bluuebunny/crossref_metadata_2025 huggingface dataset:
Protective effects of sleep duration and physical activity on cognitive performance are influenced by β‐amyloid and brain volume but not tau burden among cognitively unimpaired older adults
Authors: Aslanyan Vahan , Ortega Nancy E , Fenton Laura E. , Harrison Theresa M. , Raman Rema , Mack Wendy J , Pa Judy
Published: December 2023

Background

Sleep and physical activity have gained traction as modifiable risk factors for Alzheimer’s disease (AD). Sleep duration is linked to amyloid‐β (Aβ) clearance while physical activity is associated with brain volume maintenance. We investigate associations between sleep duration and physical activity and cognition by testing if sleep duration—cognition and physical activity—cognition are explained by Aβ deposition and brain volume, respectively. Additionally, we explore the mediating role of tau burden in these relationships.

Method

This cross‐sectional study obtained data from participants in the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study, a randomized clinical trial. Cognitively unimpaired participants underwent Aβ and tau PET and brain MRI prior to randomization. Cognitive performance was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). Self‐reported nightly sleep duration and weekly physical activity were the primary predictors. Regional Aβ and tau pathologies and volumes were the proposed variables influencing sleep duration—cognition or physical activity—cognition relationships.

Result

Aβ PET data were obtained from 4322 participants (1208 with MRI, 59% female, 29% amyloid positive). Sleep duration was associated with an Aβ composite burden (β = ‐0.005,CI:(‐0.01,‐0.001)) and Aβ burden in the anterior cingulate (ACC) (β = ‐0.012,CI:(‐0.017,‐0.006)) and medial orbitofrontal cortices (MOC) (β = ‐0.009,CI:(‐0.014,‐0.005)) but not with brain structure. Composite (β = ‐1.54,CI:(‐1.93,‐1.15)), ACC (β = ‐1.22,CI:(‐1.54,‐0.90)) and MOC (β = ‐1.44,CI:(‐1.86,‐1.02)) Aβ burden were also associated with PACC. Sleep duration—PACC association was explained by Aβ burden in path analyses (Figure 1). Physical activity was not associated with Aβ but was associated with hippocampal (β = 10.57,CI: (1.06,20.08)), parahippocampal (β = 9.3,CI:(1.69,16.91)), entorhinal (β = 14.68,CI:(1.75,27.61), and fusiform gyral (β = 38.38,CI:(5.57, 71.18)) volumes, which were also positively associated with PACC (p<0.02 for hippocampus, entorhinal cortex, and fusiform gyrus). Physical activity—cognition relationship was explained by regional volumes (Figure 2). Tau was not related to sleep duration or physical activity, and it did not moderate relationships between cognition and sleep duration or physical activity.

Conclusion

Sleep duration and physical activity are associated with cognition through independent paths of brain Aβ and brain volume, respectively, but not tau burden. Dementia risk reduction approaches that emphasize the adequate sleep duration and a physically active lifestyle may benefit those with risk for AD.
Total and posterior cerebral blood flow is associated with white matter hyperintensity volume and Alzheimer’s‐like patterns of brain atrophy in older adults
Authors: Pyne Jeffrey , Morales Clarissa , Alshikho Mohamad J , Lao Patrick J. , Turney Indira C , Gutierrez Jose , Manly Jennifer J. , Mayeux Richard , Brickman Adam M.
Published: December 2023

Background

Small vessel cerebrovascular disease, often visualized as white matter hyperintensities (WMH) on T2‐weighted MRI scans, contributes to risk, progression, and, possibly, pathogenesis of Alzheimer’s disease (AD). When considered in the context of previous neuroimaging biomarker work in AD, WMH appear to colocalize with other markers of disease risk and progression, including metabolic changes, atrophy, and tau pathology, in areas perfused by the posterior circulation. In the current study, we used a novel MR‐based method, termed phase contrast, to quantitate total cerebral blood flow in anterior and posterior circulations and test its relationship with WMH volume and an AD‐like pattern of brain atrophy in older, community‐dwelling adults.

Method

Two hundred forty‐five older adult participants (77±5.6 mean±SD age, 66% women, 42% Latinx, 30% Black, and 28% White individuals) in the Washington Heights Inwood Columbia Aging Project (WHICAP) received T1‐weighted, T2‐weighted (FLAIR), and phase contrast MR imaging. 2D phase contrast imaging can be used to quantify absolute blood flow rates with cross‐sectional velocity‐encoding of major vasculature leading into the brain. Blood flow rates in the anterior circulation (carotid arteries) and posterior circulation (vertebral arteries) were derived with Medis QFlow 4.0. WMH volume and cortical thickness in AD‐signature regions were derived with in‐house software and FreeSurfer v6.0, respectively. Separate general linear models tested the association of total, anterior, and posterior blood flow rates with WMH volumes and AD‐signature cortical thickness.

Result

Lower total cerebral blood flow was associated with increased total WMH volume (β = ‐0.14, p<0.05, 95%CI [‐1.37E‐2, ‐7.32E‐4]), an effect that was stronger for posterior flow (β_posterior = ‐0.17, 95%CI [‐3.7E‐2, 2.5E3], β_anterior = ‐0.11, 95%CI [‐1.9E‐2, 5.4E3]). Lower posterior blood flow specifically was associated with lower AD‐signature cortical thickness, but only in older participants (age interaction term: β = ‐3.14, p<0.01, 95%CI [‐2.0E‐4, ‐3.5E‐5]).

Conclusion

Lower total cerebral blood flow, particularly in the posterior circulation, is associated with increased WMH volume and decreased cortical thickness, two neuroimaging markers that are implicated in risk and progression of AD. Future work that examines whether or how diminished total cerebral blood flow accounts for the colocalization of AD biomarkers across modalities will provide insight into the vascular contributions to AD.
Dementia Risk Factors Predict Individual Differences in Cognitive Function
Authors: Hennessee Joseph P. , Katen Carson D. , Monier Sarah A. , Park Denise C.
Published: December 2023

Background

Twelve modifiable risk factors have been estimated to account for 40% of dementia incidence worldwide (Livingston et al., 2020). Growing understanding of these risk factors presents the possibility that dementia risk can be partially mitigated via non‐pharmacological means, such as changes in lifestyle (e.g., alcohol consumption, social activity). We sought to provide the first systematic investigation of whether this set of risk factors also contributes to individual differences in cognitive function in a cognitively‐normal sample, and which risk factors provide the strongest contribution.

Method

We investigated cross‐sectionally the association between eight of these risk factors and cognition in 246 cognitively‐normal adults, aged 50‐90 from the Dallas Lifespan Brain Study. Risk factors included alcohol use (drinks per week), body mass index (BMI), cigarettes smoked per day, depressive symptoms (CESD scale), years of education, exercise frequency (20+ min sessions), pulse pressure, and frequency of social activity. A general measure of cognition, fluid ability, was used as the outcome variable and it was an average of six commonly used assessments of processing speed, working memory, and reasoning.

Result

In a multiple regression controlled for age and sex, 15.6% of fluid ability variance was accounted for by years of education (R
2 = .040, p = .002), frequency of social activity (R
2 = .034, p = .004), BMI (R
2 = .030, p = .008), cigarettes smoked per day (R
2 = .020, p = .032), and depressive symptoms (R
2 = .017, p = .047), as well as non‐significant contributions from alcohol use, exercise frequency, and pulse pressure. Further analysis examining cortical amyloid‐beta burden as a predictor and moderating effects of age will be discussed.

Conclusion

The findings illustrate that levels of these modifiable risk factors affect cognition, even in a large sample of adults unselected for AD risk. We report differences in magnitude of effects for adults who showed cognitive decline over 10 years compared to those who were stable.

References: Livingston, G., Huntley, J., Sommerlad, A., Ames, D., Ballard, C., Banerjee, S., … & Mukadam, N. (2020). Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet, 396(10248), 413‐446.
Effects of clutter on reaching in posterior cortical atrophy and typical Alzheimer’s Disease
Authors: Bancroft Matthew J , Hayes Oliver S , Ocal Dilek , Brotherhood Emilie V , Hoe Juanita , Kaski Diego , McIntosh Robert D , Crutch Sebastian J , Day Brian L , Yong Keir X X
Published: December 2023

Background

Posterior cortical atrophy (PCA) is a neurodegenerative syndrome most commonly caused by Alzheimer’s disease (AD) and is often considered the most common atypical AD presentation. PCA is characterised by predominant visual rather than memory loss and occipito‐parietal/occipito‐temporal atrophy (‘visual‐spatial AD’). Characteristic visual‐spatial deficits in PCA include difficulty perceiving objects among visual clutter, consistent with excessive visual crowding. However, there is conflicting guidance and limited empirical evidence regarding management of such perceptual deficits. Here we investigate effects of clutter when reaching to objects with the upper limb.

Method

Patient (total n = 38; PCA n = 21; typical AD [tAD] n = 17) and control (n = 18) participants repeatedly reached to a visual target presented on a computer screen (white square on a grey background; n = 100 trials per participant). The target appeared in one of five positions along the medio‐lateral axis (Fig 1) and was presented under different flanker (unflanked, flanked [shape/coloured distractors]), spacing (condensed, spaced; Fig 2) and flicker conditions (static, flicker). Outcome measures were reach completion time (time from target presentation to completion of the reach) and spatial accuracy (medio‐lateral distance between target and finger position at reach completion), determined using motion capture.

Result

Reach accuracy was comparable between groups and across conditions. However, reach completion was slower in both patient groups (group: p<0.001) and PCA were particularly affected by target‐flanker spacing (group‐by‐spacing: p<0.001). When reaching to unflanked targets, completion times were quickest in control (estimated mean [95%CI]: 1.2s [1.0,1.4]), slowest in PCA (2.3s [1.9,2.6]) and intermediate in tAD groups (1.5s [1.3,1.8]; Fig.2). Slower reaching to flanked targets was particularly apparent in PCA relative to tAD and control groups, especially with condensed flankers (Fig.2). Slower reaching to flanked targets was somewhat mitigated by increasing target‐flanker spacing; exaggerated spacing effects in the PCA group are consistent with excessive visual crowding (estimated decrease in completion time spaced vs condensed: PCA: ‐14.4% [‐11.1, ‐17.7]; tAD: ‐5.2% [‐2.5, ‐7.9]; Control: ‐4.8% [‐2.9, ‐6.6]).

Conclusion

Findings suggest visual crowding – normally restricted to healthy peripheral vision – impairs reaching to targets presented in central vision in PCA. Findings may inform symptom and environment management strategies for people with visual loss arising from neurodegenerative disease.
Vision and Hearing Difficulty as a Modifier of the Effects of Cognitive Training Over 5 and 10 Years in Older Adults
Authors: Huang Alison R , Rebok George , Deal Jennifer A
Published: December 2023

Background

Cognitive training interventions are delivered visually and/or aurally. Whether sensory loss modifies its effect in older adults is unknown. We assessed differences in the effect of the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) Study, a randomized cognitive training intervention trial, by self‐reported vision and hearing difficulty.

Methods

Participants (65 years and older, cognitively/functionally healthy) were randomized to cognitive training in memory, reasoning, or speed of processing or a no‐contact control. Composite scores were created using multiple cognitive assessments in memory, reasoning, and speed of processing. Self‐reported near vision difficulty was defined as reading ordinary print in the newspaper (no difficulty/a little or some difficulty), and hearing loss was self‐reported (yes/no). Differences in the 10‐year effect of cognitive training on change in trained cognitive ability were assessed using linear mixed effect models adjusted for demographic and study design characteristics.

Results

Among 2,788 participants, 22% reported vision difficulty and 43% reported hearing loss. Participants with sensory loss benefited from all cognitive training interventions (Figure 1); however, the magnitude of benefit of reasoning training was smaller among participants with vs. without vision difficulty (10‐year difference in reasoning ability [intervention vs. control]: vision difficulty: ‐0.25, 95% CI: [‐0.88, 0.39], no vison difficulty: 0.58, 95% CI: [0.28, 0.89]). Magnitude of benefit of memory training was greater for participants with vs. without hearing loss (10‐year difference in memory ability [intervention vs. control]: hearing difficulty: 0.17, 95% CI: [‐0.37, 0.72], no hearing difficulty: ‐0.20, 95% CI: [‐0.65,0.24]). Beneficial effect of speed of processing training was similar by sensory status.

Conclusion

Participants with vision difficulty did not benefit as much from reasoning training, likely because training required more visually complex exercises (e.g., deciphering patterns across similar symbols). Memory training was more efficacious for participants with hearing loss, perhaps because training provided compensation strategies for overcoming cognitive load (increased effort for processing degraded auditory signals). Cognitive training interventions should consider sensory function in design and administration. Individuals with sensory loss have increased risk for cognitive decline and should not be excluded from cognitive training interventions as magnitude of benefit may be greater for these individuals.
Diversity in Biomarkers: Challenging Expectations of Serum Tau Positivity
Authors: Schirtzer Emily A , West Jennifer , Torres Sandra , Cassidy Stephanie , Baez‐Torres Sheila
Published: December 2023

Background

Alzheimer’s disease has been thought to affect minority populations at higher rates than the Caucasian population. While recent advancements in biomarkers have been promising, we expected to see a similar correlation with biomarker positivity rates. However, our data has revealed that serum TAU biomarker testing in older healthy populations reveals a positivity rate much higher in Caucasian vs. Black participants as well as in Non‐Hispanic vs. Hispanic participants.

Method

Data from 1,223 cognitively unimpaired trial participant subjects was analyzed. Of those participants 120 were Black and 1,066 were Caucasian. Data from 36 participants of other minority races and one participant who chose not to reveal race were also collected but for the purpose of this presentation are not being addressed at this time. Data on ethnicity was also collected, revealing 262 Hispanic and 961 Non‐Hispanic participants. Again, one participant chose not to reveal ethnicity.

Result

Percentages of positivity were collected and analyzed. While we expected to see rates of positivity two times higher for Black participants than Caucasian participants, what was actually noted was 10.5% positivity for Caucasian and 6.7% positivity for Black or African Americans. Similarly, we expected to see positivity among Hispanic participants at 1.5 times greater than Non‐Hispanic participants. What instead was noted was very similar rates of positivity with Non‐Hispanic at 10% positivity and Hispanic at 11.1% positivity.

Conclusion

In analyzing positivity rates of serum TAU among certain race and ethnicity groups, we expected to see evidence of pathology similar to rates of reported actually diagnosed diseases. However, the data obtained is trending differently. While the initial data was from a relatively small sample population, the collection of additional data will help further analyze if this trend will continue to reveal rates of positivity contradictory to what is expected.
Evaluation of the cerebral vascular morphostructural in a model for Alzheimer’s disease after the intervention with physical exercise.
Authors: Soto‐Rojas Luis Oskar , Díaz‐Cintra Sofia , Jesús Andrade José , Orta‐Salazar Erika
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common neurodegenerative disease in the world. It is characterized by impaired memory, thinking, orientation, and learning, thus affecting the quality of life of people whosuffer from it. The two pathognomonic hallmarks are the neuritic plaques and neurofibrillary tangles, however, the vascular system is also affected, aggravating the symptoms of the disease, being a possible hypothesis of the development of the disease. One of the most widely used animal models to study disease mechanisms is the 3xTg‐AD triple transgenic mouse that contains three mutations associated with familial AD (PS1M146V, APPSWE, and tauP301L). Among the non‐pharmacological treatments is physical exercise, which is a variety of planned, repetitive, and dosed physical activity, proving to be safe as part of the adjuvant treatment of the disease, however, its effect on the vascular system is unknown.

Method

A total of 40 ten‐month‐old female mice, 3xTg‐AD (n = 20) and NonTg (n = 20), equally divided into exercise and sedentary groups, were used. An intervention of voluntary physical exercise was carried out for 3 months with a frequency of 5 times a week. Subsequently, memory and learning were evaluated using the Barnes maze test. The vascular morphostructure by anatomical analysis through histological assays using markers for vascular basement membrane (anti‐Collagen IV) and pericytes (anti‐PDGFR‐β), in addition to amyloid deposits. No improvement in cognitive ability was observed, however, exercise promoted the recovery of the vascular system, as well as the reduction of amyloid deposits.

Result

No improvement in cognitive ability was observed, however, exercise promoted the recovery of the vascular system, as well as the reduction of amyloid deposits.

Conclusion

The intervention with voluntary physical exercise promotes stability of the vascular system as well as the reduction of amyloid deposits in the symptomatic stages of the disease.
Designing Attitudinal Environments to Address Stigma: Virtual Film Screenings and Panel Discussions on Dementia in a Health Promotion Program
Authors: Park Melissa , Lee Keven , Yang Seiyan , Francioni Arnaud , Sénéchal Christian , Belchior Patricia , Bourdais Marie Christine Le , Valente Thomas W.
Published: December 2023

Background

Intersectoral partnerships are critical for effective and sustainable health promotion programs. Yet stigma and misperception continue to interfere with public engagement in dementia prevention programs, outreach, and willingness to access to dementia and‐or mental health related services for persons living with Alzheimer’s and‐or related disorders and personal carers. The aim of our Public Health Agency of Canada Dementia Community Investment project, What Connects Us∼Ce Qui Nous Lie (2020‐2023), was to collaboratively cultivate sociocultural environments worth living in using shared activities and events to address stigma at the intersection of dementia, aging and mental health. In this paper, we present initial results on the effectiveness of using on‐line, community screenings of short films featuring stories about living with dementia, followed by curated panel discussions with the film directors, arts/culture partners, policy makers and other stakeholders.

Method

We employed a mixed methods ethnographic approach to describe and measure the impact of six film screenings with pre/post‐film and then later post‐discussion measures of semantic sentiment. All discussions were simultaneously interpreted, and based on open‐ended qualitative questions that had been developed with panelists prior to the screening. The qualitative questions asked for one word/phrase responses to generate word clouds in French and English. Three researchers then assessed the words/phrases until agreement on positive or negative value was reached. French words were back‐translated into English prior to analysis using suzy‐net, a natural language processor, to confirm positive/negative valence and to measure changes within each film screening and across all film screenings.

Result

There was a significant change in sentiment from negative (e.g., frustration, lies, loss, confusion) to positive sentiment (e.g., humanity, empathy, compassion, understanding) across all waves within and across the six screenings, with the most change occurring post‐discussion. In addition, partners and project‐related team members were removed from the analysis to test for partner participation confounding with the overall shift in valence remaining the same.

Conclusion

Films about living with dementia, and curated questions developed in collaboration with panelists and directors of 1st person experiences can positively impact changes in sentiment about dementia.
Structural and functional Analysis of novel 3‐Nitrotyrosine Aβ‐specific Antibodies
Authors: Kottwitz Anna Katharina , Piechotta Anke , Parthier Christoph , Linnert Miriam , Roßner Steffen , Schilling Stephan , Rahfeld Jens‐Ulrich
Published: December 2023

Background

Posttranslational modified (PTM) amyloid peptides are increasingly within the spotlight of Alzheimer’s drug research. Some of these modifications, such as the formation of pyroglutamate or isoaspartate, are associated with the deposition and increased toxicity of amyloid peptides. The role of nitration at Tyr10 of Aβ and its abundance in AD brain is less well understood. How 3NY10‐Aβ is formed is controversial, as well as the influence on aggregation behaviour. Hence, we here aimed at generation and characterization of monoclonal antibodies specific for 3NY10‐Aβ as research tool and potential therapeutic molecules.

Method

Monoclonal antibodies were developed by immunizing mice with 3NY10‐Aβ(6‐14) and derivation of corresponding hybridoma cell lines. Characterisation of the antibodies was achieved by a variety of biochemical and kinetic analyses: isothermal titration calorimetry (ITC), dot blot analysis and ThioflavinT aggregation studies. X‐ray crystallography was used for structure determination. We used immunohistochemical (IHC) staining of brain tissue from 5xFAD mice and enzyme linked immune sorbent assay (ELISA) to assess the formation of 3NY10‐Aβ in transgenic mice.

Result

Two highly affine 3NY10‐Aβ antibodies 4C3 and 3B3 have been generated, both binding 3NY10‐Aβ(1‐16) in the nanomolar range (KD4C3 = 11 nM, KD3B3 = 88,5 nM) as determined by ITC. The specificity of the antibodies was confirmed by dot blot analysis, using several post‐translationally modified Aβ‐peptides. Aggregation studies of 3NY10‐Aβ(1‐40/42) peptides in presence of 3B3 or 4C3 showed an influence of fibril formation, as could be verified by means of transmission electron microscopy. Co‐crystallisation of 4C3 Fab‐fragment and 3NY10‐Aβ(1‐16) at a resolution of 2.5 Å revealed a binding of 3NY10. To investigate the role of 3NY10‐Aβ in AD, IHC‐staining of brain from mice with AD‐like pathology (5xFAD mice) was performed. The data support presence of 3NY10‐Aβ within amyloid deposits, although staining appeared weak. Likewise, a Sandwich‐ELISA of homogenized murine brain tissue displayed no significant proportion of 3NY10‐modified Aβ in relation to the total Aβ(1‐40/42).

Conclusion

It has been demonstrated that the unique monoclonal 3NY10‐Aβ specific antibodies 4C3 and 3B3 are a suitable tool for investigating the role of 3NY10‐Aβ in AD. Future research aims to quantify the level of 3NY10‐Aβ in human brain tissue with AD‐pathology.
Molecular Signatures of Alzheimer’s Disease (AD) in SARS‐Cov‐2 Infected Mouse Brains
Authors: Parekh Parag A , Badachhape Andrew A , Menon Renuka , Ghaghada Ketan , Ronca Shannon E , Annapragada Ananth
Published: December 2023

Background

COVID‐19 is primarily a respiratory syndrome caused by SARS‐CoV‐2 infection, however, a third of COVID‐19 patients report post‐acute neurological sequelae. A close correlation between COVID‐19 and neurodegenerative diseases poses the question of viral etiology and its effect on pre‐existing disease. In this work, we performed brain transcriptomics to compare gene changes in SARS‐CoV‐infected mice and mouse models of Alzheimer’s disease (AD) pathology to investigate the relationship between neuroinflammation, immune response, and associated molecular signature of AD.

Method

K18‐hACE2 transgenic mice (6‐8 weeks old) expressing human ACE2 receptor were intranasally infected with SARS‐COV‐2 virus (Ancestral USA/WA1/2020). Mock‐infected mice were used as controls. Animals were euthanized 5‐10 days post‐infection. Brains were harvested, treated for viral deactivation, and processed for mRNA extraction. Brains harvested from an uninfected APP/PS1 mouse model of amyloid pathology (9‐12 mo old) and P301S model of tau pathology (8‐9 mo old) were used for comparison. TopHat was used to align RNA‐Seq using Bowtie mapped to the current reference mouse genome assembly. Cufflinks was used to estimate the abundance of transcripts and test for differential expression and regulation.

Result

Assessment of differentially expressed genes (p value <0.05) between SARS‐CoV‐2 infected and uninfected K18‐hACE2 brain samples were compared with RNA from uninfected mouse models of AD. The differentially expressed gene set identified 36 upregulated genes that include disrupted RNA metabolism genes, interferon‐ genes, TNF‐associated genes, ubiquitin‐associated genes, transporters, and enzymes. Downregulation of a single gene Tnfrsf17 that has also been reported in patients with severe Covid‐19 (Table 1) and AD patients was observed.

Conclusion

Brain transcriptomic profiling of SARS‐CoV‐2 infected mice revealed gene changes that are consistent with those in AD mouse models of amyloid and tau pathology. Our studies warrant further investigation of viral infections as a causative force of transcriptomic changes that precede neurodegeneration.
Teleconference group singing programs for well‐being of healthy older adults and persons with neurocognitive disorders during the COVID‐19 pandemic
Authors: Schafer Rhiana , Bonakdarpour Borna , Miller Sandra Siegel , Miller Jonathan
Published: December 2023

Background

During the COVID‐19 pandemic, older adults experienced a marked decline in well‐being, attributed largely to social isolation (Tilburg et al, 2021; Krendl et al, 2021). Previous literature shows that participatory musical interventions, like group singing, improve well‐being and provide social and emotional support (Pentikäinen et al, 2021; Johnson et al, 2020). However, the pandemic highlighted the need for research on how such programs may be administered in an online setting. The enforced shutdown of in‐person choirs in 2021 provided an opportunity for such assessment.

Method

Two types of group choir programs were conducted via teleconferencing. One program engaged participants in sing‐along to familiar music only, offered weekly (52 in 2021). The other involved structured rehearsals (14 sessions) where participants learned choir music, culminating in a recorded "virtual concert”. Program participants were 55 and older, divided into persons with neurocognitive disorders (NcD) and cognitively healthy individuals (CH). Self‐report assessments of the programs were solicited. Four Likert scale questions covered anxiety, social connections, physical well‐being, and “other” areas of well‐being. Two free response questions requested elaboration on other well‐being improvement.

Result

Results of Likert scales indicated at least moderate improvements in all measured aspects of well‐being. Feedback was overwhelmingly positive (>95%). Free response analysis revealed 7 themes, the most prominent being emotional, social, and intellectual well‐being. 87% of respondents mentioned positive effects on well‐being. Intellectual well‐being was mentioned with significant frequency by choir participants versus sing‐along (p = 0.02). While the NcD choir group was small, hampering statistical power, clear trends were present; 40% of participants in the NcD choir highlighted social well‐being (25‐29% in other groups), and 20% discussed improvements to physical well‐being (0‐6% in other groups).

Conclusion

Online group music programs administered during the COVID‐19 pandemic showed improvements in overall measures of well‐being, with different programs and participants highlighting specific aspects. These results establish feasibility for such programs as a method for providing meaningful improvement to well‐being in older adults, providing stability and connection amidst a time of disruption and isolation.
Regional White Matter Hyperintensities are Associated with Diminished Blood Flow and Microstructure in Middle Age
Authors: Alshikho Mohamad J , Pyne Jeffrey , Lao Patrick J. , Turney Indira C , Berroa Joncarlos , Gutierrez Jose , Manly Jennifer J. , Brickman Adam M.
Published: December 2023

Background

White matter hyperintensities (WMH) are areas of increased signal visualized on T2‐weighted FLAIR magnetic resonance imaging (MRI), thought to reflect macrostructural damage due to small vessel cerebrovascular disease. Previous work established an association of WMH severity, particularly in posterior regions, with risk and progression of AD in late onset and genetic forms of AD, suggesting a vascular component to disease pathogenesis and course. Examination of the emergence and correlates of cerebrovascular changes in middle age, a critical time when vascular risk appears to be most penetrant, can give insight into mechanisms linking vascular brain injury and risk for AD. In the current study, we examined the association of cerebral blood flow (CBF) and white matter microstructure with total and regional WMH volume in middle‐aged, community dwelling adults.

Method

Four hundred and ninety‐two middle‐aged participants (55+/‐11 age = 28 ‐85 years) from the community‐based Offspring Study of Mechanisms for Racial Disparities in Alzheimer’s Disease received multi‐modal MRI scanning. Regional WMH volumes were derived with in‐house software that labeled clusters of voxels within a hyperintense intensity distribution. Pulsed arterial spin labeling (PASL) sequences were processed to quantify CBF. Fractional anisotropy (FA) maps were obtained from diffusion weighted data. Total and regional WMH volumes were used as predictors for whole brain voxel‐wise correlation analyses in separate models for CBF and FA.

Result

There were negative associations between WMH volume and CBF in frontal, parietal, and occipital regions. Higher white matter hyperintensity volume was associated with lower FA, particularly in the periventricular region.

Conclusion

We found associations of increased WMH volume with diminished blood flow and white matter microstructure. Future studies are needed to explain the relationship between these changes and the risk of cognitive impairment in middle aged adults and risk for AD.
Caregivers and non‐caregivers attitudes regarding pre‐symptomatic Alzheimer’s disease testing
Authors: Makri Marina , Despoti Akylina , Gkioka Mara , Tsolaki Magda
Published: December 2023

Background

Over the past decade there has been increasing testing of biomarkers and new methods of presymptomatic screening for Alzheimer disease (AD). But still, there is little known about the beliefs of patients and family caregivers regarding testing in Greece. The aim of this study is to assess the attitudes, barriers and motivations to pre‐symptomatic AD testing, among older adults with and without an experience of AD caregiving.

Method

A total sample of 213 participants (Caregivers, N = 96 and Non‐Caregivers, N = 117) answered the ‘’Perceptions regarding pre‐symptomatic dementia testing” (Pre‐dem) questionnaire. Most participants were females (N = 179) and were 41‐50 (N = 56) and 51‐60 (N = 55) years old.

Result

A two‐sample t‐test was performed to compare the four domains in caregivers and non‐caregivers and there was no significant difference, and also compare with and without a family history of AD and there was not a significant difference in perceived harms of testing, perceived benefits of testing, and need of knowledge. There was a significant difference in acceptance of testing between participants with a history of AD (M = 4.67, SD = 3.86) and non‐history (M = 6.83, SD = 4.33); t(211) = ‐3.75, p = 0.00. A one‐way ANOVA was conducted to compare the four domains with the years of care (1‐3, 3‐5, and more than 5 years). There were no significant differences between the domains and the years of care. Finally, a one‐way ANOVA was conducted to compare the four domains with the age of the first diagnosis of the relative or friend of the caregiver (51‐55, 56‐60, 61‐65, 66‐70 and 70+). There were no significant differences between the domains and the age that the relative/friend was diagnosed.

Conclusion

This is the first study that assessed the attitudes towards dementia and genetic screening of Greek older adults with and without an experience of dementia caregiving. Both participants had similar beliefs regarding the pre‐symptomatic dementia testing, except for the acceptance of testing in participants with and without a family history of AD. There is a need for more information, education and empowerment of the caregivers regarding dementia screening but also the general public.
Experience in a primary care inpatient hospital (Comárcal) with the use of CSF results for the diferential diagnosis of Alzheimer’s disease
Authors: Oliveros‐Cid Antonio , Hojas Sarai Garcia , Agreda Delia Quilez , Obanos Maria Teresa Rubio , Oliveros‐Juste Antonio , Cimorra Belen Delgado , Carrasco Ana Chacon , Catalan Claudia Ovejas , Echeverria Aitziber Echeverria , Lopez Maria Angeles Cid , Moreno Lisbed Rondon , Salvador Fernando Jarauta
Published: December 2023

Background

To analyze the usefulness of the use of Alzheimer’s disease (AD) biomarkers in cerebrospinal fluid (CSF) since its incorporation into clinical practice, in a first‐line care hospital setting.

Method

We review clinical history, neuroimaging and neuropsychology, and results of B‐amyloid 42, B‐amyloid 42/40 ratio, total tau and p‐tau in CSF in patients who consulted for cognitive impairment. Prior to biomarker determination, they were assigned a degree of suspicion based on history, neuroimaging and neuropsychology. Afterwards, they were reclassified into probable AD/ dementia not AD/no evidence of AD or neurodegeneration according to the ATN system. Finally, the usefulness was assessed according to whether a high degree of diagnostic certainty was achieved in each case.

Result

39 patients gave ICF and were analyzed; mean age 69.5 years; cases with typical and atypical clinical course. After determination of biomarkers, they were classified according to whether they presented A+/A‐, T+/T‐ and N+/N‐; findings were correlated with previous clinical and paraclinical data and compared with them, and stratified according to the degree of diagnostic certainty provided. A high degree of diagnostic certainty was achieved in 34/39 patients.

Conclusion

determination of CSF biomarkers is a useful, affordable and decisive tool in the differential diagnosis of patients with Alzheimer’s disease, which makes it a diagnostic resource to be used preferably even in primary health care hospitals.
Mild excitotoxic effect on mitochondrial membrane potential, Ca2+ homeostasis and energy production in a mouse model of Alzheimer’s disease
Authors: Basso Emy
Published: December 2023

Background

Neurons are bound to maintain a tight control over their cellular homeostasis in order to preserve their many functions, and specifically to precisely regulate ion fluxes for the generation of action potential and neurotransmission. In particular, the energetic balance has to be finely adjusted since its alteration may hamper cellular functionality with consequent cell suffering and death. Mitochondria play a central role in the homeostatic regulation within the cells due to the many vital tasks they perform in terms of energy production, participation in the regulation of Ca2+ concentration, modulation of intracellular signaling that allow the cell to respond to external solicitation

Method

Primary hippocampal neuronal cultures of 14‐17 DIV from WT and AD mouse model were challenged with μM concentration of glutamate to induce a mild excitotoxic effect; mitochondrial membrane potential, mitochondrial an cytosolic Ca2+ transients and cytosolic ATP levels were evaluated with fluorescent probes. Cells were treated also with inhibitors of the permeability transition pore to evaluate its effect on cell functionality

Result

We observed that in a model of Familial Alzheimer’s disease, hippocampal neurons are sensitive to a modest excitotoxic signal that produces a transient cytosolic and mitochondrial matrix Ca2+ with consequent partial loss of mitochondrial membrane potential and delayed recovery of mitochondrial matrix [Ca2+] which might contribute in the activation of the mitochondria permeability transition pore and consequent impairment of mitochondrial and cellular functions. This is accompanied by a reduced cytosolic ATP content that can result in an energy deficit for the cell. A brief treatment with inhibitors of the permeability transition pore is able to reduce these effects and might have protective roles against exogenous insults to the cells and help mitigate the neuronal loss characteristic of Alzheimer’s disease.

Conclusion

AD hippocampal neurons are more sensitive to a mild excitotoxic insult that affect mitochondrial functionality and in particular the activation of the permeability transition pore (PTP). Treatment with μM concentrations of two different inhibitors of the PTP prevent mitochondrial impairment.
Functional Connectivity of Entorhinal Cortex Predicts Tau in the Elderly
Authors: Nayak Siddharth , Hojjati Seyed Hani , Feiz Farnia , Ozoria Sindy , Shteingart Jacob , Picha Saman Gholipour , Fernández Antonio , Stern Yaakov , Devanand Davangere P. , Luchsinger Jose A , Razlighi Qolamreza R
Published: December 2023

Background

Human neuroimaging efforts to understand the pathophysiology of Alzheimer’s disease (AD) have solely focused on the amyloid‐beta (Aβ) deposition and tau neurofibrillary tangle formation. Until recently, the idea of a connectivity‐based molecular functional framework for understanding AD pathophysiology was missing, which eluded researchers from connecting functional connectivity (FC) with Aβ/Tau deposition.

Method

The initial dataset includes 631 older (67.44 ± 6.48 years) adults (521 healthy controls and 110 mild cognitive impairment (MCI)) who have been imaged for Tau pathology as well as resting‐state functional magnetic resonance imaging (rsfMRI) and structural MRI scans. Using Schaefer’s 200 parcellation atlas and a regional cutoff (SUVR = 1.25), we identified four groups of tau staging based on the number of regions having higher than cutoff tau SUVR (no tau stage (N = 193), pre‐acceleration stage (N = 222), acceleration stage (N = 149), and post‐acceleration stage (N = 67)). Since the entorhinal cortex (EC) is widely regarded as the epi‐center for tau accumulation, the left and right EC time series were derived from rsfMRI data using the Desikan‐Killiany atlas and used as seed regions for our Pearson correlation coefficient based functional connectivity analysis with all 200 regions in the Schaefer atlas. Finally, linear regression models were run to predict the mean regional accumulation of tau based on the strength of mean FC between that region and EC.

Result

As shown in Fig. 1, left/right EC functional connectivity is strongly associated with the accumulation of tau in that region during the pre‐acceleration phase (left: t = 3.586, p < 0.0004; right: t = 4.404, p < 0.0001) and in the acceleration phase (left: t = 6.229, p < 0.0001; right: t = 7.577, p < 0.0001) (results not shown). The functional connectivity values from left/right EC for the pre‐acceleration phase are plotted on the surface of the brain, as shown in Fig. 2.

Conclusion

Our results provide evidence of the role of functional connectivity in tau spreading from EC to the rest of the brain and can help throw light on the dynamic patterns of tau spreading in MCI/AD subjects in different disease stages.
24‐hour rest‐activity rhythms and light exposure patterns in relation to cognitive function in a nationally representative U.S. sample
Authors: Xiao Qian , Yeung Ho Ching , Lu Jiachen , Bauer Cici
Published: December 2023

Background

Human diurnal behaviors are orchestrated by the internal circadian clock and influenced by external stimuli such as light. Aging is associated with declined circadian output and shifted circadian phase, leading to weakened rest‐activity rhythms and altered light exposure patterns, which may in turn further exacerbate circadian impairment. Limited but growing research reported that characteristics of rest‐activity rhythms were associated with risk of dementia and cognitive decline in older populations. However, there are several gaps in the literature: 1) most previous studies included predominantly white participants with relatively high socioeconomic status, limiting the generalizability of study findings to more diverse populations; 2) few studies examined the 24‐hour light exposure pattern, an environmental cue essential to healthy circadian function, in relation to cognitive function.

Methods

We applied the extended cosine model, nonparametric algorithms, and functional principal component analysis (fPCA), to characterize rest‐activity rhythms and light exposure patterns in the National Health and Nutrition Examination Survey (2011‐2014). Cognitive function was measured by word learning and recall modules from the Consortium to Establish a Registry for Alzheimer’s disease (CERAD), the Animal Fluency test, and the Digit Symbol Substitution test.

Results

Multiple rest‐activity characteristics were associated with different aspects of cognitive function, generally supporting a relationship between weakened circadian rhythms and poorer cognitive performance. For example, when compared to the highest quintile, the lowest quintile of F statistic, a measure of overall rhythmicity, was associated with a significantly lower score on the CERAD delay recall test (beta (95% confidence interval (CI)), ‐0.61 (‐0.77, ‐0.18)) and an increase in the odds of having a performance score in the lowest quartile of the study sample (odds ratio (95% CI), 1.55 (1.05, 2.29)). Moreover, measures of amplitude and rhythm fragmentation derived from nonparametric algorithms and fPCA were also associated with cognitive function. Findings were generally consistent across subgroups with different gender, age, race/ethnicity and education levels, but subgroup differences were also observed. Moreover, preliminary findings suggested a relationship between light exposure patterns and cognitive function.

Conclusions

24‐hour rest‐activity and light exposure patterns are associated with cognitive function in a diverse and nationally representative sample.
Socioeconomic determinants of cognition among older Brazilian adults: A life‐course approach
Authors: RAMOS ARI ALEX
Published: December 2023

Background

The prevalence of cognitive impairment is higher in low‐ and middle‐income countries compared to high‐income economies. Yet few nationally representative studies from Latin America have investigated life‐course socioeconomic factors related to the susceptibility to age‐associated cognitive impairment. In this study, we examined the associations of early‐ (education and food insecurity), mid‐ (employment stability), and late‐life (any personal income, household per capita income, and self‐perceived income) socioeconomic indicators with the risk of cognitive impairment, while simultaneously exploring whether gender plays an effect‐modifier role on these associations.

Method

The study population comprised Brazilian adults aged 50 years and over (N = 8710) from the Brazilian Longitudinal Study of Aging. Those with ≤ 1.5 SD on a global composite measure of cognition (N = 1005) were assigned to the cognitive impairment group. Unadjusted and mutually adjusted logistic regressions estimated odds ratios with 95% confidence intervals.

Result

Higher midlife employment stability and late‐life household per capita income were positively associated with the health of adult cognition. Moreover, secondary analyses performed separately for males and females showed the higher the early‐life educational attainment, the lower the likelihood of impaired cognition among females but not among males. Conversely, having a source of income in old age showed a buffering role against cognitive impairment in males, but this association was not observed in females. No significant associations were noted for early‐life food insecurity or late‐life self‐perceived income.

Conclusion

These findings may have implications for population health and health policy by advancing our understanding of socioeconomic determinants of mid‐to‐late‐adulthood cognition.
Plasma cell‐free RNA: a new non‐invasive biomarker for Parkinson’s disease
Authors: Beric Aleksandra , Cisterna‐García Alejandro , Chen Hsiang‐Han , Cruchaga Carlos , Ibanez Laura
Published: December 2023

Background

Parkinson’s disease (PD) is the second‐most common neurodegenerative disorder, after Alzheimer disease (AD). We aimed to create a model that can predict PD with high accuracy and specificity using plasma cell‐free RNA (cfRNA) data.

Method

We extracted RNA from 172 plasma samples (92 PD cases and 80 controls; 48% female, and median age of 73) received from the Hope Center for Neurological Disorders at Washington University in Saint Louis. After library preparation, sequencing, processing, and stringent quality control data was split into training (60%) and testing (40%) populations, both of which included 53% PD cases, 48% female, and had median age of 73. We then performed differential expression analyses using DESeq2, adjusting the by age, sex, medication and other technical variables. Following data driven identification of informative transcripts using Lasso regression, we used Ridge regression to model disease status.

Result

We identified and replicated 639 significantly dysregulated genes. Through pathway analyses we found that dysregulated genes were enriched in PD terms, as well as other neurodegenerative and in known mitochondria pathways. After predictive model training, the best model for PD in the testing population included 14 genes and had an Area Under the Receiving Operating Curve (AUC) of 0.963 (0.930, 0.996). The model had low predictive power, with AUC of 0.553 (0.421, 0.686), in differentiating between controls and AD, FTD or DLB, suggesting that it is specific to PD. More evidence of its specificity was the good performance in distinguishing between PD and AD, FTD or DLB with AUC of 0.753 (0.674, 0.833) specificity.

Conclusion

Plasma cfRNA is a powerful tool for PD prediction, being a minimally invasive biomarker that could detect PD before onset of physical symptoms and without relying on imaging data. We are working on replicating our results in an independent dataset.