bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping Medial Temporal Lobe Longitudinal Change in Preclinical Alzheimer’s Disease
Authors: Yushkevich Paul A. , Xie Long , Wisse Laura EM , Dong Mengjin , Ravikumar Sadhana , Ittyerah Ranjit , de Flores Robin , Das Sandhitsu R. , Wolk David A.
Published: December 2023

Background

The medial temporal lobe (MTL) is a site of early tau pathology and neurodegeneration in AD. In recent work [1], we reported that rates of change in MTL subregion volumes on longitudinal structural T1‐MRI differ significantly between cognitively unimpaired individuals with and without amyloid pathology (A+CU vs A‐CU), suggesting that these measures are effective biomarkers for tracking disease progression in preclinical AD. Here, we develop a specialized pipeline that quantifies pointwise longitudinal change across the MTL, revealing more informative spatial patterns of early neurodegeneration than summary volumetric longitudinal measures.

Methods

Our pipeline, SkelDBM, combines skeletonization and deformation‐based morphometry to generate maps of annualized rate of atrophy on the skeleton of an MTL template (Figure 1). SkelDBM samples subjects’ atrophy maps along the skeleton of an MTL template, increasing robustness to subject‐to‐template registration errors. We evaluate SkelDBM using a subset of ADNI data studied in [1] (Table 1). Two preclinical AD groups (A+CU and tau‐positive A+CU) are compared to a control group (A‐CU) using general linear models (GLM) with age as nuisance covariate; permutation testing is used to derive statistically significant clusters.

Results

The full A+CU vs A‐CU comparison shows significant differences in rates of change in right anterior hippocampus, right entorhinal cortex, right transentorhinal cortex, and left posterior hippocampus (Figure 2). Limiting the A+CU group to tau‐positive individuals yields more widespread differences, including most of the right anterior MTL cortex and both hippocampi. These patterns align with volumetric longitudinal data reported in [1] but provide a richer characterization of spatial atrophy patterns.

Conclusion

SkelDBM is sensitive to longitudinal atrophy occurring over relatively short periods (∼2 years) in preclinical AD and characterizes patterns of atrophy more comprehensively than summary volumetric measures. Summary measures are also subject to biases, since larger structures are typically associated with less measurement error and hence may show exaggerated statistical effects compared to smaller structures even when the underlying neurodegeneration rates are the same. Regional maps of longitudinal change may be more robust to this bias and may help discovery of “signature regions” associated with specific pathological drivers of neurodegeneration.

[1] Xie et al., Human Brain Mapping, 2020.
Analytical Choices of Timescale in the Presence of Practice and Cohort Effects in Longitudinal Cognitive Aging Research: A Simulation Study Using Linear Mixed‐Effects Models
Authors: Wang Jingxuan , Chen Ruijia , Ackley Sarah F , Zimmerman Scott C , Sims Kendra D , Hayes‐Larson Eleanor , Mayeda Elizabeth Rose , Glymour M. Maria
Published: December 2023

Background

Understanding determinants of cognitive decline relies on several modeling assumptions. Alternative longitudinal modeling strategies–such as accounting for aging using time‐on‐study (estimated based on within‐person comparisons), baseline age (estimated based on between‐person comparisons), or current age (estimated based on both within‐ and between‐person comparisons) –may produce qualitatively different results. Using simulations, we evaluated robustness of effect estimates for predictors of cognitive decline with current age (vs. time‐on‐study) as the timescale, in the context of practice and/or cohort effects.

Method

Our simulation strategy approximates the data structures of several cohort studies of cognitive aging (figure 1). For scenarios with only practice effects and with both practice and cohort effects, we performed 1,000 simulations of a cohort of 2,000 individuals with annual cognitive assessments over 3 years. Longitudinal models were fit using three timescale specifications (with and without adjustment for practice effects for each): (1) time‐on‐study adjusted for baseline age; (2) current age without adjustment for baseline age; and (3) current age adjusted for baseline age. We evaluated the bias in estimated effect associated with each specification by comparing to known simulation parameters.

Result

When practice effects were present and not accounted for, time‐on‐study and current age underestimated rate of cognitive decline (figure 2) but bias was smallest for current age as the timescale. When cohort effects were present, current age as the timescale led to biased estimates when baseline age was not adjusted for. With a correctly specified model, the variance in the estimate of the coefficient for current age was 36.3% smaller than the variance in the estimate of the coefficient for time‐on‐study with baseline adjustment. All estimates for the effect of education on cognitive decline were unbiased regardless of timescale, but 95% CIs were narrowest for current age as the timescale.

Conclusion

In this simulation, current age as the timescale that combines within‐ and between‐person estimates led to more precise estimates than time‐on‐study with baseline age adjustment. Failure to account for practice effects can bias estimates of longitudinal within‐person age effects.
Heterogeneity in Modifiable and Non‐Modifiable Risk Factors among Different Dementia Types in UK Biobank
Authors: Luo Renhao , Patel Chirag J
Published: December 2023

Background

Dementia is heterogenous and includes many subtypes, including Alzheimer’s disease (AD), frontotemporal dementia, and vascular dementia, whose risk may be expressed at different ages in life. Therefore, the modifiable antecedent risk may weigh differently in different dementia subtypes, but this heterogeneity has yet to be understood. In 2020, the Lancet Commission reported the risk for all‐cause dementia for 12 modifiable risk factors. Here, we compare the risk among these risk factors reported in the Lancet Commission 2020 to assess the heterogeneity in the association between the non‐modifiable risk factors in dementia subtypes and age groups in 450,707 participants of the UK Biobank. We also compare the risk to non‐modifiable but causal risk factors, including AD family history and the ApoE genotype.

Method

We analyzed participant data from the UK Biobank. We divided the participants into two age groups, midlife (age of diagnosis 45‐65) and late‐life (age of diagnosis greater than 65). We built four different logistic regression models corresponding to each dementia subtype in each age group, including univariate, gender‐adjusted, ethnicity‐adjusted, and gender‐ethnicity‐adjusted models. We reported the odds ratio (OR), p‐values, and 95% confidence interval. Furthermore, we compared the ORs for different risk factors from the Lancet report with those from the UK Biobank. Lastly, we ran correlations between different dementia subtypes and unknown‐cause dementia.

Result

We identified age‐dependent risk factors in different dementia types, such as ApoE genotype, hearing loss and hypertension in all‐cause and AD, and diabetes in vascular dementia. We also illustrated risk factors that are not age‐dependent risk factors, such as AD family history, air pollution, TBI, current smoking, being underweight, excessive alcohol consumption, and physical inactivity. Additionally, TBI has the greatest difference in OR compared to the Lancet report. Lastly, unknown‐underlying dementia cases have a modifiable risk profile that is highly correlated with AD and vascular dementia in both age groups.

Conclusion

Here, we illustrated the heterogeneity of dementia risk factors in different subtypes of dementia. Taken together, our results highlight that different dementia subtypes share/do not share the extent of risk, which could contribute to identifying patient populations for future clinical research.
Sex‐associated differences in plasma and cerebrospinal fluid biomarkers in Early‐onset Alzheimer’s disease
Authors: Nemes Sára , Logan Paige E. , Dage Jeff L. , Hammers Dustin B. , Fagan Anne M. , Manchella Mohit K. , Eloyan Ani , Foroud Tatiana M. , Zetterberg Henrik , Koeppe Robert , Aisen Paul S. S , Carrillo Maria C. , Blennow Kaj , Schindler Suzanne E. , Gray Julia D , Dickerson Brad C. , Rabinovici Gil D. , Apostolova Liana G.
Published: December 2023

Background

Female sex is associated with greater atrophy, amyloid and tau burden in Early‐onset Alzheimer’s Disease (EOAD) in the Longitudinal EOAD Study (LEADS). APOE‐ε4 non‐carrier‐status was found to be a further predictor of EOAD pathology. We expanded the analyses by examining the impact of sex and APOE‐ε4 on plasma and cerebrospinal fluid (CSF) biomarkers of AD. Plasma markers included: neurofilament light chain (NfL), plasma glial fibrillary acidic protein (GFAP), Aβ 42/40, and pTau231. CSF markers included: Aβ 42/40, neurogranin, tTau, pTau181, synaptosomal‐associated protein‐25 (SNAP25), YKL‐40, and visinin‐like protein‐1 (VILIP1).

Method

We included 201 amyloid‐positive EOAD, 64 amyloid‐negative Early‐onset cognitively impaired (EOnonAD), and 86 Cognitively Normal (CN) LEADS participants with plasma biomarker data. Of these 100 EOAD, 35 EOnonAD, and 38 CN participants also had CSF data. Participants were stratified by sex and APOE‐ε4 genotype. Demographics (age, education, APOE‐ε4, MMSE) and biomarker differences were compared using ANOVA within each diagnostic group. ANCOVAs were run to control for the effects of age and education on biomarkers.

Result

Compared to men, EOAD women showed greater levels of plasma NfL (p = .03), and GFAP (p<.001) while Aβ 42/40, and pTau231 were comparable. In CSF, EOAD women showed higher levels of neurogranin (p = .01), tTau (p = .01), pTau181 (p = .01) and VILIP1 (p = .02). EOnonAD women showed significantly greater plasma GFAP levels (p = .02). In the CN cohort, women had greater CSF SNAP25 levels (p = .03) while men showed a trend for higher plasma pTau231 levels (p = .05).

APOE‐ε4 carrier‐status was not associated with differences in levels of plasma or CSF biomarkers in either sex.

Conclusion

As highly selective and specific AD fluid biomarkers emerge, understanding sex‐based differences in CSF and plasma is imperative. Female sex is associated with higher levels of neurodegeneration (NfL, tTau, pTau181, neurogranin, VILIP1) in EOAD and astrogliosis (GFAP) in both EOAD and EOnonAD.

This data supports our previous findings that greater pathology burden is associated with female sex. This paves the way for further examination of sex and APOE‐ε4 genotype‐based differences in imaging and fluid biomarkers, their associations, and utility in early diagnosis.
Life course neighborhood social determinants of health and longitudinal changes in cognition in three Alzheimer’s Disease Research Center cohorts
Authors: Besser Lilah M , Meyer Oanh L. , Bateman James R. , George Kristen M , Adkins‐Jackson Paris AJ , Morris John C , Galvin James E
Published: December 2023

Background

Seminal studies on exposure to life course social determinants of health, such as neighborhood racial segregation and neighborhood poverty, suggest detrimental associations with poorer cognitive function. We aimed to test the opposite by examining the relationship between self‐reported exposure to health‐promoting neighborhood environments over the life course and cognitive function among older adults.

Method

Participants were persons living without dementia at three US Alzheimer’s Disease Research Centers (University of California, Davis in Sacramento (UCD); Washington University in Saint Louis (WU); and Wake Forest University in Winston‐Salem (WFU)). An ancillary study (K01AG063895, PI: Besser) included the Life Course Sociodemographics and Neighborhood Questionnaire (LSNEQ) comprised of indices like neighborhood measures of socioeconomic status (NSES), walking and biking frequency, and greenness from childhood, midlife, and late life. LSNEQ data were linked with late‐life cognitive test z‐scores (Animals and Vegetables Category Fluency, Trail Making Parts A and B) from the National Alzheimer’s Coordinating Center Uniform Data Set. Multivariable linear mixed effects models tested associations between the LSNEQ index scores (composite values over childhood and mid‐ and late‐life) and baseline and longitudinal change in cognitive function controlling for demographics, Center, and baseline global Clinical Dementia Rating (0 or 0.5).

Result

The sample (n = 322) included 65% women, 17% Black, 76% White, and 7% other/mixed racialized group participants and was, on average, 70±7 years old and followed for 2.5±3.2 years. Life Course NSES was lower for UCD (mean = 12.7, SD = 3.5) versus WU (mean = 13.9, SD = 3.2) and WFU (mean = 14.3, SD = 3.2). Life Course Neighborhood Walking and Biking frequency did not differ by Center. Life Course Neighborhood Greenness differed across Centers, and was lowest for WU (mean = 4.8, SD = 1.3) and highest for WFU (mean = 5.6; SD = 1.2). In multivariable analyses, greater Life Course Neighborhood Walking and Biking was associated with higher baseline Trail A scores (estimate = 0.83, 95% CI = 0.08‐1.58) and slower decline on Animals over time (estimate = 0.024, 95% CI = 0.002‐0.045). Greater Life Course Neighborhood Greenness was associated with slower decline on Vegetables over time (estimate = 0.035, 95% CI = 0.001‐0.069).

Conclusion

These preliminary findings suggest self‐reported, life course neighborhood exposures and behaviors (i.e., greenness and neighborhood walking/biking) may be associated with better cognition and slower decline in later life.
Different typologies of neighborhood resources are associated with cognitive function
Authors: Sol Ketlyne , Clarke Philippa , Zahodne Laura B.
Published: December 2023

Background

Neighborhood resources (NRes) such as libraries, grocery stores, and child/family centers may promote cognitive health via opportunities for cognitive stimulation and other health benefits. Resources are distributed differently across neighborhoods, but many studies examine effects of individual NRes on health outcomes. This study uses typologies of NRes and examines whether different types of NRes patterns contribute to Black‐White disparities in cognitive function.

Method

This cross‐sectional study of 462 non‐Hispanic Black and White older adults (Mage = 63.6; 53% Black) was drawn from the Michigan Cognitive Aging Project, a regionally‐representative, prospective longitudinal study of adults transitioning to late life in the Detroit metropolitan area. Participants’ current addresses were geocoded and linked to neighborhood data from the National Neighborhood Data Archive for the year 2017. First, a latent class analysis (LCA) using Mplus identified typological classes of NRes using fifteen indicators across all 2,813 census tracts in Michigan. Next, path analysis estimated associations among race, NRes class, and global cognition, operationalized as a composite of five factor scores (episodic memory, executive function, processing speed, language, visuospatial ability). Models adjusted for age, sex/gender, education, and population size.

Result

LCA indicated three classes of NRes: low‐resourced (48%), well‐resourced (42%), and highly‐resourced (10%) neighborhoods. Black participants had lower cognitive health and were more likely to live in low‐resourced or highly‐resourced neighborhoods than White participants. White participants were more likely to live in well‐resourced neighborhoods than Black participants. Surprisingly, living in well‐resourced neighborhoods was associated with worse cognition, compared to living in low‐resourced neighborhoods, but this association was only found among Black participants (βBlack = ‐.181, βWhite = .008). Living in highly‐resourced neighborhoods was not associated with cognition, but only 4% of the sample lived in these neighborhoods.

Conclusion

Paradoxical findings suggest additional work is needed to better disentangle the role of NRes in cognitive disparities. Findings may be driven by factors such as racial residential differences (i.e., home rental and homeownership) and/or access to resources within a neighborhood, as well as neighborhood social climate. This study adds to—and highlights the need for more comprehensive models in—research on neighborhoods and ADRD inequalities.
Spatial transcriptomics identifies disrupted circadian gene expression in a mouse model of Alzheimer’s disease
Authors: Romero Haylie K , Gerber Alon , Akhmetova Laila , Mukamel Eran A , Desplats Paula
Published: December 2023

Background

Disruptions in circadian rhythm are a common symptom of Alzheimer’s disease (AD), which occur early in disease progression and may contribute to the neurodegenerative process. However, the mechanisms that link alterations in rhythmic transcription and disease pathology are poorly understood. Here we used brain‐wide spatial transcriptomics to elucidate progressive disruptions in diurnal transcriptional rhythms in a mouse model of AD.

Method

Using Visium spatial transcriptomic technology, we investigated transcriptional changes with spatiotemporal resolution in APP23 transgenic mice, which overexpress human APP with the Swedish mutation. Sagittal brain slices from APP23 and littermate control mice were collected at 4 Zeitgeber times (ZT). We used community detection to cluster the spatial locations according to shared patterns of gene expression, which corresponded to major anatomical brain regions. Pseudobulk profiles were computed for each cluster in each sample, and these were used in subsequent differential expression analysis using DESeq2. Rhythmic gene expression was modeled as a sinusoidal function of ZT, while controlling for covariates (sex, genotype, and age) and their interaction with time. Results were further validated using non‐parametric tests for rhythmicity implemented in Metacycle.

Result

Our analysis revealed a large increase in the number of diurnally rhythmic genes in APP23 mice in several brain structures, including regions affected by neurodegeneration in AD like the hippocampus and the cortex. Additionally, many genes showed increased rhythmicity or altered circadian phase in APP23 mice in specific brain regions, when compared to controls. For example, the expression of Slc5a3, a gene involved in osmotic stress response and deregulated in human AD brains, presented strong circadian rhythms in both APP23 and controls in cortical clusters, but the amplitude of expression was significantly larger in the dentate gyrus only in APP23 mice. Importantly, this effect was observed before and after the onset of amyloid pathology.

Conclusion

These data map the changes in rhythmic gene expression over the course of AD progression in the spatiotemporal context of cortical and subcortical brain regions. Our findings elucidate molecular disruptions occurring early in the development of AD, which may drive disease progression.
Cerebral microbleeds in Down syndrome: association with demographic, genetic, fluid and imaging biomarkers of Alzheimer’s disease
Authors: Zsadanyi Sara E. , Morcillo‐Nieto Alejandra O. , Aranha Mateus Rozalem , Aragón Irina , Montal Victor , Pegueroles Jordi , Vaqué‐Alcázar Lídia , Benejam Bessy , Videla Laura , Barroeta Isabel , Fernandez Susana , Giménez Sandra , González‐Ortiz Sofía , Bargalló Núria , Ribas Laia , Arranz Javier , Rodríguez‐Baz Íñigo , Belbin Olivia , Alcolea Daniel , Blesa Rafael , Lleó Alberto , Fortea Juan , Carmona‐Iragui Maria , Bejanin Alexandre
Published: December 2023

Background

With the development of amyloid‐modifying therapeutic agents that can lead to cerebral microhaemorrhages, it is critical to meticulously characterise the natural history of cerebral microbleeds (MBs) in populations genetically predisposed to develop Alzheimer’s disease (AD), such as Down syndrome (DS). We aimed to investigate MB prevalence in a large cohort of adults with DS and define associations with demographic, genetic, fluid and imaging biomarkers of AD, and cognitive performance.

Methods

Cross‐sectional design. Adults with DS and euploid controls from the Down Alzheimer Barcelona Neuroimaging Initiative underwent a 3T‐MRI protocol, including susceptibility‐weighted imaging (SWI) acquisition. Manual tracing of MBs was performed by two independent raters using ITK‐SNAP. Participants were classified according to MB status (MB‐/MB+) and severity (0, 1, 2+ MBs). Non‐parametric statistical tests were used to assess the effect of MBs on demographic, clinical, genetic, CSF and neuroimaging AD biomarkers, and cognitive tests.

Results

We included 247 participants with DS along the AD continuum, and 167 euploid controls (Table 1). The proportion of MB+ was higher in DS participants than controls, and progressively increased with AD clinical stages and age in the DS group (Fig. 1). By contrast, MB status did not differ by APOEε4 status, intellectual disability, or sex. In DS, the MB+ group had increased white matter hyperintensity volume and decreased hippocampal volumes compared to MB‐. DS MB+ also had lower CSF Aβ42/40 ratio, higher CSF t‐tau and p‐tau‐181 concentrations, and tended toward worse cognitive performance. Most effects gradually evolved with MB severity, although significant differences were mainly between MB‐ vs MB 2+ (Fig. 2). Finally, sensitivity analyses showed that most results became non‐significant when comparing DS MB+ to a 1:1 DS MB‐ group matched for age, sex, intellectual disability and/or AD diagnosis.

Conclusion

MB presence and severity are increased in adults with DS, and worsen with clinical progression and AD pathology. Yet, matched group analyses suggest that MB have limited impact on cognition and neurodegeneration. These results provide better characterisation of the presence and effect of MB in a population with an ultra‐high risk of developing AD who could benefit from new disease modifying drugs.
Longitudinal white matter hyperintensities in Down’s syndrome
Authors: Morcillo‐Nieto Alejandra O. , Zsadanyi Sara E. , Montal Victor , Aranha Mateus Rozalem , Pegueroles Jordi , Vaqué‐Alcázar Lídia , Benejam Bessy , Videla Laura , Barroeta Isabel , Fernandez Susana , Giménez Sandra , González‐Ortiz Sofía , Bargalló Núria , Ribas Laia , Arranz Javier , Belbin Olivia , Alcolea Daniel , Blesa Rafael , Carmona‐Iragui Maria , Fortea Juan , Bejanin Alexandre
Published: December 2023

Background

Down’s syndrome (DS) is a genetically determined form of Alzheimer’s disease (AD). Typically not complicated by systemic vascular risk factors, the DS population represents a unique opportunity to unravel the complex relationship between AD and cerebrovascular disease. Here, we aim at studying the evolution over time of white matter hyperintensities (WMHs), a key hallmark of cerebrovascular disease frequently found in AD, and to assess their topographical progression and associations with AD biomarkers in adults with DS.

Method

This longitudinal study included 43 DS adults (age = 39.8±10.4y; females = 41.9%; n = 37 asymptomatic AD, n = 6 symptomatic AD) and 81 euploid controls (age = 53.7±6.2y; females = 67.3%) from the Down‐Alzheimer Barcelona Neuroimaging Initiative, with at least 2 MRI visits with T1 and FLAIR acquisitions (time delay = 3.4±1.6y). WMHs were segmented using the Lesion Prediction Algorithm implemented in the Lesion Segmentation Toolbox (SPM12). WMH volumes were extracted in 36 regions of interest and used to compute total and regional annual volume changes. Non‐parametric statistical tests were performed to assess the effect of disease severity on WMH volume changes over time and define associations between longitudinal WMHs and baseline demographic and genetic data, and fluid biomarkers.

Result

Total annual WMH volume change increased in symptomatic DS compared to both asymptomatic DS and controls (Figure 1A). Regionally, WMH load increased in regions showing WMH at baseline in all groups (Figure 2). These changes were greater and more distributed, involving layers more distant from the ventricles (especially in occipito‐parietal regions) in symptomatic DS. Age, but not sex, intellectual disability, or APOEε4 status, was associated with longitudinal WMH in DS (Figure 1B‐F): the annual WMH volume changes in DS differed from controls at age ∼45y. Finally, WMH volume changes were negatively related to CSF‐Aβ42/40 and positively related to plasma and CSF ptau‐181 and neurofilament light (Figure 3).

Conclusion

Pathological increases in WMH volume start ∼10 years before the mean age at onset for AD (53.8y) in DS and relate to underlying AD pathology and neurodegeneration. Regional analyses suggest that WMH volume changes increase with disease progression and progressively involve deeper white matter areas. Together, these results support that WMHs are tightly related to AD pathogenesis.
Pseudo‐longitudinal trajectories of cerebrovascular disease biomarkers in adults with Down syndrome across the lifespan
Authors: Lao Patrick J. , Sedaghat Amirreza , Edwards Natalie C. , Lippert Rafael V. , Rizvi Batool , Smith Anna C. , Tudorascu Dana , Rosas H. Diana , Yassa Michael A. , Handen Benjamin L. , Christian Bradley T. , Gutierrez Jose , Wilcock Donna M. , Head Elizabeth , Brickman Adam M. ,   Alzheimer’s Biomarker Consortium‐Down Syndrome
Published: December 2023

Background

Adults with Down syndrome (DS) overproduce amyloid precursor protein, develop amyloid plaques at an early age, and are diagnosed with Alzheimer’s disease (AD) dementia at a high frequency. There is emerging evidence that cerebrovascular disease is elevated across the AD continuum in older adults with DS, independent of age and vascular risk, but it is unknown when cerebrovascular disease emerges across the lifespan.

Methods

Adults with DS from the multisite Alzheimer’s Biomarker Consortium‐Down Syndrome study (ABC‐DS; n = 241; age = 25‐72, 44±10; 45% women; 77/11/12% Cognitively‐Stable/MCI‐DS/AD dementia) underwent harmonized MRI and received a cognitive diagnosis at a consensus conference. Cross‐sectional white matter hyperintensity volume (WMH; ischemic small vessel disease), enlarged perivascular space score (PVS; impaired toxin clearance), chronic infarcts (large vessel disease), and microbleeds (hemorrhagic small vessel disease/cerebral amyloid angiopathy) were fit against piece‐wise, left null regression models with age to estimate the age inflection point at which these cerebrovascular markers emerged. The residuals for each biomarker (i.e., more than expected for their age) were then regressed on diagnosis.

Results

Total WMH volume (0.01‐31.7, 4±4.6 cm3), enlarged PVS score (0‐26, 8±5), infarcts (15% have at least one), and microbleeds (12% have at least one) were present in this lifespan sample of adults with DS. There was a significant inflection point in the fourth decade of life for total WMH (37±6, p = 7E‐3), enlarged PVS (31±6, p = 3E‐6), and infarcts (31±9, p = 2E‐3), but not microbleeds (36±21, p = 0.7). Regionally, there were significant inflection points for frontal (36±6, p = 3E‐3), parietal (36±7, p = 0.02), and occipital (42±6, p = 0.02), but not temporal WMH (33±14, p = 0.3). AD dementia was associated with higher residuals in parietal (0.5±0.2, p = 0.02) and occipital WMH (0.6±0.3, p = 0.02).

Conclusion

In adults with DS, there is cerebrovascular pathology on MRI that emerges around the same age as what has been reported for amyloid PET positivity and tau PET accumulation in this population. More posterior small vessel disease for a given age may arise with a diagnosis of AD, suggesting a cerebrovascular process in AD pathogenesis. Longitudinal assessment in relation to AD biomarkers, including amyloid and tau PET, will provide additional insight.
Assessing the psychological impact of COVID‐19 on rural informal caregivers of persons living with dementia in the United States
Authors: Santoyo‐Olsson Jasmine , Romo Elizabeth Macias , Chesla Catherine , Covinsky Kenneth E , Ramirez Giselle Aguayo , Yank Veronica A.
Published: December 2023

Background

Informal caregivers of persons living with dementia (PLWD) in rural areas of the United States (U.S.) are a vulnerable population. During the COVID‐19 pandemic, rural communities experienced heightened disparities in social services, healthcare[1], and mortality[2], including suicides[3,4]. Yet, how the pandemic affected rural caregivers is largely unknown. We examined predictors of depression and stress, as well as self‐perceived impact of COVID‐19, among rural caregivers of PLWD.

Method

As part of the Rural Dementia Caregiver Project[5], U.S. rural informal caregivers of PLWD completed an online survey from March 1, 2021, through April 30, 2022. We conducted a mixed‐method analysis of responses to validated scales and an open‐ended question. Caregiver outcome measures include depressive symptoms[6] and stress[7]. Predictors include caregiver COVID‐19 limitations[8], loneliness[9], social isolation[10], and burden[11]. Linear regression analyses examined independent associations of predictors with outcomes, adjusting for age, sex, and caregiving hours spent per week. We completed thematic analysis of responses to the question, “How has COVID impacted your life as a caregiver?” to contextualize quantitative findings.

Result

A total of 152 rural caregivers completed the survey, and of those 127 responded the open‐ended question. Most (81%) caregivers were aged 50 years and older, and 82% were female. Factors positively associated with caregiver depressive symptoms were loneliness (β = 0.72, p<0.0001) and burden (β = 3.18, p<0.01). Factors positively associated with caregiver stress were loneliness (β = 0.22, p<0.05) and burden (β = 1.28, p<0.05). COVID‐19 limitations and social isolation were not associated with depressive symptoms or stress. Qualitative results confirmed quantitative results (e.g., loneliness, increased burden) and revealed other aspects of the psychosocial context of pandemic caregivers including both negative (e.g., worry, decline in care partner health) and positive (e.g., increased time with care partner) factors (Table 1).

Conclusion

We found that loneliness and care burden contributed to the psychological distress of rural caregivers of PLWD during the COVID‐19 pandemic, and identified other contextual factors of their experiences. The pandemic exacerbated existing vulnerabilities and exposed new ones. Rural caregivers should receive increased support to address the psychosocial stressors and burdens endured during the current pandemic and future catastrophic events.
The cortical glucose metabolism signatures of cognitive resilience in amyloid positive cognitively unimpaired elderly adults
Authors: Liu Lin , Sun Pan , Lan Guoyu , Cai Yue , Li Anqi , Zhu Yalin , Ma Shaohua , Guo Tengfei
Published: December 2023

Background

β‐amyloid (Aβ) positive (A+) cognitively unimpaired (CU) individuals who maintain normal cognitive function at follow‐up may have good cognitive resilience (CR). A+/CU Individuals with high CR may have hypermetabolism. In this study, we explored the cortical glucose metabolism features of CR in A+/CU elderly adults.

Method

We analyzed 855 ADNI participants with Aβ PET (18F‐florbetapir (FBP) or 18F‐florbetaben (FBB)), CSF p‐Tau181, 18F‐fluorodeoxyglucose (FDG) PET and longitudinal residual hippocampal volume (rHCV) and cognitive assessments. A+/T+/N+ were defined as AD summary cortical standardized uptake value ratio (SUVR) for FBP ≥1.11 or FBB ≥1.08, CSF p‐Tau≥23pg/ml, and rHCV≤‐0.67 respectively. We compared intensity‐ and spatial‐normalized FDG SUVR images between 96 A‐/T‐/N‐/CU individuals (Reference group) and 68 A+/CU individuals who maintained CU at follow‐up regardless of T+ or N+ (CR group). Cortical regions with higher FDG SUVR in the CR group were identified as the CR_metaROI. Baseline CR_metaROI FDG‐SUVRs were compared between different stages of AD. Finally, we determined whether CR_metaROI FDG‐SUVR can modulate the association of Aβ PET and CSF p‐Tau with longitudinal changes of cognition, controlling for age, sex, and education.

Result

CR_metaROI was primarily located in the precentral and postcentral regions (Fig. 1). AD dementia patients had lower CR_metaROI FDG SUVRs than the CU (standardized β (βstd) = ‐0.326[95% confidence interval (ci): ‐0.534, ‐0.119], p = 0.002) and MCI (βstd = ‐0.303[95%ci: ‐0.496, ‐0.111], p = 0.002) groups (Fig. 2A), and A+/CU group had higher (βstd = 0.605[95%ci: 0.352, 0.859], p<0.001) CR_metaROI FDG SUVRs than the A‐/CU group (Fig. 2B). A‐/T+ and A+/T‐ individuals had lower (βstd = ‐0.248[95%ci: ‐0.4474, ‐0.022], p = 0.031) and higher (βstd = 0.305[95%ci: 0.093, 0.516], p = 0.005) CR_metaROI FDG SUVRs than the A‐/T‐ group respectively (Fig. 2C). The A+/T‐/N+ group had higher (βstd = 0.466[95%ci: 0.153, 0.779], p = 0.004) CR_metaROI FDG SUVRs than the A‐/T‐/N‐group (Fig. 2D). Moreover, higher baseline metaROI FDG‐SUVRs were associated with slower rates of decline in memory, executive function and preclinical Alzheimer cognitive composite scores upon the same levels of Aβ PET (Fig. 3A‐C) and CSF p‐Tau (Fig. 3D‐F).

Conclusion

We identified a metabolism signature of CR in A+/CU elderly adults. These findings may provide novel insights into understanding the hypermetabolism patterns of CR in aging people.
Longitudinal sleep, pain interference, and depressive symptoms in cognitively impaired older adults
Authors: Dimitrov Theodore , Monroe Todd B , Failla Michelle D , Bruehl Stephan , Romestan Rachel , Moss Karen O , Cowan Ronald L , Anderson Alison R
Published: December 2023

Background

Poor sleep, pain, and depression are interrelated factors in older adulthood that may impair cognition. Few studies have examined associations among sleep, pain interference (i.e., how pain interferes with daily living), and depression with cognitive status. Therefore, we investigated these associations in verbally communicative older adults with and without cognitive impairment (CI). We hypothesized that individuals with CI will be more impacted by all variables in relation to the control group.

Method

Sleep (Neuro‐QoL Sleep), pain interference (Brief Pain Inventory‐Short Form), depression (15‐item Geriatric Depression Scale), and cognitive function (Telephone Interview for Cognitive Status) were investigated in older adults (ages ≥ 65) with CI (N = 16) compared to age‐ and sex‐matched controls (N = 28). Sleep, pain, and depression data were collected weekly over six weeks to allow for a detailed assessment of potential changes in symptoms. Data analyses were conducted in R using linear mixed effects models and conditional growth curve analysis.

Result

Across our sample, we found that more sleep disturbances were associated with more severe depression (p<0.001), greater pain interference was associated with more severe depression (p<0.001), and more sleep disturbances were associated with greater pain interference (p<0.001). There was a significant interaction between cognitive status and sleep disturbances on depression (p = 0.0005), such that the CI group had a stronger positive relationship between sleep disturbances with depression severity. Similarly, there was a significant interaction between cognitive status and pain interference on depression (p<0.001), such that the CI group had a stronger positive relationship between pain interference and depression severity.

Conclusion

The findings demonstrate that the relationship among sleep, pain, and depression remain a concern in older adults with CI. As sleep worsened, depression tended to increase across both groups, yet in those with CI, this finding was stronger. Similarly, as pain interference worsened, depression tended to worsen in both groups, but this association was stronger in those with CI. Additional attention to the assessment, prevention, and treatment of sleep disturbance, pain, and depression in people living with and without CI is warranted, especially as individuals with CI may have difficulties communicating these problems.
SPRINT MIND: Implications of Recents Findings for New Trials Focused on ADRD Prevention Through Vascular Pathways
Authors: Williamson Jeff D.
Published: December 2023

Background

Clinical trial proven treatments for reducing the risk of patient centered outcomes such as mild cognitive impairment (MCI) and dementia have been lacking. The impact of intensive treatment of hypertension on the incidence of Mild Cognitive Impairment (MCI) and dementia was tested in the Systolic Blood Pressure Intervention Trial (SPRINT‐MIND) by prospectively assessing the effect of intensive blood pressure control to a target systolic blood pressure of <120 mmHg versus a standard target (<140 mmHg). This presentation reviews the SPRINT results and presents more recent analyses on the reliability of the MCI classification, evidence for the impact of BP control on transition from MCI to dementia and recent evidence on the outcome trajectories after trial discontinuation.

RESULTS

At one year, mean systolic blood pressure was 121.4 mmHg in the intensive‐treatment group and 136.2 mmHg in the standard‐treatment group. Participant mean age was 67.9 years (35.6% women) and 8,626 (92.1%) completed at least one follow‐up cognitive assessment. After only 3.26 years of treatment, the 5 year assessment of cognition deonstrated a significantly lower rate of adjudicated incident MCI (HR 0.81, CI 0.67‐0.97) and a non‐significant reduction in probable dementia (HR 0.83, CI 0.69‐1.04) in th intensively treated group. The combined outcome of MCI plus probable all cause dementia was significantly lower (HR 0.85, CI 0.74‐0.97) in the intensive versus standard treatment group. Most cases occurred in persons over age 70. At 2 years, MCI classification was 10X more likely to transition to dementia than normal cognition and 30% of classified as MCI reverted to normal, consistent with other large epidemiologic studies of MCI trajectory. In secondary analyses, intensive therapy also showed the greatest benefit on persons with the highest risk for cognitive decline.

CONCLUSIONS

Among ambulatory adults at increased risk for CVD but without diabetes, treating to a SBP target <120 mmHg compared to a target of <140 mmHg reduces the risk of incident MCI and combined MCI/probable dementia. MCI classification in SPRINT MIND was highly predictive of transition to dementia, similar to large reputable observational studies and cognitively vulnerable persons benefitted the most.
Reconsideration of appropriate use criteria for amyloid PET based on real‐world experiences
Authors: Park Kee Hyung , Shim YongSoo , Choi Seong Hye , Youn Young Chul , Yang Dong Won , Kim SangYun
Published: December 2023

Background

Amyloid PET can detect brain abnormality at very early stages of AD. However, deciding which patients should undergo amyloid PET requires careful consideration, because of its expense and the lack of treatment options. Until now, 2013 recommendations for appropriate use of amyloid PET, by Amyloid Imaging Taskforce, have been used widely. However, anti‐amyloid treatment is becoming available, so it is an appropriate time to reconsider the optimal criteria for amyloid PET use. In Korea, amyloid PET is widely used in clinical practice due to its low cost and easy accessibility. Therefore, we conducted a survey to investigate the current status of amyloid PET use by dementia experts in Korea, and considered what would be the optimal criteria for using amyloid PET in the real world.

Method

The survey consisted of 52 questions, conducted using an online platform, in 2022. Fifty‐six dementia experts (34 neurologists and 22 psychiatrists) participated, mainly working at university hospitals in Korea.

Result

Experts responded positively that they would use amyloid pet in the following situations: cognitive complaint with objectively confirmed impairment (88.5%), persistent MCI (32%), progressive unexplained MCI (84.9%), possible AD or mixed pathology (63.5%), possibility to change medication (75%), among patients age under 65 in MCI (86.5%), and in AD (82.6%). In cases of probable AD, it is recommended not to take an amyloid PET scan, but only 25% of experts answered “no”. 36.4% answered positively that they would use amyloid PET, and if the patient was under 65 years old, 30.8% responded “always”. And, to the question ‘If anti‐amyloid treatment becomes available, would you be willing to perform amyloid PET scan?’, nearly 90% of experts answered that they would consider amyloid PET in MCI and Probable AD.

Conclusion

Unlike previous recommendations, amyloid PET scan is widely used in actual clinical practice in Korea. In particular, in the situation where the use of anti‐amyloid based disease modifying drugs has become a reality, contrary to the recommendations, it could be used more actively in patients with probable AD. Therefore, it is necessary to reconsider what is the appropriate amyloid PET use criteria.
A Cross‐Regional and Cross‐Generational Approach to Addressing Recruitment Barriers: The Engaging Communities of Hispanics/Latinos for Aging Research (ECHAR) Network
Authors: Medina Luis Daniel
Published: December 2023

Background

Despite being the largest and one of the fastest growing ethnic groups in the United States, Hispanics/Latinos (H/Ls) comprise only about 5% of NIH‐funded Alzheimer’s disease and related dementias (ADRD) research participant samples. Exclusion of H/Ls limits the generalizability of research findings and our understanding of brain health disparities. The Engaging Communities of Hispanics for Aging Research (ECHAR) Network is a collaborative, transdisciplinary network aimed at engaging, educating, and motivating H/Ls for participation in ADRD research by addressing several barriers to inclusion, including trust and ADRD‐related communication.

Method

ECHAR has been employing a novel, community‐engaged method – Boot Camp Translation (BCT) – to translate medical jargon into action‐based, community relevant messages by answering the questions: What are the key messages [about ADRD]? Who in my community needs to hear these messages? How do we get these messages to them? BCT was carried out in three metropolitan areas with large H/L populations: Denver, Colorado; Houston, Texas; and Las Vegas, Nevada. We also carried out BCT in groups of middle‐to‐older‐age adults as well as in younger adults. Over the course of several months, community stakeholders worked closely with the research team to co‐create ADRD communications targeted to local communities. An additional objective of ECHAR has been to invite BCT participants to form local community action boards (CABs); as members of the research infrastructure, CABs help further improve community relations and inclusion.

Result

Pre‐/post‐ comparisons showed significant improvement in subjective understanding (Cohen’s d = 0.75; p<0.001) and objective knowledge of Alzheimer’s disease (Cohen’s d = 0.79; p<0.001). Similarities were observed across the three sites; H/L community members identified key messages related to reducing stigma, emphasizing brain health and risk mitigation, and acknowledging the impact of Alzheimer’s disease on multi‐generational families/households. Participants also recommended sharing these messages with H/Ls across the lifespan using multi‐media avenues. Key cross‐regional and cross‐generational differences were also observed and will be described.

Conclusion

The ECHAR Network has developed key, culturally responsive, ADRD‐related materials as well as dissemination strategies for H/L recruitment. Moreover, by establishing CABs in each city, we have developed sustainable research infrastructure to enhance outreach.
What do we still need to know about antihypertensives and dementia prevention?
Authors: Peters Ruth
Published: December 2023

There is a substantial evidence base linking higher blood pressures to an increased risk of cognitive decline and dementia and an increasingly strong evidence base showing reduced dementia risk with blood pressure lowering. Several clinical trials including SPRINT‐MIND have strongly suggested that antihypertensive treatment to lower blood pressure reduces dementia risk. Furthermore, a recent individual participant data meta‐analysis combining data from 5 large double‐blind placebo‐controlled trials of antihypertensives in a late‐mid to early‐late life population (N = 28008) found a 13% reduction in incident dementia cases (OR0.87 (95%CI: 0.75,0.99))(1). The blood pressure difference between the two combined trial arms was ∼10mmHg in systolic blood pressure and there was no clear U shape indicating no increase in risk at lower pressures. This is supported by numerous earlier meta‐analyses of published trial and epidemiological data. Blood pressure lowering is acknowledged as one of the most promising ways in which we might reduce the risk of dementia and cognitive decline.

Despite this substantial progress and although we are arguably closer than ever before to answering the question of whether blood pressure lowering reduces dementia risk, there have been no double‐blind placebo‐controlled trials that have definitively shown dementia risk reduction with antihypertensive use. In the absence of strong results, recommendations for antihypertensive use inevitably remain cautious. Furthermore, not only do we still lack a definitive blood pressure dementia risk reduction trial, such a trial would need to be large and complex. Uncertainties also exist about how to deliver treatment against the backdrop of widespread antihypertensive use to reduce cardiovascular risks such as stroke or heart attack. Research is also still progressing on key practical questions. For example, whether we should have a goal blood pressure for brain health, how far we should lower blood pressure to reduce dementia risk, what is the ideal treatment package and how much do factors such as age and frailty matter? We present the key evidence so far and an ongoing pilot trial designed to answer the leading questions in the field.

(1)Peters et al Eur Heart J 2022