bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive dysfunction induced by ketamine and xylazine anesthesia is associated with tau hyperphosphorylation following CaMKII activation
Authors: Brouillette Jonathan , Hector Audrey , McAnulty Christina , Piche‐Lemieux Maude‐Eloise , Alves‐Pires Claire , Buée‐Scherrer Valérie , Buee Luc
Published: December 2020

Background

Recent studies indicate that anesthesia is likely to contribute to the development and exacerbation of neurodegenerative disorders such as Alzheimer’s disease (AD). Although it is well established that tau hyperphosphorylation is induced following anesthesia and is a major neuropathological hallmark of AD, the relationship between tau pathology and post‐anesthetic memory impairment remains unclear. The main objective of this study was to determine if tau phosphorylation and cognitive function in mice are altered by ketamine/xylazine, a common regimen of general anesthesia used in animal research and veterinary medicine.

Method

Mice were anesthetized with intraperitoneal (ip) injections of ketamine/xylazine, and tau phosphorylation was evaluated in hypothermic and normothermic conditions 1 h and 6 h following anesthesia. To delineate the mechanisms underlying tau phosphorylation, we assessed by electrophoresis the levels of phosphorylation and activity of various kinases and phosphatases known to regulate tau phosphorylation. Post‐anesthetic memory deficits induced by ketamine/xylazine were examined in two different behavioral paradigms, the Y maze and passive avoidance task (PAT).

Result

Ketamine and xylazine have an additive and rapid effect on the phosphorylated state of tau. Mechanistically, we found that activation of calmodulin‐dependent protein kinase II (CaMKII) is the major upstream molecular event leading to tau hyperphosphorylation following ketamine/xylazine anesthesia in mice. Moreover, we observed that intracerebroventricular (icv) injection of the selective CaMKII inhibitor KN93 attenuated tau hyperphosphorylation and post‐anesthetic memory deficits induced by ketamine/xylazine in the Y maze and PAT paradigms. Ketamine/xylazine also had a marked impact on many other key molecular signaling pathways involving ERK, GSK3, STEP, Akt, Src, and the GluN2B subunit of the NMDAR.

Conclusion

This study demonstrates that cognitive impairments induced by ketamine/xylazine exposure are associated with tau hyperphosphorylation mainly through CaMKII activation in mice. Our results also revealed major molecular and cognitive effects of the widely used anesthetic ketamine/xylazine in animal research and veterinary practice, and call for high precaution and careful monitoring when used in laboratory animal settings to avoid artifactual results.
Ventricular anteroposterior ratio is the most reliable feature to differentiate bvFTD from healthy controls and other dementias
Authors: Manera Ana Laura , Dadar Mahsa , Collins Louis , Ducharme Simon
Published: December 2020

Background

Using morphometric analysis, we recently found ventricular expansion to be the most prominent differentiator of behavioural‐variant frontotemporal dementia (bvFTD) from healthy controls and a potentially sensitive marker of disease progression [Manera et al. 2019]. Here, we performed volumetric analysis on the lateral ventricles to find a reliable differentiator of bvFTD from Alzheimer’s Disease (AD), mild cognitive impairment (MCI), the language variants of FTD (Semantic‐Variant, SV, and Progressive‐Nonfluent‐Aphasia, PNFA), and controls.

Method

We included 825 subjects (59 bvFTD, 28 SV, 30 PNFA, 322 MCI, 127 AD, and 259 controls) with a total of 3800 timepoints from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI). Lateral ventricles were automatically segmented for all timepoints, using a previously validated pipeline. Using a lobe atlas, ventricular volumes (VV) were calculated for frontal, parietal, temporal, and occipital lobes in the left and right hemispheres. Using coronal slice y=120 in the brain atlas, ventricles were also divided into anterior and posterior halves. All volumes were normalized for intracranial volume and log‐transformed to achieve normal distribution. Regression models were used to assess volumetric and ratio differences between cohorts at baseline (Model1:feature∼1+Diagnostic‐Group+Age+Sex). Longitudinal mixed‐effects models were used to assess longitudinal differences in ventricular features (antero‐posterior ventricular ratio and total VV) between bvFTD and other cohorts (Model2:feature∼1+ Diagnostic‐Group +Age+ Diagnostic‐Group:Age+Sex+1|ID). The variables of interest were Diagnostic‐Group (Model 1) and the interaction between Diagnostic‐Group and Age (Diagnostic‐Group:Age, Model 2). ID was considered as a categorical random effect. All results were corrected for multiple comparisons (Bonferroni).

Result

Figures 1 and 2 show the volumetric and ratio differences between cohorts. Controlling for age and sex, the antero‐posterior ratio was the only feature that was significantly different in bvFTD (Mean±SD:1.37±0.47) compared to all other diagnostic groups (Controls:1.00±0.24,p<0.001; MCI: 0.97±0.22,p<0.001; AD: 0.92±0.22,p<0.001; SV:1.00±0.22,p<0.001; PNFA:1.12±0.48,p=0.004). Total ventricle volume increased with age in all cohorts (p<0.001,Figure 3). bvFTD patients showed a faster increase in the ventricular antero‐posterior ratio compared to all other diagnostic groups (Figure 4, p<0.01).

Conclusion

The antero‐posterior ratio of the lateral ventricles, in both cross‐sectional and longitudinal analyses, was the most reliable ventricular feature differentiating bvFTD from controls and other dementias.
Depression accelerates longitudinal progression of hippocampal atrophy and cognitive decline in preclinical Alzheimer’s disease
Authors: Park Jee Eun , Byun Min Soo , Yi Dahyun , Lee Jun Ho , Byeon Gihwan , Jung Gijung , Lee Jun‐Young , Kim Yu Kyeong , Sohn Chul‐Ho , Lee Dong Young
Published: December 2020

Background

Although depression is very common in the preclinical stage of Alzheimer’s disease (AD), it is still unclear whether depression moderates the progression of AD or not. In the present study, we aimed to investigate the moderation of depression on the relationship between β‐amyloid (Aβ) deposition and progression of hippocampal atrophy and cognitive decline in cognitively normal (CN) older adults.

Method

Two‐hundred eighty nine CN older adults (55–90 years; 48.4% female; 14.2% Aβ+) from an ongoing prospective cohort study, the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), were followed up for 24 months. All participants underwent annual clinical assessments on depressive symptoms and cognitive function, and biennial [11C] Pittsburgh compound B‐PET and three‐dimensional MRI scans. Depression was defined based on the following: 1) depression diagnosed by a psychiatrist, 2) Geriatric Depression Scale score ≥ 11, or 3) the presence of any depressive symptom on Neuropsychiatric Inventory.

Result

Among the subjects, 73.4% (n = 212) were followed up for two years and twelve converted to mild cognitive impairment. Association between Aβ and depression was not observed at baseline. There was a significant Aβ positivity x Depression x Time interaction effect on hippocampal volume (F = 4.252, p = 0.042) and verbal memory (F = 7.488, p = 0.007) even after controlling for age, sex, educational level, APOE genotype, subjective memory complaint, and baseline white matter hyper intensity volume. Aβ positive individuals with depression showed faster decline of hippocampal atrophy and verbal memory decline than those in other subgroups for two years.

Conclusion

The findings indicate that the presence of depression may accelerate hippocampal atrophy and episodic memory loss in older adults with preclinical AD.
The IUSM‐Purdue Alzheimer’s Disease Drug Discovery Center: A member of the NIH‐funded TREAT‐AD consortium
Authors: Palkowitz Alan David , Lamb Bruce T. , Oblak Adrian L. , Reeves Cristian A. Lasagna , Territo Paul R. , Rizzo Stacey J. Sukoff
Published: December 2020

Background

The Target Enablement to Advance Therapeutics for Alzheimer’s Disease (TREAT‐AD) Consortium is a newly formed NIA initiative designed to accelerate the discovery of new medicines for Alzheimer’s Disease. It is comprised of two drug discovery centers: OPEN‐AD and the Indiana University School of Medicine‐Purdue University Alzheimer’s Disease Drug Discovery Center (IUSM‐Purdue ADDD Center). The strategic goal of the consortium is to integrate sophisticated capability for early drug discovery and contribute to a broad study of emerging Alzheimer’s Disease target hypotheses to create new classes of potential therapeutics.

Method

The TREAT‐AD consortium will establish itself as a strategic and operational partner for the NIA‐Funded AMP‐AD, MODEL‐AD other AD directed translational research programs. By design, this will provide drug discovery capability to bridge the foundational work in target discovery (AMP‐AD) with newly discovered molecules characterized in next generation AD animal models based on human pathology, genetics and translational biomarkers (MODEL‐AD). Additionally, the TREAT‐AD consortium will make all data and research tools available to the scientific community to catalyze new research efforts.

Result

The IUSM‐Purdue ADDD Center has assembled a world‐class team of scientists and capabilities that will pursue a research strategy focusing on neuro‐immune pathways implicated in Alzheimer’s Disease with the following aims: Create a dynamic portfolio of well characterized AD drug discovery targets representing novel intervention hypotheses that capitalizes on significant investments in basic research and emerging disease understanding. Perform advanced pre‐clinical target validation and enablement studies to prioritize the best opportunities for therapeutic discovery. Create high quality and well characterized Lead molecules for prioritized targets that meet rigorous milestone criteria and are valued opportunities for further translational investment. Create a robust and flexible data sharing platform to enable global researchers with data and Target Enablement Packages to expand on the work of the Center.

Conclusion

This presentation will provide an overview of the TREAT‐AD Consortium and the scientific strategy and plans for the IUSM‐Purdue ADDD Center.
Lifetime cigarette smoking and later‐life brain health: The population‐based 1946 British Birth Cohort
Authors: James Sarah‐Naomi , Lane Christopher A , Parker Thomas D , Keshavan Ashvini , Buchanan Sarah M , Keuss Sarah E , Cash David M , Malone Ian B , Barnes Jo , Sudre Carole H , Coath William , Prosser Lloyd , Nicholas Jennifer M , Murray‐Smith Heidi , Wong Andrew , Hughes Alun , Chaturvedi Nishi , Fox Nick C , Richards Marcus , Schott Jonathan M
Published: December 2020

Background

Cigarette smoking is implicated as a risk factor for dementia, but the underlying mechanisms are poorly understood. In a population‐based sample free of dementia, we examine associations between smoking patterns over the life course and imaging markers associated with dementia.

Method

Dementia‐free participants from Insight 46 (n=458, 49% female, age 69‐71), a sub‐study of the 1946 British Birth Cohort, underwent 18F‐florbetapir Aβ‐PET and multi‐modal MR imaging including T1, T2, FLAIR and multi‐shell diffusion‐weighted sequences. Information on smoking frequency and cessation (current/former/never) were obtained at multiple timepoints, spanning ages 15‐69 years. Pack‐years were calculated as number of cigarettes smoked/day divided by 20, multiplied by years of smoking. Age and sex adjusted regression analyses examined relationships between smoking metrics and later‐life imaging measures; including Aβ‐PET status, brain, hippocampal and white matter hyperintensity (WMH) volumes, normal appearing white matter (NAWM) fractional anisotropy (FA), mean diffusivity (MD), neurite density index (NDI) and orientation dispersion index (ODI), and Alzheimer’s disease (AD)‐related cortical thickness.

Result

Increased smoking pack‐years was associated with alterations in NAWM microstructure metrics (lower FA and NDI; higher MD and ODI) and smaller brain and hippocampal volume (Figure 1). There was no significant relationship with Aβ‐PET status (OR=0.99 [95% CI 0.97,1.01]), WMH volume or AD‐related cortical thickness (Figure 1). Unlike current smokers (n=16, 3%), former smokers (n=285, 61%) had comparable NAWM microstructure metrics to those who had never smoked (n=163, 35%).

Conclusion

In a population‐based sample without dementia or other major neurological problems, increased smoking frequency and duration over 50 years was associated with altered white matter microstructural metrics, and smaller brain and hippocampal volumes. However, there was no evidence that smoking was associated with markers of AD pathology (amyloid‐PET, AD‐related cortical thickness) or cerebral small vessel disease (WMH). Former smokers were comparable to non‐smokers on measures of microstructural metrics, suggesting that smoking‐related microstructural changes may at least partly be reversible. Stopping or reducing smoking may help reduce risks to brain health via microstructural pathways.
Computerized neuropsychological tests undertaken on digital platforms are cost effective, achieve high engagement, distinguish and are highly sensitive to longitudinal change: Data from the PROTECT and GBIT studies
Authors: Hampshire Adam , Ballard Clive , Williams Gareth
Published: December 2020

Background

Cost effective and sensitive neuropsychological measures are needed for cohort studies and clinical trials.

Method

10,000 people from the PROTECT on‐line cohort study (people > 50) in the UK participated in a longitudinal study of computerized neuropsychology using the PROTECT and COGTRACK batteries (attention, sustained attention, working memory, executive function, episodic memory, reaction time). A factor analysis mapped tasks to key cognitive domains and evaluated changes associated with age and MCI. Monte Carlo methodology was used to identify the best composite for sensitivity to change in cognitively normal individuals (training set) and in MCI. Using ADNI methodology the sample size required to detect a 25% treatment effect with 80% power to a 5% level of significance was determined. The GBIT study is a collaboration with the BBC using a digital platform to assess people across the lifespan. The assessment included computerized neuropsychological assessment (same domains assessed in PROTECT), and a lexicon assessment.

Result

10,714 people participated (73% female, mean age 61.7). The 5 factors were confirmed, and performance on these domains was highly correlated with increasing age (p<0.0001) and distinguished MCI from cognitively normal individuals (p<.0001). 92% of participants completed follow‐up neuropsychological testing. An optimal composite of 8 items spanning these domains achieved an effect size of 0.50 for change at 1 year in the 9051 individuals with normal cognition, requiring 1017 participants per arm for a prevention RCT. The same composite achieved an effect size of 0.83 for 1 year change in 783 people with stage 2 or stage 3 MCI, requiring 360 people per arm for an RCT. Power was further improved over 2 years, with enrichment factors and with repeated testing to reduce variability. The GBIT study recruited >240,000 participants, identifying age related decline in all aspects of cognitive function, except the lexicon which increased with age. Lifestyle factors significantly influenced age related changes.

Conclusion

Digital platforms provide a cost effective ($4 per participant per year) and engaging way to conduct cohort studies and clinical trials. Computerized neuropsychology on digital platforms achieved high levels of sensitivity to change with clear advantages for clinical trials.
A single‐ and multiple‐ascending dose study to evaluate the safety and pharmacokinetics of oral PU‐AD, an epichaperome inhibitor to treat Alzheimer’s disease
Authors: Silverman Michael , Wallner Barbara , Key Cassandra , Duggan Susan M. , Reynolds Laurie
Published: December 2020

Background

Breakdown of regulatory pathways designed to prevent aggregation and accumulation of disease‐associated proteins contributes to or causes Alzheimer’s Disease (AD). Under these conditions epichaperomes form and take control of pathological pathways. PU‐AD is a small‐molecule, orally bioavailable inhibitor specific to epichaperomes with little or no effect on normal cells, and has shown dramatic beneficial effects in animal models of AD. We describe the first‐in‐man trial of PU‐AD.

Objectives

This Phase 1, double‐blind, placebo‐controlled, single and multiple‐ascending dose study evaluated the safety and pharmacokinetics (PK) of single and multiple doses of oral PU‐AD.

Methods

Cohorts of 8 subjects were randomly assigned to active treatment or placebo in a 6:2 ratio. Single doses of oral PU‐AD were 10 mg, 20 mg, and 30 mg in healthy subjects ages 18‐60 years, and daily doses of 20 mg and 30 mg daily for 7 days in healthy subjects >59 years old. Safety was evaluated through observation of adverse event incidence and severity; and changes from baseline in clinical laboratory test results, vital signs, physical examinations, or electrocardiogram results. Plasma PK parameters of PU‐AD were determined, and cerebrospinal fluid (CSF) was sampled for PU‐AD concentration and for biomarkers of neurodegenerative disease in the multiple‐dose cohorts.

Results

PU‐AD was well‐tolerated, with an adverse event profile comparable to that of placebo. No adverse events were serious, severe, or led to withdrawal of dosing. Additionally, there were no other clinically significant safety findings to report. PK was dose‐proportional between 10 mg to 30 mg and showed minimal accumulation with repeated dosing. CSF analyses will be presented.

Conclusion

PU‐AD, a novel and selective epichaperome inhibitor shown to be efficacious in animal AD models, warrants further evaluation in an AD population. This first‐in‐man trial demonstrated that PU‐AD is well‐tolerated, has favorable plasma PK and CSF exposure, and is a candidate for advancement into Phase 2A trials in AD populations to evaluate target engagement and pharmacological effects.
Relation between alpha‐synuclein and core CSF biomarkers in Alzheimer's disease
Authors: Monge‐Argilés José Antonio , García‐Ayllón María‐Salud , García Victoria Monge , Rueda Francisco Navarrete , Robles Jorge Manzanares , Gasparini‐Berenguer Ruth , Leiva‐Santana Carlos , Romero‐Lorenzo Raquel , Sáez‐Valero Javier
Published: December 2020

Background

Up to 50% of Alzheimer´s disease (AD) cases exhibit significant Lewy bodies (LB) pathology in addition to plaques and tangles. It has been hypothesized that Aβ, tau and alpha‐synuclein (α‐syn) proteins promote the accumulation of one another. We evaluated the relation between those CSF proteins in a well‐characterized patient mild cognitive impairment (MCI) cohort.

Method

Between 2010‐2015, we included 81 MCI patients (Petersen criteria 2006) from the out‐patient consultation of Neurology Service in University General Hospital of Alicante and 18 control subjects. After a long term follow‐up (mean: 53 months), 25 patients were diagnosed with stable MCI, 32 MCI due to AD (MCI‐AD) and 24 MCI due to Lewy body dementia (MCI‐LBD). Levels of central core AD‐CSF biomarkers Aβ1‐42 (Aβ42), T‐tau (total‐tau) and P‐tau [phospho‐tau (181P)] were measured using ELISA (Innotest, Innogenetics/Fujirebio). Determination of α‐syn levels in CSF were performed using the LEGEND MAXTM human α‐synuclein ELISA kit (BioLegend, San Diego, USA). Rho of Spearman correlation coefficients among CSF protein levels were evaluated.

Result

CSF α‐syn significantly positively correlated with T‐tau (Rho= 0.41, p=0.17 ) and P‐tau (Rho=0.57, p=0.001) exclusively for MCI‐AD patients. As expected, the tau proteins significantly positively correlated between them in every patient ΄s group and control subjects. No other significant correlations were found.

Conclusion

The exclusive correlation between CSF α‐syn and tau protein levels in MCI‐AD patients, support a pathophysiologic connection between the metabolisms of these proteins, even at the early stages of the illness. In our opinion, the role of α‐syn should be included into the new pathogenetic theories of AD.
The association between overall social support availability and memory by age and sex: An analysis of the Canadian Longitudinal Study on Aging
Authors: Ohman Avery Arres , Maxwell Colleen J , Tyas Suzanne L , Oremus Mark
Published: December 2020

Background

Accompanying rapidly aging populations is an increase in the prevalence of age‐related memory decline. Modifiable factors such as social support availability (SSA) are important to study because they may affect memory function. However, the impact of SSA on memory may vary by sex or age, and evidence on the topic has not been gathered from large‐scale, population‐based studies of middle‐ and older‐aged adults. This cross‐sectional study explores whether the association between overall SSA and memory differs by sex or age group in 45‐ to 85‐year old persons recruited into the Canadian Longitudinal Study on Aging (CLSA).

Method

The Comprehensive Cohort of the CLSA (n=30,097) is comprised of adults recruited within 25‐50 kilometers of 11 urban centres across Canada. We used multiple linear regression to explore the association between memory (measured using the Rey Auditory Verbal Learning Test immediate [REY I] and delayed recall [REY II]) and SSA (measured using the 19‐item Medical Outcomes Survey‐Social Support Survey), controlling for sociodemographic, health‐related, and health behaviour covariates. The analyses incorporated the CLSA’s weight and strata variables to account for the complex sampling design. We built separate models by age group (45‐54, 55‐64, 65‐74 and ≥75 years) and sex (males, females) to assess effect modification.

Result

Results demonstrated positive associations between SSA and memory. For sex, the regression coefficients (β) were larger for males versus females: REY I (β 0.09, 95% confidence interval [CI] 0.06‐0.12; β 0.06, 95% CI 0.03‐0.09, for males and females, respectively); REY II (β 0.07, 95% CI 0.03‐0.10; β 0.03, 95% CI 0.00‐0.07, for males and females, respectively). The strongest associations by age were observed in the 65‐74 age group for REY I (β 0.08, 95% CI 0.04‐0.12) and the 45‐54 age group for REY II (β 0.07, 95% CI 0.02‐0.11).

Conclusion

Results indicate that individuals with higher levels of SSA might have better memory function, with larger effects observed in males versus females, and varying effects observed by age group. This research points to subgroups that may benefit optimally from social support initiatives developed to promote healthy cognitive function.
The effect of APOE ɛ2/ɛ4 genotype on the incidence of Alzheimer's disease (AD) and mild cognitive impairment (MCI) in African Americans
Authors: Ren Dianxu , Lopez Oscar L. , Lingler Jennifer , Conley Yvette
Published: December 2020

Background

The APOE Ɛ2Ɛ4 genotype has been recently reported to associate with increased risk of AD and MCI among non‐Latino whites besides the effects of increased risk of Ɛ4 allele (Ɛ3Ɛ4, Ɛ4Ɛ4). However, there was no study to date on the effects of the Ɛ2Ɛ4 genotype among African American population. The purpose of this study was to examine the associations of APOE Ɛ2Ɛ4 with incident AD dementia and incident of Mild Cognitive Impairment (MCI) among African Americans using the large national dataset from National Alzheimer’s Coordinating Center (NACC).

Methods

We used NACC dataset from 2005 to September 2019 and restricted our analysis to subjects who were African Americans, had an APOE genotype available, first visit with dementia free for AD cohort and both dementia and MCI free for MCI cohort, had a minimum of one follow‐up visit. The subjects were classified into 4 groups based on APOE genotyping: Ɛ2Ɛ4, Ɛ2 (Ɛ2Ɛ2, Ɛ2Ɛ3), Ɛ4 (Ɛ4Ɛ4, Ɛ3Ɛ4), with Ɛ3Ɛ3 carriers serving as the reference group. Cox proportional hazard models were performed to examine the associations of APOE Ɛ2Ɛ4 with incident AD and MCI respectively after controlling age, gender, education, baseline cognitive status and year of initial visit. Adjusted hazard ratio (aHR) and 95% confidence interval (CI) were reported.

Results

Among AD cohort (N = 2,007), Ɛ2Ɛ4 accounted for 4.9%, Ɛ2/2 and Ɛ2/3 15%, Ɛ3/4 and Ɛ4/4 34.3%, and Ɛ3Ɛ3 45.8%. Over an average of 4.6 years follow‐up, 216 (10.8%) developed AD dementia with the range from 6.3% to 15.7% across 4 groups. Comparing to Ɛ3Ɛ3 carriers, Ɛ2Ɛ4 carriers had a similar risk of incident AD (7.1% vs 8.9%; aHR = 0.85, 95% CI (0.39, 1.84), P = 0.679). Among MCI cohort (N = 1,480), the average follow‐up was 4.5 years and 336 (22.7%) developed MCI with the range from 20.8% to 26.5% across 4 groups. Comparing to Ɛ3Ɛ3 carriers, Ɛ2Ɛ4 carriers had a similar risk of incident MCI (21.1% vs 20.8%; aHR = 0.88, 95% CI (0.51, 1.50), P = 0.637).

Conclusions

Unlike the effects on non‐Latino whites, APOE Ɛ2Ɛ4 genotype is not associated with the increased risk of AD and MCI among African Americans.
Cross‐sectional differences in symptomatic presentation and cognitive performance among participants with LATE‐NC compared to FTLD‐TDP
Authors: Teylan Merilee , Mock Charles , Gauthreaux Kathryn , Culhane Jessica E. , Chen Yen‐Chi , Chan Kwun Chuen Gary , Kukull Walter A. , Nelson Peter T , Katsumata Yuriko
Published: December 2020

Background

Transactive response DNA‐binding protein 43 (TDP‐43) is misfolded and aberrantly phosphorylated in FTLD‐TDP. It is also the key proteinopathic feature in limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC). There has been some controversy as to the similarities and differences between FTLD‐TDP and LATE. We examined how the symptomatic presentation and cognitive performance compare between autopsy‐confirmed LATE‐NC and FTLD‐TDP.

Method

Participants with LATE‐NC or FTLD‐TDP were identified at autopsy using data from the National Alzheimer’s Coordinating Center Neuropathology Data Set v10. Participants were excluded if they had other rare neuropathologic diseases or had their last clinic visit greater than 36 months from their date of death. Presence of cognitive, behavioral, and motor symptoms were compared among those with a dementia diagnosis at their last visit. Linear regression analyses with generalized estimating equations were run to test for mean differences between the two groups on five cognitive domain z‐scores (episodic memory, attention/working memory, executive function, semantic memory, global composite score) calculated from neuropsychological test scores at their last visit. Models were stratified based on global CDR score (CDR=0.5‐1, 2‐3) and adjusted for neuropsychological test battery, age at death, sex, years of education, Alzheimer’s disease neuropathologic change, presence of Lewy bodies, and presence of microinfarcts.

Result

We identified 233 LATE‐NC and 86 FTLD‐TDP participants. LATE‐NC participants were older at death and more likely to be an APOE ε4 carrier than those with FTLD‐TDP. Dementia participants with LATE‐NC were less likely to demonstrate language impairment, apathy, disinhibition, and personality changes, but were more likely to have visuospatial impairments, visual hallucinations, and delusions compared to FTLD‐TDP participants. Examining the differences in mean cognitive domain z‐scores, participants with LATE‐NC and a global CDR score of 0.5‐1 performed significantly better in the language domain compared to those with FTLD‐TDP. Significant differences in mean z‐scores were not observed among other cognitive domains, or among participants with a global CDR score of 2‐3.

Conclusion

In this sample, there were symptomatic differences between LATE‐NC and FTLD‐TDP among participants with dementia. Difference in the language domain could be detected in mild stages of impairment through neuropsychological test scores.
Whole brain generative model identifies neurotransmitter alterations underlying Alzheimer's disease progression
Authors: Khan Ahmed F , Palomero‐Gallagher Nicola , Zilles Karl , Medina Yasser Iturria
Published: December 2020

Background

Alzheimer’s disease (AD) involves heterogeneous aberrations in multiple biological processes, although their causal molecular mechanisms are not fully understood. As the primary neuronal signalling molecules, neurotransmitters regulate a variety of biological processes pathological in AD, such as the coupling between neural activity and vascular response. However, due to the infeasibility of mapping most neurotransmitters in‐vivo, alterations during disease progression are not well characterized. We propose multi‐modal, subject‐specific models of neuroimaging alterations as functions of local neurotransmitter concentrations, which we combine with clinical data to identify specific neurotransmitters prominently altered during AD progression.

Method

(1) We used the methods described in [Iturria‐Medina et al., Neuroimage, 152:60–77, 2017] to pre‐process longitudinal neuroimaging data (amyloid β and tau protein distributions, cerebral blood flow, r‐fMRI, glucose metabolism, and grey matter density) for 141 healthy and 302 diseased subjects from ADNI. (2) Using the densities of 15 neurotransmitter receptors from multiple cortical areas [Palomero‐Gallagher & Zilles, Neuroimage, 197:716–741, 2019] and 4 serotonin‐type PET templates [Lanzenberger et al., Biological psychiatry, 61(9):1081–1089, 2007], we built subject‐specific, generative models of changes in neuroimaging in terms of (i) other neuroimaging modalities, (ii) network propagation, and (iii) first‐order receptor‐moderated interactions. (3) By evaluating the monotonicity of receptor‐associated coefficients with aging‐related cognitive measures (memory performance, executive function, MMSE, CDR, and ADAS), we identified receptors with a significant causal role in AD progression.

Result

Notably, the model explains 50%‐77% of observed variance in all imaging bio‐markers across clinical groups (HC, EMCI, LMCI, AD). Significant receptor‐imaging interactions with AD progression were identified for (i) NMDA and cholinergic receptors for amyloid distribution, (ii) nicotinic acetylcholine and serotonergic receptors for tau distribution, (iii) glutamatergic NMDA and D1 dopaminergic receptors for blood flow, (iv) GABAergic, cholinergic, dopaminergic and serotonergic receptors for neural activity, (v) GABA receptors for glucose metabolism, and (vi) GABAergic and serotonergic receptors for gray matter density.

Conclusion

A generative, multi‐modal neuroimaging model including 19 receptors allowed, for the first time, the in‐vivo identification of receptor alterations underlying AD progression and its associated cognitive/clinical deterioration. Critically, identified receptors are significant molecular controllers of typical multi‐modal alterations in AD (including tau and amyloid accumulation, vascular dysregulation, and extended brain atrophy).
Effects of azeliragon on ADAS‐cog and CDR domains and individual items in patients with mild Alzheimer's disease and type 2 diabetes (T2D)
Authors: Burstein Aaron H. , Dunn Imogene , Gooch Ann M. , Valcarce Carmen
Published: December 2020

Background

Azeliragon, an oral antagonist of the receptor for advanced glycation endproducts (RAGE), was evaluated in an 18‐month Phase 3 study as a treatment for patients with mild Alzheimer’s disease (AD) (the STEADFAST Study). Post‐hoc analyses in a T2D subgroup (HbA1c ≥ 6.5%) found that azeliragon‐treated patients exhibited less cognitive decline (ADAS‐cog11), less whole brain atrophy, less hippocampal atrophy, less ventricular enlargement, and reduced plasma inflammatory cytokine concentrations compared to patients treated with placebo. The current retrospective exploratory analysis was performed to evaluate ADAS‐cog and CDR symptom domains and individual test items to ascertain which were sensitive to treatment effects.

Method

STEADFAST was a randomized, double‐blind, placebo‐controlled trial in 875 patients with probable mild AD (MMSE 21‐26, CDR global 0.5‐1) receiving stable acetylcholinesterase inhibitors and/or memantine, evaluating the efficacy and safety of 18 months of treatment with azeliragon 5 mg/day relative to placebo. STEADFAST included two separate studies (A‐Study completed as planned, B‐Study prematurely terminated following negative results from the A‐Study) under a single protocol. Patients in the A‐Study with T2D (HbA1c ≥ 6.5%) were analyzed with mean changes from baseline calculated for ADAS‐cog11 and CDR individual item and symptom domain scores. Standard effects sizes were determined using Cohen d. Treatment differences in Month 18 change from baseline were evaluated using both t‐test (presented herein) and Wilcoxon test.

Result

Forty‐seven patients (26 azeliragon, 21 placebo of whom 19 and 17 had Month 18 data) were analyzed. ADAS‐cog Language and Praxis domains were nominally significantly different favoring azeliragon (p=0.01 and p=0.049, respectively) with Cohen d values of 0.86 and 0.66. A trend for less decline in the Memory domain (p=0.07, effect size 0.62) was noted. No significant differences were noted on CDR cognitive or functional domains. Nominal significant differences favoring azeliragon were noted for ADAS‐cog comprehension (p=0.005, effect size 0.99), ideational praxis (p=0.012, effect size 0.84) and spoken language (p=0.067, effect size 0.62) items and the CDR Memory item (p=0.032, effect size 0.73).

Conclusion

Results suggest that azeliragon may have benefits over placebo with less decline in memory, language, and praxis over 18 months in patients with mild AD and T2D.
Specific signatures of circulating extracellular vesicles emerged as novel biological tools for the detection of biomarkers for MCI and Alzheimer's disease
Authors: Ramassamy Charles
Published: December 2020

Background

Alzheimer’s disease (AD) is characterized by a series of overlapping pathophysiological cascades, including the aggregation of β‐amyloid plaques and the formation of neurofibrillary tangles derived from hyperphosphorylated tau proteins. Actually, the search for peripheral biomarkers for AD that reflect AD‐related processes in the brain has received considerable attention but the clinical utility of blood‐based biomarkers is not validated. Accumulating evidence supports the central role of exosomes or extracellular vesicles (EVs) in the pathophysiology of AD. In the brain, they can act as vehicles for the cell‐to‐cell transfer of the AD pathogenic proteins. Our objectives were to demonstrate that some proteins cargo in the circulating EVs represent a great potential in harbor disease‐specific molecular signatures of brain disorders, making them an ideal source of biomarkers.

Method

We have isolated EVs from plasma (pEVs) of control, MCI and AD subjects at different stages of the disease (mild, moderate, severe). Then, their size, shape and density were characterized by transmission electronic microscopy and nanoparticles tracking analysis (NTA). The presence of pEVs specific proteins TSG101, CD63, GAPDH were confirmed by Western Blot and AD‐related proteins were quantified by Luminex assay.

Result

Our data showed that the levels of these proteins were higher in pEVs than in plasma indicating that the pEVs represent a sensitive tool to screen peripheral biomarkers. We observed a reduction of tTau in pEVs from MCI subjects while the APP concentration was reduced in pEVs from MCI and early AD. Interestingly, pTau‐T181 and APP concentrations in pEVs were correlated with cognitive performances (MMSE , MoCA). Aβ42 and pTau‐T181 levels in pEVs were unchanged in MCI but elevated in moderate AD patients compared to controls. Abnormal levels of APP and pTau‐T181/tTau ratio in pEVs levels demonstrated good accuracy to define MCI and AD staging.

Conclusion

Taken together, these results demonstrated that the identification of these proteins in pEVs could have great implication in differentiating MCI individuals to AD patients and to monitor the disease progression. This work was supported by the Chaire Louise & André on Alzheimer’s disease, Foundation Armand‐Frappier (CR) and CIHR grant (TF).
Differences in structural and functional DMN connectivity in amyloid‐positive AMCI who converted to AD dementia
Authors: Balthazar Marcio Luiz Figueredo , Magalhaes Thamires Naela Cardoso , Rezende Thiago Junqueira Ribeiro , de Campos Brunno , Ramalho Luciana , Joaquim Helena Passarelli Giroud , Talib Leda Leme , Forlenza Orestes Vicente , Cendes Fernando
Published: December 2020

Background

Default Mode Network (DMN) has emerged as a potential biomarker of Alzheimer’s disease (AD), but it is not clear if it can differentiate amnestic mild cognitive impairment (aMCI) in the spectrum of AD (with altered amyloid‐ aMCI‐Aβ+) who will evolve to dementia.

Methods

34 aMCI subjects with evidence of AD pathophysiology (low Aβ42 < 540 pg/mL) were followed for a median of 13 months. All subjects had CDR score of 0.5 (with an obligatory memory score of 0.5), poor performance on RAVLT, considering age and education and Fazekas Scale 0 or 1. White Matter (WM) microstructure was evaluated by diffusion tensor imaging ‐ DTI MultiAtlas; FC by UF2C; HV by Freesurfer softwares. We considered conversion from aMCI to AD dementia if CDR score changed from 0.5 to 1. We performed MANOVAs to differentiate the groups, considering age and time of reevaluation as covariables. Afterwards, we analyzed ROC curves with the variables that were significantly different between the groups.

Results

We found 8/34 converters (23.5%). Converters were older (p=0.049), but no other differences were found regarding sex, education, time of reevaluation and global cognitive performance in the first evaluation between the groups. aMCI‐Aβ+ converters had higher levels of tau (p=0.035), p‐tau (p=0.011) and a tendency to have smaller right HV (p=0.07). We did not find any significant result concerning DMN FC. However, we found that right cingulum parahippocampal bundle radial diffusivity was higher in aMCI‐Aβ+ converters (p=0.017), indicating myelinic dysfunction. Regarding ROC curve analyses, all significant variables showed moderate diagnostic accuracy: right cingulum parahippocampal bundle (AUC = 0.806), t‐tau (AUC = 0.788) and p‐tau (AUC = 0.706).

Conclusion

We found that structural (right parahippocampal cingulum bundle) but not functional DMN connectivity alterations may differentiate aMCI‐Aβ+ subjects who converted to AD dementia.
Type 2 diabetes and dementia in the Health and Retirement Study: A Mendelian randomization approach
Authors: Ware Erin B , Bustamante Ana Cristina Morataya , Fu Mingzhou , Bakulski Kelly M
Published: December 2020

Background

Type 2 diabetes mellitus (T2DM) and dementia are leading causes of mortality and disability in the US. T2DM has been associated with dementia; however, causality has not been established. The aim of this study is to test for an association between T2DM and dementia status using a Mendelian randomization approach.

Method

Participants from the 2010 wave of the longitudinal Health and Retirement Study, a nationally representative survey of US adults over the age of 50, and who were of European or African genetic ancestry were included in the study (n=10,571). History of T2DM was self‐reported. Cognitive status was defined from clinically validated cognitive assessments as dementia, cognitively impaired non‐dementia, or normal cognition. Cumulative genetic risk for T2DM and dementia was determined using polygenic risk scores. Multivariable logistic regression was used to test the association between cumulative genetic risk for T2DM and cognitive status adjusting for age, sex, education, APOE‐ε4 carrier status, and genetic principal components. The inverse variance method was used to test inferred causality using Mendelian randomization.

Result

Among included participants, 20.75% had T2DM and 21.8% had dementia or cognitive impairment. Among European ancestry participants, T2DM was associated with 1.28 times odds of cognitive impairment non‐dementia (95% confidence interval: 1.09‐1.50) relative to normal cognition. A one standard deviation increase in cumulative genetic risk for T2DM was associated with 1.43 times higher odds of T2DM (95% confidence interval: 1.33‐1.54). Cumulative genetic risk for T2DM was not associated with dementia status or cognitive‐impairment non‐dementia in either ancestry (P>0.05); lack of association here is an important assumption of Mendelian randomization. Using Mendelian randomization, we did not observe evidence for an inferred causal association between T2DM and cognitive impairment (odds ratio: 1.08; 95% confidence interval: 0.86‐1.37).

Conclusion

Consistent with prior research, T2DM was associated with cognitive status. In the current study; however, evidence for inferred causality was not observed. Prevention of T2DM and cognitive decline are critical for public health.
Mendelian randomization of smoking behavior on cognitive status among older Americans
Authors: Bakulski Kelly M , Fu Mingzhou , Faul Jessica D , Jin Yuan , Ware Erin B
Published: December 2020

Background

Smoking is associated with dementia status, and smoking behavior has a genetic component. In this study, we jointly test the associations between cumulative genetic risk for smoking, smoking behavior, and cognitive status.

Method

We conducted a cross‐sectional study using the 2010 wave of the Health and Retirement Study. First, we used logistic regression to test the relationship between cumulative genetic risk for smoking and current smoking behavior. Second, we tested the association between smoking behavior and cognitive status. Third, we checked the assumption that cumulative genetic risk for smoking was not associated with cognitive status. All analyses were adjusted for age, sex, years of education, rural/urban residence and five ancestry‐specific genetic principal components. Analyses were stratified by ancestry. Finally, a Mendelian randomization framework was used to test inferred causal relationships between smoking behavior and cognitive status via genetic instruments.

Result

Among European ancestry participants (n = 8,735), one standard deviation increase in smoking polygenic score was associated with 1.28 times odds of current smoking behavior (95% confidence interval: 1.18, 1.38) relative to never smoking. Current smoking was associated with 1.62 times odds of cognitive impairment (95% confidence interval: 1.29, 2.01) relative to never smokers and those with normal cognition. No association was observed between smoking polygenic score and cognitive status, an important assumption of the Mendelian randomization framework. Using the smoking genetic instrument, a significant inferred causal relationship was observed between current smoking and cognitive impairment (P=0.02, 1.53 odds ratio, 95% confidence interval: 1.07, 2.18).

Conclusion

These findings demonstrate current smoking is likely causally related to cognitive impairment. Promotion of smoking cessation is important for public health and brain health specifically. Studies on dose and duration of smoking on cognition are critically needed, as well as in research non‐European ancestries.
Association of metabolic syndrome and cognitive function in a population‐based cross‐sectional study of adults aged 60 years or older
Authors: Karanth Shama D. , Katsumata Yuriko , Nelson Peter T. , Kryscio Richard J. , Schmitt Frederick A , Slade Emily , Vsevolozhskaya Olga , Fardo David W. , Abner Erin L.
Published: December 2020

Background

Metabolic syndrome (MetS) is defined by the presence of five cardiovascular risk factors: diabetes, hypertension, high body weight, and hypercholesterolemia. Each factor has been reported to associate with cognition, but the association of MetS with cognitive function is not well understood. The current study explored the association of MetS with cognition in a nationally representative sample of elderly adults in the United States.

Method

Cross‐sectional data from the National Health and Nutrition Examination Survey (NHANES 2011‐2014) were obtained for participants age ≥60 years. MetS was defined per American Heart Association criteria (≥ 3/5 factors). Cognitive performance was based on components of the Consortium to Establish a Registry in Alzheimer’s disease (CERAD) neurocognitive battery. A composite z‐score was calculated for each CERAD component; z‐scores were then averaged to estimate global cognition (Figure 1). Memory complaint was based on self‐report. Linear regression models were fit to evaluate the association between global cognition and MetS, and logistic regression was used to evaluate the association of memory complaint with MetS; we used survey statistics to account for the complex NHANES sampling design.

Result

Included participants (n=2593) were mean 69.4 years old; 54.8% (n=1318) were female. MetS was present in 60.9% (n=1633) of participants. After adjustment for age, sex, race/ethnicity, education, alcohol use, poverty, marital status, and memory complain, MetS was associated with almost 1/3 standard deviation lower mean global cognition compared to participants with no MetS factors (β= ‐0.28; 95%CI ‐0.46,‐0.10), while participants with 1‐2 MetS conditions had similarly lower cognitive scores relative to participants with none (β= ‐0.23; 95%CI ‐0.42,‐0.04) (Table 1). After adjustment for age, sex, race/ethnicity, education, alcohol use, poverty, marital status, and z‐score, MetS was not significantly associated with memory complaint (OR=0.90; 95%CI 0.33, 2.45).

Conclusion

Our findings suggest that MetS was associated with lower cognitive performance in older adults, but this association may be modified by participant characteristics. Participants who did not meet criteria for MetS but had 1‐2 risk factors showed similar cognitive performance to those with MetS, so focusing on dichotomous MetS classifications may obscure cognitive risks for those individuals who don’t fully meet the MetS criteria.
Trends in sex/gender differences across whites, blacks, and Hispanics
Authors: Avila Justina F , Rentería Miguel Arce , Vonk Jet MJ , Manly Jennifer J
Published: December 2020

Background

We determined if later birth year is associated with an increased verbal memory advantage for women and examined whether childhood socio‐economic status (CSES) and adult socio‐economic status (ASES) explain secular trends similarly across Whites, Blacks, and Hispanics.

Method

Participants were 5,258 non‐Hispanic White (White), non‐Hispanic Black (Black), and Hispanic men and women in the Washington/Hamilton Heights Inwood Columbia Aging Project (WHICAP) who were administered neuropsychological tests of memory at 18 to 24 month intervals for up to 25 years. Multiple‐group latent growth curve modeling examined trajectories across birth cohorts (before 1925 vs 1925 and later) within sex/gender by race/ethnicity subgroups after adjusting for immigration status (yes/no). Factor scores for CSES (parental education, occupation, and sibship size) and ASES (educational attainment, income, and occupational status) were examined as potential mediators.

Result

Overall, people born after 1925 and women had higher initial memory performance than people in the earlier birth cohort and men, respectively. However, the benefit of later birth year was restricted to White men and women and Black women, and there was no benefit among Black men or Hispanic men and women. White and Black women demonstrated a similar memory advantage over White and Black men, respectively. This advantage widened for Black women in the later born cohort, but remained similar for later born White women. Hispanic men and women obtained similar memory scores across birth cohorts. While earlier birth year was associated with more rapid rate of decline across racial/ethnic groups, men and women within each birth cohort declined at the same rate. The influence of birth cohort on memory was fully mediated by CSES for White men and mediated by ASES among White and Black women.

Conclusion

The verbal memory advantage of women varies across and within birth cohorts and racial/ethnic groups. Later birth year was associated with an increased memory advantage for Black women over Black men. Secular trends were differentially explained by childhood and adult SES for White men and White and Black women.