bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome‐wide analysis of longitudinal Alzheimer’s disease biomarker endophenotypes
Authors: Jacobson Tanner Y. , Nho Kwangsik , Risacher Shannon L. , Gao Sujuan , Saykin Andrew J.
Published: December 2020

Background

Alzheimer’s disease (AD) is characterized by a pathophysiological cascade, in part detectable using imaging and fluid biomarkers, that evolves over many years. Our goal was to study the interaction between genetic risk and longitudinal trajectories of selected AD endophenotypes using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset.

Method

Longitudinal data included amyloid beta (PET and CSF), total tau and phosphorylated tau (CSF), FDG PET (3 ROIs), MRI measures of atrophy (8 ROIs) and white matter hyperintensities (WMHI), and composite scores from cognitive tests for memory and executive function (full list of endophenotypes, sample size, and covariates in Table 1). Genetic association with longitudinal phenotypes was performed using Linear Mixed Modelling (LMM; LME4 R package), modeling the SNP main effect and SNP x time effects, with time x subject as a random effect and participant age as the time variable. SNP P‐values from the LMM were analyzed for gene enrichment using MAGMA, with a 10kb boundary around genes for SNP to gene assignment. A stringent significance threshold was set to P ≤ 6.25 × 10−9 based on Bonferroni correction for the top 8 principal components explaining 85% of variance across all tested phenotypes. LD trimming was performed to identify top SNPs for genetic regions. MAGMA gene based association was FDR corrected to P ≤ 0.05.

Result

Multiple genetic regions (26) were associated with the main SNP effect, including the APOE ε4 locus, which was significant on all measures except WMHI. Time interaction identified the APOE ε4 allele as study wide significant with cognitive measures and 5 MRI ROIs. Apart from APOE, 7 SNPs were identified that met genome‐wide significance, including SNPs intronic to BORCS5, HLA‐DPA1, and GRIN3A (Figure 1). Gene based association identified 21 genes, 14 primarily associated with MRI atrophy measures, 3 WMHI, 2 with CSF tau, 1 with amyloid PET, and 1 with cognitive measures (Figure 2).

Conclusion

Genetic association analysis of longitudinal trajectories of AD biomarker phenotypes identified both genes and pathways previously implicated with AD, as well as several novel loci. These findings may point to new targets for diagnostic and therapeutic development.
Cortical atrophy signatures and machine learning MR‐based classification of primary progressive aphasia variants
Authors: Ezzo Rania , Cordella Claire , Dickerson Brad C. , Collins Jessica A.
Published: December 2020

Background

Primary Progressive Aphasia (PPA) is a rare neurodegenerative disorder characterized by progressive language impairment and three clinical phenotypes: semantic variant (svPPA), logopenic variant (lvPPA) and non‐fluent variant (nfvPPA). The goals of the present study were to 1) identify the group brain atrophy “signatures” of each PPA clinical phenotype, 2) determine the degree of individual variability in the spatial extent of atrophy within each clinical phenotype, and 3) explore the ability of a machine learning algorithm to classify patients based on regional atrophy values.

Method

Anatomical MRIs were collected from patients with a clinical diagnosis of svPPA (N=22), lvPPA, (N=21), nfvPPA, (N=18), and age‐matched healthy controls (N=25). Group‐level atrophy “signatures” were created using whole‐brain group GLMs comparing cortical thickness of each PPA variant to the control group. Next, group percent overlap maps were created by binarizing each patient’s z‐normalized atrophy map (relative to the control group, thresholded z<‐1.5), adding those maps together, and then dividing by each group’s N. Finally, a linear support vector machine (SVM) was applied to w‐scored atrophy values (controlling for intracranial volume, age, and sex), from brain regions identified as being most frequently affected within each patient group.

Result

100% of svPPA patients demonstrated atrophy in the left anterior temporal lobe. Atrophy patterns in the lvPPA and nfvPPA groups were more heterogeneous; 80% of lvPPA patients demonstrated atrophy in the left posterior superior temporal, middle temporal, inferior temporal, and fusiform gyri; and 60% of nfvPPA patients demonstrated atrophy in the left pars opercularis, caudal middle frontal, and superior frontal gyri. The linear SVM classified individual patients with a total precision (true positives/true positives+false positives) = 91.6% (svPPA=98.4%, lvPPA=88.2%, nfvPPA=78.3%) and a recall, or sensitivity (true positives/true positives+false negatives) = 90.0% (svPPA=95.45%, lvPPA=88.25%, nfvPPA=76.25%). The features identified as most important for classification were the left temporal pole, middle temporal gyrus, and insula.

Conclusion

Our results provide further evidence that the PPA variants have distinct neuroimaging profiles that can support diagnosis, with svPPA and lvPPA patients exhibiting fairly homogenous atrophy signatures. We further showed that a linear SVM applied to regional atrophy values can classify individual patients with high accuracy.
Clinician‐reported features in MBI/MCI and early dementia in genetic FTLD
Authors: Gottesman Reena T. , Barker Megan S. , Cosentino Stephanie , Manoochehri Masood , Boeve Bradley F. , Boxer Adam L. , Rosen Howard J. , Forsberg Leah , Heuer Hilary W. , Brushaber Danielle , Huey Edward , Rascovsky Katya ,   the ARTFL/LEFFTDS Consortium
Published: December 2020

Background

Frontotemporal dementia (FTD) can present with significant phenotypic heterogeneity. Most cases of sporadic FTD do not present for diagnosis until functional impairment is evident, making it difficult to identify and characterize the earliest features of FTD. Focusing on participants from families with known FTD‐causing pathogenic mutations allows for the characterization of the earliest features of FTD in genetic carriers.

Method

The ARTFL and LEFFTDS consortia (AG063911, AG045390, NS092089, AG016976) are joint, multi‐center cohort studies of patients with FTLD, including symptomatic and asymptomatic family members. For this study, a subset of ARTFL/LEFFTDS participants from families with known genetic mutations were selected if they were determined by a study physician to have (a) a phenotype of Mild Behavioral / Cognitive Impairment (MBI/MCI) and CDR®+NACC‐FTLD = 0.5 (44 participants, 19 C9orf72, 12 GRN, 13 MAPT mutations), or (b) CDR®+NACC‐FTLD = 1 (33 participants, 16 C9orf72, 10 GRN, 7 MAPT mutations). We examined the NACC Uniform Data Set (UDS) B9F form, bvFTD criteria. Pearson chi‐squared tests compared the frequency of identified bvFTD features between MBI/MCI and bvFTD participants.

Result

The most common bvFTD diagnostic criteria features questionably or definitely present in the 44 MBI/MCI participants were Apathy and Disinhibition, both at 30% (Within the early FTLD group: Apathy at 70% and Disinhibition at 72%). Neuropsychological testing deficits consistent with bvFTD were present in 27% (72%), and loss of empathy in 25% (72%). Impaired daily functioning was next at 16% (81%), Ritualistic behaviors were observed in 7%, (36%) and Hyperorality in 5% (33%). Chi‐squared tests revealed significant differences between the two groups for all features, with the largest numerical and statistical difference in impaired daily functioning.

Conclusion

Apathy and Disinhibition were the most common neuropsychiatric symptoms noted in FLTD MBI/MCI. Development of impairments in daily functioning best distinguished the MBI/MCI and FTLD groups. This may be related to the requirement of functional impairment for the diagnosis of dementia. The relative frequency of different features in early dementia of genetic FTLD is similar to that reported in sporadic bvFTD. As more longitudinal data is collected, within‐subject assessment of the development of features in genetic bvFTD over time will be instructive.
White matter disintegration along tracts measured by diffusion tensor imaging in people with MCI
Authors: Haddad Seyyed Mohammad Hassan , Faria‐Pieruccini Frederico , Montero‐Odasso Manuel , Bartha Robert
Published: December 2020

Background

Gradual disintegration of white matter (WM) tracts has been observed in Alzheimer’s disease (AD) by postmortem histological analyses and in‐vivo neuroimaging. Previous diffusion tensor imaging (DTI) studies have shown changes in fractional anisotropy (FA) and radial diffusivity (RD) indicative of microstructural changes in select WM regions in AD and mild cognitive impairment (MCI). However, the precise location of microstructural damage along WM tracts at the early stages of cognitive decline is still unknown. In the current study, DTI metrics along the major WM tracts were measured and compared in healthy elderly and MCI subjects to localize microstructure changes.

Method

Diffusion tensor images (32 directions, b=1000 s/mm2) were acquired on a 3 Tesla Siemens Tim Trio and a 3 Tesla Siemens Prisma Fit MRI scanner in healthy elderly (N=40) and people with MCI (N=44) as part of the Gait and Brain Study in London, Ontario. FA and RD were quantified along 18 major WM tracts in each subject using TRACULA in FreeSurfer. The average FA and RD of each tract were compared between groups using a MANOVA (for FA and RD separately) adjusted for age, sex, education, comorbidity, and MoCA score. If the MANOVA was significant (p<0.05), post‐hoc tests were conducted to identify the tracts on which the DTI metrics differed between the groups. Then, the DTI metrics were examined along these identified tracts to localize observed differences.

Result

The MANOVA detected significant differences in both FA (p‐value=0.018) and RD (p‐value=0.019) in the 18 tracts studied between controls and MCI subjects. Post‐hoc tests showed that specifically, FA in right cingulum‐cingulate gyrus endings (rh_ccg) (Fig. 1) and in left superior longitudinal fasciculus‐parietal endings (lh_slfp), and RD in rh_ccg and left uncinate fasciculus (lh_unc) (p‐value < 0.05) differed between the groups. Comparison along the rh_ccg using t‐test (p‐value < 0.05) revealed that FA and RD differed significantly between the groups in the posterior portion of this tract (Figures 2 and 3).

Conclusion

Tract specific white matter disruption in the cingulum gyrus in people with MCI was localized in the posterior part of the rh_ccg tract adjacent to the posterior cingulate (Fig. 1).
Targeting mitochondrial complex I enhances reserve capacity through super‐complex structural assembly
Authors: Flannery Padraig Flannery , Pichurin Nicholas , Trushin Sergey , Trushina Eugenia
Published: December 2020

Background

Alzheimer’s disease (AD) is a devastating neuropathological condition where age is the greatest risk factor. There is currently an estimated global prevalence upward of 46.8 million individuals and recent efforts to combat the clinical presentation of AD through late‐stage Amyloid‐beta (Aβ) targeted therapeutic intervention has not been successful, underscoring the need for novel approaches to slow disease progression. Accumulating evidence proposes that mitochondrial and metabolic homoeostasis is an early dysfunction which occurs decades before the presentation of clinical symptoms. Indeed AD has been classified as type‐3 diabetes, suggesting the need to target metabolic modifiers to slow or even abrogate neurodegeneration. We have recently reported that targeting the oxidative phosphorylation (OXPHOS) system through mild inhibition of NADH dehydrogenase (Complex I) with our small molecules partial Complex I inhibitors (MCIi) can halt the development of cognitive and behavioral phenotypes associated with AD. We have also demonstrated that this modulation of mitochondrial complex I, through reversible inhibition at the Flavin Mononucleotide (FMN) domain, serves to enhance mitochondrial bioenergetics and function and protects against oxidative stress. We hypothesize that this mechanism of improved bioenergetics may be due to transformed OXPHOS super‐complex assembly, which can lead to a more efficient bioenergetics system and protect against extrinsic stress.

Methods

To test this hypothesis, we examined bioenergetics and the assembly of mitochondrial OXPHOS complexes and super‐complexes in mitochondria from primary cortical neurons and synaptosomes isolated from the brain tissue of non‐transgenic and 3xTgAD mice treated with MCli using respiratory XF Seahorse analysis, BNPAGE and 2D‐BNPAGE.

Results

Our analyses demonstrates that MCIi can acutely alter the assembly of super‐complexes within the OXPHOS system and protect against stress through enhanced spare respiratory capacity while preserving ATP level, which may aid in the enhancement of mitochondrial bioenergetics and function in AD.

Conclusion

Partial complex I inhibitors can induce positive bioenergetics through super‐complex assembly
Feasibility of a health coaching intervention with mobile health technology in older adults with mild cognitive impairment or risk factors for dementia
Authors: Krivanek Taylor , McFeeley Brittany , Daffner Kirk R , Gale Seth A
Published: December 2020

Background

There is growing evidence that adherence to brain‐healthy behaviors can reduce the risk of dementia and rate of decline. Current standard of care, however, does not systematically promote or monitor adherence to brain health guidelines. We recently demonstrated that a health coaching intervention, which included weekly phone calls, facilitated greater adherence to lifestyle recommendations and improved quality of life. The current study is investigating the impact of supplementing health coaching with digital health technology, including a mobile platform and wearable fitness trackers.

Method

In an ongoing six‐month trial, we are measuring the effect of a clinic‐embedded, technology‐augmented health coaching program on adherence to brain health recommendations. Forty patients with mild cognitive impairment (MCI) or risk factors for dementia are being randomized to the Brain Health Champion (BHC) intervention or a counseling and education (CE) control. In BHC, participants work with a health coach to set personalized goals, reinforced by weekly video calls, mobile messaging, and in‐person visits every six weeks. In CE, usual clinical care is supplemented with educational materials mailed every six weeks. Using validated questionnaires, wearable fitness trackers, and photographed food logs, changes in physical activity, diet, and social/cognitive engagement are being determined.

Result

Of the 12 participants enrolled to date, 83% have been adherent to use of mobile technology and fitness trackers. In BHC, 93% of weekly video calls have been completed, and coaches and participants have exchanged an average of 7 text messages per week. BHC participants have been more likely to continue wearing and monitoring their fitness trackers after the required assessment period (75% BHC vs. 40% CE). 66% of all participants report that they would like their doctors to have access to data from mobile health applications, and 56% report that they would like to incorporate mobile health into their regular medical care.

Conclusion

A health coaching intervention for MCI patients and at‐risk older adults using digital health technology is feasible and shows promise for use in wider health care settings. The intervention’s impact on the adoption of brain‐healthy behaviors is being measured and an interim report will be provided.
Regional cerebral perfusion alterations in subjective cognitive decline measured by arterial spin labeling MRI
Authors: Schwarz Claudia , Hetzer Stefan , Benson Gloria , Horn Nora , Wurdack Katharina , Wirth Miranka , Flöel Agnes
Published: December 2020

Background

Individuals with subjective cognitive decline (SCD) are at high risk of developing Alzheimer's disease (AD) (Jessen et al., 2014). Changes in cerebral perfusion, particularly cerebral blood flow (CBF), are a feature of AD and has also been shown in pre‐dementia stages (Binnewijzend et al., 2016). This study investigates regional CBF and its association with cognition in individuals with SCD and healthy older adults.

Method

Cognitive performance and cerebral perfusion were assessed in 81 individuals with SCD (age 68±5 years) and 46 healthy controls (age 71±6 years). Regional CBF (mL/100g/min) was assessed by arterial spin labeling MRI and quantified in AD‐vulnerable regions (Wirth et al., 2016). The preclinical Alzheimer’s cognitive composite (PACC5) and composite scores for selected cognitive domains were calculated. General linear models were conducted to assess group differences in regional CBF as well as associations between regional CBF and cognitive performance. Interaction effect of group and regional CBF on cognitive performance was determined using the same method. All analyses were adjusted for potential confounders (including sex, age, and body mass index).

Result

Participants with SCD showed decreased CBF in the hippocampus (p=.038) and the basal ganglia (p=.014) compared to healthy controls. Moreover, participants with SCD exhibited greater CBF in the inferior temporal gyrus than healthy controls (p=.006). Across all participants, CBF in the basal ganglia was positively associated with executive function (p=.016), memory (p=.018), and PACC5 (p=.001). Exploratory investigations within each group revealed these associations only in healthy controls (p=.032, .037, .004, respectively). However, no effect of group was found on the relationship between regional CBF and cognitive performance.

Conclusion

Our findings indicate that alterations of cerebral perfusion are already detectable in the stage of SCD, in particular in the hippocampus, basal ganglia, and inferior temporal gyrus. In addition, cognitive performance was positively associated with CBF in the basal ganglia across all subjects; however, this effect was mainly driven by the healthy controls. Thus, our findings may point towards early pathological changes affecting the association between regional CBF and cognition in SCD, which needs to be evaluated in further studies.
Endothelial progenitor cells are depleted in older adults with cognitive impairment and white matter volume loss
Authors: Marshall Anisa J. , Gaubert Aimee , Yew Belinda , Ho Jean K. , Jang Jung Yun , Blanken Anna E. , Dutt Shubir , Sible Isabel J. , Kapoor Arunima , Li Yanrong , McIntosh Elissa C. , Rodgers Kathleen E. , Nation Daniel A.
Published: December 2020

Background

Depletion of endothelial progenitor cells (EPCs) has been linked to vascular disease and both mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. EPCs have been shown to support oligodendrocyte precursor cell proliferation in the oligovascular niche, suggesting a potential role in protecting white matter (WM) integrity. We studied the relationship between in vitro EPC proliferation and both WM volume and cognitive function.

Method

Sixty‐three community dwelling older adults (Mage = 70.94; SDage = 7.39), free of dementia or clinical stroke, underwent venipuncture, neuropsychological testing, and brain MRI. Blood leukocyte fractions were cultured over one week in colony forming unit (CFU)‐Hill media to produce EPCs. On the 5th day, colonies were counted. Cognitive function was measured by a comprehensive neuropsychological battery and the Clinical Dementia Rating (CDR) Scale. WM volumes were measured by Region‐of‐interest (ROI) analysis on T1‐MPRAGE scans using FreeSurfer 5.3. Univariate Analysis of Covariance (ANCOVA) compared CFU‐Hill counts and CDR scores, and multiple linear regression analyses determined the relationship between CFU‐Hill counts, neuropsychological tests and WM ROIs, after controlling for age, sex and education.

Result

CFU‐Hill counts were depleted in participants with CDR = 0.5 [F(1, 51) = 5.84, p = 0.02]. Lower CFU‐Hill counts were associated with worse performances on tests of executive functioning [(1) Animals: F(4, 60) = 4.10, p = 0.005; ΔR2 = 0.16; β= 0.41; ΔF = 12.51, p = 0.001; (2) Fruits and Vegetables: F(4, 60) = 4.00, p = 0.006; β=0.36; ΔR2 = 0.12; ΔF = 7.54, p = 0.009; (3) Trails B: F(4, 44)=9.43; p <0.001; β= 0.24; ΔR2 = 0.057; ΔF = 4.69, p = 0.036]. Posterior corpus callosum volume positively predicted CFU‐Hill counts [F(5, 42)=2.62; p =0.038; β= 0.41; ΔR2 = 0.14; ΔF = 7.69, p = 0.008].

Conclusion

Findings suggest EPCs may be linked to impaired cognition and WM volume loss in older adults, potentially implicating EPCs in protecting against vascular‐related WM injury and resulting executive dysfunction. Further studies of EPCs, WM integrity, and executive dysfunction are warranted to evaluate a potential protective role for EPCs in cerebrovascular disease with implications for dementia risk assessment and prevention.
Behavioral RCT using internet‐based social interactions: Why some gain and some do not
Authors: Dodge Hiroko H , Hampstead Benjamin M , Potempa Kathleen , Struble Laura , Asgari Meysam , Silbert Lisa C , Croff Raina , Wild Katherine , Lahna David , Schwartz Daniel L , Kaye Jeffrey , McDonald Mattie , Lindsley Jacob , Team I‐CONECT
Published: December 2020

Background

Increasing social interaction could be a promising intervention for improving the cognitive well‐being of socially isolated older adults. However, we expect that the efficacy of a social intervention can differ across subjects due to personality traits, preference for specific activities, and different pathological stages, even within the same clinical diagnosis. For most behavioral intervention studies, the priority of randomized controlled trials is not necessarily to gain a statistically significant intervention effect, but to find which subjects benefit from the specific intervention. Factoring this potential heterogeneity into the efficacy analysis of randomized controlled trials (RCT) will be discussed.

Methods

Building upon our previously completed NIH‐funded project (ClinicalTrials.gov #: NCT01571427), we developed a multi‐site RCT to examine whether conversation‐based cognitive stimulation has a positive effect on domain‐specific cognitive functions and higher‐order objectively measured IADL (Instrumental Activities of Daily Living). We target socially isolated older adults with either normal cognition or mild cognitive impairment (Internet‐Based Conversational Engagement Clinical Trial (I‐CONECT), ClinicalTrials.gov # NCT02871921). The experimental group engages in semi‐structured video‐chat conversation with trained conversational staff 4 times per week for 6 months (high dose) and twice per week for additional 6 months (maintenance dose). In addition to the main outcomes of neuropsychological test scores, we aim to determine factors which lead to heterogeneities in efficacy including: baseline brain atrophy and connectivity using MRI/fMRI, personality, Apoe genotype, mood and nature of social isolation (emotional vs. structural).

Results

While recruiting socially isolated subjects is challenging, as of January, 2020, our study has reached out 26,000 subjects, screened 195 subjects, and 131 subjects were ultimately randomized with 40% of those being eligible for MRI assessment. Baseline recruitment will continue until March of 2021. Carefully considered outcomes, covariates and mediating factors are being collected in this RCT. This presentation will examine some of the key heterogeneities observed in our ongoing baseline sample, and discuss potential implications these differences may have on our future efficacy analysis.

Conclusions

Our project serves as a reference for developing individualized, targeted community intervention strategies with high adherence with maintainable life style modifications.
Factors affecting computerized cognitive training performance: The relations between age, education level, and repetitive use
Authors: Şahiner Melike , Cınar Nilgun , Şahiner Türker AH
Published: December 2020

Background

Data on CCT performances of the population over 40 is rather complicated. Rehabilitation focused approaches widely believe that repetitive use would improve the CCT performance in time. Yet as evaluation period decreases, the error margin increases, often leading to false positive or negative results. In this study, CCT performances were evaluated according to age, education level and number of repeated courses.

Method

BEYNEX is a non‐commercial web‐application that allows users to do daily cognitive activities, including playing 3 different 5‐minute long computer games and answering questions on ADL. For this study, BEYNEX provided personal access to 100 individuals, who applied online to participate, yet didn’t have any cognition related diagnosis or treatment. The group completed the activities daily, and exercised with a 3‐minute physical exercise video. All exercises designed within the parameters used by clinicians and are completely unique. Patients’ total activity time, ADL and game performances were monitored only by clinicians under 9 different graphics (ADL, Memory, Visual Perception, Speed, Problem‐solving, Flexibility, Attention, Language Skills, Arithmetic). The acceptance criteria was based on completing at least 1 course (*completing 20 minutes of exercises for 33 times) within any period of time.

Result

100 individuals are between the age of 38‐89 and are educated between 5‐18 years. Each completed at least 1 to maximum of 90 courses in total (Fig.1,2). No significant correlation was found between the “number of courses” completed by the individual and 8 cognitive parameters BEYNEX measures. While “Memory, Speed, Flexibility, Attention, Visual Perception” parameters and “Age” showed significant negative correlations, there was no relation with “Problem Solving, Language, Arithmetic” and “Age” parameters. Only “Attention” level parameters shows positive correlation with the “Education Level” increases, (Fig 3).

Conclusion

When monitoring cognitive parameters with CCT, the most important performance indicator is the age of the patient. Exercises should be chosen according to age. The education level of the patient and the effect of exercising are often negligible. The results of this study are promising for diagnostic software. In near future, it may be possible to remotely diagnose with smart software systems which are not affected by repetitive use or education levels.
Lower average daily step count is associated with poorer executive function and rurality in a veteran cohort
Authors: Silbert Lisa C , Wall Rachel C , Beattie Zachary , Dodge Hiroko H , Mattek Nora , Riley Thomas , Kaye Jeffrey
Published: December 2020

Background

An active lifestyle is associated with better cognitive health in older individuals. This relationship is understudied in U.S. Veterans, a population at risk of cognitive impairment due to the high prevalence of associated risk factors and comorbidities. Passive monitoring of daily activities provides objective measures of activity that may serve as a sensitive index of day‐to‐day function and dementia risk.

Method

Participants (age > 57) were enrolled as part of Collaborative Aging Research using Technology (CART), a multi‐site study examining the feasibility of unobtrusive remote sensing and monitoring of physical, cognitive, and health‐related activities. The Veteran cohort consists of volunteers living in largely rural communities in the Pacific Northwest, self‐identified as being a Veteran, and included their cohabitant, if applicable. Daily step counts were acquired using a wrist‐worn device. Baseline one‐month averages were compared with rurality and cognitive function.

Result

114 nondemented participants residing in 67 homes underwent neuropsychological assessment and passive monitoring of daily activities (55% male, age 70.7, MOCA 23.4). 70% resided in a rural area (rural‐urban commuting area (RUCA) score > 4 ) and 29% had > three vascular risk factors. Participants with 14+ days of gait activity measured within a one‐month period near baseline cognitive assessments not using a walker in the home were included (n = 107). Average daily step count obtained over an average of 27.7 days was 3,065 (median 2,515) and was greater in large rural towns compared with small‐isolated rural (p = 0.07) or urban (p = 0.04) towns. After adjusting for potential confounders, lower average daily steps were associated with worse performance in executive function, a relationship observed in Veterans in large rural, but not urban or small rural towns.

Conclusion

In a cohort comprised primarily of rural Veteran’s and their spouses, lower average number of steps per day is associated with poorer executive function and this relationship varied by rurality. Real‐world monitoring of daily activities may identify those at greatest risk of cognitive decline for interventional studies aimed at dementia prevention in older individuals, and is of particular relevance in rural settings, where access to specialty care is limited.
Differential alterations of spatial and nonspatial memory circuits within hippocampal CA1 in 3XTG‐AD mice
Authors: Tian Chengju , Reyes Isabel , Masurkar Arjun V.
Published: December 2020

Background

Area CA1 of hippocampus is highly vulnerable to Alzheimer’s disease (AD), with denser pathology towards the subiculum versus the CA2 border. Spatial and non‐spatial memory processing in CA1 is also segregated along this transverse axis. Towards CA2, deep and superficial CA1 pyramidal neurons (PNs) uniquely process spatial information from medial entorhinal cortex (MEC) and CA3. Towards subiculum, deep and superficial CA1 PNs differentially integrate non‐spatial information from lateral entorhinal cortex (LEC) and CA3. It is unclear how AD affects these distinct processing architectures, and if it is reflective of the known gradient of AD pathology within CA1.

Method

MEC or LEC of 3xTg‐AD (12‐24 month old) and age‐matched wild type (WT) mice were injected with an AAV expressing channelrhodopsin (ChrR2). Acute hippocampal slices were prepared two weeks later. Whole cell patch clamp recordings were performed on deep and superficial CA1 PNs, with MEC or LEC axons optogenetically activated by blue light and CA3 axons activated by extracellular stimulation in stratum radiatum. In separate mice, immunohistochemistry (IHC) was performed for AD pathology.

Result

IHC confirmed increased AD pathology in 3xTg‐AD mice towards subiculum versus CA2. Near CA2, 3xTg‐AD mice (compared to WT) showed reduced MEC input responses in both deep (0.7mV vs. 1.8mV, n=7 each, p<0.05) and superficial PNs (0.8mV vs. 2.0mV, n=8 each, p<0.05). In contrast, CA3 input responses were unchanged in deep PNs but was surprisingly increased in superficial PNs (10.4mV vs. 6.6mV, n=8 each, p<0.05). Near subiculum, 3xTg‐AD mice (compared to WT) showed a reduction in LEC input response only in superficial PNs (0.9mV, n=8, vs. 1.7mV, n=7, p<0.05). Response to CA3 input was also selectively reduced in superficial PNs (3.0mV, n=8, vs. 8.2mV, n=7, p<0.01).

Conclusion

Spatial and non‐spatial memory circuits in CA1 are differentially affected in 3xTg‐AD mice, in a synapse‐ and cell type‐specific manner. Furthermore, they are not merely a direct reflection of AD pathology gradient in CA1, and may be also reflective of indirect or compensatory mechanisms related to the disease. These results also have implications on dysfunctional in vivo activity of CA1 PNs related to AD‐induced memory deficits.
PRADI cohort case‐control study on related factors of Alzheimer’s disease
Authors: Feliciano‐Astacio Briseida E. , Beecham Gary W , Silva Concepcion , Mena Pedro Ramon , Inciute Jovita D. , Tejada Sergio , Adams Larry D. , Rodriguez Vanessa C. , Celis Katrina , Prough Michael , Bussies Parker , Sierra‐Lopez Carolina B. , Contreras Maricarmen , Manrique Patricia , Feliciano Nereida I. , Chinea Angel , McCauley Jacob L , Acosta Heriberto , Vance Jeffery M. , Cuccaro Michael L. , Pericak‐Vance Margaret A. ,   PRADI: Puerto Rico Alzheimer’s disease and related Dementias Initiative
Published: December 2020

Background

Alzheimer’s disease (AD) has become a burden of social and economic importance, affecting millions of families and society at large. The Puerto Rico Alzheimer and Related Dementias Initiatives (PRADI) cohort was developed to investigate AD and genetics factors of AD in the Puerto Rican population. PRADI recruitment was a snowball sampling, with both island‐wide geographic distribution, as well as extensions to PR communities in the continental US. In this study we assessed the relationship between AD and cardiovascular risk factors of AD in the PR population.

Method

We assessed over 700 elderly PR individuals for dementia, as well as medical history. Affection status was assessed using standard AD clinical criteria (NINCDS‐ADRDA) or mild cognitive impairment. All medical history was obtained by a self‐report or informant report. Differences between affected and unaffected were initially tested using a chi‐square test (for sex, diabetes, hypercholesterolemia, heart disease, hypertension, and stroke) and a t‐test for the age of the exam. Follow‐up analyses on stroke were performed using logistic regression with age at exam and sex as covariates in the model.

Result

The analysis revealed no differences sex differences between AD and unaffected (p‐value > 0.05). Similarly, affected and unaffected showed similar levels of type 2 diabetes, hypercholesterolemia, heart disease, and hypertension (p‐value > 0.05). Affected individuals did however show an increase in stroke incidence (14.0% vs 5.2%; p‐value = 8.3e‐5). This difference persisted even when controlling for age of exam and sex. We did see a difference in age of exam between cases and controls, but this is likely due to ascertainment scheme.

Conclusion

This analysis suggests that stroke may be a contributing factor to dementia in the PR population. However, given biases in the ascertainment scheme, additional assessments need to be performed. Additionally, work is ongoing to assess the role of ancestry and genetic factors in this association.
Analysis of individual families implicates noncoding DNA variation and multiple biological pathways in Alzheimer’s disease risk
Authors: Wijsman Ellen M. , Day Tyler R. , Thornton Timothy A. , Horimoto Andrea R. , Blue Elizabeth E. , Bis Josh C. , Sohi Harkirat K. , Nato Alejandro Q. , Nafikov Rafael A. , Navas Patrick , Saad Mohamad , Tsuang Debby W. , Barral Sandra , Vardarajan Badri N. , Beecham Gary W. , Martin Eden R. , van Duijn Cornelia M. , Pericak‐Vance Margaret A. , Mayeux Richard ,   Alzheimer’s Disease Sequencing Project
Published: December 2020

Background

Late‐onset Alzheimer’s disease (AD) is a complex disorder with multiple genetic risk factors. Linkage and association analysis have mapped dozens of loci in pooled analysis of many pedigrees or large numbers of unrelated cases and controls. Identification of the underlying DNA risk variants in the regions of interest (ROIs) has been complicated by both the genetic heterogeneity and the cost, until recently, of comprehensive DNA sequencing in ROIs. The known loci also leave much heritability unexplained.

Method

We used the families in the AD Sequencing Project (ADSP) discovery family sample to identify variants of interest from whole genome sequences (WGS), and through the variants, genes implicated in risk. We used SNP‐based multipoint linkage analysis to identify ROIs with rare VOIs, carrying out analysis without trimming pedigrees. We pursued all ROIs with family‐specific lodmax scores >1.9, reducing the variants of interest by several filters. We carried out pedigree‐based genotype imputation from the available WGS data, followed by family‐based association analysis, filtered for low population minor allele frequency. We prioritized genes with a low false‐discovery rate for association of single‐cell transcription in brain with AD disease state (PMID:31209304), and genes with high expression in bulk brain (PMID: 24309898).

Result

We obtained 46 distinct ROIs representing lodmax1.9‐3.5 per ROI in each of 26 of the 110 ADSP discovery families analyzed. 29 ROIs further investigated in 16 of the families yielded 59 prioritized genes, with 1‐11 genes/ROI. Only 4 out of 321 variants that passed all filters in these genes were in exons, with minimal overlap with genes identified in AD GWASs. Only one ROI occurred in two families, with evidence for a shared‐haplotype between these families, implicating FBXO2 and FBXO44. Both genes are implicated in ubiquitination, while FBXO2 interacts with BACE1. Multiple pathways, both known and new, are implicated, including the ubiquitin‐proteasome system, neural development and maintenance, and mitochondrial functions.

Conclusion

This analysis underscores the evidence for extensive genetic heterogeneity and rare variants underlying AD risk, along with multiple potential mechanisms. The preponderance of prioritize non‐coding variants suggests alterations in gene regulation and/or expression as an aspect of AD genetic risk.
Trajectory of clinical symptoms accelerates after 10 years of amyloid
Authors: Birdsill Alex C. , Koscik Rebecca L. , Cody Karly Alex , Betthauser Tobey J. , Erickson Claire M. , Chin Nathaniel A. , Christian Bradley T. , Carlsson Cynthia M. , Asthana Sanjay , Johnson Sterling C.
Published: December 2020

Background

Understanding the time between amyloid biomarker detection and the onset of cognitive and functional symptoms will be critical in making care planning decisions and determining an optimal time period for potential interventions. Previous studies have suggested that amyloid, as measured with Pittsburg compound B (PiB), can be detected 15‐20 years before symptom onset. However, the designs of these studies do not—on an individual basis—provide an understanding of the duration between amyloid accumulation and symptom onset. Recent research from several groups has suggested that the rate of amyloid accumulation is consistent across individuals, making it possible to estimate the chronicity of amyloid positivity from a single PET scan. In relation to this measure of amyloid chronicity, we examined trajectories of cognitive and functional symptoms, as measured by the Clinical Dementia Rating Scale (CDR).

Method

The sample included 347 study visits from 84 amyloid positive (A+) participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention or the Wisconsin Alzheimer’s Disease Research Center (Table 1). For participant visits that administered the Quick Dementia Rating System (QDRS), the equivalent CDR sum of boxes (CDR‐SB) score was calculated. A mixed effects model with random slope and intercept was used to evaluate the association between chronicity and CDR‐SB (with covariates APOE4 carriage, sex and baseline age). To investigate potential non‐linearity in chronicity’s association with CDR‐SB, a chronicity‐by‐baseline chronicity category (<0, 0‐5, 5‐10, 10‐15, 15‐20 and >20 years) interaction was examined (<0=reference range).

Result

Spaghetti plots display the trajectories of CDR‐SB values in relation to amyloid chronicity; shading indicates clinical guidelines for interpreting CDR‐SB (Figure 1). The results of the model indicate that the trajectory of CDR‐SB is significantly greater after 10 years of amyloid chronicity (Table 2 & Figure 2).

Conclusion

Largely consistent with previous studies, the results indicate that clinical symptoms begin to emerge after 10 years of amyloid positivity. However, symptom severity appeared to vary greatly between 10 – 30 years of amyloid chronicity. Future research will aim to identify other processes that may contribute to decline as well as genetic and modifiable factors that may promote resiliency and delay the onset of clinical symptoms.
Surface‐based amyloid and tau correlates of digital clock drawing performance
Authors: Mayblyum Danielle V. , Sanchez Justin S , Thibault Emma G. , Jacobs Heidi I.L. , Farrell Michelle E. , Rubinstein Zoe B. , Buckley Rachel F. , Sperling Reisa A. , Rentz Dorene M. , Papp Kathryn V. , Johnson Keith A.
Published: December 2020

Background

Using a digital pen to record performance on neuropsychological tasks allows for the capture of much more subtle and nuanced aspects of cognitive performance. Previous research showed that lower DCTClock summary score was associated with greater entorhinal tau in clinically‐normal older adults (CN) (Rentz, AAIC 2019). Additionally, spatial reasoning was related to elevated entorhinal tau, inferior temporal tau, and neocortical amyloid. Given the observed cognitive heterogeneity in early stages of AD, we explored the relationship between different aspects of digital clock performance and amyloid and tau pathology across the cortical surface.

Method

CN from the Harvard Aging Brain Study completed both a spontaneous (COM) and copy (COP) clock drawing test using a digital pen. We used a summary score (DCTScore) and four main composite scores (drawing efficiency, simple motor, information processing and spatial reasoning) calculated by Digital Cognition Technologies. Participants also underwent [11C]PiB‐PET (n = 112) and [18F]T807‐PET (n = 116) acquisition within one year of cognitive testing. We utilized a vertex‐wise analysis with a cluster‐wise multiple comparison correction (minimum cluster extent=100mm2) and a threshold of ‐log(p)>2 to analyze relationships with clock scores across the vertices, adjusting for age, sex, and education.

Result

Lower DCTScore strongly correlated with greater amyloid signal in the frontal lobe, with some significant clusters also observed within the lateral temporal and inferior parietal cortices (Figure 1). Lower DCTScore also related to elevated tau signal in the right lateral temporal and inferior parietal lobes. Tau was most strongly associated with COM spatial reasoning score in the right lateral temporal lobe (Figure 2), reflecting known functional associations with this region; this was not reflected with COP spatial reasoning scores.

Conclusion

In clinically‐normal older adults, lower scores on clock drawing were associated with greater cortical amyloid and tau. Lower spatial reasoning scores were related to tauopathy, but only in spontaneous clock drawing, supporting the notion that more complex cognitive tasks are compromised earlier in the clinical continuum. More fine‐grained measurements of cognition using digital tasks in relation to neuroimaging markers has the potential to improve our understanding of the pathogenesis of early AD.
Cerebrospinal fluid phosphorylated tau interacts with MMP2 and MMP3: Associations with cognitive performance in older adults
Authors: Meier Shelby E. , Khan Omair A. , Liu Dandan , Bown Corey W. , Moore Elizabeth E. , Pechman Kimberly R. , Acosta Lealani Mae Y. , Bell Susan P. , Blennow Kaj , Zetterberg Henrik , Gifford Katherine A. , Hohman Timothy J. , Jefferson Angela L.
Published: December 2020

Background

Matrix metalloproteinases (MMPs) are enzymes that facilitate extracellular matrix remodeling. In Alzheimer’s disease (AD), the MMP system becomes dysregulated and may contribute to disease pathophysiology; however, limited work has examined clinical consequences of MMPs. Thus, we investigated cerebrospinal fluid (CSF) MMP2, MMP3, and MMP9 concentrations in relation to cognitive performance as well as the interaction between MMPs and AD core neuropathology (CSF amyloid beta (Aβ42) and phosphorylated tau (p‐tau)) on cognitive outcomes.

Methods

Vanderbilt Memory and Aging Project participants free of clinical dementia underwent fasting lumbar puncture for CSF acquisition and neuropsychological assessment (n=153, 73±7 years, 67% male). CSF samples were analyzed in batch using commercially available ELISAs. Linear regression models individually related CSF MMP levels to neuropsychological performance, adjusting for age, sex, race/ethnicity, education, cognitive diagnosis, Framingham Stroke Risk Profile, and apolipoprotein E (APOE)‐ε4 carrier status. Models were repeated with CSF Aβ42 and p‐tau concentrations as interaction terms.

Results

Increased CSF MMP9 related to worse language (p‐values<0.03) and episodic memory performances (p=0.03); however, CSF MMP2 and MMP3 main effects were null (p‐values>0.07). CSF Αβ42 did not interact with MMP2, MMP3, or MMP9 concentrations on any neuropsychological outcome (p‐values>0.09). By contrast, CSF p‐tau interacted with CSF MMP2 and MMP3 levels on language performance (p‐values<0.02), and CSF p‐tau interacted with CSF MMP2 levels on episodic memory performance (p=0.01). Increased CSF MMP2 and MMP3 associations with worse language and episodic memory performances were driven by p‐tau negative participants, whereas (unexpectedly) increased CSF MMP2 was associated with better language performance among p‐tau positive participants.

Conclusion

Among older adults without clinical dementia or stroke, increased CSF MMP9 related to worse cognitive performance, suggesting extracellular matrix remodeling may be one pathway underlying the development of cognitive impairment. CSF p‐tau, but not Αβ42, interacted with MMP2 and MMP3 concentrations on cognitive performance. P‐tau may interact with MMPs on clinical expression of pathology in complex ways, such that increased CSF levels of MMPs may only be associated with worse cognition in non‐demented older adults in the absence of concomitant neuropathology. Funding: Alzheimer’s Association IIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373.
Resistance exercise improves cognitive and brain health in overweight older adults
Authors: Furlano Joyla , Nagamatsu Lindsay
Published: December 2020

Background

Approximately 50% of Canadian older adults over the age of 60 are overweight or obese (based on body mass index; BMI). Individuals with high BMI (≥25) often experience cognitive and brain deficits (e.g., impaired memory, cortical atrophy, reduced neural activation), and are at high risk of dementia. One promising lifestyle intervention that may improve these deficits is exercise. For example, 6 months of aerobic training has been found to improve cognitive and brain function in overweight older adults, however studies examining whether resistance training (RT) can produce comparable results in this population is limited.

Method

We conducted a 6‐month, thrice‐weekly randomized controlled trial of RT in overweight older adults. Twenty‐four participants aged 60‐80 (sedentary; BMI ≥25) were randomized into one of two groups: 1) progressive resistance (weight) training, or 2) balance and tone (BAT; control; stretching exercises). At pre‐ and post‐intervention (0 and 6 months, respectively), we measured associative memory performance during functional MRI, and obtained high resolution T1 weighted structural images from a 3T scanner.

Result

Six months of RT showed significant improvements in memory performance (6.38% reduced error rate) compared to BAT. Similarly, structural imaging showed increased hippocampal volume for RT (+0.04%) as well as increased percent signal change (neural activation) in memory‐related brain regions of interest, including the hippocampus, parahippocampal gyrus, lingual gyrus, and medial temporal gyrus, suggesting improved functional brain health overtime.

Conclusion

Overall, our findings offer a feasible, cost‐efficient lifestyle intervention strategy to improve cognitive and brain health in overweight older adults.