Term Disease Progression in Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer's Disease: Structural Brain Biomarkers. - Marizzoni, Moira; Ferrari, Clarissa; Jovicich, Jorge; Albani, Diego; Babiloni, Claudio; Cavaliere, Libera; Didic, Mira; Forloni, Gianluigi; Galluzzi, Samantha; Hoffmann, Karl-Titus; Molinuevo, José Luis; Nobili, Flavio; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients. OBJECTIVE: To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression. METHODS: APOE ɛ4 specific CSF Aβ42/P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42/P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes in ADAS-cog13, 2) with Aβ42/P-tau status, time, and Aβ42/P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers. RESULTS: Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients who declined faster (interaction, p = 0.003). Lateral ventricle volume and medial temporal lobe measures were the biomarkers most sensitive to disease progression (interaction, p≤0.042). Enrichment through ventricular volume reduced the sample size that a clinical trial would require from 13 to 76%, depending on structural outcome variable. The biomarker needing the lowest sample size was the hippocampal subfield GC-ML-DG (granule cells of molecular layer of the dentate gyrus) (n = 82 per arm to demonstrate a 20% atrophy reduction). CONCLUSION: MRI structural biomarkers can enrich prodromal AD with fast progressors and significantly decrease group size in clinical trials of disease modifying drugs.

Predictors of Age of Diagnosis and Survival of Alzheimer's Disease in Down Syndrome. - Sinai, Amanda; Mokrysz, Claire; Bernal, Jane; Bohnen, Ingrid; Bonell, Simon; Courtenay, Ken; Dodd, Karen; Gazizova, Dina; Hassiotis, Angela; Hillier, Richard; McBrien, Judith; McCarthy, Jane; et al. (J Alzheimers Dis, 2018)
BACKGROUND: People with Down syndrome (DS) are an ultra-high risk population for Alzheimer's disease (AD). Understanding the factors associated with age of onset and survival in this population could highlight factors associated with modulation of the amyloid cascade. OBJECTIVE: This study aimed to establish the typical age at diagnosis and survival associated with AD in DS and the risk factors associated with these. METHODS: Data was obtained from the Aging with Down Syndrome and Intellectual Disabilities (ADSID) research database, consisting of data extracted from clinical records of patients seen by Community Intellectual Disability Services (CIDS) in England. Survival times when considering different risk factors were calculated. RESULTS: The mean age of diagnosis was 55.80 years, SD 6.29. Median survival time after diagnosis was 3.78 years, and median age at death was approximately 60 years. Survival time was associated with age of diagnosis, severity of intellectual disability, living status, anti-dementia medication status, and history of epilepsy. Age at diagnosis and treatment status remained predictive of survival time following adjustment. CONCLUSION: This study provides the best estimate of survival in dementia within the DS population to date, and is in keeping with previous estimates from smaller studies in the DS population. This study provides important estimates and insights into possible predictors of survival and age of diagnosis of AD in adults with DS, which will inform selection of participants for treatment trials in the future.
Keywords: Age of Onset; Alzheimer Disease; Down Syndrome; England; Female; Humans; Male; Middle Aged; Risk Factors; Survival Analysis

Preoperative Phosphorylated Tau Concentration in the Cerebrospinal Fluid Can Predict Cognitive Function Three Years after Shunt Surgery in Patients with Idiopathic Normal Pressure Hydrocephalus. - Nakajima, Madoka; Miyajima, Masakazu; Ogino, Ikuko; Akiba, Chihiro; Kawamura, Kaito; Kamohara, Chihiro; Fusegi, Keiko; Harada, Yoshinao; Hara, Takeshi; Sugano, Hidenori; Tange, Yuichi; Karagiozov, Kostadin; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is commonly treated by cerebrospinal fluid (CSF) shunting. However, the long-term efficacy of shunt intervention in the presence of comorbid Alzheimer's disease (AD) pathology is debated. OBJECTIVE: To identify AD-associated CSF biomarkers predictive of shunting surgery outcomes in patients with iNPH. METHODS: Preoperative levels of total and phosphorylated Tau (p-Tau) were measured in 40 patients with iNPH divided into low (<30 pg/mL) and high (≥30 pg/mL) p-Tau groups and followed up for three years after lumboperitoneal shunting. The modified Rankin Scale (mRS), Mini-Mental State Examination (MMSE), Frontal Assessment Battery, and iNPH Grading Scale scores were compared between the age-adjusted low (n = 24; mean age 75.7 years [SD 5.3]) and high (n = 11; mean age 76.0 years [SD 5.6]) p-Tau groups. RESULTS: Cognitive function improved early in the low p-Tau group and was maintained thereafter (p = 0.005). In contrast, the high p-Tau group showed a gradual decline to baseline levels by the third postoperative year (p = 0.040). Although the p-Tau concentration did not correlate with the preoperative MMSE score, a negative correlation appeared and strengthened during follow-up (R2 = 0.352, p < 0.001). Furthermore, the low p-Tau group showed rapid and sustained mRS grade improvement, whereas mRS performance gradually declined in the high p-Tau group. CONCLUSIONS: Preoperative CSF p-Tau concentration predicted some aspects of cognitive function after shunt intervention in patients with iNPH. The therapeutic effects of shunt treatment were shorter-lasting in patients with coexisting AD pathology.

Prevalence and Determinants of Agonistic Autoantibodies Against α1-Adrenergic Receptors in Patients Screened Positive for Dementia: Results from the Population-Based DelpHi-Study. - Thyrian, Jochen René; Hertel, Johannes; Schulze, Lara N; Dörr, Marcus; Prüss, Harald; Hempel, Petra; Bimmler, Marion; Kunze, Rudolf; Grabe, Hans Jörgen; Teipel, Stefan; Hoffmann, Wolfgang (J Alzheimers Dis, 2018)
BACKGROUND: There is a need to assess promising biomarkers for diagnosis and treatment response in real-life settings. Despite the important role of vascular risk factors, cardiovascular biomarkers have played a minor role in dementia research. Agonistic autoantibodies (agAAB) directed against G-protein-coupled receptors (GPCR) are discussed as modulators of pathology and clinical manifestation. OBJECTIVE: 1) Describe prevalence of agAAB directed against GPCR, especially agABB against α1-adrenergic receptors (α1-AR-agAAB) and agABB directed against β2-adrenergic receptors (β2-AR-agAAB) and 2) identify factors associated with agAAB in people with dementia during routine care. METHODS: Blood samples and data from 95 subjects who screened positive for dementia from a primary care cohort, analyzed using an enzyme-linked immunosorbent assay (ELISA) for detecting agAAB. Sociodemographic and clinical data were assessed, and medical records checked. RESULTS: In 40 (42%) samples, agAAB was detected, with n = 29 (31%) representing α1-AR-agAAB and n = 21 (22%) β2-AR-agAAB. There was no association between the presence of any antibody and a formal diagnosis of dementia. However, patients with coronary heart disease were more likely (OR = 4.23) to have α1-AR-agAAB than those without coronary heart disease. There were no associations between agAAB and age, sex, education, or cognitive impairment. DISCUSSION: For the first time, we show that autoantibodies have a significant prevalence in people with dementia in a routine care setting. Previous findings were restricted to highly selective samples. We replicated the association between α1-AR-agAAB in patients with coronary heart diseases but were not able to find other factors associated with the presence of agAAB.

Prevalence of Potentially Inappropriate Medication Use in Older Inpatients with and without Cognitive Impairment: A Systematic Review. - Redston, Mitchell R; Hilmer, Sarah N; McLachlan, Andrew J; Clough, Alexander J; Gnjidic, Danijela (J Alzheimers Dis, 2018)
BACKGROUND: Older people with cognitive impairment, including dementia and delirium, are high users of acute care services internationally. Potentially inappropriate medication (PIM) use may be associated with adverse outcomes, including hospital re-admission, functional disability, and mortality. OBJECTIVE: This systematic review aimed to quantify and compare the prevalence of PIMs in older inpatients with and without cognitive impairment. METHODS: A systematic search of observational studies was performed independently assessed by two reviewers in Embase, Medline, PsycINFO, International Pharmaceutical Abstracts, Scopus, and Informit. Articles published in English during the period January 2007-June 2017 that reported PIM prevalence in hospital inpatients ≥ 65 years were included. PIMs were defined as the presence of polypharmacy (multiple medication use) and using implicit or explicit tools, such as the Beers criteria, and 'Screening Tool of Older Person's Prescriptions' (STOPP). RESULTS: 47 articles were included. In studies measuring polypharmacy (n = 15), the prevalence of PIMs ranged from 53.2% to 89.8% and 30.4% to 97.1% for inpatients with and without cognitive impairment, respectively, and 24.0% to 80.0% when cognitive status was unreported. In studies employing explicit and implicit tools (n = 35), the prevalence of PIMs when cognitive impairment was reported ranged from 20.6% to 80.5% using the Beers criteria, and 39.3% to 88.5% using STOPP. When cognitive status was unreported, the prevalence of PIMs ranged from 7.0% to 79.2% using the Beers criteria, and 20.0% to 63.4% using STOPP. CONCLUSION: Our findings suggest a high prevalence of PIMs in older inpatients with and without cognitive impairment. Future studies should investigate the impact of PIM use on patient-centered outcomes, such as functional status and quality of life, to inform enhanced acute care services.
Keywords: Aged; Cognitive Dysfunction; Dementia; Humans; Inpatients; Polypharmacy; Potentially Inappropriate Medication List; Prevalence; Quality of Life

Prevalence, Semiology, and Risk Factors of Epilepsy in Alzheimer's Disease: An Ambulatory EEG Study. - Horváth, András; Szűcs, Anna; Hidasi, Zoltán; Csukly, Gábor; Barcs, Gábor; Kamondi, Anita (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is the primary cause of cognitive decline. A growing body of evidence suggests that AD patients have a higher risk to develop epileptic seizures; however, results are contradictory due to different methodological approaches of previous studies. OBJECTIVE: We aimed to identify the prevalence, semiology, and risk factors of epilepsy in AD using long-term EEG. METHODS: We selected forty-two AD patients and examined them using 24-hour ambulatory EEG. Neurological and epileptological data were collected with retro- and prospective methods. We analyzed the semiology of the identified seizures and the possible risk factors using logistic regression analysis. RESULTS: We identified seizures confirmed by EEG in 24%. The majority of the seizures were aware focal (72%) without any motor activity (55%). We found epileptiform discharges without seizures in 28%. Patients with seizures and only with epileptic EEG activity showed similar clinical and demographical features. Higher education (OR:1.8) and lower Addenbrooke Examination Score (OR: 0.9) were identified as risk factors of epilepsy. Increase of 0.1 point in the Verbal-Language/Orientation-Memory ratio (VLOM) was associated with higher epilepsy risk as well (OR:2.9). CONCLUSION: Epilepsy is a frequent comorbidity of AD. Since most of the seizures are aware non-motor focal seizures, sensitive EEG techniques are required for precise diagnosis of epilepsy. Long-term ambulatory EEG is a safe and well-tolerated option. Epileptiform EEG in AD signals the presence of concomitant epilepsy. Clinicians have to pay attention to comorbid epilepsy in dementia patients with high education, with high VLOM ratio and severe stage.

The Price of Stress: High Bedtime Salivary Cortisol Levels Are Associated with Brain Atrophy and Cognitive Decline in Stroke Survivors. Results from the TABASCO Prospective Cohort Study. - Tene, Oren; Hallevi, Hen; Korczyn, Amos D; Shopin, Ludmila; Molad, Jeremy; Kirschbaum, Clemens; Bornstein, Natan M; Shenhar-Tsarfaty, Shani; Kliper, Efrat; Auriel, Eitan; Usher, Sali; Stalder, Tobias; et al. (J Alzheimers Dis, 2018)
BACKGROUND AND OBJECTIVE: Previous studies suggest that excessive cortisol levels after stroke are associated with cognitive dysfunction. However, limited data exist regarding associations between post-stroke cortisol levels, brain abnormalities, genetic factors, and cognitive outcome. We sought to study these issues in a longitudinal stroke survivors cohort. METHODS: Data from 182 cognitively intact ischemic stroke patients from the TABASCO study were available. Saliva cortisol levels (bedtime and post-awakening) and cognitive assessments were obtained on admission, and 6, 12, and 24 months thereafter. During hospitalization, patients underwent 3T MRI scans and APOE genotyping. RESULTS: Higher bedtime cortisol levels immediately post-stroke were associated with larger neurological deficits (p < 0.001), brain atrophy (p = 0.025), worse white matter integrity (p = 0.003), and worse cognitive results up to 24 months post-stroke. These findings remained significant when adjusted for age, gender, education, smoking, stroke severity, apolipoprotein E4 (ApoE4) status, and body mass index. ApoE4 negatively modified the relation between cortisol and memory. As a group, participants who presented with high admission bedtime cortisol levels continued to present relatively elevated bedtime levels across all examined time-points, and this group had inferior memory and executive functioning scores compared to the lower cortisol group 24 months post-stroke (p = 0.05, p = 0.035, respectively). Post-awakening cortisol levels were not associated with neuroimaging findings or cognitive scores. CONCLUSIONS: High bedtime salivary cortisol levels post-stroke may provide information about dysregulation of diurnal HPA-axis activity under acute challenge conditions, and predict worse cognitive outcome. ApoE4 genotype might modify this association. These findings call for specific stress management interventions in stroke survivors.

Prodromal Alzheimer's Disease Demonstrates Increased Errors at a Simple and Automated Anti-Saccade Task. - Holden, John G; Cosnard, Alexandre; Laurens, Brice; Asselineau, Julien; Biotti, Damien; Cubizolle, Stéphanie; Dupouy, Sandrine; Formaglio, Maıté; Koric, Lejla; Seassau, Magali; Tilikete, Caroline; Vighetto, Alain; et al. (J Alzheimers Dis, 2018)
Saccade alterations are potential early signs of Alzheimer's disease. However, uncertainty persists in how early and reliably automated saccade recording systems detect impairments. This multicenter pathophysiological case-control transversal study explored saccade execution in carefully diagnosed amnestic mild cognitive impairment patients fulfilling research criteria for prodromal Alzheimer's disease (n = 29), as compared to both aged-matched mild Alzheimer's disease patients (n = 23) and controls (n = 27). Auto-coded saccades from horizontal (gap) vertical (step) stimulus elicited pro-saccades, and anti-saccade (gap) tasks were compared across the 3 groups. Mild cognitive impairment patients committed significantly more anti-saccade errors compared to controls (46.9 versus 24.3%, p < 0.001). Conventional analyses of the auto-coded stimulus elicited saccades parameters did not distinguish the amnestic mild cognitive impairment from controls or the mild Alzheimer's disease group. However, an offline analysis of manually coded saccade latencies, using resampling statistics did reveal subtle differences among the groups. Analysis of the manually coded data revealed that the mild Alzheimer's disease group had a reliably larger self-corrected error-rate than in amnestic mild cognitive impairment and controls (p = 0.003). Analysis of the manually coded saccade latencies, using more sensitive lognormal bootstrap analysis revealed a continuum, from amnestic mild cognitive impairment to mild Alzheimer's disease, of an increased severity of impaired inhibition of stimulus elicited saccades and correct voluntary saccade initiation. Anti-saccade error rates and psychometric measures of executive and several other cognitive functions were moderately and negatively correlated. Overall, inhibitory impairments in stimulus elicited saccades, characteristic of Alzheimer's disease, may be detected early in presumed prodromal patients using a simple, automated anti-saccade task.

Progress and Challenges in Frontotemporal Dementia Research: A 20-Year Review. - Hodges, John R; Piguet, Olivier (J Alzheimers Dis, 2018)
The landscape of frontotemporal dementia (FTD) has evolved remarkably in recent years and is barely recognizable from two decades ago. Knowledge of the clinical phenomenology, cognition, neuroimaging, genetics, pathology of the different subtypes of FTD, and their relations to other neurodegenerative conditions, has increased rapidly, due in part, to the growing interests into these neurodegenerative brain conditions. This article reviews the major advances in the field of FTD over the past 20 years, focusing primarily on the work of Frontier, the frontotemporal dementia clinical research group, based in Sydney, Australia. Topics covered include clinical presentations (cognition, behavior, neuroimaging), pathology, genetics, and disease progression, as well as interventions and carer directed research. This review demonstrates the improvement in diagnostic accuracy and capacity to provide advice on genetic risks, prognosis, and outcome. The next major challenge will be to capitalize on these research findings to develop effective disease modifying drugs, which are currently lacking.

Progress of Brain Amyloid Deposition in Familial Alzheimer's Disease with Taiwan D678H APP Mutation. - Weng, Yi-Ching; Hsiao, Ing-Tsung; Huang, Chu-Yun; Huang, Kuo-Lun; Liu, Chi-Hung; Chang, Ting-Yu; Yen, Tzu-Chen; Lin, Kun-Ju; Huang, Chin-Chang (J Alzheimers Dis, 2018)
BACKGROUND: The amyloid AV-45 (florbetapir) positron emission tomography (PET) has been used in the study of the familial Alzheimer's disease (FAD) with the D678H amyloid precursor protein (APP) mutation. In addition, the progress of the disease remains unknown. OBJECTIVE: We aim to investigate the progression rate of amyloid accumulation in FAD patients with this mutation by neuroimages analysis. METHODS: The clinical course, changes in cognitive function, brain magnetic resonance imaging (MRI) and 18F-AV-45 PET scan were investigated in FAD patients and sporadic AD (sAD) patients. We compared the amyloid deposition pattern in serial brain 18F-AV-45 PET scan among the FAD, familial mild cognitive impairment (FMCI), and sMCI and sAD patients. RESULTS: Seven familial patients received a follow-up survey. The follow up duration for brain AV-45 PET was from 1.54 to 3.61 years. In 4 FMCI patients, an increased regional SUVR was noted, and the annual change rates were increased from 1.03% to 18.82%. However, a decreased regional SUVR was noted in 3 FAD patients and the annual change rates were from -2.62% to -16.03%. As compared with the sAD and sMCI patients, the annual change rate is statistically significant in FAD and FMCI patients respectively. CONCLUSIONS: The data indicate a biphasic course with an initial increase and then a decrease of SUVR in brain amyloid PET scan in familial APP mutation patients. The data also reveal that the novel Taiwan APP (D678H) mutation has a more amyloid burden than the sAD patients, particularly in an MCI stage.

The Progression of Neuropsychiatric Symptoms in Alzheimer's Disease During a Five-Year Follow-Up: Kuopio ALSOVA Study. - Hallikainen, Ilona; Hongisto, Kristiina; Välimäki, Tarja; Hänninen, Tuomo; Martikainen, Janne; Koivisto, Anne M (J Alzheimers Dis, 2018)
BACKGROUND: An improved understanding of the role of neuropsychiatric symptoms (NPS) in the course of Alzheimer's disease (AD) has recently emerged. NPS lead to hospitalization and caregiver stress, but are more variable during the course of the disease than other symptoms. Knowledge about the role of specific NPS in disease progression and prognosis is especially limited. OBJECTIVES: To examine the relationship between specific NPS and AD severity during a 5-year follow-up period, and to determine which baseline NPS predict AD progression. METHODS: 236 persons with very mild (CDR 0.5) or mild (CDR 1) AD at baseline and their caregivers were followed up for five years as part of the ALSOVA study. The Neuropsychiatric Inventory was used to assess NPS, and AD severity progression was measured with the Clinical Dementia Rating Sum of Boxes. Data was analyzed with Generalized Estimated Equations and Linear Mixed Models. RESULTS: The baseline NPS that best predicted AD progression were delusions, agitation, and aberrant motor behavior, while AD severity during follow-up was associated with hallucinations, delusions, agitation, apathy, aberrant motor behavior, and sleep and appetite disturbances. CONCLUSIONS: Persons with mild AD presenting delusions, agitation, and aberrant motor behavior at the time of diagnosis could have a more rapidly progressing disease, and some NPS are associated with AD severity. These results highlight the importance of evaluating NPS at the time of AD diagnosis, and the need to offer additional support to persons presenting delusions, agitation and aberrant motor behavior, and their caregivers.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Anxiety; Caregivers; Delusions; Disease Progression; Female; Finland; Hallucinations; Humans; Linear Models; Male; Motor Activity; Multivariate Analysis; Neuropsychological Tests; Severity of Illness Index

Prominent Non-Memory Deficits in Alzheimer's Disease Are Associated with Faster Disease Progression. - Scheltens, Nienke M E; Tijms, Betty M; Heymans, Martijn W; Rabinovici, Gil D; Cohn-Sheehy, Brendan I; Miller, Bruce L; Kramer, Joel H; Wolfsgruber, Steffen; Wagner, Michael; Kornhuber, Johannes; Peters, Oliver; Scheltens, Philip; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is a heterogeneous disorder. OBJECTIVE: To investigate whether cognitive AD subtypes are associated with different rates of disease progression. METHODS: We included 1,066 probable AD patients from the Amsterdam Dementia Cohort (n = 290), Alzheimer's Disease Neuroimaging Initiative (n = 268), Dementia Competence Network (n = 226), and University of California, San Francisco (n = 282) with available follow-up data. Patients were previously clustered into two subtypes based on their neuropsychological test results: one with most prominent memory impairment (n = 663) and one with most prominent non-memory impairment (n = 403). We examined associations between cognitive subtype and disease progression, as measured with repeated Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale sum of boxes (CDR sob), using linear mixed models. Furthermore, we investigated mortality risk associated with subtypes using Cox proportional hazard analyses. RESULTS: Patients were 71±9 years old; 541 (51%) were female. At baseline, pooled non-memory patients had worse MMSE scores (23.1±0.1) and slightly worse CDR sob (4.4±0.1) than memory patients (MMSE 24.0±0.1; p < 0.001; CDR sob 4.1±0.1; p < 0.001). During follow-up, pooled non-memory patients showed steeper annual decline in MMSE (-2.8±0.1) and steeper annual increase in CDR sob (1.8±0.1) than memory patients (MMSE - 1.9±0.1; pinteraction<0.001; CDR sob 1.3±0.1; pinteraction<0.001). Furthermore, the non-memory subtype was associated with an increased risk of mortality compared with the memory subtype at trend level (HR = 1.36, CI = 1.00-1.85, p = 0.05). CONCLUSIONS: AD patients with most prominently non-memory impairment show faster disease progression and higher risk of mortality than patients with most prominently memory impairment.

Proteomic Profiling of Mouse Brains Exposed to Blast-Induced Mild Traumatic Brain Injury Reveals Changes in Axonal Proteins and Phosphorylated Tau. - Chen, Mei; Song, Hailong; Cui, Jiankun; Johnson, Catherine E; Hubler, Graham K; DePalma, Ralph G; Gu, Zezong; Xia, Weiming (J Alzheimers Dis, 2018)
Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by two pathological hallmarks: Tau-containing neurofibrillary tangles and amyloid-β protein (Aβ)-containing neuritic plaques. The goal of this study is to understand mild traumatic brain injury (mTBI)-related brain proteomic changes and tau-related biochemical adaptations that may contribute to AD-like neurodegeneration. We found that both phosphorylated tau (p-tau) and the ratio of p-tau/tau were significantly increased in brains of mice collected at 3 and 24 h after exposure to 82-kPa low-intensity open-field blast. Neurological deficits were observed in animals at 24 h and 7 days after the blast using Simple Neuroassessment of Asymmetric imPairment (SNAP) test, and axon/dendrite degeneration was revealed at 7 days by silver staining. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to analyze brain tissue labeled with isobaric mass tags for relative protein quantification. The results from the proteomics and bioinformatic analysis illustrated the alterations of axonal and synaptic proteins in related pathways, including but not being limited to substantia nigra development, cortical cytoskeleton organization, and synaptic vesicle exocytosis, suggesting a potential axonal damage caused by blast-induced mTBI. Among altered proteins found in brains suffering blast, microtubule-associated protein 1B, stathmin, neurofilaments, actin binding proteins, myelin basic protein, calcium/calmodulin-dependent protein kinase, and synaptotagmin I were representative ones involved in altered pathways elicited by mTBI. Therefore, TBI induces elevated phospho-tau, a pathological feature found in brains of AD, and altered a number of neurophysiological processes, supporting the notion that blast-induced mTBI as a risk factor contributes to AD pathogenesis. LC/MS-based profiling has presented candidate target/pathways that could be explored for future therapeutic development.

Protofibrillar and Fibrillar Amyloid-β Binding Proteins in Cerebrospinal Fluid. - Rahman, M Mahafuzur; Westermark, Gunilla T; Zetterberg, Henrik; Härd, Torleif; Sandgren, Mats (J Alzheimers Dis, 2018)
Aggregation and deposition of misfolded amyloid-β (Aβ) peptide in the brain is central to Alzheimer's disease (AD). Oligomeric, protofibrillar, and fibrillar forms of Aβ are believed to be neurotoxic and cause neurodegeneration in AD, but the toxicity mechanisms are not well understood and may involve Aβ-interacting molecular partners. In a previous study, we identified potential Aβ42 protofibrillar-binding proteins in serum and cerebrospinal fluid (CSF) using an engineered version of Aβ42 (Aβ42CC) that forms protofibrils, but not fibrils. Here we studied binding of proteins to Aβ42 fibrils in AD and non-AD CSF and compared these with protofibrillar Aβ42CC-binding partners. Aβ42 fibrils sequestered 2.4-fold more proteins than Aβ42CC protofibrils. Proteins with selective binding to fibrillar aggregates with low nanomolar affinity were identified. We also found that protofibrillar and fibrillar Aβ-binding proteins represent distinct functional categories. Aβ42CC protofibrils triggered interactions with proteins involved in catalytic activities, like transferases and oxidoreductases, while Aβ42 fibrils were more likely involved in binding to proteoglycans, growth factors and neuron-associated proteins, e.g., neurexin-1, -2, and -3. Interestingly, 10 brain-enriched proteins were identified among the fibril-binding proteins, while protofibril-extracted proteins had more general expression patterns. Both types of Aβ aggregates bound several extracellular proteins. Additionally, we list a set of CSF proteins that might have potential to discriminate between AD and non-AD CSF samples. The results may be of relevance both for biomarker studies and for studies of Aβ-related toxicity mechanisms.

Psychometric Properties of Apathy Scales in Dementia: A Systematic Review. - Mohammad, Dana; Ellis, Courtney; Rau, Allison; Rosenberg, Paul B; Mintzer, Jacobo; Ruthirakuhan, Myuri; Herrmann, Nathan; Lanctôt, Krista L (J Alzheimers Dis, 2018)
Apathy is a prevalent and problematic neuropsychiatric symptom in those with dementia that is emerging as a treatment target, necessitating accurate assessment. While many apathy scales are available, not all have been developed for use exclusively in dementia, and psychometric properties may vary across different populations. This systematic review aimed to provide an overview of the psychometric properties of apathy scales used in Alzheimer's disease (AD) and related dementias, as well as rate the methodological quality of supporting studies. In addition, for those scales identified, performance in clinical trials was reviewed. A search was conducted through Medline, Psychinfo, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. Articles that reported psychometric properties of an apathy scale in an AD or mixed dementia population were included. Of 15 articles, the methodological quality ratings of the studies ranged from adequate to excellent. Three clinical trials and two pooled analyses of clinical trials were included that used apathy scales evaluated in this review. Three scales emerged. The Neuropsychiatric Inventory apathy subscale (NPI-apathy) and the Apathy Evaluation Scale (AES) had the greatest number of studies evaluating psychometric properties and were also used in the clinical trials and have shown sensitivity to change. The Dementia Apathy Interview and Rating demonstrated excellent values of internal consistency, validity, and reliability for use in an AD population. Future research should address comparative scale performance and assess ability to distinguish subtypes of apathy. Validation may include evaluation of performance against specific imaging defined deficits.

Putative Dementia Cases Fluctuate as a Function of Mini-Mental State Examination Cut-Off Points. - Rosa, Ilka M; Henriques, Ana G; Wiltfang, Jens; da Cruz E Silva, Odete A B (J Alzheimers Dis, 2018)
As the population ages, there is a growing need to quickly and accurately identify putative dementia cases. Many cognitive tests are available; among those commonly used are the Cognitive Dementia Rating (CDR) and the Mini-Mental Status Examination (MMSE). The aim of this work was to compare the validity and reliability of these cognitive tests in a primary care based cohort (pcb-Cohort). The MMSE and the CDR were applied to 568 volunteers in the pcb-Cohort. Distinct cut-off points for the MMSE were considered, namely MMSE 27, MMSE 24, and MMSE PT (adapted for the Portuguese population). The MMSE 27 identified the greatest number of putative dementia cases, and, as determined by the ROC curve, it was the most sensitive and specific of the MMSE cut-offs considered. Putative predictive or risk factors identified included age, literacy, depression, and diabetes mellitus (DM). DM has previously been indicated as a risk factor for dementia and Alzheimer's disease. Comparatively, the MMSE 27 cut-off has the greatest sensibility (94.9%) and specificity (66.3%) when compared to MMSE PT and MMSE 24. Upon comparing MMSE and CDR scores, the latter identified a further 146 putative dementia cases, thus permitting one to propose that in an ideal situation, both tests should be employed. This increases the likelihood of identifying putative dementia cases for subsequent follow up work, thus these cognitive tests represent important tools in patient care. Further, this is a significant study for Portuguese populations, where few of these studies have been carried out.
Keywords: Age Factors; Aged; Aged, 80 and over; Cohort Studies; Community Health Planning; Cross-Sectional Studies; Dementia; Female; Humans; Male; Mental Status and Dementia Tests; Middle Aged; Neuropsychological Tests; ROC Curve

Quality of Life, Care Resource Use, and Costs of Dementia in 8 European Countries in a Cross-Sectional Cohort of the Actifcare Study. - Handels, Ron L H; Sköldunger, Anders; Bieber, Anja; Edwards, Rhiannon Tudor; Gonçalves-Pereira, Manuel; Hopper, Louise; Irving, Kate; Jelley, Hannah; Kerpershoek, Liselot; Marques, Maria J; Meyer, Gabriele; Michelet, Mona; et al. (J Alzheimers Dis, 2018)
BACKGROUND: With 10.5 million people with dementia in Europe and $301 billion associated costs, governments face challenges organizing access to care. OBJECTIVE: To examine the costs related to formal and informal care use and quality of life for people with dementia in eight European countries, and explore the association with unmet needs. METHODS: Cross-sectional data from 451 persons with dementia and their informal caregivers of the Actifcare cohort study were obtained. Formal and informal care use was multiplied by country specific unit prices of services. Needs were measured using the CANE and health-related quality of life (HRQOL) of the person with dementia (both self- and proxy-rated) and informal caregiver's quality of life using EQ-5D-5L, ICECAP-O, DEMQOL-U, and CarerQol utility scores. The association between costs and country, European region, and unmet needs was assessed using multi-level linear regression. RESULTS: Self-rated EQ-5D-5L utility score was higher than proxy-rated (0.84 and 0.71, respectively). Informal caregivers' utility score was 0.84. Across eight countries annual mean costs of formal and informal care were approximately € 17,000. Unmet needs were not associated with annual costs of care, nor with proxy-rated HRQOL, but were associated with self-rated HRQOL. CONCLUSION: We found varying relationships between unmet needs and quality of life, and no association between unmet needs and care costs, although the results were sensitive to various factors. Future research should further investigate the relation between unmet needs, quality of life and costs to generate a better understanding of the effects of (un)timely access to care.

Quantifying the Diagnostic Pathway for Patients with Cognitive Impairment: Real-World Data from Seven European and North American Countries. - Ritchie, Craig W; Black, Christopher M; Khandker, Rezaul K; Wood, Robert; Jones, Eddie; Hu, Xiaohan; Ambegaonkar, Baishali M (J Alzheimers Dis, 2018)
To ensure that patients with dementia and their caregivers receive appropriate treatment and support, early diagnosis is essential but remains challenging. Real-world data from a multi-national, cross-sectional survey of physicians and their patients were analyzed to quantify the diagnostic pathway for dementia, including a focus on severity of patients' cognitive impairment (CI) at the time of symptom onset, referral and subsequent diagnosis. Data were collected for 7,620 patients with CI. Most patients saw a healthcare professional within 1 year of first symptoms and received a diagnosis within 3-7 months of initial consultation. However, only 20% of patients received a diagnosis before their disease progressed beyond the prodromal stage and 23.5% already had moderate CI at diagnosis. These findings show that the goal of identifying and diagnosing CI at the earliest stages of disease is, for many patients, not achieved. Efforts toward public awareness and proactive, earlier detection and intervention, must be maintained-indeed where possible invigorated.

Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers. - Ramos de Matos, Mafalda; Ferreira, Catarina; Herukka, Sanna-Kaisa; Soininen, Hilkka; Janeiro, André; Santana, Isabel; Baldeiras, Ines; Almeida, Maria Rosário; Lleo, Alberto; Dols-Icardo, Oriol; Alcolea, Daniel; Benussi, Luisa; et al. (J Alzheimers Dis, 2018)
Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

Rab10 Phosphorylation is a Prominent Pathological Feature in Alzheimer's Disease. - Yan, Tingxiang; Wang, Luwen; Gao, Ju; Siedlak, Sandra L; Huntley, Mikayla L; Termsarasab, Pichet; Perry, George; Chen, Shu G; Wang, Xinglong (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles (NFTs), senile plaques (SPs), and a progressive loss of neuronal cells in selective brain regions. Rab10, a small Rab GTPase involved in vesicular trafficking, has recently been identified as a novel protein associated with AD. Interestingly, Rab10 is a key substrate of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine protein kinase genetically associated with the second most common neurodegenerative disease Parkinson's disease. However, the phosphorylation state of Rab10 has not yet been investigated in AD. Here, using a specific antibody recognizing LRRK2-mediated Rab10 phosphorylation at the amino acid residue threonine 73 (pRab10-T73), we performed immunocytochemical analysis of pRab10-T73 in hippocampal tissues of patients with AD. pRab10-T73 was prominent in NFTs in neurons within the hippocampus in all cases of AD examined, whereas immunoreactivity was very faint in control cases. Other characteristic AD pathological structures including granulovacuolar degeneration, dystrophic neurites and neuropil threads also contained pRab10-T73. The pRab10-T73 immunoreactivity was diminished greatly following dephosphorylation with alkaline phosphatase. pRab10-T73 was further found to be highly co-localized with hyperphosphorylated tau (pTau) in AD, and demonstrated similar pathological patterns as pTau in Down syndrome and progressive supranuclear palsy. Although pRab10-T73 immunoreactivity could be noted in dystrophic neurites surrounding SPs, SPs were largely negative for pRab10-T73. These findings indicate that Rab10 phosphorylation could be responsible for aberrations in the vesicle trafficking observed in AD leading to neurodegeneration.

The Rationale and Design of the Reducing Pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR) Trial. - Kehoe, Patrick G; Blair, Peter S; Howden, Beth; Thomas, David L; Malone, Ian B; Horwood, Jeremy; Clement, Clare; Selman, Lucy E; Baber, Hannah; Lane, Athene; Coulthard, Elizabeth; Passmore, Anthony Peter; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Anti-hypertensives that modify the renin angiotensin system may reduce Alzheimer's disease (AD) pathology and reduce the rate of disease progression. OBJECTIVE: To conduct a phase II, two arm, double-blind, placebo-controlled, randomized trial of losartan to test the efficacy of Reducing pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR). METHODS: Men and women aged at least 55 years with mild-to-moderate AD will be randomly allocated 100 mg encapsulated generic losartan or placebo once daily for 12 months after successful completion of a 2-week open-label phase and 2-week placebo washout to establish drug tolerability. 228 participants will provide at least 182 subjects with final assessments to provide 84% power to detect a 25% difference in atrophy rate (therapeutic benefit) change over 12 months at an alpha level of 0.05. We will use intention-to-treat analysis, estimating between-group differences in outcomes derived from appropriate (linear or logistic) multivariable regression models adjusting for minimization variables. RESULTS: The primary outcome will be rate of whole brain atrophy as a surrogate measure of disease progression. Secondary outcomes will include changes to 1) white matter hyperintensity volume and cerebral blood flow; 2) performance on a standard series of assessments of memory, cognitive function, activities of daily living, and quality of life. Major assessments (for all outcomes) and relevant safety monitoring of blood pressure and bloods will be at baseline and 12 months. Additional cognitive assessment will also be conducted at 6 months along with safety blood pressure and blood monitoring. Monitoring of blood pressure, bloods, and self-reported side effects will occur during the open-label phase and during the majority of the post-randomization dispensing visits. CONCLUSION: This study will identify whether losartan is efficacious in the treatment of AD and whether definitive Phase III trials are warranted.
Keywords: Activities of Daily Living; Alzheimer Disease; Antihypertensive Agents; Atrophy; Blood Pressure Monitors; Brain; Clinical Trials, Phase II as Topic; Disease Progression; Double-Blind Method; Female; Humans; Losartan; Magnetic Resonance Imaging; Male; Multivariate Analysis; Quality of Life; Randomized Controlled Trials as Topic; Regression Analysis; Renin-Angiotensin System

Reduced Cerebrovascular Reserve Capacity as a Biomarker of Microangiopathy in Alzheimer's Disease and Mild Cognitive Impairment. - Urbanova, Barbora Soukupova; Schwabova, Jaroslava Paulasova; Magerova, Hana; Jansky, Petr; Marková, Hana; Vyhnálek, Martin; Laczó, Jan; Hort, Jakub; Tomek, Ales (J Alzheimers Dis, 2018)
BACKGROUND: Cerebral microangiopathy in Alzheimer's disease (AD) causes chronic hypoperfusion and probably accelerates neurodegenerative changes. OBJECTIVE: We hypothesize microvascular impairment could be present already in mild cognitive impairment (MCI) and can be revealed using transcranial color-coded sonography (TCCS) and the breath-holding maneuver. METHODS: Three groups of subjects (AD in the stage of dementia, MCI, and cognitively normal controls) with detailed neuropsychological testing and low cerebrovascular burden (no history of stroke, no intra- or extracranial artery stenoses, and no severe vascular lesions on brain MRI), underwent a TCCS assessment of peak systolic (PSV), mean flow (MFV), and end diastolic velocities (EDV) and resistance and pulsatility indices (RI, PI) in large intracranial vessels bilaterally. Cerebrovascular reserve capacity was assessed using the breath-holding index (BHI) in middle cerebral artery (MCA) bilaterally. The ultrasound parameters were compared between the groups, correlated with neuropsychological tests, and compared between amnestic and non-amnestic MCI subtypes. RESULTS: Fourteen AD (3 males, 67.9±11.1 years, MMSE 18.0±4.6), 24 MCI (13 males, 71.9±7.3 years, MMSE 28.0±1.6), and 24 risk factor-matched controls (14 males, 67.8±6.4 years, MMSE 29.1±1.2) were enrolled. Significant differences were found between AD and controls in MFV, EDV, RI, PI in right MCA after breath holding, in PSV, MFV, EDV in left MCA after breath holding, and in BHI on the left side. The left BHI correlated positively with verbal memory test. CONCLUSION: Results show decreased cerebrovascular reserve capacity in AD as a sign of impaired cerebral hemodynamic status without severe underlying atherosclerosis. This can be identified using TCCS and BHI.

Regional White Matter Hyperintensity Influences Grey Matter Atrophy in Mild Cognitive Impairment. - Vipin, Ashwati; Foo, Heidi Jing Ling; Lim, Joseph Kai Wei; Chander, Russell Jude; Yong, Ting Ting; Ng, Adeline Su Lyn; Hameed, Shahul; Ting, Simon Kang Seng; Zhou, Juan; Kandiah, Nagaendran (J Alzheimers Dis, 2018)
The association between cerebrovascular disease pathology (measured by white matter hyperintensities, WMH) and brain atrophy in early Alzheimer's disease (AD) remain to be elucidated. Thus, we investigated how WMH influence neurodegeneration and cognition in prodromal and clinical AD. We examined 51 healthy controls, 35 subjects with mild cognitive impairment (MCI), and 30 AD patients. We tested how total and regional WMH is related to specific grey matter volume (GMV) reductions in MCI and AD compared to controls. Stepwise regression analysis was further performed to investigate the association of GMV and regional WMH volume with global cognition. We found that total WMH volume was highest in AD but showed the strongest association with lower GMV in MCI. Frontal and parietal WMH had the most extensive influence on GMV loss in MCI. Additionally, parietal lobe WMH volume (but not hippocampal atrophy) was significantly associated with global cognition in MCI while smaller hippocampal volume (but not WMH volume) was associated with lower global cognition in AD. Thus, although WMH volume was highest in AD subjects, it had a more pervasive influence on brain structure and cognitive impairment in MCI. Our study thus highlights the importance of early detection of cerebrovascular disease, as its intervention at the MCI stage might potentially slow down neurodegeneration.

Relationship Between Amyloid-β Positivity and Progression to Mild Cognitive Impairment or Dementia over 8 Years in Cognitively Normal Older Adults. - Dang, Christa; Harrington, Karra D; Lim, Yen Ying; Ames, David; Hassenstab, Jason; Laws, Simon M; Yassi, Nawaf; Hickey, Martha; Rainey-Smith, Stephanie; Robertson, Joanne; Sohrabi, Hamid R; Salvado, Olivier; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Preclinical Alzheimer's disease (AD) is defined by cerebral amyloid-β positivity (Aβ+) in cognitively normal (CN) older adults. OBJECTIVE: To estimate the risk of progression to the symptomatic stages of AD due to PET Aβ+ and the extent that progression was influenced by other demographic, genetic, and clinical characteristics in a large prospective study. METHODS: Fine-Gray subdistribution modeling was used to examine the risk of progression from CN to MCI/dementia due to Aβ+, APOEɛ4 carriage, and their interaction in the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging CN cohort (n = 599) over 8 years. RESULTS: 17.7% Aβ+ and 8.1% Aβ-progressed over 8 years (OR: 2.43). Risk of progression for Aβ+ was 65-104% greater than Aβ-. Aβ+ APOEɛ4 carriers were at 348% greater risk than all other participants. Significant risk factors of progression in Aβ+ were age (HR: 1.05), PET SUVR (HR: 2.49) and APOE ɛ4 carriage (HR: 2.63); only age was a significant risk factor in Aβ-(HR: 1.09). Aβ-progressors were not near the threshold for Aβ+. These relationships were not moderated by hypertension, diabetes, obesity, or stroke/TIA. CONCLUSION: Aβ+ is an important prognostic marker for progression from CN to MCI/dementia in older adults and APOEɛ4 carriage provides further predictive value in the presence of Aβ+. These data suggest that Aβ-associated clinical progression is consistent with clinical-pathological models of AD, whereas progression in the absence of elevated Aβ deposition may be the result of neuropathological processes other than AD that accumulate with age.

Relationships between Cognition and Activities of Daily Living in Alzheimer's Disease During a 5-Year Follow-Up: ALSOVA Study. - Saari, Toni; Hallikainen, Ilona; Hänninen, Tuomo; Räty, Hannu; Koivisto, Anne (J Alzheimers Dis, 2018)
BACKGROUND: Impaired cognition and activities of daily living (ADL) are core symptoms of Alzheimer's disease (AD), but their relationship is unclear. OBJECTIVES: To explore relationships between cognitive domains and functional ability during 5-year follow-up in persons with AD. METHODS: We analyzed ALSOVA study data from 236 individuals with very mild or mild AD at baseline. The CERAD Neuropsychological Battery (CERAD-NB) was used as a cognitive measure and Alzheimer's Disease Cooperative Study ADL (ADCS-ADL) as a functional measure, analyzing the IADL and BADL sub-scores separately. Annual regression models and linear mixed-effect models (LMMs) covering a 5-year follow-up period were used. RESULTS: Annually, the CERAD-NB total and especially Verbal Fluency, Clock Drawing, and Constructional Praxis were associated with the total ADCS-ADL and IADL scores increasingly yet modestly, and to a lesser extent the BADL score. In the LMMs, the same measures and MMSE were associated with ADL. CONCLUSION: Measures of executive function and visuoconstructive skills appear to be associated with caregiver-interview based ADL measure during the progression of AD.

Relationships Between Lower Olfaction and Brain White Matter Lesions in Elderly Subjects with Mild Cognitive Impairment. - Heinrich, Juliette; Vidal, Jean-Sébastien; Simon, Axelle; Rigaud, Anne-Sophie; Hanon, Olivier; Epelbaum, Jacques; Viollet, Cécile; Duron, Emmanuelle (J Alzheimers Dis, 2018)
BACKGROUND: Olfactory impairment is reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD) and is associated with hippocampal atrophy. In elderly people, dementia with AD neuropathology and white matter lesions (WML) is common. In this context, olfactory impairment could also depend on the presence of WML. OBJECTIVE: To assess the cross-sectional relationship between olfaction and WML in elderly subjects with MCI. METHODS: Consecutive subjects, >65 years old, diagnosed as MCI after a comprehensive neuropsychological assessment in an expert memory center, with a brain MRI performed within a year and without major depressive state, were included. Olfaction was assessed by the Brief Smell Identification Test (BSIT). Two trained neuroradiologists, blind to cognitive and olfaction status, visually assessed hippocampal atrophy according to Scheltens' scale and WML according to Fazekas criteria. RESULTS: Seventy-five MCI subjects (mean age (SD) = 77.1 (6.2) years, 74.7% of women) were included. After adjustment for age and sex, factors associated with low BSIT scores were older age (p = 0.007), lower BMI (p = 0.08), lower MMSE score (p = 0.05), lower FCRST (p = 0.008), hippocampal atrophy (p = 0.04), periventricular WML (p = 0.007), and deep WML burden (p = 0.005). In multivariate analysis, severe deep WML (OR (95% CI) = 6.29 (1.4-35.13), p = 0.02) remained associated with low BSIT score independently from hippocampal atrophy. CONCLUSION: In elderly MCI subjects, low olfactory performances are associated with WML, whose progression may be slowed by vascular treatments. A longitudinal study to evaluate whether the progression of WML, hippocampal atrophy and low olfactory function, can predict accurately conversion from MCI to dementia is ongoing.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Atrophy; Cognitive Dysfunction; Cross-Sectional Studies; Disease Progression; Female; Humans; Logistic Models; Longitudinal Studies; Magnetic Resonance Imaging; Male; Multivariate Analysis; Neuropsychological Tests; Olfaction Disorders; Severity of Illness Index; White Matter

REM Sleep Behavior Disorder and Alzheimer's Disease: Definitely No Relationship? - Galbiati, Andrea; Carli, Giulia; Hensley, Michael; Ferini-Strambi, Luigi (J Alzheimers Dis, 2018)
Rapid eye movement (REM) sleep behavior disorder (RBD) is a REM sleep parasomnia characterized by the loss of the typical muscular atonia present during healthy REM sleep. RBD can occur in the absence of other neurological conditions or in association with a neurodegenerative disorder. It is now well established that RBD is a strong predictor of neurodegeneration, in particular synucleinopathies, such as Parkinson's disease, Lewy body dementia (LBD), or multiple system atrophy. However, some longitudinal studies report that a minority of patients develop either overlapping form of dementia or Alzheimer disease's (AD). Although AD is reported as a possible development in patients with RBD, it is in a limited number of cases and there are concerns about the accuracy of the diagnostic criteria. Neuropsychological impairments identified in cross-sectional studies of RBD patients describe a profile similar to that observed in dementia related to synucleinopathies. However, only deficits in executive function predict the development of neurodegeneration. Longitudinal studies reported the development of AD in RBD patients in about 7% of cases with variability ranging from 3% and 11%. Since the majority of longitudinal investigations do not report AD as a possible development for RBD patients the proportion may be overestimated. The study of the relationship between RBD and AD may be confounded by two factors that lead to misdiagnosis: the use of clinical criteria alone and the overlap between the clinical features and neuropathology of AD and LBD. Future studies to investigate this association must use updated diagnostic criteria incorporating ancillary investigations.

Retinoic Acid Enhances Apolipoprotein E Synthesis in Human Macrophages. - Clemens, Vera; Regen, Francesca; Le Bret, Nathalie; Heuser, Isabella; Hellmann-Regen, Julian (J Alzheimers Dis, 2018)
Apolipoprotein E (ApoE) represents a pivotal target in Alzheimer's disease (AD) and is modulated through retinoic acid (RA), an endogenous neuroprotective and anti-inflammatory compound. A major source of ApoE are microglia, which are pathologically activated in AD. Activated microglia are known to block RA signaling. This suggests a vicious cycle between inflammation, RA signaling, and ApoE homeostasis in AD pathogenesis. To test this hypothesis, we investigated effects of RA and proinflammatory activation on ApoE synthesis in primary human macrophage-derived microglial-like cells. Our results indicate that proinflammatory activation attenuates ApoE synthesis, an effect blocked by RA.
Keywords: Alzheimer Disease; Apolipoproteins E; Cells, Cultured; Humans; Macrophages; Signal Transduction; Tretinoin

A Retrospective Belgian Multi-Center MRI Biomarker Study in Alzheimer's Disease (REMEMBER). - Niemantsverdriet, Ellis; Ribbens, Annemie; Bastin, Christine; Benoit, Florence; Bergmans, Bruno; Bier, Jean-Christophe; Bladt, Roxanne; Claes, Lene; De Deyn, Peter Paul; Deryck, Olivier; Hanseeuw, Bernard; Ivanoiu, Adrian; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Magnetic resonance imaging (MRI) acquisition/processing techniques assess brain volumes to explore neurodegeneration in Alzheimer's disease (AD). OBJECTIVE: We examined the clinical utility of MSmetrix and investigated if automated MRI volumes could discriminate between groups covering the AD continuum and could be used as a predictor for clinical progression. METHODS: The Belgian Dementia Council initiated a retrospective, multi-center study and analyzed whole brain (WB), grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), cortical GM (CGM) volumes, and WM hyperintensities (WMH) using MSmetrix in the AD continuum. Baseline (n = 887) and follow-up (FU, n = 95) T1-weighted brain MRIs and time-linked neuropsychological data were available. RESULTS: The cohort consisted of cognitively healthy controls (HC, n = 93), subjective cognitive decline (n = 102), mild cognitive impairment (MCI, n = 379), and AD dementia (n = 313). Baseline WB and GM volumes could accurately discriminate between clinical diagnostic groups and were significantly decreased with increasing cognitive impairment. MCI patients had a significantly larger change in WB, GM, and CGM volumes based on two MRIs (n = 95) compared to HC (FU>24months, p = 0.020). Linear regression models showed that baseline atrophy of WB, GM, CGM, and increased CSF volumes predicted cognitive impairment. CONCLUSION: WB and GM volumes extracted by MSmetrix could be used to define the clinical spectrum of AD accurately and along with CGM, they are able to predict cognitive impairment based on (decline in) MMSE scores. Therefore, MSmetrix can support clinicians in their diagnostic decisions, is able to detect clinical disease progression, and is of help to stratify populations for clinical trials.

Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology. - Hampel, Harald; Toschi, Nicola; Babiloni, Claudio; Baldacci, Filippo; Black, Keith L; Bokde, Arun L W; Bun, René S; Cacciola, Francesco; Cavedo, Enrica; Chiesa, Patrizia A; Colliot, Olivier; Coman, Cristina-Maria; et al. (J Alzheimers Dis, 2018)
The Precision Neurology development process implements systems theory with system biology and neurophysiology in a parallel, bidirectional research path: a combined hypothesis-driven investigation of systems dysfunction within distinct molecular, cellular, and large-scale neural network systems in both animal models as well as through tests for the usefulness of these candidate dynamic systems biomarkers in different diseases and subgroups at different stages of pathophysiological progression. This translational research path is paralleled by an "omics"-based, hypothesis-free, exploratory research pathway, which will collect multimodal data from progressing asymptomatic, preclinical, and clinical neurodegenerative disease (ND) populations, within the wide continuous biological and clinical spectrum of ND, applying high-throughput and high-content technologies combined with powerful computational and statistical modeling tools, aimed at identifying novel dysfunctional systems and predictive marker signatures associated with ND. The goals are to identify common biological denominators or differentiating classifiers across the continuum of ND during detectable stages of pathophysiological progression, characterize systems-based intermediate endophenotypes, validate multi-modal novel diagnostic systems biomarkers, and advance clinical intervention trial designs by utilizing systems-based intermediate endophenotypes and candidate surrogate markers. Achieving these goals is key to the ultimate development of early and effective individualized treatment of ND, such as Alzheimer's disease. The Alzheimer Precision Medicine Initiative (APMI) and cohort program (APMI-CP), as well as the Paris based core of the Sorbonne University Clinical Research Group "Alzheimer Precision Medicine" (GRC-APM) were recently launched to facilitate the passageway from conventional clinical diagnostic and drug development toward breakthrough innovation based on the investigation of the comprehensive biological nature of aging individuals. The APMI movement is gaining momentum to systematically apply both systems neurophysiology and systems biology in exploratory translational neuroscience research on ND.
Keywords: Alzheimer Disease; Animals; Brain; Humans; Neurology; Neurophysiology; Precision Medicine; Systems Biology; Translational Medical Research

Risk Factors Associated with Cortical Thickness and White Matter Hyperintensities in Dementia Free Okinawan Elderly. - Silbert, Lisa C; Lahna, David; Promjunyakul, Nutta-On; Boespflug, Erin; Ohya, Yusuke; Higashiuesato, Yasushi; Nishihira, Junko; Katsumata, Yuriko; Tokashiki, Takashi; Dodge, Hiroko H (J Alzheimers Dis, 2018)
BACKGROUND: Cortical gray matter (GM) and white matter (WM) deterioration are signals of neurodegeneration and increased dementia risk; however, their specific etiologies in dementia-free aging is unclear. OBJECTIVE: The objective of this study was to examine potentially modifiable risk factors of GM and WM degeneration in a well-characterized cohort of dementia-free elderly. METHODS: 96 Okinawan elderly participants (age 83.6) from the Keys to Optimal Cognitive Aging Project (KOCOA) underwent MRI and cognitive evaluation. Serum markers of inflammation (interleukin-6 (IL-6), high sensitivity C-reactive protein), cerebrovascular disease (systolic blood pressure (SBP) 140+, hemoglobin A1C (HgbA1C), total cholesterol), and essential minerals (copper (Cu), magnesium, and calcium) were examined in relation to mean cortical thickness (MCT) and white matter hyperintensities (WMH), adjusting for age and gender. Voxel-based morphometry (VBM) analyses identified relationships between regional GM density and the above markers. RESULTS: Decreased MCT was associated with SBP 140 + (p = 0.029) and increased serum IL-6 (p = 0.036), HgbA1C (p = 0.002), and Cu (p = 0.025). In VBM analyses, increased IL-6, HgbA1C, and Cu were associated with decreased GM density in temporal lobe regions. HgbA1C (p = 0.004) was associated with greater WMH volume. CONCLUSIONS: Peripheral markers of Cu, CVD risk, and inflammation are associated with MRI-markers of decreased brain health in dementia-free Okinawan elderly, with regional cortical thinning in areas involved in early accumulation of Alzheimer's disease pathology. Results identify potentially modifiable biomarkers as targets in the prevention of dementia in older individuals.

Risk of Alzheimer's Disease in Obstructive Sleep Apnea Syndrome: Amyloid-β and Tau Imaging. - Elias, Alby; Cummins, Tia; Tyrrell, Regan; Lamb, Fiona; Doré, Vincent; Williams, Robert; Rosenfeld, J V; Hopwood, Malcolm; Villemagne, Victor L; Rowe, Christopher C (J Alzheimers Dis, 2018)
BACKGROUND: An association between obstructive sleep apnea (OSA) and Alzheimer's disease has been suggested but little is known about amyloid-β and tau deposition in this syndrome. OBJECTIVE: To determine amyloid and tau burden and cognitive function in OSA in comparison with those without a diagnosis of OSA. METHODS: The status of OSA was determined by asking participants about history of polysomnographic diagnosis of OSA and the use of Continuous Positive Airway Pressure (CPAP). A comprehensive neuropsychological battery measured cognitive function. Positron emission tomography (PET) was used to measure standardized uptake value ratio (SUVR) of 18F-florbetaben and 18F-AV1451, to quantify amyloid and tau burden. RESULTS: 119 male Vietnam veterans completed assessment. Impairment in visual attention and processing speed and increased body mass index (BMI) were seen in subjects with OSA compared with those without a diagnosis OSA. The cortical uptake of 18F-florbetaben was higher in the OSA group than in the control group (SUVR: 1.35±0.21 versus 1.27±0.16, p = 0.04). There were more apolipoprotein E ɛ4 allele (APOE ɛ4) carriers in the OSA group than in the control group. In multilinear regression analysis, the significance of OSA in predicting 18F-florbetaben uptake remained independent of age and vascular risk factors but not when BMI or APOE ɛ4 was adjusted. The reported use of CPAP (n = 14) had no effect on cognitive or amyloid PET findings. There was no significant difference in 18F-AV1451 uptake between the two groups. CONCLUSIONS: Obstructive sleep apnea is associated with Alzheimer's disease pathology, but this relationship is moderated by APOE ɛ4 and BMI.

Risk of Conversion to Dementia in a Mild Behavioral Impairment Group Compared to a Psychiatric Group and to a Mild Cognitive Impairment Group. - Taragano, Fernando E; Allegri, Ricardo F; Heisecke, Silvina L; Martelli, María I; Feldman, Mónica L; Sánchez, Viviana; García, Virginia A; Tufro, Graciela; Castro, Diego M; Leguizamón, Patricio Perez; Guelar, Verónica; Ruotolo, Eva; et al. (J Alzheimers Dis, 2018)
BACKGROUND: There is insufficient available information on behavioral changes in the absence of cognitive impairment as factors increasing the risk of conversion to dementia. OBJECTIVE: To observe and analyze patients with mild behavioral impairment (MBI), mild cognitive impairment (MCI), and a psychiatry group (PG) to compare the risk of progression to dementia. METHODS: From 677 initially assessed ≥60-year-old patients, a series of 348 patients was studied for a five-year period until censoring or conversion to dementia: 96 with MBI, 87 with MCI, and 165 with general psychiatry disorders, including 4 subgroups: Anxiety, Depression, Psychosis and Others. All patients were assessed with clinical, psychiatric, neurological, neuropsychological, and neuroimaging studies. RESULTS: From 348 patients, 126 evolved to dementia (36.2%). Conversion was significantly higher in MBI (71.5%), followed by the MCI-MBI overlap (59.6%) and MCI (37.8%) groups, compared to PG (13.9%) (Log-rank p < 0.001). MCI patients mostly converted to Alzheimer's dementia, while MBI converted to frontotemporal dementia and Lewy body dementia. Patients in PG converted to Lewy body dementia and frontotemporal dementia. CONCLUSION: Conversion to dementia is significantly higher in patients with neuropsychiatric symptoms. The MBI concept generates a new milestone in the refining of diagnosis of neurodegenerative diseases and the possibility of creating neuropsychiatric profiles. Its earlier identification will allow new possibilities for therapeutic intervention.

Role of Amyloid-β and Tau Proteins in Alzheimer's Disease: Confuting the Amyloid Cascade. - Gulisano, Walter; Maugeri, Daniele; Baltrons, Marian A; Fà, Mauro; Amato, Arianna; Palmeri, Agostino; D'Adamio, Luciano; Grassi, Claudio; Devanand, D P; Honig, Lawrence S; Puzzo, Daniela; Arancio, Ottavio (J Alzheimers Dis, 2018)
The "Amyloid Cascade Hypothesis" has dominated the Alzheimer's disease (AD) field in the last 25 years. It posits that the increase of amyloid-β (Aβ) is the key event in AD that triggers tau pathology followed by neuronal death and eventually, the disease. However, therapeutic approaches aimed at decreasing Aβ levels have so far failed, and tau-based clinical trials have not yet produced positive findings. This begs the question of whether the hypothesis is correct. Here we have examined literature on the role of Aβ and tau in synaptic dysfunction, memory loss, and seeding and spreading of AD, highlighting important parallelisms between the two proteins in all of these phenomena. We discuss novel findings showing binding of both Aβ and tau oligomers to amyloid-β protein precursor (AβPP), and the requirement for the presence of this protein for both Aβ and tau to enter neurons and induce abnormal synaptic function and memory. Most importantly, we propose a novel view of AD pathogenesis in which extracellular oligomers of Aβ and tau act in parallel and upstream of AβPP. Such a view will call for a reconsideration of therapeutic approaches directed against Aβ and tau, paving the way to an increased interest toward AβPP, both for understanding the pathogenesis of the disease and elaborating new therapeutic strategies.

Role of ASK1/p38 Cascade in a Mouse Model of Alzheimer's Disease and Brain Aging. - Hasegawa, Yu; Toyama, Kensuke; Uekawa, Ken; Ichijo, Hidenori; Kim-Mitsuyama, Shokei (J Alzheimers Dis, 2018)
To examine the role of ASK1 in Alzheimer's disease (AD), we generated 5XFAD mice deficient in ASK1 and investigated the characteristics of old 5XFAD and wild-type mice with ASK1 deficiency. ASK1 deficiency improved cognitive function in 24-month-old 5XFAD mice, which was associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade seems to play some role in the pathogenesis of AD in mice. In 24-month-old wild-type mice, ASK1 deficiency increased cerebral vasoreactivity to acetazolamide and significantly reduced brain soluble Aβ, which were also associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade may contribute to brain aging of wild-type mice. Collectively, our present results provided the evidence suggesting the involvement of ASK1/p38 cascade in AD and brain aging.
Keywords: Aging; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Avoidance Learning; Disease Models, Animal; Gene Expression Regulation; MAP Kinase Kinase Kinase 5; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Transgenic; Presenilin-1; Reaction Time

Role of the Glyoxalase System in Alzheimer's Disease. - Jiang, Lianying; Wang, Jiafeng; Wang, Zhigang; Huang, Wenhui; Yang, Yixia; Cai, Zhiyou; Li, Keshen (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disease. The main pathological features of AD are the formation of amyloid-β deposits in the anterior cerebral cortex and hippocampus as well as the formation of intracellular neurofibrillary tangles. Thus far, accumulating evidence shows that glycation is closely related to AD. As a final product resulting from the crosslinking of a reducing sugar or other reactive carbonyls and a protein, the advanced glycation end products have been found to be associated with the formation of amyloid-β and neurofibrillary tangles in AD. As a saccharification inhibitor, the glyoxalase system and its substrate methylglyoxal (MG) were certified to be associated with AD onset and development. As an active substance of AGEs, MG could cause direct or indirect damage to nerve cells and tissues. MG is converted to D-lactic acid after decomposition by the glyoxalase system. Under normal circumstances, MG metabolism is in a dynamic equilibrium, whereas MG accumulates in cells in the case of aging or pathological states. Studies have shown that increasing glyoxalase activity and reducing the MG level can inhibit the generation of oxidative stress and AGEs, thereby alleviating the symptoms and signs of AD to some extent. This paper focuses on the relevant mechanisms of action of the glyoxalase system and MG in the pathogenesis of AD, as well as the potential of inhibiting the production of advanced glycation end products in the treatment of AD.

The Role of the Gut Microbiota in the Metabolism of Polyphenols as Characterized by Gnotobiotic Mice. - Pasinetti, Giulio Maria; Singh, Risham; Westfall, Susan; Herman, Francis; Faith, Jeremiah; Ho, Lap (J Alzheimers Dis, 2018)
A growing body of experimental data suggests that microbes in the gut influence behavior and can alter brain physiology and neurochemistry. Although promising, researchers are only starting to understand the potential of the gut microbiota for use in neurological disease. Recent evidence demonstrated that gastrointestinal activities are linked to mood disorders such as anxiety, depression, and most recently, cognitive functions in age-related neurodegenerative disorders. Studies from our group and others are uncovering new evidence suggesting that the gut microbiota plays a crucial role in the metabolism and bioavailability of certain dietary compounds and synthetic drugs. Based on this evidence, this review article will discuss the implications of the gut microbiota in mechanisms of bioavailability and biotransformation with an emphasis on dietary polyphenol compounds. This will be followed by a survey of ongoing innovative research identifying the ability of individual gut bacteria to enhance the bioavailability of gut-derived, brain-penetrating, bioactive polyphenol metabolites that ultimately influence mechanisms associated with the promotion of resilience against psychological and cognitive impairment in response to stress. Lastly, current research initiatives aimed at promoting the generation of brain bioactive polyphenol metabolites by specialized gut microbes will be discussed, specifically the use of gnotobiotic mice to develop bioengineered second generation probiotics. We propose that leveraging the gut microbial ecosystem to generate brain targeted bioactive metabolites from dietary polyphenols can attenuate lifestyle risk factors and promote resilience against age-related cognitive decline.

The Role of Verb Fluency in the Detection of Early Cognitive Impairment in Alzheimer's Disease. - Alegret, Montserrat; Peretó, Mar; Pérez, Alba; Valero, Sergi; Espinosa, Ana; Ortega, Gemma; Hernandez, Isabel; Mauleón, Ana; Rosende-Roca, Maitee; Vargas, Liliana; Rodríguez-Gómez, Octavio; Abdelnour, Carla; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Verb fluency (VF) is the less commonly used fluency test, despite several studies suggesting its potential as a neuropsychological assessment tool. OBJECTIVE: To investigate the presence of VF deficits in mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) dementia; to assess the usefulness of VF in the detection of cognitively healthy (CH) people who will convert to MCI, and from MCI to dementia; and to establish the VF cut-offs useful in the cognitive assessment of Spanish population. METHODS: 568 CH, 885 MCI, and 367 mild AD dementia individuals were administered the VF test and a complete neuropsychological battery. Longitudinal analyses were performed in 231 CH and 667 MCI subjects to search for VF predictors of diagnosis conversion. RESULTS: A worsening on VF performance from CH, MCI to AD dementia groups was found. Lower performances on VF were significantly related to conversion from CH to MCI/MCI to dementia. When the effect of time to conversion was analyzed, a significant effect of VF was found on the faster conversion from CH to MCI, but not from MCI to dementia. Moreover, VF cut-off scores and sensitivity/specificity values were calculated for 6 conditions (3 age ranges by 2 educational levels). CONCLUSION: The VF test may be a useful tool for the differential diagnosis of cognitive failure in the elderly. Since VF deficits seem to take place in early stages of the disease, it is a suitable neuropsychological tool for the detection not only of CH people who will convert to MCI, but also from MCI to dementia.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cognitive Dysfunction; Cross-Sectional Studies; Early Diagnosis; Executive Function; Female; Humans; Language Tests; Logistic Models; Longitudinal Studies; Male; Middle Aged; Proportional Hazards Models; Sensitivity and Specificity; Spain

Roles of Mitochondrial 17β-Hydroxysteroid Dehydrogenase Type 10 in Alzheimer's Disease. - He, Xue-Ying; Isaacs, Charles; Yang, Song-Yu (J Alzheimers Dis, 2018)
17β-Hydroxysteroid dehydrogenase type 10 is a multifunctional, homotetrameric, mitochondrial protein encoded by the HSD17B10 gene at Xp 11.2. This protein, 17β-HSD10, is overexpressed in brain cells of Alzheimer's disease (AD) patients. It was reported to be involved in AD pathogenesis as the endoplasmic reticulum-associated amyloid-β binding protein (ERAB) and as amyloid-β binding alcohol dehydrogenase (ABAD). However, the exaggerated catalytic efficiencies for ERAB/ABAD in these reports necessitated the re-characterization of the catalytic functions of this brain enzyme. In addition to isoleucine metabolism, 17β-HSD10 is also responsible for the mitochondrial metabolism of neurosteroids such as 5α-androstane-3α,17β-diol and 17β-estradiol. These neurosteroids are inactivated by the oxidation catalyzed by 17β-HSD10. Since neurosteroid homeostasis is presumably essential for cognitive function, analysis of the impact of 17β-HSD10 and its inhibitor, amyloid-β peptide (Aβ), on the metabolism of neuroactive steroids offers a new approach to AD pathogenesis.
Keywords: 3-Hydroxyacyl CoA Dehydrogenases; Alzheimer Disease; Amyloid beta-Peptides; Brain; Endoplasmic Reticulum; Humans; Mitochondria; Neurotransmitter Agents; Oxidation-Reduction

S-[18F]THK-5117-PET and [11C]PIB-PET Imaging in Idiopathic Normal Pressure Hydrocephalus in Relation to Confirmed Amyloid-β Plaques and Tau in Brain Biopsies. - Leinonen, Ville; Rauramaa, Tuomas; Johansson, Jarkko; Bottelbergs, Astrid; Tesseur, Ina; van der Ark, Peter; Pemberton, Darrel; Koivisto, Anne M; Jääskeläinen, Juha E; Hiltunen, Mikko; Herukka, Sanna-Kaisa; Blennow, Kaj; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Detection of pathological tau aggregates could facilitate clinical diagnosis of Alzheimer's disease (AD) and monitor drug effects in clinical trials. S-[18F]THK-5117 could be a potential tracer to detect pathological tau deposits in brain. However, no previous study have correlated S-[18F]THK-5117 uptake in PET with brain biopsy verified tau pathology in vivo. OBJECTIVE: Here we aim to evaluate the association between cerebrospinal fluid (CSF) AD biomarkers, S-[18F]THK-5117, and [11C]PIB PET against tau and amyloid lesions in brain biopsy. METHODS: Fourteen patients with idiopathic normal pressure hydrocephalus (iNPH) with previous shunt surgery including right frontal cortical brain biopsy and CSF Aβ1 - 42, total tau, and P-tau181 measures, underwent brain MRI, [11C]PIB PET, and S-[18F]THK-5117 PET imaging. RESULTS: Seven patients had amyloid-β (Aβ, 4G8) plaques, two both Aβ and phosphorylated tau (Pτ, AT8) and one only Pτ in biopsy. As expected, increased brain biopsy Aβ was well associated with higher [11C]PIB uptake in PET. However, S-[18F]THK-5117 uptake did not show any statistically significant correlation with either brain biopsy Pτ or CSF P-tau181 or total tau. CONCLUSIONS: S-[18F]THK-5117 lacked clear association with neuropathologically verified tau pathology in brain biopsy probably, at least partially, due to off-target binding. Further studies with larger samples of patients with different tau tracers are urgently needed. The detection of simultaneous Aβ and tau pathology in iNPH is important since that may indicate poorer and especially shorter response for CSF shunt surgery compared with no pathology.

Sally-Anne Test in Patients with Alzheimer's Disease Dementia. - Takenoshita, Shintaro; Terada, Seishi; Yokota, Osamu; Kutoku, Yumiko; Wakutani, Yosuke; Nakashima, Makoto; Maki, Yohko; Hattori, Hideyuki; Yamada, Norihito (J Alzheimers Dis, 2018)
Social cognition has recently been recognized as one of the essential cognitive domains. Some reports suggested that patients with Alzheimer's disease dementia (ADD) presented significant theory of mind deficits even in the mild condition. However, most previous studies included only small numbers of patients with ADD. The present study administered the first-order false belief (Sally-Anne) test to 116 consecutive patients with ADD from the outpatient units of the Memory Clinic and compared the characteristics of the two groups with correct and incorrect answers on the test. Then various clinical characteristics were evaluated. Only 37.1% of patients with ADD correctly answered the Sally-Anne test with the right explanation. Comparison between the two groups of correct and incorrect answers revealed a significant association between the frontal assessment battery score and the result of the Sally-Anne test in the multiple logistic regression analyses. Thus, patients with ADD presented a significant deficit in social cognition even in the mild condition. Frontal dysfunction was thought to be related to the deficits in mild ADD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cognition Disorders; Disease Progression; Female; Humans; Logistic Models; Male; Neuropsychological Tests; Social Behavior Disorders; Theory of Mind

Self- and Informant-Reported Memory Complaints: Frequency and Severity in Cognitively Intact Individuals and those with Mild Cognitive Impairment and Neurodegenerative Dementias. - Rahman-Filipiak, Annalise M; Giordani, Bruno; Heidebrink, Judith; Bhaumik, Arijit; Hampstead, Benjamin M (J Alzheimers Dis, 2018)
BACKGROUND: Subjective memory complaints (SMCs) are incorporated into the diagnosis of mild cognitive impairment (MCI) and neurodegenerative dementias; however, the relative frequency of SMCs in cognitively intact older adults and those with different types of dementia is poorly understood. Similarly, the concordance between self- versus informant-reported SMCs has not been compared across different diagnostic groups. OBJECTIVE: This study aimed to evaluate the frequency of self-reported (Objective 1) and informant-reported (Objective 2) SMCs in cognitively intact adults or those diagnosed with MCI or a neurodegenerative dementia. Agreement between participant and informant complaints was also evaluated (Objective 3). METHODS: Baseline evaluation data were drawn from 488 participants (Mage = 70.49 years; Medu = 15.62 years) diagnosed as cognitively intact, non-amnestic MCI, amnestic single domain MCI, amnestic multi-domain MCI, possible/probable Alzheimer's disease, dementia with Lewy bodies, or frontotemporal dementia. Participants and their informants completed the Memory Assessment Clinic Questionnaire. RESULTS: One-way ANCOVAs controlling for age, education, and depression revealed no group differences in severity of self-reported SMCs. In contrast, informant memory ratings followed the expected clinical pattern, with comparable and most impaired ratings given to participants with any dementia diagnosis, followed by those with any MCI diagnosis, followed by cognitively intact participants. There was inconsistent agreement between self- and informant-reported SMC ratings in any of the impaired groups. CONCLUSIONS: Given greater diagnostic specificity and internal consistency of informant report, clinicians should weigh this information more heavily than self-report in the diagnostic process.

Separating Symptomatic Alzheimer's Disease from Depression based on Structural MRI. - Klöppel, Stefan; Kotschi, Maria; Peter, Jessica; Egger, Karl; Hausner, Lucrezia; Frölich, Lutz; Förster, Alex; Heimbach, Bernhard; Normann, Claus; Vach, Werner; Urbach, Horst; Abdulkadir, Ahmed (J Alzheimers Dis, 2018)
Older patients with depression or Alzheimer's disease (AD) at the stage of early dementia or mild cognitive impairment may present with objective cognitive impairment, although the pathology and thus therapy and prognosis differ substantially. In this study, we assessed the potential of an automated algorithm to categorize a test set of 65 T1-weighted structural magnetic resonance images (MRI). A convenience sample of elderly individuals fulfilling clinical criteria of either AD (n = 28) or moderate and severe depression (n = 37) was recruited from different settings to assess the potential of the pattern recognition method to assist in the differential diagnosis of AD versus depression. We found that our algorithm learned discriminative patterns in the subject's grey matter distribution reflected by an area under the receiver operator characteristics curve of up to 0.83 (confidence interval ranged from 0.67 to 0.92) and a balanced accuracy of 0.79 for the separation of depression from AD, evaluated by leave-one-out cross validation. The algorithm also identified consistent structural differences in a clinically more relevant scenario where the data used during training were independent from the data used for evaluation and, critically, which included five possible diagnoses (specifically AD, frontotemporal dementia, Lewy body dementia, depression, and healthy aging). While the output was insufficiently accurate to use it directly as a means for classification when multiple classes are possible, the continuous output computed by the machine learning algorithm differed between the two groups that were investigated. The automated analysis thus could complement, but not replace clinical assessments.

Severe Agitation in Dementia: An Explorative Secondary Data Analysis on the Prevalence and Associated Factors in Nursing Home Residents. - Palm, Rebecca; Sorg, Christian G G; Ströbel, Armin; Gerritsen, Debby L; Holle, Bernhard (J Alzheimers Dis, 2018)
BACKGROUND: The phenomena of severe agitation is not well understood and often not adequately treated. OBJECTIVE: This article determines the prevalence and associated factors of severe agitation in nursing home residents with dementia. METHODS: Secondary data analysis within an observational study in German nursing homes with n = 1,967 participants. We assessed severity of agitation with the Neuropsychiatric Inventory Questionnaire (NPI-Q) and defined the construct of agitation as a composite score of the NPI-Q items agitation/aggression, disinhibition, and irritability/lability; the dependent variable of severe agitation was considered as being present in residents who scored 'severe' in at least one of these symptoms. A binary logistic regression model was calculated to estimate associations. RESULTS: The prevalence of severe agitation was 6.3% (n = 124). The strongest associations were found for elation/euphoria (OR 7.6, CI 3.1-18.5), delusions (OR 7.3, CI 4.0-13.2), apathy/indifference (OR 2.8, CI 1.7-4.7), anxiety (OR 2.2, CI 1.2-3.8), nighttime behaviors (OR 2.4, CI 1.4-4.2), motor disturbances (OR 2.4, CI 1.4-4.1), and male sex (OR 2.4. CI 1.3-4.2). CONCLUSION: Severe agitation in nursing home residents with dementia is a relevant clinical issue as approximately 70% of residents have a dementia. Residents with elation/euphoria and delusions may have a stronger risk of showing severe agitation. We consider delusions as a possible cause of agitation and therefore a prelude to agitation. Although it might be possible that elation/euphoria follows from agitation, we hypothesize that the residents first experience elation/ euphoria and exhibit agitation afterwards.

Single Subject Classification of Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia Using Anatomical, Diffusion Tensor, and Resting-State Functional Magnetic Resonance Imaging. - Bouts, Mark J R J; Möller, Christiane; Hafkemeijer, Anne; van Swieten, John C; Dopper, Elise; van der Flier, Wiesje M; Vrenken, Hugo; Wink, Alle Meije; Pijnenburg, Yolande A L; Scheltens, Philip; Barkhof, Frederik; Schouten, Tijn M; et al. (J Alzheimers Dis, 2018)
BACKGROUND/OBJECTIVE: Overlapping clinical symptoms often complicate differential diagnosis between patients with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Magnetic resonance imaging (MRI) reveals disease specific structural and functional differences that aid in differentiating AD from bvFTD patients. However, the benefit of combining structural and functional connectivity measures to-on a subject-basis-differentiate these dementia-types is not yet known. METHODS: Anatomical, diffusion tensor (DTI), and resting-state functional MRI (rs-fMRI) of 30 patients with early stage AD, 23 with bvFTD, and 35 control subjects were collected and used to calculate measures of structural and functional tissue status. All measures were used separately or selectively combined as predictors for training an elastic net regression classifier. Each classifier's ability to accurately distinguish dementia-types was quantified by calculating the area under the receiver operating characteristic curves (AUC). RESULTS: Highest AUC values for AD and bvFTD discrimination were obtained when mean diffusivity, full correlations between rs-fMRI-derived independent components, and fractional anisotropy (FA) were combined (0.811). Similarly, combining gray matter density (GMD), FA, and rs-fMRI correlations resulted in highest AUC of 0.922 for control and bvFTD classifications. This, however, was not observed for control and AD differentiations. Classifications with GMD (0.940) and a GMD and DTI combination (0.941) resulted in similar AUC values (p = 0.41). CONCLUSION: Combining functional and structural connectivity measures improve dementia-type differentiations and may contribute to more accurate and substantiated differential diagnosis of AD and bvFTD patients. Imaging protocols for differential diagnosis may benefit from also including DTI and rs-fMRI.

A Small Molecule Inhibitor of Plasminogen Activator Inhibitor-1 Reduces Brain Amyloid-β Load and Improves Memory in an Animal Model of Alzheimer's Disease. - Akhter, Hasina; Huang, Wen-Tan; van Groen, Thomas; Kuo, Hui-Chien; Miyata, Toshio; Liu, Rui-Ming (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is a major cause of dementia in the elderly with no effective treatment. Accumulation of amyloid-β peptide (Aβ) in the brain is a pathological hallmark of AD and is believed to be a central disease-causing and disease-promoting event. In a previous study, we showed that deletion of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue type and urokinase type plasminogen activators (tPA and uPA), significantly reduced brain Aβ load in APP/PS1 mice, an animal model of familial AD. In this study, we further show that oral administration of TM5275, a small molecule inhibitor of PAI-1, for a period of 6 weeks, inhibits the activity of PAI-1 and increases the activities of tPA and uPA as well as plasmin, which is associated with a reduction of Aβ load in the hippocampus and cortex and improvement of learning/memory function in APP/PS1 mice. Protein abundance of low density lipoprotein related protein-1 (LRP-1), a multi ligand endocytotic receptor involved in transporting Aβ out of the brain, as well as plasma Aβ42 are increased, whereas the expression and processing of full-length amyloid-β protein precursor is not affected by TM5275 treatment in APP/PS1 mice. In vitro studies further show that PAI-1 increases, whereas TM5275 reduces, Aβ40 level in the culture medium of SHSY5Y-APP neuroblastoma cells. Collectively, our data suggest that TM5275 improves memory function of APP/PS1 mice, probably by reducing brain Aβ accumulation through increasing plasmin-mediated degradation and LRP-1-mediated efflux of Aβ in the brain.

Stabilized Low-n Amyloid-β Oligomers Induce Robust Novel Object Recognition Deficits Associated with Inflammatory, Synaptic, and GABAergic Dysfunction in the Rat. - Watremez, William; Jackson, Joshua; Almari, Bushra; McLean, Samantha L; Grayson, Ben; Neill, Joanna C; Fischer, Nicolas; Allouche, Ahmad; Koziel, Violette; Pillot, Thierry; Harte, Michael K (J Alzheimers Dis, 2018)
BACKGROUND: With current treatments for Alzheimer's disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-β oligomers (Aβo). These small soluble Aβo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies. OBJECTIVE: The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-β1-42 oligomers (Aβo1-42) on cognitive, inflammatory, synaptic, and neuronal markers in the rat. METHODS: Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Aβo1-42 (10μL). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1β, IL-6, TNF-α), synaptic (PSD-95, SNAP-25), and neuronal (n-acetylaspartate, parvalbumin-positive cells) markers were investigated in different brain regions (prefrontal and frontal cortex, striatum, dorsal and ventral hippocampus). RESULTS: Acute ICV administration of Aβo1-42 induced robust and enduring NOR deficits. These deficits were reversed by acute administration of donepezil and rolipram but not risperidone. Postmortem analysis revealed an increase in inflammatory markers, a decrease in synaptic markers and parvalbumin containing interneurons in the frontal cortex, with no evidence of widespread neuronal loss. CONCLUSION: Taken together the results suggest that acute administration of soluble low-n Aβo may be a useful model to study the early mechanisms involved in AD and provide us with a platform for testing novel therapeutic approaches that target the early underlying synaptic pathology.

Structural Anatomical Investigation of Long-Term Memory Deficit in Behavioral Frontotemporal Dementia. - Bertoux, Maxime; Flanagan, Emma C; Hobbs, Matthew; Ruiz-Tagle, Amparo; Delgado, Carolina; Miranda, Marcelo; Ibáñez, Agustín; Slachevsky, Andrea; Hornberger, Michael (J Alzheimers Dis, 2018)
Although a growing body of work has shown that behavioral variant frontotemporal dementia (bvFTD) could present with severe amnesia in approximately half of cases, memory assessment is currently the clinical standard to distinguish bvFTD from Alzheimer's disease (AD). Thus, the concept of "relatively preserved episodic memory" in bvFTD remains the basis of its clinical distinction from AD and a criterion for bvFTD's diagnosis. This view is supported by the idea that bvFTD is not characterized by genuine amnesia and hippocampal degeneration, by contrast to AD. In this multicenter study, we aimed to investigate the neural correlates of memory performance in bvFTD as assessed by the Free and Cued Selective Reminding Test (FCSRT). Imaging explorations followed a two-step procedure, first relying on a visual rating of atrophy of 35 bvFTD and 34 AD patients' MRI, contrasted with 29 controls; and then using voxel-based morphometry (VBM) in a subset of bvFTD patients. Results showed that 43% of bvFTD patients presented with a genuine amnesia. Data-driven analysis on visual rating data showed that, in bvFTD, memory recall & storage performances were significantly predicted by atrophy in rostral prefrontal and hippocampal/perihippocampal regions, similar to mild AD. VBM results in bvFTD (pFWE<0.05) showed similar prefrontal and hippocampal regions in addition to striatal and lateral temporal involvement. Our findings showed the involvement of prefrontal as well as medial/lateral temporal atrophy in memory deficits of bvFTD patients. This contradicts the common view that only frontal deficits explain memory impairment in this disease and plead for an updated view on memory dysfunctions in bvFTD.

Subjective Cognitive Decline Is Associated with Greater White Matter Hyperintensity Volume. - van Rooden, Sanneke; van den Berg-Huysmans, Annette A; Croll, Pauline H; Labadie, Gerda; Hayes, Jessica M; Viviano, Raymond; van der Grond, Jeroen; Rombouts, Serge A R B; Damoiseaux, Jessica S (J Alzheimers Dis, 2018)
BACKGROUND: Research in older adults with subjective cognitive decline (SCD) has mainly focused on Alzheimer's disease (AD)-related MRI markers, such as hippocampal volume. However, small vessel disease (SVD) is currently established as serious comorbidity in dementia and its preliminary stages. It is therefore important to examine SVD markers in addition to AD markers in older adults presenting with SCD. OBJECTIVE: The aim of our study was to elucidate the role of SVD markers in late middle-aged to older adults with and without SCD in addition to the commonly found role of AD markers (hippocampal volume). METHODS: 67 healthy late middle-aged to older adults participated in this study (mean age 68 years); 25 participants with SCD and 42 participants without SCD. We evaluated quantitative as well as qualitative AD markers (i.e., hippocampal volume and medial temporal lobe atrophy (MTA) scale) and SVD markers (i.e., white matter hyperintensities (WMH) volume, Fazekas scale, microbleeds, and lacunar infarcts), and neuropsychological function and amount of memory complaints. RESULTS: We found a significant effect of SCD on hippocampal atrophy, as assessed using the MTA scale, but not on hippocampal volume. In addition, we found a significant effect of SCD, and amount of memory complaints, on WMH volume and Fazekas score, suggesting larger WMH volumes in participants with SCD. CONCLUSION: SVD MRI markers are related to amount of memory complaints, in addition to the commonly observed AD MRI markers, as demonstrated by the greater WMHs in healthy late middle-aged to older adults with SCD.

Subtle Cognitive Impairment and Alzheimer's Disease-Type Pathological Changes in Cerebrospinal Fluid are Common Among Neurologically Healthy Subjects. - Haapalinna, Fanni; Kokki, Merja; Jääskeläinen, Olli; Hallikainen, Merja; Helisalmi, Seppo; Koivisto, Anne; Kokki, Hannu; Paajanen, Teemu; Penttinen, Janne; Pikkarainen, Maria; Rautiainen, Minna; Soininen, Hilkka; et al. (J Alzheimers Dis, 2018)
BACKGROUND: The neuropathology of Alzheimer's disease (AD) has previously been shown to be rather common among the elderly. OBJECTIVE: The aim of this study was to inspect the associations between cerebrospinal fluid (CSF) AD biomarker concentrations, age, the APOEɛ4 allele, cardiovascular diseases, diabetes, and cognitive performance in a cohort of a neurologically healthy population. METHODS: This study included 93 subjects (42 men, mean age 67 years) without previous neurological symptoms or subjective cognitive complaints. Their cognition was assessed, and CSF biomarkers and APOEɛ4 status were analyzed. RESULTS: Of the studied subjects, 8.6% (n = 8) had a pathological CSF AD biomarker profile. An increase in age correlated positively with CSF tau pathology and negatively with global cognitive performance. CONCLUSION: AD-type pathological changes in CSF and subtle cognitive impairment are common within a population with no previous memory complaints. Age was the main risk factor for the changes.

Subtypes Based on Neuropsychological Performance Predict Incident Dementia: Findings from the Rush Memory and Aging Project. - Zammit, Andrea R; Muniz-Terrera, Graciela; Katz, Mindy J; Hall, Charles B; Ezzati, Ali; Bennett, David A; Lipton, Richard B (J Alzheimers Dis, 2018)
BACKGROUND: In a previous report, we used latent class analysis (LCA) to identify natural subgroups of older adults in the Einstein Aging Study (EAS) based on neuropsychological performance. These subgroups differed in demographics, genetic profile, and prognosis. Herein, we assess the generalizability of these findings to an independent sample, the Rush Memory and Aging Project (MAP), which used an overlapping, but distinct neuropsychological battery. OBJECTIVE: Our aim was to identify the association of natural subgroups based on neuropsychological performance in the MAP cohort with incident dementia and compare them with the associations identified in the EAS. METHODS: MAP is a community-dwelling cohort of older adults living in the northeastern Illinois, Chicago. Latent class models were applied to baseline scores of 10 neuropsychological measures across 1,662 dementia-free MAP participants. Results were compared to prior findings from the EAS. RESULTS: LCA resulted in a 5-class model: Mixed-Domain Impairment (n = 71, 4.3%), Memory-specific-Impairment (n = 274, 16.5%), Average (n = 767, 46.1%), Frontal Impairment (n = 222, 13.4%), and a class of Superior Cognition (n = 328, 19.7%). Similar to the EAS, the Mixed-Domain Impairment, the Memory-Specific Impairment, and the Frontal Impairment classes had higher risk of incident Alzheimer's disease when compared to the Average class. By contrast, the Superior Cognition had a lower risk of Alzheimer's disease when compared to the Average class. CONCLUSIONS: Natural cognitive subgroups in MAP are similar to those identified in EAS. These similarities, despite study differences in geography, sampling strategy, and cognitive tests, suggest that LCA is capable of identifying classes that are not limited to a single sample or a set of cognitive tests.

Sulforaphane Inhibits the Generation of Amyloid-β Oligomer and Promotes Spatial Learning and Memory in Alzheimer's Disease (PS1V97L) Transgenic Mice. - Hou, Ting-Ting; Yang, He-Yun; Wang, Wei; Wu, Qiao-Qi; Tian, Yuan-Ruhua; Jia, Jian-Ping (J Alzheimers Dis, 2018)
Abnormal amyloid-β (Aβ) aggregates are a striking feature of Alzheimer's disease (AD), and Aβ oligomers have been proven to be crucial in the pathology of AD. Any intervention targeting the generation or aggregation of Aβ can be expected to be useful in AD treatment. Oxidative stress and inflammation are common pathological changes in AD that are involved in the generation and aggregation of Aβ. In the present study, 6-month-old PS1V97L transgenic (Tg) mice were treated with sulforaphane, an antioxidant, for 4 months, and this treatment significantly inhibited the generation and aggregation of Aβ. Sulforaphane also alleviated several downstream pathological changes that including tau hyperphosphorylation, oxidative stress, and neuroinflammation. Most importantly, the cognition of the sulforaphane-treated PS1V97L Tg mice remained normal compared to that of wild-type mice at 10 months of age, when dementia typically emerges in PS1V97L Tg mice. Pretreating cultured cortical neurons with sulforaphane also protected against neuronal injury caused by Aβ oligomers in vitro. These findings suggest that sulforaphane may be a potential compound that can inhibit Aβ oligomer production in AD.

Supplemental Retinal Carotenoids Enhance Memory in Healthy Individuals with Low Levels of Macular Pigment in A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. - Power, Rebecca; Coen, Robert F; Beatty, Stephen; Mulcahy, Riona; Moran, Rachel; Stack, Jim; Howard, Alan N; Nolan, John M (J Alzheimers Dis, 2018)
BACKGROUND: There is a biologically plausible rationale whereby the dietary carotenoids lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ), which are collectively referred to as macular pigment (MP) in the central retina (macula), support the maintenance of cognition via their antioxidant and anti-inflammatory properties. OBJECTIVE: To investigate the impact of supplemental L, Z, and MZ on memory, executive function, and verbal fluency among healthy individuals with low MP levels. METHODS: In this double-blind, placebo-controlled, randomized clinical trial, subjects (n = 91; mean±SD age = 45.42±12.40; % male = 51.6) consumed a daily formulation of 10 mg L, 10 mg MZ, and 2 mg Z (n = 45) or placebo (n = 46) for 12 months. Cognitive domains assessed included verbal and visual learning, immediate and delayed memory, executive function, and verbal fluency. MP and serum carotenoid concentrations of L, Z, and MZ were also measured. RESULTS: Following 12-month supplementation, individuals in the active group exhibited statistically significant improvements in memory when compared to the placebo group (paired associated learning [PAL] memory score [rANOVA, p = 0.009]; PAL errors [rANOVA, p = 0.017]). Furthermore, the observed reduction in the number of errors made in the PAL task among those in the intervention group was positively and significantly related to observed increases in MP volume (p = 0.005) and observed increases in serum concentrations of L (p = 0.009). CONCLUSION: This randomized, double-blind, placebo-controlled clinical trial demonstrates a memory-enhancing effect of daily supplementation with L, Z, and MZ in healthy subjects with low MP at baseline. The implications of these findings for intellectual performance throughout life, and for risk of cognitive decline in later life, warrant further study.
Keywords: Adult; Cognition; Dietary Supplements; Double-Blind Method; Executive Function; Female; Healthy Volunteers; Humans; Lutein; Macular Pigment; Male; Memory, Episodic; Middle Aged; Retina; Vision Tests; Zeaxanthins

A Systematic Review and Aggregated Analysis on the Impact of Amyloid PET Brain Imaging on the Diagnosis, Diagnostic Confidence, and Management of Patients being Evaluated for Alzheimer's Disease. - Fantoni, Enrico R; Chalkidou, Anastasia; O' Brien, John T; Farrar, Gill; Hammers, Alexander (J Alzheimers Dis, 2018)
BACKGROUND: Amyloid PET (aPET) imaging could improve patient outcomes in clinical practice, but the extent of impact needs quantification. OBJECTIVE: To provide an aggregated quantitative analysis of the value added by aPET in cognitively impaired subjects. METHODS: Systematic literature searches were performed in Embase and Medline until January 2017. 1,531 cases over 12 studies were included (1,142 cases over seven studies in the primary analysis where aPET was the key biomarker; the remaining cases included as defined groups in the secondary analysis). Data was abstracted by consensus among two observers and assessed for bias. Clinical utility was measured by diagnostic change, diagnostic confidence, and patient management before and after aPET. Three groups were further analyzed: control patients for whom feedback of aPET scan results was delayed; aPET Appropriate Use Criteria (AUC+) cases; and patients undergoing additional FDG/CSF testing. RESULTS: For 1,142 cases with only aPET, 31.3% of diagnoses were revised, whereas 3.2% of diagnoses changed in the delayed aPET control group (p < 0.0001). Increased diagnostic confidence following aPET was found for 62.1% of 870 patients. Management changes with aPET were found in 72.2% of 740 cases and in 55.5% of 299 cases in the control group (p < 0.0001). The diagnostic value of aPET in AUC+ patients or when FDG/CSF were additionally available did not substantially differ from the value of aPET alone in the wider population. CONCLUSIONS: Amyloid PET contributed to diagnostic revision in almost a third of cases and demonstrated value in increasing diagnostic confidence and refining management plans.

Tau Proteolysis in the Pathogenesis of Tauopathies: Neurotoxic Fragments and Novel Biomarkers. - Quinn, James P; Corbett, Nicola J; Kellett, Katherine A B; Hooper, Nigel M (J Alzheimers Dis, 2018)
With predictions showing that 131.5 million people worldwide will be living with dementia by 2050, an understanding of the molecular mechanisms underpinning disease is crucial in the hunt for novel therapeutics and for biomarkers to detect disease early and/or monitor disease progression. The metabolism of the microtubule-associated protein tau is altered in different dementias, the so-called tauopathies. Tau detaches from microtubules, aggregates into oligomers and neurofibrillary tangles, which can be secreted from neurons, and spreads through the brain during disease progression. Post-translational modifications exacerbate the production of both oligomeric and soluble forms of tau, with proteolysis by a range of different proteases being a crucial driver. However, the impact of tau proteolysis on disease progression has been overlooked until recently. Studies have highlighted that proteolytic fragments of tau can drive neurodegeneration in a fragment-dependent manner as a result of aggregation and/or transcellular propagation. Proteolytic fragments of tau have been found in the cerebrospinal fluid and plasma of patients with different tauopathies, providing an opportunity to develop these fragments as novel disease progression biomarkers. A range of therapeutic strategies have been proposed to halt the toxicity associated with proteolysis, including reducing protease expression and/or activity, selectively inhibiting protease-substrate interactions, and blocking the action of the resulting fragments. This review highlights the importance of tau proteolysis in the pathogenesis of tauopathies, identifies putative sites during tau fragment-mediated neurodegeneration that could be targeted therapeutically, and discusses the potential use of proteolytic fragments of tau as biomarkers for different tauopathies.

TDP-43 Neuropathologic Associations in the Nun Study and the Honolulu-Asia Aging Study. - Flanagan, Margaret E; Cholerton, Brenna; Latimer, Caitlin S; Hemmy, Laura S; Edland, Steven D; Montine, Kathleen S; White, Lon R; Montine, Thomas J (J Alzheimers Dis, 2018)
Transactive response binding protein-43 (TDP-43) cytoplasmic neuronal and glial aggregates (pathologic TDP-43) have been described in multiple brain diseases. We describe the associations between neuropathologically confirmed TDP-43 and cognition in two population-based cohorts: the Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS). In the HAAS, there was a significant association between hippocampal sclerosis (HS) and TDP-43 (OR = 11.04, p < 0.0001, 95% CI 3.57-34.13). In the NS, there were significant associations between TDP-43 and HS (OR = 16.44, p > 0.001 95%, CI 7.10-38.00) and Alzheimer's disease (AD) severity (OR = 1.74, p = 0.009, 95% CI 1.15-2.64). When cognitive scores were added to the model, HS remained significant but the other variables were not. When HS was removed from the model, the overall model remained significant and the associations between cognitive performance and TDP-43 (OR = 2.11, p = 0.022, 95% CI 1.11-4.02) were significant. In the NS, there was a significant association between cognitive performance and TDP-43 (OR 1.94 p = 0.005, 95% CI 1.22-3.09) (HS remained significant, but AD did not). When HS was removed from the model, only CERAD was significant (OR = 2.43 p < 0.001, 95% CI 1.58-3.74). These results support a consistent association between pathologic TDP-43, HS, and the development of cognitive impairment in two large studies of brain aging, while the relationship between AD pathology and TDP-43 may vary according to cohort-specific features.

Three VCP Mutations in Patients with Frontotemporal Dementia. - Wong, Tsz Hang; Pottier, Cyril; Hondius, David C; Meeter, Lieke H H; van Rooij, Jeroen G J; Melhem, Shami; van Minkelen, Rick; van Duijn, Cornelia M; Rozemuller, Annemieke J M; Seelaar, Harro; Rademakers, Rosa; van Swieten, John C (J Alzheimers Dis, 2018)
Valosin-containing protein (VCP) is involved in multiple cellular activities. Mutations in VCP lead to heterogeneous clinical presentations including inclusion body myopathy with Paget's disease of the bone, frontotemporal dementia and amyotrophic lateral sclerosis, even in patients carrying the same mutation. We screened a cohort of 48 patients with familial frontotemporal dementia (FTD) negative for MAPT, GRN, and C9orf72 mutations for other known FTD genes by using whole exome sequencing. In addition, we carried out targeted sequencing of a cohort of 37 patients with frontotemporal lobar degeneration with Transactive response DNA-binding protein 43 (TDP-43) subtype from the Netherlands Brain bank. Two novel (p.Thr262Ser and p.Arg159Ser) and one reported (p.Met158Val) VCP mutations in three patients with a clinical diagnosis of FTD were identified, and were absence in population-match controls. All three patients presented with behavioral changes, with additional semantic deficits in one. No signs of Paget or muscle disease were observed. Pathological examination of the patient with VCP p.Arg159Ser mutation showed numerous TDP-43 immunoreactive (IR) neuronal intranuclear inclusions (NII) and dystrophic neurites (DN), while a lower number of NII and DN were observed in the patient with the VCP p.Thr262Ser mutation. Pathological findings of both patients were consistent with FTLD-TDP subtype D. Furthermore, only rare VCP-IR NII was observed in both cases. Our study expands the clinical heterogeneity of VCP mutations carriers, and indicates that other additional factors, such as genetic modifiers, may determine the clinical phenotype.

A Three-Factor Structure of Cognitive Functioning Among Unimpaired Carriers and Non-Carriers of Autosomal-Dominant Alzheimer's Disease. - Guzmán-Vélez, Edmarie; Jaimes, Sehily; Aguirre-Acevedo, Daniel C; Norton, Daniel J; Papp, Kathryn V; Amariglio, Rebecca; Rentz, Dorene; Baena, Ana; Henao, Eliana; Tirado, Victoria; Munoz, Claudia; Giraldo, Margarita; et al. (J Alzheimers Dis, 2018)
BACKGROUND: There is a need to find cognitive markers that can help identify individuals at risk for Alzheimer's disease (AD), and that can be used to reliably measure cognitive decline. OBJECTIVE: We tested whether a theoretically driven three-factor structure would characterize cognitive functioning in individuals who are genetically-determined to develop AD due to a mutation in Presenilin-1 (PSEN1) gene. We also examined whether these factors could distinguish cognitively unimpaired PSEN1 mutation carriers from age-matched non-carrier family members. METHODS: 1,395 cognitively unimpaired members of a Colombian kindred with the PSEN1 E280A mutation were included in the study. A confirmatory factor analysis examined the fit of the three-factor model comprising episodic memory (MMSE memory recall, CERAD-COL Word list recall, and Constructional praxis recall), executive function (Phonemic fluency and WCST perseverative errors), and psychomotor processing speed (TMT-A and WAIS-III Digit Symbol). RESULTS: The three-factor model provided an excellent fit for all participants (p = 0.24; RMSEA = 0.01). Further, the episodic memory (p = 0.0004, d = 0.25) and executive functioning (p = 0.001, d = 0.18) factors distinguished cognitively unimpaired carriers from non-carriers. The episodic memory factor provided the earliest indication of preclinical cognitive decline at 35 years of age, nine years before individuals' estimated age of clinical onset. CONCLUSIONS: The three theoretically derived cognitive factors provide a reliable measure of cognition and may be useful for the early detection of AD, as well as for measuring disease progression. However, longitudinal studies are needed to confirm that these factors can be used to track the progression of cognitive decline in preclinical AD.

Tocotrienol-Rich Fraction of Palm Oil Improves Behavioral Impairments and Regulates Metabolic Pathways in AβPP/PS1 Mice. - Durani, Lina Wati; Hamezah, Hamizah Shahirah; Ibrahim, Nor Faeizah; Yanagisawa, Daijiro; Nasaruddin, Muhammad Luqman; Mori, Masaki; Azizan, Kamalrul Azlan; Damanhuri, Hanafi Ahmad; Makpol, Suzana; Wan Ngah, Wan Zurinah; Tooyama, Ikuo (J Alzheimers Dis, 2018)
We have recently shown that the tocotrienol-rich fraction (TRF) of palm oil, a mixture of vitamin E analogs, improves amyloid pathology in vitro and in vivo. However, precise mechanisms remain unknown. In this study, we examined the effects of long-term (10 months) TRF treatment on behavioral impairments and brain metabolites in (15 months old) AβPP/PS1 double transgenic (Tg) Alzheimer's disease (AD) mice. The open field test, Morris water maze, and novel object recognition tasks revealed improved exploratory activity, spatial learning, and recognition memory, respectively, in TRF-treated Tg mice. Brain metabolite profiling of wild-type and Tg mice treated with and without TRF was performed using ultrahigh performance liquid chromatography (UHPLC) coupled to high-resolution accurate mass (HRAM)-orbitrap tandem mass spectrometry (MS/MS). Metabolic pathway analysis found perturbed metabolic pathways that linked to AD. TRF treatment partly ameliorated metabolic perturbations in Tg mouse hippocampus. The mechanism of this pre-emptive activity may occur via modulation of metabolic pathways dependent on Aβ interaction or independent of Aβ interaction.

Traumatic Brain Injury and Age of Onset of Dementia with Lewy Bodies. - Nguyen, Trung P; Schaffert, Jeff; LoBue, Christian; Womack, Kyle B; Hart, John; Cullum, C Munro (J Alzheimers Dis, 2018)
BACKGROUND: Traumatic brain injury (TBI) with loss of consciousness (LOC) has been associated with earlier onset of mild cognitive impairment, frontotemporal dementia, Parkinson's disease, and Alzheimer's disease (AD), but has not been examined as a risk factor for earlier onset of dementia with Lewy bodies (DLB). OBJECTIVE: The purpose of this study was to assess the association between a history of TBI and the age of onset of DLB. METHOD: Data from 576 subjects with a clinical diagnosis of DLB were obtained from the National Alzheimer's Coordinating Center (NACC). Analyses of Covariance examined whether self-reported history of remote TBI with LOC (i.e., >1 year prior to the first Alzheimer's Disease Center visit) was associated with earlier DLB symptom onset. RESULTS: Controlling for sex, those with a history of remote TBI had an approximately 1.5-year earlier clinician-estimated age of onset (F = 0.87, p = 0.35) and 0.75-years earlier age of diagnosis (F = 0.14, p = 0.71) of DLB compared to those without a history of TBI, though the differences did not reach statistical significance. Analysis of subjects with autopsy-confirmed diagnoses was underpowered due to the low number of TBI+ subjects. CONCLUSIONS: Remote TBI with LOC was not significantly associated with DLB onset, despite being a significant risk factor for cognitive decline and earlier age of onset in other neurodegenerative conditions. Replication of these results using a larger cohort of DLB subjects with and without a TBI history who have undergone autopsy is indicated, as our TBI+ subjects did show a slightly earlier onset of about 1.5 years. Further investigations into other potential DLB risk factors are also warranted.

Treatment of Atrial Fibrillation in Patients with Dementia: A Cohort Study from the Swedish Dementia Registry. - Subic, Ana; Cermakova, Pavla; Religa, Dorota; Han, Shuang; von Euler, Mia; Kåreholt, Ingemar; Johnell, Kristina; Fastbom, Johan; Bognandi, Liselia; Winblad, Bengt; Kramberger, Milica G; Eriksdotter, Maria; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Patients with dementia might have higher risk for hemorrhagic complications with anticoagulant therapy prescribed for atrial fibrillation (AF). OBJECTIVE: This study assesses the risks and benefits of warfarin, antiplatelets, and no treatment in patients with dementia and AF. METHODS: Of 49,792 patients registered in the Swedish Dementia Registry 2007-2014, 8,096 (16%) had a previous diagnosis of AF. Cox proportional hazards models were used to calculate the risk for ischemic stroke (IS), nontraumatic intracranial hemorrhage, any-cause hemorrhage, and death. RESULTS: Out of the 8,096 dementia patients with AF, 2,143 (26%) received warfarin treatment, 2,975 (37%) antiplatelet treatment, and 2,978 (37%) had no antithrombotic treatment at the time of dementia diagnosis. Patients on warfarin had fewer IS than those without treatment (5.2% versus 8.7%; p < 0.001) with no differences compared to antiplatelets. In adjusted analyses, warfarin was associated with a lower risk for IS (HR 0.76, CI 0.59-0.98), while antiplatelets were associated with increased risk (HR 1.25, CI 1.01-1.54) compared to no treatment. For any-cause hemorrhage, there was a higher risk with warfarin (HR 1.28, CI 1.03-1.59) compared to antiplatelets. Warfarin and antiplatelets were associated with a lower risk for death compared to no treatment. CONCLUSIONS: Warfarin treatment in Swedish patients with dementia is associated with lower risk of IS and mortality, and a small increase in any-cause hemorrhage. This study supports the use of warfarin in appropriate cases in patients with dementia. The low percentage of patients on warfarin treatment indicates that further gains in stroke prevention are possible.
Keywords: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dementia; Female; Hemorrhage; Humans; Longitudinal Studies; Male; Registries; Risk Factors; Stroke; Survival Analysis; Sweden; Warfarin

TTC7 and Hyccin Regulate Neuronal Aβ42 Accumulation and its Associated Neural Deficits in Aβ42-Expressing Drosophila. - Sun, Minghao; Zhao, Yinghui; Han, Men; Zhang, Baozhu; Zhang, Xiao; Zhang, Qichao; Lim, Nastasia K-H; Wang, Wen-An; Huang, Fu-De (J Alzheimers Dis, 2018)
Neuronal amyloid-β (Aβ) accumulation plays an important role in the pathogenesis of Alzheimer's disease (AD). The conformation and toxicity of Aβ are regulated by lipids on the plasma membrane. Previously, we found downregulation of Rolling Blackout (RBO) or phosphatidylinositol-4-kinase type IIIα (PI4KIIIα) reduces neuronal Aβ accumulation and associated neural deficits in a Drosophila model expressing Aβ42. In mammals, the homologs of RBO and PI4KIIIα were reported to form a plasma membrane-localized complex with a scaffold protein TTC7 and cytosolic protein Hyccin/FAM126A to tightly control the plasmalemmal level of phosphatidylinositol-4-phosphate. Here, we show genetic downregulation of Drosophila TTC7 and Hyccin also reduces neuronal Aβ accumulation and associated synaptic and motor defects as well as premature death in Aβ42-expressing flies, while overexpression of TTC7 and Hyccin produced the opposite effect. These results, together with our previous study, demonstrate that RBO/TTC7/PI4KIIIα/Hyccin regulate neuronal Aβ accumulation and associated neural deficits in the Drosophila model, further supporting the RBO/Efr3-PI4KIIIα complex as a potential therapeutic target for AD.

Urine-Based Biomarkers for Alzheimer's Disease Identified Through Coupling Computational and Experimental Methods. - Yao, Fang; Hong, Xiaoyu; Li, Shuiming; Zhang, Yan; Zhao, Qing; Du, Wei; Wang, Yong; Ni, Jiazuan (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is a chronic neurodegenerative disorder contributing to nearly 70% of dementia cases. However, no diagnostic protein biomarkers are available in urine. In this study, we combined computational and experimental methods to identify urinary biomarkers for AD. First, by analyzing brain tissue-based gene expression data of AD, 2,754 differentially expressed genes were identified, 559 of which were predicted to encode urine-excretory proteins that might act as candidate protein biomarkers of AD. GO enrichment analyses implied that they were mainly involved in microtubule-based process, myelin sheath, and calcium ion binding, suggesting that they might be associated with AD pathogenesis. In order to verify these proteins in urine, an iTRAQ experiment was carried out to analyze urine samples from AD patients and healthy controls, and 15 proteins were detected. Based on the expression changes of these proteins, 4 proteins were chosen for further validation by ELISA experiment, and SPP1, GSN, and IGFBP7 were found to be differentially expressed in the urine of AD patients. After a literature survey, we found that they were involved in AD pathophysiology and might serve as new urine biomarkers for AD. To our knowledge, this is the first time that urine biomarkers for AD were identified by combining computational and experimental methods. Furthermore, this is the first time SPP1, GSN, and IGFBP7 have been reported as potential urine protein biomarkers for AD. Therefore, our findings might provide significant guidance for finding early biomarkers of AD in urine.

Vascular Cognitive Impairment and the Gut Microbiota. - Li, Sinian; Shao, Yiming; Li, Kanglan; HuangFu, Changmei; Wang, Wenjie; Liu, Zhou; Cai, Zhiyou; Zhao, Bin (J Alzheimers Dis, 2018)
Vascular cognitive impairment (VCI), the second most common cause of dementia in elderly people, is a term that refers to all forms of cognitive disorders that can be attributed to cerebrovascular disease such as manifestations of discrete infarctions, brain hemorrhages, and white matter lesions. The gut microbiota (GM) has emerged recently as an essential player in the development of VCI. The GM may affect the brain's physiological, behavioral, and cognitive functions through the brain-gut axis via neural, immune, endocrine, and metabolic pathways. Therefore, microbiota dysbiosis may mediate or affect atherosclerosis, cerebrovascular disease, and endothelial dysfunction, which are the predominant risk factors for VCI. Moreover, the composition of the GM includes the bacterial component lipopolysaccharides and their metabolic products including trimethylamine-N-oxide and short-chain fatty acids. These products may increase the permeability of the intestinal epithelium, leading to systemic immune responses, low-grade inflammation, and altered signaling pathways that are associated with the pathogenesis of VCI. In this review, we discuss the proposed mechanisms of the GM in the maintenance of VCI and how it is implicated in acquired metabolic diseases, particularly in VCI regulation.

VEGFR1 and VEGFR2 in Alzheimer's Disease. - Harris, Rachel; Miners, James Scott; Allen, Shelley; Love, Seth (J Alzheimers Dis, 2018)
Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. Despite upregulation of VEGF in the brain in Alzheimer's disease (AD), probably in response to amyloid-β, vasoconstriction, and tissue hypoxia, there is no consequent increase in microvessel density. VEGF binds to and activates VEGF receptor 2 (VEGFR2), but also binds to VEGF receptor 1 (VEGFR1), which exists in less-active membrane-bound and inactive soluble (sVEGFR1) forms and inhibits pro-angiogenic signaling. We have investigated whether altered expression of VEGF receptors might account for the lack of angiogenic response to VEGF in AD. We assessed the cellular distribution and protein level of VEGFR1 and VEGFR2 in parietal cortex from 50 AD and 36 age-matched control brains, and related the findings to measurements of VEGF and von Willebrand factor level (a marker of microvessel density) in the same tissue samples. VEGFR2 was expressed by neurons, astrocytes and endothelial cells. VEGFR1 was expressed predominantly neuronally and was significantly reduced in AD (p = 0.02). Western blot analysis on a subset of brains showed reduction in VEGFR1:sVEGFR1 in AD (p = 0.046). The lack of angiogenesis despite cerebral hypoperfusion in AD is not explained by altered expression of VEGFR2 or total VEGFR1; indeed, the downregulation of VEGFR1 may represent a pro-angiogenic response to the hypoperfusion. However, the relative increase in sVEGFR1 would be expected to have an anti-angiogenic effect which may be a factor in AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Case-Control Studies; Endothelial Cells; Female; Gene Expression Regulation; Humans; Male; Middle Aged; Neovascularization, Pathologic; RNA, Messenger; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

Vestibular Loss Predicts Poorer Spatial Cognition in Patients with Alzheimer's Disease. - Wei, Eric X; Oh, Esther S; Harun, Aisha; Ehrenburg, Matthew; Agrawal, Yuri (J Alzheimers Dis, 2018)
The vestibular system is an important contributor to balance control, spatial orientation, and falls risk. Recent evidence has shown that Alzheimer's disease (AD) patients have a higher prevalence of vestibular impairment relative to healthy controls. We sought to evaluate whether vestibular loss is specifically associated with poor spatial cognitive skills among patients with mild cognitive impairment (MCI) and AD. We enrolled 50 patients (22 MCI and 28 AD) from an interdisciplinary Memory Clinic and measured vestibular physiologic function in all patients. Spatial cognitive function was assessed using the Money Road Map Test (MRMT) and the Trail Making Test Part B (TMT-B). General cognitive function was assessed with the Mini-Mental Status Examination (MMSE). In multivariable linear regression analyses adjusted for age, gender, education level, and MMSE, MCI and AD patients with vestibular loss made significantly more errors on the MRMT relative to patients with normal vestibular function (β= 7.3, 95% CI 2.4, 12.1 for unilateral vestibular loss and β= 6.4, 95% CI 1.9, 10.9 for bilateral vestibular loss). We further stratified AD patients into "spatially normal" and "spatially impaired" groups based on MRMT performance, and found that the prevalence of vestibular loss was significantly higher in the spatially impaired AD group relative to the spatially normal AD group. These findings support the hypothesis that vestibular loss contributes specifically to a decline in spatial cognitive ability in MCI and AD patients, independently of general cognitive decline, and may predict a "spatially impaired" subtype of AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Bilateral Vestibulopathy; Cognitive Dysfunction; Cross-Sectional Studies; Female; Humans; Linear Models; Male; Multivariate Analysis; Neuropsychological Tests; Prospective Studies; Spatial Navigation; Vestibular Function Tests

Voxel-Based Acetylcholinesterase PET Study in Early and Late Onset Alzheimer's Disease. - Hirano, Shigeki; Shinotoh, Hitoshi; Shimada, Hitoshi; Ota, Tsuneyoshi; Sato, Koichi; Tanaka, Noriko; Zhang, Ming-Rong; Higuchi, Makoto; Fukushi, Kiyoshi; Irie, Toshiaki; Kuwabara, Satoshi; Suhara, Tetsuya (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by chronic progressive cognitive decline and displays underlying brain cholinergic dysfunction, providing a rationale for treatment with cholinomimetic medication. The clinical presentations and courses of AD patients may differ by age of onset. OBJECTIVE: The objective of the present study was to illustrate the regional differences of brain acetylcholinesterase (AChE) activity as quantified by N-[11C]methylpiperidinyl-4-acetate ([11C]MP4A) and PET using parametric whole brain analysis and clarify those differences as a function of age. METHODS: 22 early onset AD (EOAD) with age at onset under 65, the remaining 26 as late onset AD (LOAD), and 16 healthy controls (HC) were enrolled. Voxel-based AChE activity estimation of [11C]MP4A PET images was conducted by arterial input and unconstrained nonlinear least-squares method with subsequent parametrical analyses. Statistical threshold was set as Family Wise Error corrected, p-value <0.05 on cluster-level and cluster extent over 30 voxels. RESULTS: Voxel-based group comparison showed that, compared to HC, both EOAD and LOAD showed cortical AChE decrement in parietal, temporal, and occipital cortices, with wider and stringent cortical involvement in the EOAD group, most prominently demonstrated in the temporal region. There was no significant correlation between age and regional cerebral AChE activity except for a small left superior temporal region in the AD group (Brodmann's area 22, Zmax = 5.13, 396 voxels), whereas no significant cluster was found in the HC counterpart. CONCLUSION: Difference in cortical cholinergic dysfunction between EOAD and LOAD may shed some light on the cholinomimetic drug efficacy in AD.

Which Risk Factors Causally Influence Dementia? A Systematic Review of Mendelian Randomization Studies. - Kuźma, Elżbieta; Hannon, Eilis; Zhou, Ang; Lourida, Ilianna; Bethel, Alison; Levine, Deborah A; Lunnon, Katie; Thompson-Coon, Jo; Hyppönen, Elina; Llewellyn, David J (J Alzheimers Dis, 2018)
BACKGROUND: Numerous risk factors for dementia are well established, though the causal nature of these associations remains unclear. OBJECTIVE: To systematically review Mendelian randomization (MR) studies investigating causal relationships between risk factors and global cognitive function or dementia. METHODS: We searched five databases from inception to February 2017 and conducted citation searches including MR studies investigating the association between any risk factor and global cognitive function, all-cause dementia or dementia subtypes. Two reviewers independently assessed titles and abstracts, full-texts, and study quality. RESULTS: We included 18 MR studies investigating education, lifestyle factors, cardiovascular factors and related biomarkers, diabetes related and other endocrine factors, and telomere length. Studies were of predominantly good quality, however eight received low ratings for sample size and statistical power. The most convincing causal evidence was found for an association of shorter telomeres with increased risk of Alzheimer's disease (AD). Causal evidence was weaker for smoking quantity, vitamin D, homocysteine, systolic blood pressure, fasting glucose, insulin sensitivity, and high-density lipoprotein cholesterol. Well-replicated associations were not present for most exposures and we cannot fully discount survival and diagnostic bias, or the potential for pleiotropic effects. CONCLUSIONS: Genetic evidence supported a causal association between telomere length and AD, whereas limited evidence for other risk factors was largely inconclusive with tentative evidence for smoking quantity, vitamin D, homocysteine, and selected metabolic markers. The lack of stronger evidence for other risk factors may reflect insufficient statistical power. Larger well-designed MR studies would therefore help establish the causal status of these dementia risk factors.

White Matter Hyperintensity Predicts the Risk of Incident Cognitive Decline in Community Dwelling Elderly. - Ding, Ding; Xiong, Yunyun; Zhao, Qianhua; Guo, Qihao; Chu, Shuguang; Chu, Winnie W C; Luo, Jianfeng; Liang, Xiaoniu; Zheng, Li; Hong, Zhen; Wong, Lawrence K S; Mok, Vincent C T (J Alzheimers Dis, 2018)
BACKGROUND: Unlike western countries, data on white matter hyperintensity (WMH) in community dwelling elderly in Asian population is very limited. OBJECTIVE: To examine the relation between baseline WMH burden and the risk of incident cognitive decline in a community-based cohort with Chinese-dwelling elderly. METHODS: We prospectively evaluated the incident cognitive decline for 226 participants in the Shanghai Aging Study. Baseline WMH severity was visually rated by the age-related white matter changes (ARWMC) scale based on MRI. Cox proportional hazards regression model was used to estimate the relative risk (RR) of total ARWMC scale, global ARWMC score, presence of lacune and microbleed, for incident cognitive decline by adjusting potential confounders. RESULTS: Forty subjects were identified with incident cognitive decline (new onset 34 mild cognitive impairment and 6 dementia) during a median duration of 6 years follow-up. The incidence of cognitive decline was 3.0 (95% confidence interval [CI] 2.2-4.1) per 100 person-years. Increasing total ARWMC scale [RR1.21 (95% CI 1.06-1.39), p = 0.004)], confluent WMH [RR3.16 (95% CI 1.50-6.64), p = 0.002), and presence of lacunes [RR 2.73 (95% CI 1.21-6.15)] at baseline were independent predictors of incident cognitive decline. CONCLUSION: Our study demonstrated that confluent WMH may increase the risk of incident cognitive decline by 3 folds in community dwelling subjects. Small vessel disease may cause heavy burden of cognitive impairment in the elderly in China.
Keywords: Aged; China; Cognitive Dysfunction; Female; Humans; Independent Living; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Proportional Hazards Models; Prospective Studies; Risk Factors; White Matter

Zinc Exacerbates Tau Pathology in a Tau Mouse Model. - Craven, Kristen M; Kochen, William R; Hernandez, Carlos M; Flinn, Jane M (J Alzheimers Dis, 2018)
Hyperphosphorylated tau protein is a key pathology in Alzheimer's disease (AD), frontotemporal dementia, chronic traumatic encephalopathy, and Parkinson's disease. The essential trace element zinc exacerbates tauopathy in vitro as well as in a Drosophila model of AD. However, the interaction has never been assessed behaviorally or biochemically in mammals. Zinc supplementation is prevalent in society, finding use as a treatment for macular degeneration and cataracts, and is also taken as an immune system booster with high levels appearing in multivitamins marketed toward the elderly. Using a transgenic mouse model that contains the human gene for tau protein (P301L), we assessed the effects of excess chronic zinc supplementation on tau pathology. Behavioral tests included nest building, circadian rhythm, Morris Water Maze, fear conditioning, and open field. Biochemically, total tau and Ser396 phosphorylation were assessed using western blot. Number of tangles were assessed by Thioflavin-S and free zinc levels were assessed by Zinpyr-1. Tau mice demonstrated behavioral deficits compared to control mice. Zinc supplementation exacerbated tauopathic deficits in circadian rhythm, nesting behavior, and Morris Water Maze. Biochemically, zinc-supplemented tau mice showed increased phosphorylation at pSer396. Zinc supplementation in tau mice also increased tangle numbers in the hippocampus while decreasing free-zinc levels, demonstrating that tangles were sequestering zinc. These results show that zinc intensified the deficits in behavior and biochemistry caused by tau.

The 2002 NIMH Provisional Diagnostic Criteria for Depression of Alzheimer's Disease (PDC-dAD): Gauging their Validity over a Decade Later. - Sepehry, Amir A; Lee, Philip E; Hsiung, Ging-Yuek R; Beattie, B Lynn; Feldman, Howard H; Jacova, Claudia (J Alzheimers Dis, 2017)
Presented herein is evidence for criterion, content, and convergent/discriminant validity of the NIMH-Provisional Diagnostic Criteria for depression of Alzheimer's Disease (PDC-dAD) that were formulated to address depression in Alzheimer's disease (AD). Using meta-analytic and systematic review methods, we examined criterion validity evidence in epidemiological and clinical studies comparing the PDC-dAD to Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV), and International Classification of Disease (ICD 9) depression diagnostic criteria. We estimated prevalence of depression by PDC, DSM, and ICD with an omnibus event rate effect-size. We also examined diagnostic agreement between PDC and DSM. To gauge content validity, we reviewed rates of symptom endorsement for each diagnostic approach. Finally, we examined the PDC's relationship with assessment scales (global cognition, neuropsychiatric, and depression definition) for convergent validity evidence. The aggregate evidence supports the validity of the PDC-dAD. Our findings suggest that depression in AD differs from other depressive disorders including Major Depressive Disorder (MDD) in that dAD is more prevalent, with generally a milder presentation and with unique features not captured by the DSM. Although the PDC are the current standard for diagnosis of depression in AD, we identified the need for their further optimization based on predictive validity evidence.

A 24-Week Multi-Modality Exercise Program Improves Executive Control in Older Adults with a Self-Reported Cognitive Complaint: Evidence from the Antisaccade Task. - Heath, Matthew; Shellington, Erin; Titheridge, Sam; Gill, Dawn P; Petrella, Robert J (J Alzheimers Dis, 2017)
Exercise programs involving aerobic and resistance training (i.e., multiple-modality) have shown promise in improving cognition and executive control in older adults at risk, or experiencing, cognitive decline. It is, however, unclear whether cognitive training within a multiple-modality program elicits an additive benefit to executive/cognitive processes. This is an important question to resolve in order to identify optimal training programs that delay, or ameliorate, executive deficits in persons at risk for further cognitive decline. In the present study, individuals with a self-reported cognitive complaint (SCC) participated in a 24-week multiple-modality (i.e., the M2 group) exercise intervention program. In addition, a separate group of individuals with a SCC completed the same aerobic and resistance training as the M2 group but also completed a cognitive-based stepping task (i.e., multiple-modality, mind-motor intervention: M4 group). Notably, pre- and post-intervention executive control was examined via the antisaccade task (i.e., eye movement mirror-symmetrical to a target). Antisaccades are an ideal tool for the study of individuals with subtle executive deficits because of its hands- and language-free nature and because the task's neural mechanisms are linked to neuropathology in cognitive decline (i.e., prefrontal cortex). Results showed that M2 and M4 group antisaccade reaction times reliably decreased from pre- to post-intervention and the magnitude of the decrease was consistent across groups. Thus, multi-modality exercise training improved executive performance in persons with a SCC independent of mind-motor training. Accordingly, we propose that multiple-modality training provides a sufficient intervention to improve executive control in persons with a SCC.

Abnormalities of Cortical Neural Synchronization Mechanisms in Subjects with Mild Cognitive Impairment due to Alzheimer's and Parkinson's Diseases: An EEG Study. - Babiloni, Claudio; Del Percio, Claudio; Lizio, Roberta; Noce, Giuseppe; Cordone, Susanna; Lopez, Susanna; Soricelli, Andrea; Ferri, Raffaele; Pascarelli, Maria Teresa; Nobili, Flavio; Arnaldi, Dario; Famá, Francesco; et al. (J Alzheimers Dis, 2017)
The aim of this retrospective and exploratory study was that the cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms might reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) and Parkinson's disease (PDMCI) as compared to healthy subjects. Clinical and rsEEG data of 75 ADMCI, 75 PDMCI, and 75 cognitively normal elderly (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) was matched between the ADMCI and PDMCI 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 (ROC) classified these sources across individuals. Results showed that compared to the Nold group, the posterior alpha2 and alpha3 source activities were more abnormal in the ADMCI than the PDMCI group, while the parietal delta source activities were more abnormal in the PDMCI than the ADMCI group. The parietal delta and alpha sources correlated with MMSE score and correctly classified the Nold and diseased individuals (area under the ROC = 0.77-0.79). In conclusion, the PDMCI and ADMCI 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 these rsEEG markers for clinical applications and drug discovery.

Accuracy of Clinical Diagnosis of Dementia with Lewy Bodies versus Neuropathology. - Skogseth, Ragnhild; Hortobágyi, Tibor; Soennesyn, Hogne; Chwiszczuk, Luiza; Ffytche, Dominic; Rongve, Arvid; Ballard, Clive; Aarsland, Dag (J Alzheimers Dis, 2017)
BACKGROUND: The first consensus criteria for dementia with Lewy bodies (DLB) published in 1996 were revised in 2005, partly because the original clinical criteria had suboptimal sensitivity. Few studies have assessed the accuracy of the 2005 criteria applied prospectively in newly diagnosed patients who have been followed longitudinally. OBJECTIVE: To explore the correlation between clinical and pathological diagnoses in patients with DLB and Parkinson's disease with dementia (PDD). METHODS: From a prospective referral cohort study with enriched recruitment of patients with DLB and PDD, we included the first 56 patients coming to autopsy. Patients had mild dementia at inclusion and were followed annually until death with standardized clinical assessments. Pathological assessment was performed blind to clinical information according to standardized protocols and consensus criteria for DLB. RESULTS: 20 patients received a pathological diagnosis of Lewy body disease; the corresponding clinical diagnoses were probable DLB (n = 11), PDD (n = 5), probable (n = 2) or possible (n = 2) Alzheimer's disease (AD). Of 14 patients with a clinical diagnosis of probable DLB, 11 had DLB/PDD and 3 had AD at pathology. One patient with clinically possible DLB fulfilled criteria for pathological AD. Sensitivity, specificity, positive predictive value, and negative predictive values for probable DLB were 73%, 93%, 79%, and 90%. CONCLUSION: Our findings suggest that the international clinical consensus criteria for DLB perform reasonably well. However, false positive and false negative diagnoses still occur, indicating that the criteria need to be improved, that biomarkers may be needed, and that neuropathological feedback is vital to improve accuracy.

Activation of Macrophages and Microglia by Interferon-γ and Lipopolysaccharide Increases Methylglyoxal Production: A New Mechanism in the Development of Vascular Complications and Cognitive Decline in Type 2 Diabetes Mellitus? - Dhananjayan, Karthik; Gunawardena, Dhanushka; Hearn, Nerissa; Sonntag, Tanja; Moran, Chris; Gyengesi, Erika; Srikanth, Velandai; Münch, Gerald (J Alzheimers Dis, 2017)
Methylglyoxal (MGO), a dicarbonyl compound derived from glucose, is elevated in diabetes mellitus and contributes to vascular complications by crosslinking collagen and increasing arterial stiffness. It is known that MGO contributes to inflammation as it forms advanced glycation end products (AGEs), which activate macrophages via the receptor RAGE. The aim of study was to investigate whether inflammatory activation can increase MGO levels, thereby completing a vicious cycle. In order to validate this, macrophage (RAW264.7, J774A.1) and microglial (N11) cells were stimulated with IFN-γ and LPS (5 + 5 and 10 + 10 IFN-γ U/ml or μg/ml LPS), and extracellular MGO concentration was determined after derivatization with 5,6-Diamino-2,4-dihydroxypyrimidine sulfate by HPLC. MGO levels in activated macrophage cells (RAW264.7) peaked at 48 h, increasing 2.86-fold (3.14±0.4 μM) at 5 U/ml IFN-γ+5 μg/ml LPS, and 4.74-fold (5.46±0.30 μM) at 10 U/ml IFN-γ+10 μg/ml LPS compared to the non-activated controls (1.15±0.02 μM). The other two cell lines, J774A.1 macrophages and N11 microglia, showed a similar response. We suggest that inflammation increases MGO production, possibly exacerbating arterial stiffness, cardiovascular complications, and diabetes-related cognitive decline.

Adherence to Clinical Practice Guidelines during Dementia Work-Up in a Real-World Setting: A Study from the Registry of Dementias of Girona. - Turró-Garriga, Oriol; Calvó-Perxas, Laia; Vilalta-Franch, Joan; Hernández-Ferrándiz, Marta; Flaqué, Margarita; Linares, Marta; Cullell, Marta; Gich, Jordi; Casas, Isabel; Perkal, Héctor; Garre-Olmo, Josep (J Alzheimers Dis, 2017)
BACKGROUND: There are several position statements and clinical practice guidelines (CPG) for diagnosing dementia. OBJECTIVE: Our aims were to evaluate the adherence to CPG among specialists in the 7 memory clinics included in the Registry of Dementias of Girona (ReDeGi), and to compare the results between 2007-2011 and 2012-2015. We also determined the time and number of visits required to achieve a diagnosis, the supplementary tests ordered, and the drugs prescribed according to dementia subtypes. METHODS: Medical charts of a stratified random sample of 475 ReDeGi cases were reviewed. Basic dementia work-up was evaluated using as a reference evidence-based CPG. An Index of Adherence (AI) was calculated using the following items in the medical chart: cognitive symptomatology; functional disability evaluation; physical examination; neurological examination; psychiatric examination; brief cognitive examination; activities of daily living performance examination; blood test; structural neuroimaging (CT-scan or MRI). RESULTS: The mean AI to CPG among specialists was of 8.2 points, and it improved from 7.9 points in 2007-2011 to 8.5 points in 2012-2015 (Cohen's d = 0.46). A lower adherence was detected in the most severe cases. A dementia diagnosis required 3.5 visits, regardless of the subtype of dementia, although milder cases required more time, more visits, and more supplementary tests than severe cases. CONCLUSION: The adherence to CPG in the catchment area of the ReDeGi is high, and an epidemiological surveillance system such as the ReDeGi may help in improving it. Dementia guidelines should establish procedures adapted to clinical practice, with simplified recommendations for most severe cases.

Alterations in the Peripheral Immune System in Dementia. - Busse, Mandy; Michler, Enrico; von Hoff, Franz; Dobrowolny, Henrik; Hartig, Roland; Frodl, Thomas; Busse, Stefan (J Alzheimers Dis, 2017)
Alterations in the immune response that result in inflammation might play a role in the pathology of dementias. In order to analyze changes of the peripheral immune system associated with different types of dementias, we determined several innate and adaptive cell populations in whole blood using flow cytometry. We included patients with Alzheimer's disease (AD; n = 60), vascular dementia (VaD; n = 20), and frontotemporal dementia (FTD; n = 12) at the time point of diagnosis and 24 age-matched neuropsychiatric healthy persons. Monocytes and NK cells were diminished in VaD, but not in AD and FTD. B cell and T cell numbers were decreased in all investigated forms of dementia. Changes in the contribution of naïve/memory T cells were only present in AD. Correlation and regression analyses revealed associations between altered immune cell populations and Q Albumin as marker for the integrity of the blood-cerebrospinal fluid-barrier, Mini-Mental State Examination values, and age. The peripheral immune system is altered in AD, VaD, and FTD. However, each disorder presents unique changes in the investigated cell types indicating different mechanisms underlying the pathology.