bluuebunny/crossref_metadata_2025 huggingface dataset:
Lower baseline cerebral oxygen extraction and metabolic rate are associated with faster cognitive decline and brain atrophy over a longitudinal follow‐up period
Authors: Robb W Hudson , Khan Omair A. , Ahmed Humza A. , Cambronero Francis E. , Kim Darcie S , Houston Michelle , Shah Krish U , Pechman Kimberly R. , Liu Dandan , Gifford Katherine A. , Hohman Timothy J. , Jefferson Angela L.
Published: December 2022

Background

Oxygen extraction fraction (OEF), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2) are complexly interrelated. Low OEF and CMRO2 are promising early indicators of Alzheimer’s disease (AD) pathophysiology. To better understand how alterations in cerebral oxygen utilization relate to abnormal brain aging, we investigated baseline oxygen metabolism variables (OEF, CBF, CMRO2) in relation to longitudinal cognition and brain structure, and if these associations were different among individuals at genetic risk for sporadic AD (i.e., apolipoprotein E (APOE)‐ε4 carriers).

Methods

Vanderbilt Memory and Aging Project participants (n=244, 74±7 years, mean follow‐up=3.7 years) underwent serial neuropsychological testing and multimodal 3T brain MRI. We used T2‐relaxation‐under‐spin‐tagging to calculate OEF and pseudo‐continuous arterial spin‐labeling to assess grey matter CBF. CMRO2 was calculated as: CMRO2=OEF*CBF*arterial oxygen content. Linear mixed‐effects regression models related time x oxygen metabolism variable (one predictor per model) to longitudinal cognitive and brain MRI outcomes. Models were adjusted for baseline age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive status, intracranial volume (for MRI outcomes), APOE‐ε4 status, and time. Models were repeated testing anAPOE‐ε4 status x oxygen metabolism variable x time interaction term.

Results

Lower baseline OEF was associated with faster hippocampal atrophy (p=0.02). Lower baseline CBF was associated with faster cortical thinning in regions susceptible to AD‐related neurodegeneration (p=0.008). Lower baseline CMRO2 was associated with faster language decline (p=0.01) and hippocampal atrophy (p=0.01) and inferior lateral ventricle volume increase (reflecting faster atrophy of adjacent tissue; p=0.02). OEF interacted with APOE‐ε4 status on executive function (p=0.002), language (p=0.006), and visuospatial performances (p=0.02), and inferior lateral ventricle volume (p=0.007). CBF interacted with APOE‐ε4 status on executive function performance (p=0.0003). CMRO2 interacted with APOE‐ε4 status on temporal lobe volume (p=0.03). In stratified models, lower baseline OEF and CMRO2 tended to relate to faster brain health decline among APOE‐ε4 carriers.

Conclusions

Lower OEF, CBF, and CMRO2 are associated with worse brain health trajectories over a 4‐year follow‐up. Assessing oxygen metabolism variables in combination may provide more comprehensive insight into longitudinal brain aging and serve as an early biomarker of disease, particularly among older adults at genetic risk for AD.

Funding

T32‐AG058524, IIRG‐08‐88733, R01‐AG034962, R01‐NS100980
ABCA7*V1599M variant in 5xFAD mice mediates differences in amyloid‐beta pathology and reactive gliosis
Authors: Butler Claire Ann , Javonillo Dominic I , Houchin Lauren A , Kawauchi Shimako , Phan Jimmy , Da Cunha Celia , Tran Katelynn , Milinkeviciute Giedre , Tenner Andrea J , LaFerla Frank , MacGregor Grant R , Green Kim N
Published: December 2022

Background

In several large genome‐wide association studies (GWAS), genetic polymorphisms of ATP‐binding cassette transporter subfamily A member 7 (Abca7) have been identified as a risk factor for late‐onset Alzheimer’s Disease (LOAD). ABCA7 is a member of a family of ATP‐binding cassette (ABC) transporters and functions as a transmembrane protein mediating the release of cholesterols and phospholipids from cellular membranes. Previous studies have also proposed its role in mediating phagocytic clearance of amyloid beta (Aβ) oligomers within macrophages in the brain.

Method

To study the effects of ABCA7 on the development of AD relevant pathologies we introduced an equivalent coding sequence change that has been identified as a risk variant for LOAD (V1613M) into the C57BL/6 mouse genome using CRISPR/Cas9 (V1599M). We set out to characterize the ABCA7V1599M variant and investigate its impact on AD pathology when crossed with 5xFAD transgenic mice, generating four distinct groups: WT, ABCA7V1599M homozygous, 5xFAD, and 5xFAD x ABCA7V1599M homozygous. Characterization was performed using histological staining and biochemical approaches.

Result

Coronal brain sections from 4‐month‐old mice (n=5‐6 mice/sex/genotype) revealed significantly reduced burden of dense‐core Aβ plaques in confocal images of both subiculum and visual cortical regions of 5xFAD x ABCA7V1599M mice compared to 5xFAD mice characterized by reduced Thioflavin‐S staining. Biochemical analysis mirrored these findings and demonstrated reductions of both soluble and insoluble Aβ40 and Aβ42 levels within these same brain regions. To examine reactive gliosis to plaque burden, we immuno‐stained for ionized calcium binding adaptor molecule 1 (IBA1) and glial fibrillary protein (GFAP) to visualize microglia and reactive astrocytes, respectively. Confocal analysis revealed reduced densities of both IBA1+ microglia and GFAP+ reactive astrocytes within subiculum and cortical regions of 5xFAD x ABCA7V1599M mice compared to 5xFAD mice. We also found reduced plaque‐associated neuritic damage in 5xFAD x ABCA7V1599M mice upon immuno‐staining for lysosome‐associated membrane glycoprotein 1 (LAMP1) to examine neuritic dystrophy

Conclusion

Together, these results characterize the effects of the Abca7em1Aduci
allele and its ABCA7V1599M missense mutation on 5xFAD‐mediated pathology, specifically in Aβ plaque development, glial morphology, and neuritic damage.
The role of Tau RNA complex formation in tau function and tauopathy disorders
Authors: McMillan Pamela , Benbow Sarah J , Uhrich Rikki , Baum Misa , Strovas Timothy J , Baker Jeremy D , Kraemer Brian C
Published: December 2022

Background

Pathological tau characterizes Alzheimer’s disease, FTLD‐tau, and other tauopathy disorders. Canonically, tau functions as a microtubule binding and stabilizing protein. The molecular mechanisms of tau mediated neurodegeneration remain incompletely understood. Recent studies from our group and others have shown that RNA binding proteins modulate the severity of tau pathology. Further, RNA has previously been demonstrated to drive tau aggregation in vitro. We hypothesize that tau itself may interact physically with RNA and/or RNA binding proteins, thereby altering tau MT related functions.

Methods

We employed biophysical and biochemical approaches to measure tau/RNA binding. To generate reagents for characterizing tau RNA complexes (TRCs) in human disease, we raised monoclonal antibodies as a tool to assess the formation of tau RNA complexes in human disease and animal models of disease.

Results

We show tau binds single stranded RNA with high affinity but low sequence specificity. Tau seems to bind RNA homopolymers with higher affinity that with tubulin (α/β) dimers. Since poly(A) RNA is the most abundant RNA homopolymer in living cells and known poly(A) RNA binding proteins modulate tauopathy phenotypes, we investigated the ability of poly(A) RNA to form complexes with tau in vitro. Incubation of purified tau with poly(A) RNA promotes the formation of TRCs that appear as oligomeric tau species (N= ∼6‐20) by size exclusion chromatography. Tau binding to RNA inhibits tau microtubule polymerization activity. We generated a monoclonal antibody against purified TRCs and generated a conformation dependent monoclonal antibody called TRC35 that recognizes purified AD fibril tau over recombinant non‐fibrillar tau. Poly(A) binding proteins control TRC35+ accumulation in tau transgenic mice. We observe TRC35+ tau deposits in a wide variety of tauopathy disorders including Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration, and Pick’s disease.

Conclusions

Tau binds RNA with high affinity. This tau RNA binding activity antagonizes tau action as microtubule stabilizing protein. Tau RNA binding stimulates tau oligomerization and the formation of a disease relevant conformational epitope. Poly(A) RNA binding proteins modulate TRC35+ deposits of pathological tau in model systems and Alzheimer’ s disease. TRC35+ lesions occur in diverse tauopathy disorders.
English language proficiency and patterns of use as related to cognitive change in native Spanish speakers of the Hispanics/Latinos of the Hispanic Community Health Study/Study of Latinos‐Investigation of Neurocognitive Aging
Authors: Lamar Melissa , Tarraf Wassim , Wu Benson , Perreira Krista M , Lipton Richard B. , Khambaty Tasneem , Cai Jianwen , Llabre Maria M , Gallo Linda C , Daviglus Martha L , González Hector M
Published: December 2022

Background

Given mixed results regarding the role of bilingualism in cognitive aging, investigators are increasingly studying continuous measures of bilingualism (e.g., levels of language proficiency or use) as opposed to a dichotomous “yes/no” one, to better characterize the bilingual experience. We investigated associations of continuous measures of bilingualism and cognition.

Method

Eligible Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants self‐reported their and their parents’ birth outside the 50 United States and Spanish as their first language, and used Spanish for baseline cognitive testing at their HCHS/SOL visit (2008‐2011) and comparable cognitive testing 7‐years later as part of the SOL‐Investigation of Neurocognitive Aging (SOL‐INCA; 2015–2018). Composite scores for baseline self‐reported Spanish/English language proficiency (reading/speaking) and patterns of use (thinking/socializing) were rated using a Likert scale from 1 = only Spanish to 4 = English>Spanish. Cognitive testing at both visits included test‐specific and a global composite score(s) of verbal learning and memory, Word Fluency, and Digit Symbol Substitution (DSS). Survey linear regression models examined the associations between our two bilingualism scores (separately) and cognition (at follow‐up, and standardized measures of 7‐year change) adjusting for age, sex, education, depressive symptoms, income, Hispanic/Latino background, and field center.

Result

There were 4,005 eligible participants (unweighted mean SOL‐INCA population age∼56 years, 56% female). Higher levels of second‐language (English) proficiency (β = 0.050, SE = 0.015, p<0.001) and patterns of use (β = 0.035, SE = 0.010, p<0.001) were associated with higher levels of global cognition at follow‐up (Figure), specifically, Fluency and DSS (p‐values<0.001). Only higher levels of second‐language proficiency were associated with better than predicted change in cognition, specifically, Fluency (β = 0.060, SE = 0.023, p<0.01).

Conclusion

In an analytic sample of mid‐ to late‐life native Spanish speakers currently living in the US, second‐language (English) proficiency and patterns of use at baseline were associated with better cognitive outcomes over seven years of follow‐up. Associations of bilingualism composites and cognition suggest distinctions in the bilingual experience may differentially relate to level versus 7‐year change in cognition for Hispanics/Latinos. Investigations of foreign language learning on cognition in older adults, some of which have found no cognitive benefit, may be enhanced by using continuous measures of second‐language proficiency and, perhaps, patterns of language use.
Effects of multilingualism on cognition among older Indian adults in the nationally representative LASI‐DAD study
Authors: Petrosyan Sarah , Renteria Miguel Arce , Manly Jennifer J , Narayanan Shrikanth , Lee Jinkook
Published: December 2022

Background

Multilingualism is hypothesized to protect late life cognition such that older multilinguals demonstrate better cognitive functioning compared to monolinguals. However, several studies have failed to find evidence of a multilingual advantage among aging populations. Methodological differences such as inconsistent accounting of critical environmental and sociocultural factors (e.g., educational experiences, lifecourse socioeconomic status, residential urbanicity) associated with multilingualism may explain these inconsistent findings. Furthermore, the lack of research conducted in low‐ and middle‐income countries limit the generalizability of these findings. India offers a unique opportunity to study the role of multilingualism in cognitive aging, given its rich linguistic and sociocultural diversity.

Method

The current study utilizes a national representative sample of older Indian adults from the Harmonized Diagnostic Assessment of Dementia for the Longitudinal Study in India (LASI‐DAD). Respondents included 4,088 adults aged 60 and over, speaking over 40 different languages and dialects (73.6% monolingual, 26.4% report speaking ≥2 languages). We evaluated the association of multilingualism with global cognitive functioning after accounting for critical demographic and health factors such as age, sex, urbanicity, total consumption, diabetes, and hearing loss, among others. We also assessed whether this association differed by region and education.

Result

Overall, multilingualism was associated with better global cognition after controlling for demographic and health confounds. There was an interaction between region and multilingualism such that there was a greater benefit of multilingualism on cognition in South India compared to North India. The effect of multilingualism on cognition also differed by level of education, with the greatest benefit among multilinguals with higher levels of education. However, stratified models demonstrated that multilingualism was positively associated with cognition, regardless of education, in South India, whereas this association was only observed among those with higher educational attainment in North India.

Conclusion

In India, multilingualism was associated with better cognition, but this association differed by region and educational attainment. Future research should investigate regional variations in lifecourse factors that may explain the differences in the multilingual advantage observed across North and South India. Furthermore, future studies should deconstruct multilingualism (e.g., age of acquisition, proficiency) in order to evaluate their association with cognition cross‐sectionally and longitudinally.
Bilingualism Appears to be Protective Against Cognitive Decline Related to Amyloid Burden in Mexican Americans: An HABS‐HD Study
Authors: Petersen Melissa , Hall James , Johnson Leigh , Braskie Meredith N , Yaffe Kristine , Rissman Robert A. , Toga Arthur W. , O'Bryant Sid E. ,   Health and Aging Brain Study‐ Health Disparities (HABS‐HD) Study Team
Published: December 2022

Background

Bilingualism has been considered to exert protective effects from neurodegeneration and age‐related diseases such as Alzheimer’s Disease (AD). The protective effect is considered to be due to differences in grey and white matter between monolingual and bilinguals; however, no work to date has looked at differences in additional AD brain pathology. The aim of this study was to fill this gap and examine among Mexican Americans the impact of amyloid burden on cognitive functioning stratified by language status.

Method

Data were analyzed on n = 111 Mexican Americans (n = 45 Monolingual; n = 66 Bilingual) participants from a study of health disparities. All participants underwent cognitive testing and PET amyloid imaging, which was conducted using a Siemens Biograph Vision 450 PET/CT scanner with florbetaben. SUVR regions of interest (ROIs) included Frontal, Anterior/Posterior Cingulate, Lateral Parietal, and Lateral Temporal cortex and were derived using the cerebellum as a reference region in FreeSurfer. Linear regressions were conducted with each ROI included as a predictor variable and cognitive functioning as the outcome variable. Covariates included age, sex, and education. Analyses were split by language status (monolingual, bilingual).

Result

Among monolingual Mexican Americans, higher Global and Lateral Temporal SUVR were significantly related to poorer performance across measures of executive functioning (p = 0.039 and p = 0.038) and processing speed (p = 0.013 and p = 0.027); Global SUVR showed a trend towards significance on a measure of verbal fluency (p = 0.052). In the same group, Frontal SUVR was significant related to poorer performance across measures of global cognition (p = 0.046), executive functioning (p = 0.015), processing speed (p = 0.007) and verbal fluency (p = 0.037), the latter two were also significantly related to Anterior/Posterior Cingulate SUVR (p = 0.008 and p = 0.029). In addition, higher Lateral Parietal SUVR was significantly related to poorer performance on a measure of processing speed (p = 0.030). Among bilingual Mexican Americans, Frontal and Anterior/Posterior Cingulate SUVR were positively associated with semantic fluency (p = 0.049 and p = 0.043).

Conclusion

Amyloid burden was found to be related to poorer cognitive functioning across multiple domains specifically among monolinguals. Those who identified as bilingual did not present with the same relationship between amyloid uptake and cognitive functioning further supporting the potential protective effect of bilingualism.
Automatic Extraction of Oculographic Signals as Digital Biomarkers for Alzheimer's Disease
Authors: Meyer Trevor , Moro‐Velazquez Laureano , Motley Seneca , Butala Ankur , Paul Ashley , Samus Quincy M , Irazoqui Pedro , Dehak Najim , Oh Esther S
Published: December 2022

Background

Similar to other neurological diseases, subtle early neurological changes that occur in Alzheimer’s Disease (AD) are difficult to quantify and track objectively. One relevant bio‐signal is eye movement, as it presents a unique window into cognitive processes as a direct measure of real‐time inputs to the brain. Eye‐tracking allows us to estimate timestamped activity of neural function and begin to infer and quantify attention, reprocessing (eg. word revisits), and many other aspects relevant to assessing AD. The goal of this study was to investigate the saccadic movements and trial progress during administration of the Stroop test in AD compared to normal controls.

Method

5 AD subjects and 12 age‐matched cognitively normal controls were recruited from the Johns Hopkins Memory and Alzheimer’s Treatment Center and the Movement Disorders Clinic at the Johns Hopkins University School of Medicine. An Eyelink Portable Duo in head‐free‐to‐move mode was used to track eye movements. Movement of the eyes were analyzed by automatically segmenting saccade movements throughout a trial. We then analyzed the eye movements in the context of cognitive performance, by identifying when subjects progress to each word in the Stroop test. We compared the performance of each group using a Wilcoxon RankSum test with the SciPy package using Python.

Result

Preliminary results show that 60% (3/5) of AD subjects were unable to complete the Stroop task in 80 seconds. Individuals with AD had more saccades (p=0.105) with greater saccadic overshoot (p=0.092) and a greater maximum saccade velocity (p=0.035) on average compared to cognitively normal controls. AD subjects also took much longer to complete the first (p=0.114) and second lines (p=0.092) compared to healthy controls, suggesting initial confusion and hesitation.

Conclusion

AD subjects change their gaze more often with greater speed and less precision than age‐matched controls. These data demonstrate feasibility of using automatic quantitative evaluation of eye movements in AD. In the future, we will determine the utility of using this tool for early detection of AD and tracking its progression, along with combining other measures such as voice and handwriting (multimodal) to provide insights into early physiological changes in AD.
Considering sex in mild‐to‐moderate Alzheimer’s disease clinical trials: A meta‐analysis of ADCS trials
Authors: Dahdoul Thabat A , Gillen Daniel L. , Grill Joshua D
Published: December 2022

Background

Nearly two thirds (62%) of Alzheimer’s disease (AD) patients in the United States are women (Nebel 2018; Rajan, 2021). Our goal in this project was to assess whether women are proportionately represented in AD clinical trials and whether sex was associated with other baseline patient characteristics.

Methods

We used data from nine mild‐to‐moderate AD trials conducted by the AD Cooperative Study (ADCS): Docosahexaenoic acid (DHA), FYN Kinase, Homocysteine, Huperzine (Hu), IV immunoglobulin (IVIg), nonsteroidal anti‐inflammatory drugs (NSAIDs), Resveratrol (Res), Simvastatin, Valproate. Sample sizes ranged from 120 (Res) to 642 (IVIg) participants. We compared the proportions of females enrolled to disease prevalence estimates. We conducted a random effects meta‐analysis to estimate female participation rates across the nine trials. Specifically, we used a generalized linear mixed effects model with logit link and random intercept to estimate the marginal and trial specific prevalence of female participants. To compare participant characteristics by sex we pooled samples across trials and used unadjusted chi‐square (categorical variables) and t‐tests (continuous variables).

Results

The proportion of females enrolled exceeded 50% in each trial, with the exception of the FYN Kinase trial (44.7%). In all but the Hu trial, the rate of female enrollment was less than the estimated female disease prevalence. The estimated prevalence of female participants across all trials was estimated to be 56% (95% CI 0.53 to 0.58) (Figure 1). Females were similar to males in terms of age and APOE genotypes. Compared to males, females had lower education, less often enrolled with a spouse, less often lived with their study partner, and more often were from an underrepresented racial or ethnic group.

Conclusions

Though these trials recruited more females than males, on average, women were still underrepresented compared to national disease prevalence estimates. Female and male participants exhibited psychosocial differences in education, race, and study partner characteristics that could affect trial outcomes and should be further investigated.
Sex‐specific molecular profiling to understand pathology and identify causal genes and drug targets for Alzheimer’s disease
Authors: Sung Yun J , Do Anh , Timsina Jigyasha , Wang Lihua , Wang Fengxian , Cruchaga Carlos
Published: December 2022

Background

Alzheimer’s disease (AD) is a highly heterogeneous multifactorial disease. Genetic influences on AD are strong as shown by several pathogenic genes and over 50 AD GWAS loci. There are also clear sex differences in AD risk and progression. Women are at a higher risk of developing AD and present faster progression. A recent GTEx study also highlights sex differences in the genetic regulation of gene expression. Despite these established sex differences, sex‐specific molecular findings in AD are still limited.

Method

We generated and performed analysis using 713 CSF proteomic data that passed QC obtained from Knight‐ADRC and DIAN samples. The sample includes 190 late onset clinical AD patients and 509 age‐ and gender‐matched cognitively healthy individuals. Age at lumbar puncture and surrogate variables (to account for unmeasured heterogeneity) were included as covariates. To evaluate sex‐specific molecular signatures, we performed sex‐stratified analysis by separately analyzing 333 males and 366 females.

Result

In male CSF tissues, 99 proteins significantly associated with late onset AD status (FDR P < 0.05) and 131 proteins in female CSF tissues. Those proteins were enriched in pathways involved in the endolysosome and proteasome pathway including HSP70. We identified 44 proteins presenting a suggestive evidence of sex‐specific effects on AD status. In particular, several proteins that were previously reported to be associated with AD risk show sex‐specific effects. Downregulation of LRIG3 improves cognitive impairment and alleviate neuronal damage in hippocampus tissues in AD rats through modulating the PI3K/Akt pathway. We found that LRIG3 was associated in males only and would not have been identified through a combined analysis that simply included sex as a covariate (P = 3.4×10‐3 in males; P > 0.5 in females; P = 0.067 in all).

Conclusion

This study demonstrates that 800 proteins in 700 CSF tissues can provide a suggestive information on sex‐specific proteomic profiles. We will extend our sex‐specific analysis using our recently generated 7000 proteomic data to fully understand the biology of the disease and determine the role of sex in disease, create sex‐specific genes and prediction models. This will provides insights for clinically translatable interventions for prevention and treatment.
Evaluation of PVC methods on head‐to‐head FTP and MK6240
Authors: Dominguez Pablo Aguilar , Ward Tyler J. , Harrison Theresa M. , Landau Susan M. , Lopresti Brian J , Minhas Davneet S , Klunk William E , Jagust William J. , Baker Suzanne L.
Published: December 2022

Background

MK6240 and Flortaucipir (FTP) are tau PET tracers with differing off‐target signal. Due to partial volume effects (PVE), this off‐target may spill into neighboring cortical regions. We applied different partial volume correction (PVC) methods to MK6240 and FTP images acquired in the same participants within two months to evaluate the performance of the methods within and between tracers.

Method

15 subjects (Table1) were scanned using MK6240 (SUVR calculated 70‐90min and 90‐110min) and FTP (80‐100min) on a Siemens Biograph mCT and smoothed to 8mm3 resolution. T1 MRIs were segmented using FreeSurfer 7.1. Five different PVC methods were tested: 2 compartment, 3 compartment, Van‐Cittert (VC), geometric transfer matrix (GTM) and region‐based voxelwise (RBV). Different ROI configurations were used when applying GTM/RBV. To determine how well the PVCed data fit the original data, PVCed images were smoothed back to the 8mm3 resolution and compared to the original image within SPM‐segmented gray matter, white matter, CSF, skull and meninges (Figure1).

Result

VC fit the original data best after smoothing (Figure2), but had the highest correlation with the original data (Figure3c), meaning VC does not correct the data as much as the other methods and therefore does not address the PVE issue. 2 and 3 compartment fit the gray and white matter well (Figure2) while showing low R2 between the original and PVC data (Figure3). However, these methods assume zero signal outside the cortex, resulting in poor fit of extracortical areas and leading to over‐amplification of the cortical signal. GTM and RBV perform well for both tracers in all 5 regions. Their correlations between original and PVC data are between 2/3 compartment and VC, indicating these methods correct the data. PVC improves the correlation between FTP and MK6240; the highest correlation between tracers is achieved when the same PVC method is applied to both tracers (r2=0.9 for 2 and 3 compartment, r2=0.89 for GTM, r2=0.88 for RBV, r2=0.84 for VC, r2=0.80 for original).

Conclusion

GTM/RBV assume non‐zero signal outside the cortex resulting in a better fit of the original data, correct the data more than VC, and improve the correlation between MK6240 and FTP.
Cerebrospinal fluid levels of growth associated protein 43 (GAP‐43) are associated with Alzheimer’s disease biomarkers, cognition, and functional changes
Authors: Bolton Corey J , Khan Omair A. , Liu Dandan , Moore Elizabeth E. , Houston Michelle , Pechman Kimberly R. , Blennow Kaj , Zetterberg Henrik , Hohman Timothy J. , Gifford Katherine A. , Jefferson Angela L.
Published: December 2022

Background

Growth‐associated protein 43 (GAP‐43) is a presynaptic protein involved in synaptic plasticity implicated in Alzheimer’s disease (AD). This study investigates cerebrospinal fluid (CSF) levels of GAP‐43 in relation to AD fluid biomarkers and clinical outcomes. To determine how associations change across disease states, interactions with cognitive and amyloid status are examined.

Method

Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=153, 72±7 years, 37% mild cognitive impairment (MCI)) underwent fasting lumbar puncture, 3T brain MRI, neuropsychological assessment, and informant‐reported functional activities questionnaire (FAQ). CSF GAP‐43, b‐amyloid1‐42 (Ab1‐42), tau, and phosphorylated‐tau (p‐tau) were analyzed in batch. An AD‐signature imaging composite was calculated by summing cortical thickness measurements from brain regions commonly affected by AD (Schwarz et al., 2016). Linear mixed effects models cross‐sectionally related GAP‐43 to CSF AD biomarkers, structural neuroimaging, cognitive, and FAQ variables adjusting for baseline age, sex, education, race/ethnicity, apolipoprotein E (APOE)‐e4 status, modified Framingham Stroke Risk Profile, and cognitive status. Follow‐up models assessed GAP‐43 x cognitive status (normal cognition (NC), MCI) and GAP‐43 x amyloid positivity interactions on outcomes.

Result

In main effect models, higher CSF GAP‐43 was associated with higher CSF tau (p<0.0001) and CSF p‐tau (p<0.0001); worse semantic fluency (p<0.02), visuospatial (p<0.007) and episodic memory performances (p=0.06); and worse FAQ scores (p=0.003). Remaining models were null (p‐values>0.23). GAP‐43 interacted with cognitive status on all CSF biomarkers, AD‐signature composite cortical thickness, visuospatial, executive functioning, and memory performances, and FAQ score (p‐values<0.06). CSF GAP‐43 interacted with amyloid positivity on CSF tau and CSF p‐tau, and memory composite score (p‐values<0.03). Stratified results suggested most associations were slightly stronger in participants with MCI (p‐values<0.02) versus NC and in amyloid positive (p‐values<0.02) versus negative participants.

Conclusion

We found higher CSF GAP‐43 levels were associated with tau and p‐tau pathology, AD‐related neurodegeneration on MRI, and worse cognitive and functional scores. Results were more prominent in individuals at increased risk for AD‐type dementia (i.e., participants who were amyloid positive or have MCI). These findings extend prior work by highlighting the importance of synaptic dysfunction in the AD clinical syndrome.
Can Machine Learning advance or hinder statistical modelling of dementia risk in the Population.
Authors: Richardson Connor Duncan
Published: December 2022

Background

Machine learning and Artificial intelligence is a rapidly growing area of health research in predicting individual and population disease risk. Predicting dementia in the population using neuropathology data is particularly challenged due to the lack of brain donation recourses. Machine learning is growing in popularity due to an increased focus on collecting health data and its powerful ability to compute complex statistics using smaller datasets while handling missing data.

There is debate in the research community on the reliability of machine learning for predicting dementia. The thinking behind many machine learning techniques emphasizes use of very large amounts of data, whereas more classical statistical techniques emphasize a prediction of risk based on more specific and targeted data often resulting in smaller sample sizes.

If these techniques complement or contradict each other’s ability to accurately predict risk of dementia in the population is yet unknown. Understanding this is paramount for the future of dementia research considering the ever‐growing integration between Neuropathology, data and statistical science

Method

We applied machine learning techniques for feature ranking and classification as an unbiased comparison of neuropathological features and assessment of their diagnostic performance using a cohort (n = 507) from the Cognitive Function and Ageing Studies (CFAS). This could then be compared to more traditional statistical modelling using logistic regression.

Result

Decision Tree Classification gave clear and easy to interpret roots for dementia risk, visualising a hierarchy from pathologies that is less clear than logistic regression and odds ratios. It produces an individualised look at dementia risk based on specific combinations of pathology that is unclear in the statistical regression model however, does not deal with missing data well.The random forest model is strong in predicting cases of dementia however it misclassifies healthy cases as dementia cases 52% of the time.TDP 43 contributes the most to the model and Lewy bodies contributes the least.

Conclusion

Machine learning has the potential to analyse neuropathology of dementia in sophisticated ways, however almost half of dementia cases remained misclassified. This points towards a more complex model of dementia pathology that requires further neuropathological assessments and collection of high quality cohort data to analyse.
Indigenous cultural understandings of Alzheimer’s disease and related dementias – research and engagement (ICARE): relationships between cultural strengths, education and stigma
Authors: Lambrou Nickolas H. , Blind Melissa J , Ketcher Dana , Pederson Collette , Johnson January , Hill Annamarie , Dertinger Melinda , Chiovitte Jessica , Trudeau Rhonda , Pitawanakwat Karen , Strong Lois , Summers Marlene , Martin Wesley , Warry Wayne , Lewis Jordan P , Zuelsdorff Megan , Gleason Carey E. , Jacklin Kristen
Published: December 2022

Background

Evidence indicates Alzheimer’s disease and related dementias (ADRD) and chronic diseases considered risk factors for developing ADRD disproportionately affect Indigenous people. However, little is known regarding lived experiences, needs and resiliencies across the ADRD disease trajectory in Indigenous communities. This work highlights preliminary data from the ICARE study (R56 AG 62307); a project that explored factors impacting ADRD across the disease trajectory. This research focuses on thematic trends and relationships between education, cultural strengths and stigma emerging from the analysis of Sequential Focus Groups (SFGs) data.

Method

Community‐based participatory research and phenomenology guided qualitative study design, recruitment, data collection and analysis. We conducted SFGs in four tribal community sites in the US and Canada. All participants had professional health care experience working with Indigenous people with dementia (PWD). Each site held between 4‐5 sequential virtual focus groups with consistent participants lasting between 30‐90 minutes. Community‐based researchers led these sessions focused on understandings within the contexts of early, mid and late‐stage dementia.

Result

Participants (N = 17) were aged 18+, and worked with Indigenous PWD (M = 11.09 years; SD = 9.25). Additionally, 41% reported caring for a loved one with dementia. Preliminary analysis suggests thematic shifts within the contexts of early, mid, and late‐stage ADRD, including cultural understandings of ADRD. Participants described a need for education in early‐stage, service access in middle‐stage, and safety and retrospective recommendations for education in late‐stage. Notably, aspects of stigma appeared thematically through each stage, and appeared antithetical to other consistent subthemes of community needs (e.g., education) and cultural strengths (e.g., connectedness, storytelling).

Conclusion

SFGs revealed nuances of cultural and community level factors influencing the impact of ADRD across the disease trajectory in four diverse Indigenous communities. Preliminary data provide lines of inquiry for ICARE R01 NIH (R01AG062307), such as exploring culturally appropriate education and outreach as inroads to developing effective interventions and reducing stigma, isolation and the burden of ADRD on AI/FN communities. Notions of stigma require further investigation and may reflect Western ideology and disconnection from traditional teachings resulting from colonization.
Exploration of visual hallucinations – FDG‐PET associations in DLB and MCI‐LB with and without visual hallucinations
Authors: Christine Cliatt Brown J , Miyagawa Toji , Przybelski Scott A. , Min Paul H , Jordan Lennon , Lesnick Timothy G. , Graff‐Radford Jonathan , Jones David T. , Savica Rodolfo , Botha Hugo , Ramanan Vijay K , Knopman David S. , Petersen Ronald C. , Fields Julie A. , Machulda Mary M. , Forsberg Leah K. , Diaz‐Galvan Patricia , Li Wentao , Jack Clifford R. , Kantarci Kejal , Lowe Val J. , Boeve Bradley F.
Published: December 2022

Background

Several hypotheses exist regarding the neurologic substrate underlying visual hallucinations (VH) in Dementia with Lewy Bodies (DLB). Studies have suggested an association with regional cerebral hypometabolism in the primary visual or visual association cortices on FDG‐PET. We compared regional cerebral glucose metabolism and posterior cingulate island sign (CIS) ratios in DLB and in Mild Cognitive Impairment with Lewy Bodies (MCI‐LB) participants with (VH+) and without (VH‐) VH.

Method

Participants with clinically probable DLB or MCI‐LB and an FDG‐PET scan were identified from the Mayo ADRC database. Responses on the Visual Hallucinations and Delusions Questionnaire and Neuropsychiatric Inventory were used to assess presence or absence of VH. Standardized uptake value ratios (SUVr) were used to calculate regional cerebral glucose hypometabolism in the primary visual cortex (PVC), lateral occipital cortex (LOC), and whole occipital cortex (WOC). The CIS ratio was defined as posterior cingulate divided by the sum of the precuneus plus cuneus FDG‐PET uptake ratio.

Result

Two cohorts were identified (27 DLB and 18 MCI‐LB, 87% male). Eighteen DLB participants were VH+ and 9 were VH‐, whereas 5 MCI‐LB were VH+ and 13 were VH‐. There were no statistically significant differences in demographic (age, sex, education) and clinical features (MoCA, CDR, presence of other core DLB features, and UPDRS) between VH+ vs VH‐ in those with DLB, and between VH+ vs VH‐ in those with MCI‐LB. Similarly, there were no statistically significant differences in DLB between VH+ vs VH‐ in PVC (1.55±0.14 vs 1.58±0.15), LOC (1.22±0.16 vs 1.28±0.12), WOC (1.29±0.15 vs 1.34±0.11), or CIS ratio (1.16±0.08 vs 1.14±0.10), nor in MCI‐LB between VH+ vs VH‐ in PVC (1.68±0.19 vs 1.58±0.14), LOC (1.40±0.21 vs 1.32±0.14), WOC (1.45±0.20 vs 1.37±0.14), or CIS ratio (1.17±0.08 vs 1.19±0.10) (P>0.05 for all comparisons).

Conclusion

These findings do not support a direct correlation between regional cerebral glucose metabolism and VH in DLB or MCI‐LB. Further work in DLB and MCI‐LB with larger numbers is warranted. Other neurologic substrates and mechanisms, such as REM sleep intrusions during wakefulness, neurotransmitter dysfunction, and disruption of functional connectivity across brain regions should be explored as contributors to VH in DLB.
Identification of Genetic Variants and Serum Metabolites Associated with Blood‐derived Mitochondrial DNA Copy Number
Authors: Tong Tong , Farrell John , Zhu Congcong , Khurshid Zainab , Martin Eden R. , Bush William S. , Pericak‐Vance Margaret A. , Wang Li‐San , Schellenberg Gerard D. , Haines Jonathan L. , Lunetta Kathryn L. , Farrer Lindsay A. , Zhang Xiaoling , Project Disease Sequencing
Published: December 2022

Background

Mitochondrial DNA Copy Number (mtDNA‐CN) can be used to estimate mitochondrial function and it varies across tissues and cell types. Blood‐derived mtDNA‐CN has been studied in aging‐related diseases including Alzheimer’s Disease (AD). However, little is known about the genetic contribution to variation of blood‐derived mtDNA‐CN and how this variation affects the level of serum metabolites.

Method

We developed a fast computational pipeline to accurately estimate mtDNA‐CN using whole genome sequence data from blood samples from European ancestry (EA, 2,885 AD cases and 2,777 controls), African American (AA, 1,118 AD cases and 1,725 controls), and Caribbean Hispanic (CH, 1,022 AD cases and 1,949 controls) participants of the Alzheimer’s Disease Sequencing Project (ADSP). In the combined sample and within each population group. We tested association of blood‐derived mtDNA‐CN with 17,569,705 variants (minor allele count≥20) genome‐wide using a linear mixed effect model including covariates for age, sex, sequencing center, PCR, AD status, polygenic risk score of blood cell count, and principal components of ancestry. We also tested the associations of mtDNA‐CN and levels of 175 serum metabolites in 1,521 subjects from Alzheimer’s Disease Neuroimaging Initiative.

Result

In the total sample, we identified genome‐wide significant (GWS) associations with variants from 24 independent loci. The top‐ranked SNP (rs1455130415 in NDUFS8, (p=3.25x10‐42) was also GWS in EAs (p=3.96x10‐28) and AAs (p=2.20x10‐27). SNP rs997412864 (p=5.13x10‐9) in GCAT was found associated with mtDNA‐CN in EAs, but not in other groups. Association of SNP rs1237233197 (p=1.40x10‐8) in NDUFS7 was specific to AAs. Measurements of two long‐chain acylcarnitine, C14:2‐OH (p=4.91x10‐7) and C18:2 (p=1.81x10‐5), were negatively associated with mtDNA‐CN after Bonferroni correction (P<2.9x10‐4). Ornithine, a non‐proteinogenic amino acid, was also negatively associated with mtDNA‐CN (p=2.32x10‐4).

Conclusion

We identified GWS association of blood‐derived mtDNA‐CN with a variant in a nuclear‐encoded mitochondrial gene, NDUFS8, which encodes a subunit of Complex I. In addition, mtDNA‐CN was significantly associated with two acylcarnitine metabolites and ornithine whose levels were previously reported to be decreased in blood of AD patients. These results provide more insight about the role of mitochondrial function in AD pathogenesis and suggest that blood‐derived mtDNA‐CN may be a useful biomarker for AD.
APOE4 genotype associations with longitudinal change in hippocampal microstructure
Authors: Zhu Alyssa H , Nir Talia M , Gari Iyad Ba , Dixon Daniel , Islam Tasfiya , Villalon‐Reina Julio E , Thompson Paul M , Jahanshad Neda
Published: December 2022

Background

Apolipoprotein E4 (APOE4) is a major risk factor for late‐onset Alzheimer’s disease (AD). Associations between APOE4 genotype and hippocampal atrophy have been reported, but few longitudinal studies have evaluated microstructural changes. There is evidence that risk conferred by APOE4 may be partially driven by factors such as cerebral iron burden, neuronal injury, and inflammation. Brain iron concentration and other microstructural properties may be detected in vivo using quantitative susceptibility mapping (QSM) and diffusion‐weighted MRI (dMRI). Here, we characterized the effects of APOE4 genotype on longitudinal changes in hippocampal QSM and dMRI microstructural measures in a population‐based sample of adults from the UK Biobank (UKB).

Method

598 UKB participants of European ancestry (baseline age: 48‐78 years) with baseline and ∼2 year follow‐up brain MRI data were analyzed (Figure 1A). Four dMRI measures were derived from diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI; Figure 1B). Median dMRI and QSM hippocampal measures were extracted and averaged across hemispheres. For comparison with microstructure, bilateral hippocampal volume was also estimated. Linear regressions were used to test associations between change in six hippocampal measures (FollowUp‐Baseline) and number of E4 alleles (e3e3/e3e4/e4e4) adjusting for the time‐interval between scans, baseline MRI measure, age, sex, age‐by‐sex, age2, age2‐by‐sex, education, and the first 4 genetic ancestry principal components. Age‐dependent effects were explored in post‐hoc analyses including a sensitivity analysis stratifying associations by age (< 65 or ≥ 65 yrs) and evaluation of APOE4‐by‐age interactions.

Result

Compared to e3e3 homozygotes, E4 carriers had significantly greater increases in MD and ISOVF and greater decreases in ND (p<critical FDR threshold; q=0.05; Table 1). E4 carriers ≥65 had nominally greater increases in MD and ISOVF and greater decrease in volume (p<0.05); APOE4‐by‐age interactions were found for changes in ISOVF and volume (p<0.05; Figure 2).

Conclusion

Disease risk conferred by the APOE4 genotype may be linked with greater inflammation (greater diffusivity) or neuronal loss. E4 associations with atrophy were only found in the subset of older participants, suggesting that detection of microstructural changes may precede volumetric changes in the hippocampus.
Neurofibrillary Tangles Prediction Based On MRI
Authors: Saifullah Khalid , Tazwar Mahir , Evia Arnold M , Tamhane Ashish A , Bennett David A , Schneider Julie A , Arfanakis Konstantinos
Published: December 2022

Background

Neurofibrillary tangles, one of the hallmark pathologies of Alzheimer’s disease, are closely related to brain atrophy and cognitive decline. The purpose of this work was to develop an MRI‐based classifier of neurofibrillary tangles by combining ex‐vivo MRI and neuropathology in brain autopsies from a large number of community‐based older adults.

Method

Cerebral hemispheres from 878 older adults participating in three longitudinal, clinical pathologic cohort studies of aging: the Rush Memory and Aging Project (MAP), the Religious Orders Study (ROS), and the Minority Aging Research Study (MARS) (Fig. 1) were included in this work. All hemispheres were imaged at room temperature while immersed in 4% formaldehyde solution using clinical 3T MRI scanners, once within 24 hours postmortem and a second time approximately 30 days postmortem followed by detailed neuropathologic examination.

An SVM classifier with l2 regularization was trained to distinguish participants at a Braak stage of V‐VI from those at a Braak stage of 0‐IV, based on features extracted from ex‐vivo MRI as well as demographic information (age, sex). The MRI features included volumetric, cortical thickness, subcortical shape, diffusion, and R2 measurements. When a feature contained multiple measurements per person, they were used to train a separate model that generated a separate risk score which was used as a feature in the final model. Because different groupings of features were available on different subgroups of the participants, the performance of the classifier was tested in a total of 74 participants (Fig. 2) that had measurements on all features.

Result

The average AUC of the classifier based on all MRI and demographic features was 0.87 with 82% mean sensitivity and 77% mean specificity (Fig. 3). In comparison, recently published work combining in‐vivo MRI and pathology data trained an MRI‐based classifier of people at Braak stage V‐VI vs. 0‐II and achieved an AUC=0.69 [1].

Conclusion

Successful completion of ex‐vivo to in‐vivo translation of our work may result in a non‐invasive classifier of neurofibrillary tangles aiding in refined participant selection and targeted therapies. Reference: [1] Dallaire‐Théroux, Caroline et al., Braak neurofibrillary tangle staging prediction from in vivo MRI metrics, Alzheimer's & dementia, vol. 11, 2019.