bluuebunny/crossref_metadata_2025 huggingface dataset:
Does discrimination mediate the association between education and later‐life cognitive outcomes in a cohort of Black Americans? An example of parametric g‐estimation with latent variables in the STAR study
Authors: Cintron Dakota W , Glymour M Maria , Whitmer Rachel A , Mungas Dan M , Gilsanz Paola , Barnes Lisa L , Calmasini Camilla , Eng Chloe W , George Kristen M , Peterson Rachel L
Published: December 2021

Background

Identifying mediators between education and later‐life cognition is an important step in developing prevention measures. We evaluate everyday and major lifetime discrimination as potential mediators of the impact of education on later‐life cognition. To address bias that might occur due to either time‐varying confounding or unreliable measurement of discrimination, we use a novel parametric g‐estimation approach.

Method

Participants in the Study of Healthy Aging in African Americans (STAR, n = 764, ages 52‐90) self‐reported education (high school [HS] degree, general educational development [GED], or less [ref]; bachelor’s degree; or graduate degree). Validated measures of everyday discrimination (9‐items assessing frequency with 6‐point Likert responses) and major lifetime discrimination (9‐items, dichotomous yes‐no), were conceptualized as latent variables (Table 1). The observed cognitive outcome was the average of the verbal episodic memory, semantic memory, and executive function Spanish and English Neuropsychological Assessment Scales (SENAS). We used linear regression to estimate the total effect of education on later‐life cognition and parametric g‐estimation with latent discrimination measures to estimate the controlled direct effect (CDE) of education on cognition if the discrimination measures were set to their sample averages. Models were adjusted for measurement error in the discrimination measures using Fuller’s Method. Standard errors were bootstrapped.

Result

Most participants were female (68.32%) and the average age was 69.0 (Table 2). Both bachelor’s (b=0.41[0.21,0.60]) and graduate (b=0.43[0.22,0.64]) degrees were associated with better cognition compared to HS/GED or less (Table 3). More education was associated with higher levels of major lifetime discrimination. The CDEs of a bachelor’s and graduate degree, if everyone had the average level of everyday and major life discrimination, were 0.32[0.06,0.61] and 0.55[0.24,0.82], respectively (Table 3 and as a function of different fixed averages in Figure 2).

Conclusion

This study provides a novel demonstration of parametric g‐estimation methods that correct for measurement error with latent variables and allow for possible feedback between education and early and late‐life confounders. Accounting for exposure to discrimination slightly increased the magnitude of the association between graduate education and cognition in this older sample of Black American adults, because education was associated with greater exposure to major life discrimination.
Association of the volume, duration, and intensity of physical activity with incident dementia: A COSMIC collaborative cohort study
Authors: Wu Wanqing , Ding Ding , Zhao Qianhua , Xiao Zhenxu , Ganguli Mary , Haan Mary , Lima‐Costa Maria Fernanda , Costa Erico , Ng Tze Pin , Gureje Oye , Scarmeas Nikolaos , Brodaty Henry , Lipton Richard B , Katz Mindy J , Lipnicki Darren M , Sachdev Perminder S ,   for Cohort Studies of Memory in an International Consortium (COSMIC)
Published: December 2021

Background

Consistent evidence suggested that physical activity (PA) may delay dementia onset. However, the dose‐response association between PA and dementia remains unclear. This study aimed to examine the association between the volume, duration, and intensity of PA and incident dementia among older adults across diverse geographic regions.

Method

We harmonized longitudinal data from nine community‐based cohorts in seven countries covering five continents in the Cohort Studies of Memory in an International Consortium (COSMIC). The frequency and duration of performing various PAs per week were collected through questionnaires. Each activity was assigned a metabolic equivalent value (MET). The volume of each PA (MET‐hours) was calculated as the MET multiplied by the hours spent performing the activity. The average PA intensity was calculated as the total volume divided by the total duration hours of PA. Incident dementia was diagnosed after a median of 5.4 years of follow‐up. To explore the dose‐response associations, participants who reported doing regular PA were categorized into subgroups with stratified levels of the volume, duration, or intensity of PA. Multivariate Cox regression models were used to estimate the hazard ratios (HRs) of incident dementia in each group with the lowest volume, duration, or intensity as the reference group. Age, sex, educational year, cohort, APOE, body mass index, smoking, hypertension, diabetes, stroke, and depression were adjusted as the confounders.

Result

A total of 8849 participants (51921 person‐years of follow‐up) were included in our analysis. Compared to engaging in low‐intensity activities (2.3≤MET≤3), engaging in moderate to high‐intensity activities was associated with a lower risk of incident dementia (3.004, adjusted HR=0.58, 95% CI=0.40‐0.84; p for trend=0.004) . There was no significant dose‐response relationship between the volume or duration of PA and the risk of incident dementia.

Conclusion

Our analysis demonstrated a dose‐response association between PA intensity (but not volume or duration) and dementia risk. This evidence could potentially enrich the current recommendations for the protective effect of PA on dementia onset. While waiting for additional evidence from randomized interventions, older adults may be encouraged to perform a higher intensity of PA to preserve cognition.
Longitudinal association between falls and Alzheimer’s disease and related dementia (ADRD) in the community dwelling elderly population
Authors: Tyagi Pallavi
Published: December 2021

Background

Falls are higher amongst elderly with ADRD and are a major cause of functional impairment and increased mortality. The primary purpose of this study was to examine if fall status of community dwelling elderly residents with and without ADRD differ over a four year period and additionally, does receipt of rehabilitation in any year modify this association.

Method

Data for this analysis was drawn from the 2015‐2018 National Health and Aging Trends Study (NHATS). Participants included sample persons (N=3,235) age 65 and older who resided in the community or residential care facilities that were not nursing homes. Baseline characteristics of individuals in ADRD (n= 264) and non‐ADRD group (n=2,971) was compared using chi square statistic. A generalized estimating equation model (multivariate logistic regression) was used to estimate odds ratio of falls in the two groups, adjusted for sociodemographic and clinical conditions that are predictors of fall risk.

Result

At baseline, ADRD group comprised of older, increased number of racial/ethnic minorities other than non‐Hispanic Whites, more frail individuals who reported increased use of assistive device (AD) and had a presence of depression. Those in the non‐ADRD group at baseline had significantly decreased odds for falls, however no statistically significant change was observed for fall status over four years in the two groups (non‐ADRD vs ADRD) and this association was not modified by receipt of rehabilitation. Males had decreased odds ratio (OR 0.87, 95% CI ‐0.22, ‐0. 012) for falls compared to females in both groups and compared to non‐Hispanic Whites, those who were non‐Hispanic Blacks (OR 0.59, 95% CI ‐0.66, ‐0.36) and Blacks (0.58, 95%CI ‐0.82, ‐0.25) had decreased odds ratio for falls. Those who used AD, had depression and received rehabilitation services showed increased odds for falls. No differences were found in terms of fall status for those who lived alone and were frail.

Conclusion

Future studies should examine the bi‐directional interplay between falls and rehabilitation with inclusion of other predictors of fall risk in elderly with ADRD. This can provide further evidence on whether rehabilitation can be used as an effective non‐pharmacological intervention in the management of elderly with ADRD.
The association between self‐reported sleep and hippocampus volume in mid‐life to older cognitively unimpaired individuals
Authors: Kholghi Mahnoosh , Fazlollahi Amir , Lupton Michelle K. , Bourgeat Pierrick , McAloney Kerrie , Zhang Qing , Fripp Jurgen , Karunanithi Mohan , Martin Nicholas G. , Breakspear Michael ,   PISA (Prospective Imaging Study of Aging: Genes, Brain and Behaviour)
Published: December 2021

Background

Sleep disturbances and hippocampal atrophy both increases with normal ageing. However, there are mixed findings in the literature regarding the association of sleep and Hippocampus Volume (HV) in humans, from an inverse to no relationship between HV and poor sleep, or even a direct association in one study. We aim to first investigate the effect of age and the apolipoprotein E (APOE) on self‐reported sleep measures in mid‐life to older (43–77‐year‐old) cognitively unimpaired (CU) individuals, and then explore any relationship between their hippocampus volume and sleep across age.

Method

170 middle to old age (43 to 77 years of age) CU adults (age 60.8.2±6.4, 129 Females, and 96 APOE ε4 carriers) underwent 3T MRI scan and completed the Pittsburgh sleep quality index (PSQI) as part of the PISA study. Generalized Additive Models (GAM) were used to study the effect of age and APOE on different sleep variables and also examine the relationship between sleep and hippocampus volume. HV was normalised using total intracranial volume. Gender and APOE were used as independent covariates.

Result

No significant difference found on sleep between ε4 carriers and ε4 non‐carriers. There was a significant association between age and some of the self‐reported sleep measures (i.e., PSQI subscales). With ageing, sleep efficiency decreased (p‐value=0.01), sleep latency increased (p‐value=0.05), and sleep became poorer (p‐value=0.05), as the PSQI global score increased (). Also, male subjects reported a better sleep quality (p‐value=0.02), and less usage of sleep medications (p‐value=0.04) compared to females. There was no association between sleep and HV.

Conclusion

Ageing has a significant effect on some aspects of sleep, including sleep efficiency and sleep latency. Among cognitively unimpaired mid‐life to older adults, females are more prone to poor sleep than men. However, no sleep‐HV association was observed.
Marine n‐3 fatty acids and cognitive change among older adults in the VITAL randomized trial
Authors: Kang Jae Hee , Vyas Chirag M , Okereke Olivia I , Ogata Soshiro , Albert Michelle , Lee I‐Min , D'Agostino Denise , Buring Julie E , Cook Nancy R , Grodstein Fran , Manson JoAnn E
Published: December 2021

Background

High intake of marine omega‐3 (n‐3) fatty acids has been associated with lower risk of cognitive decline; however, few large‐scale, long‐term randomized trials have been conducted. We evaluated n‐3 supplementation (1 gram/day, including 840 mg of EPA + DHA) and change in cognitive function over 2‐3 years.

Method

Community‐dwelling participants aged 60+ years (mean[SD]=70.9[5.8]y) in the Vitamin D and Omega‐3 Trial (VITAL) were included: 3424 had cognitive function assessment by phone (VITAL‐Cog; 8 neuropsychological tests; mean follow‐up=2.8 years) and 794 were evaluated in‐person at the Harvard Clinical and Translational Science Center (CTSC‐Cog; 9 neuropsychological tests; mean follow‐up=2.0 years). The primary, pre‐specified outcome was a global composite score (average z‐scores across all tests) of change over two assessments. We used multivariable‐adjusted linear mixed models and meta‐analyzed the results for the two settings.

Result

We observed no significant effect of n‐3 supplementation on the global composite score: the mean difference in annual rate of change for the n‐3 versus placebo group was ‐0.01 standard units (95% CI:‐0.02,0.003) in VITAL‐Cog and ‐0.002 (95% CI:‐0.04,0.03) in CTSC‐Cog; the pooled mean difference was ‐0.01 (95%CI:‐0.02,0.003; p=0.15). For secondary outcomes of change in verbal memory, executive function/attention and general cognition, we observed null results to trends of adverse associations with n‐3 treatment versus placebo that were not statistically significant after multiple‐testing correction. In pre‐specified secondary analyses, we observed no significant interaction of the intervention with baseline plasma omega‐3 fatty acid levels for the global composite score (pooled p‐interaction=0.37).

Conclusion

Marine n‐3 supplementation (1 gram/day) did not confer cognitive benefits over 2‐3 years in community‐dwelling older adults.
Skin carotenoid content is associated with speed of processing in cognitively normal older adults
Authors: Sullivan Debra K , Taylor Matthew K , Gibson Cheryl A , Backes James M , Burns Jeffrey M
Published: December 2021

Background

Brain and retinal carotenoid content have been linked to cognitive function in older adults. Although skin carotenoid is correlated with retinal content, the relationship of skin carotenoid and cognition in older adults is unknown. Measurement of skin carotenoid is non‐invasive, quick, and easy to obtain. The purpose of this study was to evaluate the relationship between skin carotenoid concentration and cognitive performance in a population of cognitively normal, older adults.

Method

Baseline data from 101 cognitively normal older adults participating in a nutrition intervention study (Nutrition Interventions for Cognitive Enhancement study; NICE study) were analyzed. Skin carotenoid content was measured using pressure‐mediated reflection spectroscopy by the Veggie Meter® (Longevity Link Corporation). A comprehensive cognitive battery was conducted by a trained psychometrician. The NICE cognitive battery includes three age and education corrected cognition tests from the NIH‐Toolbox Cognition Battery – the Pattern Comparison Processing Speed, Flanker Inhibitory Control and Attention, and Dimensional Change Card Sort Tests. We tested the relationship between skin carotenoid content and corrected NIH‐Toolbox test T‐scores using ordinary least squares regression adjusted for sex and BMI. Statistical model assumptions were evaluated through residual analyses. Statistical analyses were performed using R (v. 3.6.2; R Foundation, Vienna, Austria) and statistical significance was set at p < 0.05.

Result

Most participants were female (80.2%) and overweight (BMI of 28.3 ± 4.5 kg/m2) with a mean age of 71.8 ± 4.9 years. Mean skin carotenoid content was 275.1 ± 81.8. Higher skin carotenoid content was correlated with faster speed of processing (Pattern Comparison Processing Speed Test: b = ‐0.21, p = 0.03), but skin carotenoids were not related to tests of attention or executive function (Flanker Inhibitory Control and Attention Test: b = 0.12, p = 0.26 and Dimensional Change Card Sort Test: b = 0.07, p = 0.47).

Conclusion

The measurement of skin carotenoids may be a useful tool to identify a modifiable risk factor for Alzheimer’s Disease. These findings will be further investigated utilizing the final sample size of the NICE Study (n=200).
Feasibility of the Savvy Caregiver program for care providers of LGBTQ adults living with Alzheimer’s disease and related dementias
Authors: Flatt Jason D , Pollock Kiera , Lee Rebecca , Song Yeonsu , Wharton Whitney , Anderson Joel G
Published: December 2021

Background

By 2030, there will be nearly six million lesbian, gay, bisexual, transgender, and/or queer (LGBTQ) older adults aged 50 and older in the U.S.; this number will more than double by 2050. Approximately 350,000 LGBTQ older adults in the U.S. currently have Alzheimer’s disease and related dementias (ADRD), with projections nearing 1 million by 2030. LGBTQ older adults face distinct challenges impacting their ability to receive adequate and inclusive care, as well as services for informal caregivers due to living alone, the inability to rely on traditional family supports, higher risks for disability, and experiencing discrimination when seeking aging‐related social services.

Methods

We partnered with the Los Angeles LGBT Center, Senior Services to evaluate the: 1) Adaptation of the Savvy Caregiver training program for care providers of LGBTQ older adults living with AD; and 2) Determine the feasibility and acceptability of the Savvy program. Data comes from caregivers (n=18) who completed the 6 session, 12‐hour training for Savvy.

Results

The average age of care providers was 66 (range: 52‐82), and over half (56%) identified as a LGB and 6% as transgender. Overall, care providers were very satisfied with the overall program, strategies, information, and activities of the tailored Savvy Caregiver program. For instance, all participants (100%) reported being more knowledgeable of dementia care and that they would recommend the program to others. Nearly 90% of participants found the content to be relevant to their personal situation, reported gaining new skills, and felt that the class format/number of sessions was appropriate.

Discussion

We developed a community partnership with the Los Angeles LGBT Center on the needs of LGBTQ older adults living with ADRD and their care providers. This is the first known study regarding the adaptability and feasibility of the Savvy Caregiver program for care providers of LGBTQ older adults living with ADRD. There is need for additional research to promote culturally relevant aging services and behavioral interventions for care providers of LGBTQ older adults living with ADRD.
In Covid‐19 pandemic, quarantine measures affect daily living activities in normal individuals, but do not change the cognitive state
Authors: Şahiner Türker AH , Şahiner Melike , Cinar Nilgun ,   Beynex Research Group
Published: December 2021

Background

The coronavirus COVID‐19 pandemic is the defining global health crisis of our time. Due to the measures taken to prevent the disease and especially the curfew, the social life of people has been severely affected. It is a matter of curiosity how the cognitive state is affected during this period.

Method

BEYNEX computerized cognitive training (CCT) has been used in android and ios environments as a smartphone and tablet application in July 2020. In this application, the scores obtained from the gamified cognitive exercises presented on the internet are presented in 8 different cognitive parameters in graphics (Memory, Visual Perception, Speed, Problem‐solving, Flexibility, Attention, Language Skills, Arithmetic). All exercises designed within the parameters used by clinicians and are completely unique. Every 2 weeks, users are asked questions that evaluate themselves and their daily life activities. The data of the user, who scores between 1 and 10 for each question, is also stored graphically.

Result

The BEYNEX/Turkey data used in this study belong to the last four months of 2020 when quarantine measures are gradually increased. Data of an average of 250 people aged 20 to 85 were analyzed in a total of 4 months between September / December 2021. When the monthly data of the users were compared in the 4‐month period with quarantine, there was no statistical difference in 8 different cognitive parameters (Figure 1) (Table 1). However, there were important statistical differences in their responses to the questions they evaluated themselves (Figure 2) (Table 2). Less time spent on hobbies, reading, shopping, and friend conversations, while much more time on sleep and social media (Table 3). Interestingly, users rated their memory and emotional states with a high score.

Conclusion

With internet applications, societal analyzes give results in a noticeably short time with a very low cost. Contrary to popular belief, large crises affect individual lifestyle more than cognitive parameters. It is obvious that cognitive impairment will occur if the measures involve much longer time frames.
Clinical validation of the Lumipulse G β‐amyloid ratio (1‐42/1‐40) in a subset of ADNI CSF samples
Authors: Esquivel Rianne N. , Benina Natalya , Hawkins Douglas M. , De Simone Francesca , Le Bastard Nathalie , Vandijck Manu , Gannon Sara , Latham Jessica , Radwan Rachel R. , Dickson Diana
Published: December 2021

Background

The CSF Lumipulse G β‐Amyloid Ratio (1‐42/1‐40) provides a potential alternative to amyloid PET testing for patients with cognitive impairment to receive an assessment of their amyloid status. Clinical validation of amyloid CSF biomarkers for Alzheimer’s Disease (AD) is critical to ensure accurate assessment of patients. A cutoff of 0.058 was previously established in the Amsterdam Dementia Cohort consisting of 235 individuals with various cognitive complaints and corresponding amyloid PET imaging results. Here we present clinical validation of the cutoff in a blinded clinical study of Alzheimer’s Disease Neuroimaging Initiative (ADNI) CSF samples measured on the Lumipulse G1200.

Method

A subset of CSF samples from the ADNI biobank was used to validate the cutoff of 0.058. Samples included had amyloid PET images derived from an FDA approved tracer (Florbetapir F18) and method and subjects were ≥50 years (n=274). Demographics included 69% amyloid‐PET positive; mean age 73 years; 44% female; MMSE range 12‐30; and diagnoses: mild cognitive impairment (n=170) or AD (n=104). CSF Aβ42 and Aβ40 were measured using the LUMIPULSE G1200 (Fujirebio). Positive and negative percent agreement (PPA and NPA) and Overall Percent Agreement (OPA) were calculated based on agreement with PET imaging results. Three independent neuroradiologists (2 readers and an adjudicator, when necessary) blinded to all other clinical data, reviewed the scans and provided a visual interpretation according to FDA‐approved labeling. The adjudicated PET read was used in the analysis. Clinical data for the ADNI samples were not received until after testing was completed.

Result

At a set cutoff of 0.058 the Lumipulse G β‐Amyloid Ratio (1‐42/1‐40) demonstrated a PPA and NPA of 86.3% (CI 80.7% – 90.5%) and 92.9% (CI 85.3% – 96.7%) respectively with an OPA of 88.3% (CI 84.0%‐91.6%).

Conclusion

The Lumipulse G β‐Amyloid Ratio (1‐42/1‐40) ratio strongly correlates with PET status. Performance of the CSF Aβ42/Aβ40 ratio reflects published agreement obtained by readers when interpreting PET images. Importantly, use of the CSF ratio can reduce costs to patients and provide greater ease of access to testing. In conjunction with clinical assessment the Aβ42/Aβ40 ratio can serve as a highly effective biomarker to assess amyloid status.
Cornel iridoid glycoside protects against STAT1‐dependent synapse and memory deficits by increasing NMDA receptor expression in tau transgenic mice
Authors: Ma Denglei
Published: December 2021

Background

P301S transgenic mice is an animal model of tauopathy and Alzheimer’s disease (AD), exhibiting tau pathology and synaptic dysfunction. Cornel iridoid glycoside (CIG) is an active ingredient extracted from Cornus officinalis, a traditional Chinese herb. The purpose of the present study was to investigate the effects and mechanisms of CIG on tau pathology and synaptic dysfunction using P301S mice.

Method

Intragastric administration of CIG for 3.5 months was applied to P301S mice from 9‐month‐old to 12.5‐month‐old of age. Objective recognition test and Y maze task were used to test the cognitive impairments of P301S mice. Electrophysiological recording was applied to record long‐term potential. Transmission electron microscopy was used to investigate the the ultrastructure and number of synapse. Immunohistochemical staining was applied to detect tau phosphorylation. Western blotting was used to detect the expression levels of related proteins.

Results

Intragastric administration of CIG for 3.5 months improved learning and memory abilities, increased the survival rate of P301S mice. Electrophysiological recordings and transmission Electron microscopy study showed that CIG improved synaptic plasticity, increased the ultrastructure and number of synapse. Moreover, CIG increased the expression of N‐methyl‐D‐aspartate receptors (NMDARs) subunits GluN1, GluN2A and GluN2B, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptor (AMPAR) subunit GluA1. The major mechanism of CIG involved in the regulation of synaptic dysfunction was to inhibited the activation of Janus kinase‐2 (JAK2) /signal transducer and activator of transcription 1 (STAT1) signaling pathway and STAT1‐induced suppression of NMDAR expression.

Conclusion

Based on our findings, CIG might be a promising candidate for the prevention of tauopathy such as AD.
The Living Alone with Cognitive Impairment (LACI) project: Bridging research and policy to expand long‐term services and supports
Authors: Graham Carrie , Johnson Julene K , Torres Jacqueline M , Glymour M Maria , Keiser Sahru , Tran Thi , Portacolone Elena
Published: December 2021

Background

There are an estimated 4.3 million people living alone with cognitive impairment (PLACI) in the United States. The COVID‐19 pandemic and the isolation incurred by shelter‐in‐place has likely exacerbated cognitive impairment in older adults who live alone. Access to formal long‐term services and supports (LTSS) is critical to this population because they lack cohabitants to assist with activities of daily living and navigating LTSS. The Living Alone with Cognitive Impairment (LACI) Project seeks to bridge research and policy to develop actionable and timely policy recommendations to address the needs of PLACI through new expansions of LTSS.

Method

Seventeen Policy Advisory Group (PAG) members were recruited, including representatives from state and local government, dementia and aging advocacy organizations, LTSS providers, and LTSS policy experts. A total of 17 individual meetings were conducted with PAG members and one webinar convening of the group.

Result

The PAG identified preliminary recommendations in three areas, including: 1) important areas of inquiry for qualitative and quantitative research to address the needs of PLACI, 2) best practices for addressing equity across diverse racial/ethnic minority groups, and 3) preliminary policy recommendations that leverage existing innovations at the state and federal level. The LACI Project team is actively incorporating the PAG feedback by: a) modifying research questions for the quantitative and qualitative research, b) convening a Community Advisory Group to ensure that the research is guided by diverse community members, and c) crafting preliminary policy recommendations based on PAG input.

Conclusion

Engaging the expertise of an advisory group to develop policy recommendations to increase LTSS for PLACI is a promising method of bridging research and policy. The engagement of policy experts ensures by ensuring that research is designed to address the most important policy gaps and all policy recommendations are actionable and timely.
Validation of technology to monitor sleep and bed occupancy in older men and women
Authors: Ravindran Kiran Kumar Guruswamy , Monica Ciro della , Atzori Giuseppe , Enshaeifar Shirin , Mahvash‐Mohammadi Sara , Dijk Derk‐Jan , Revell Victoria
Published: December 2021

Background

Nocturnal disturbance is frequently observed in dementia and is a major contributor to institutionalisation. Unobtrusive technology that can quantify sleep/wake and determine bed occupancy during the major nocturnal sleep episode may be beneficial for long‐term clinical monitoring and the carer. Such technologies have, however, not been validated in older people. Here we assessed the performance of the Withings Sleep Mattress (WSM) in a heterogenous older population to ensure external validity.

Method

Eighteen participants (65 – 80 years, 10M:8F) completed 7‐12 days of sleep/wake monitoring at home prior to an overnight laboratory session. WSM performance was compared to gold‐standard (laboratory polysomnography [PSG] with video) and silver standard (actiwatch [AWS] and sleep diary at home). WSM data were downloaded from a third party API and the minute‐to‐minute sleep/wake timeseries extracted and time‐ordered to create a sleep profile. Discontinuities in the timeseries were labelled as ‘missing data’ events.

Results

Participants contributed 107 nights with WSM and PSG or AWS data. In the laboratory, the overall epoch to epoch agreement (accuracy) of sleep/wake detection of WSM compared to PSG was 0.71 (sensitivity 0.8; specificity 0.45) and to AWS was 0.74 (sensitivity 0.77; specificity 0.53). Visual inspection of video recordings demonstrated that 20 of 21 ‘missing data’ events were true ‘out of bed’ events. These events were always associated with an increase in activity (AWS). At home, all 97 WSM ‘missing data’ events that occurred within the major nocturnal sleep episode defined by sleep diary data, were associated with an increase in activity levels in the AWS data and 36 of these events were also associated with an increase in light levels, indicating that the participant had left the bed. In several participants, data recorded by the WSM during daytime coincided with reported naps in the sleep diary.

Conclusion

Although WSM cannot reliably distinguish between sleep and wake, the presence/absence of data in WSM seem to be an accurate representation of whether older people are in or out of bed (bed occupancy). Thus, in dementia, this contactless, low‐burden technology may be able to provide information about nocturnal disturbances and daytime naps in bed.
Cortical microstructural changes in autosomal dominant Alzheimer’s disease
Authors: Torso Mario , Ridgway Gerard R , Hardingham Ian , Tzaferou Dimitra , Benzinger Tammie L.S. , Chance Steven A ,   Dominantly Inherited Alzheimer Network (DIAN)
Published: December 2021

Background

Autosomal dominant Alzheimer's Disease (ADAD) is an important area of study to understand the pathogenesis of AD. Previous studies suggested that mutations in the genes coding for amyloid precursor protein cause early deposition of amyloid‐β peptide (Aβ), resulting in an amyloid‐induced inflammatory response and cortical microstructural changes during the cognitively asymptomatic phase, several years before clinical onset. The aim of this work was to investigate the cortical microstructural changes in an ADAD population, using novel diffusion tensor imaging (DTI) metrics that are correlated with specific neuropathology and disruption of cortical minicolumns.

Method

A total of 270 individuals from families with known mutations in the PSEN1, PSEN2, and APP genes (168 mutation carriers and 102 non‐carriers) from the Dominantly Inherited Alzheimer’s Network (DIAN) were included in the study. 3DT1 and DTI scans at baseline were used to calculate the cortical grey matter fraction, cortical thickness, mean diffusivity (MD), and three novel cortical diffusivity measures, namely: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the diffusion components perpendicular to the minicolumns (PerpPD), and the principal diffusion component parallel with the minicolumns (ParlPD). A multivariate General Linear model (GLM) was used to investigate cross‐sectional differences. Mutation carrier status was added as a fixed factor, and “sex” and “age” as covariates. Differences across the clinical spectrum are evaluated with box‐plots of metrics grouped by clinical dementia rating (CDR) Figure 1.

Result

Differences in cortical diffusivity measures were found between mutation carriers and non‐carriers. The GLM results revealed a significant main effect of mutation carrier status (p<0.05) as well as age (p<0.001) and sex (p<0.001). Between‐subjects effects revealed that PerpPD (p<0.0001), ParlPD (p<0.0001), and MD (p<0.0001) were significantly higher in the mutation carrier group. As expected, the cortical grey matter fraction (p<0.005) and cortical thickness (p<0.01) were significantly lower in the mutation carrier group.

Conclusion

In autosomal dominant (inherited) Alzheimer’s disease, differences emerge in several novel cortical diffusivity measures, years before the expected diagnosis based on parental age of onset. These findings support using cortical diffusivity measures as a surrogate of cortical microstructure quality for identification of the early stages of AD.
Constrained harmonization algorithm for pooling multi‐site datasets
Authors: Lokhande Vishnu Suresh , Mishra Akshay , Diers Kersten , Düzel Emrah , Reuter Martin , Bendlin Barbara B , Singh Vikas
Published: December 2021

Background

Pooling datasets from multiple studies can significantly improve statistical power: larger sample sizes can enable the identification of otherwise weak disease‐specific patterns. When modern learning methods are utilized (e.g., for predicting progression to dementia), differences in data acquisition‐methods / scanner‐protocols can enable the model to “cheat”, i.e. utilizes site‐specific artifacts rather than disease‐specific features. In this study, we develop a method to harmonize the performance of DNN classifiers across scanners/sites, via so‐called fairness constraints, thereby encouraging consistent behavior while controlling for site‐specific nuisance variables.

Method

We conducted two studies: (a) to demonstrate feasibility of pooling across sites (Site‐Pooling) and (b) to pool data across scanners (Scanner‐Pooling). For Site‐Pooling, our analysis included summaries from Freesurfer processed T1‐weighted images of the Wisconsin Alzheimer's Disease Research Center (ADRC) and German Center for Neurodegenerative Diseases (DZNE). The Freesurfer summaries were used to train a two layer neural network classifier and five‐fold cross‐validation performance was assessed. For Scanner‐Pooling experiments, Freesurfer processed MR images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used to train a deep 3D convolutional network. Performance average on a held‐out test dataset was evaluated. In both cases, a constraint to equalize the performance of the trained classifier across the domains (sites/scanners) was incorporated during training.

Result

Table 1 shows the results of AD/MCI classification for site‐pooling analysis. Our proposed method is compared against a naive pooling approach which does not incorporate the “harmonization constraint”. As shown, the proposed method improves the “difference of errors” measure by 8% / 7% and with only a small drop in overall error rates. Figure 1 illustrates the results from our scanner‐pooling analysis. The performance across the three scanners, GE, Siemens and Philips, is evaluated pair‐wise. A consistent improvement in harmonization is observed and only ∼2% drop in overall error rate is seen.

Conclusion

We provide a harmonization constraint based algorithm to mitigate site specific differences when performing analysis of pooled brain imaging datasets in AD studies. In contrast to a method which modifies the data, we achieve harmonization by constraining the classifier to perform similarly across sites/groups/scanners, improving reproducibility.
Development and external validation of a novel dementia risk prediction score in the UK Biobank cohort
Authors: Anatürk Melis , Patel Raihaan , Georgiopoulos Georgios , Newby Danielle , Topiwala Anya G , de Lange Ann‐Marie G , Cole James H , Jansen Michelle G , Ebmeier Klaus P , Singh‐Manoux Archana , Kivimaki Mika , Suri Sana
Published: December 2021

Background

Globally, up to 40% of dementia cases may be prevented if several key risk factors, such as low education and obesity, are targeted. This has motivated interest into the development of risk scores that aim to quantify an individual’s risk of developing dementia within a given time frame. However, translation to a clinical setting has been hampered by either a lack of external validation, poor out‐of‐sample performance, or the integration of measures (e.g., MRI, cognitive testing) that are costly or time intensive to administer.

This study aimed to develop a novel dementia risk score suitable for a primary care setting and compare its discrimination accuracy with other risk scores.

Method

208,108 UK Biobank (UKB) participants were examined, with cases of incident dementia (mean time to diagnosis ± SD = 5.91 years ± 2.02) identified through self‐report, hospital inpatient records and death certificates (n = 1,270, 0.6%). The dataset was randomly split into a training (80%) and test set (20%). Potential predictors (n = 30) included Apolipoprotein E4 (APOE4) status and cardiovascular, medical and lifestyle factors collected at baseline. Logistic LASSO regression was employed for variable selection and logistic regression was then used to derive beta coefficients for each predictor included in the UKB dementia risk score (UKB‐DRS). The area under the curve (i.e., AUC) was used to compare the discriminative ability of the UKB‐DRS to the CAIDE, ANU‐ADRI, Dementia Risk Score (i.e., DRS) and Framingham risk score, in both the test set and the Whitehall II study (WHIII, n = 2,974), which served as an external dataset.

Result

The UKB‐DRS consisted of age, sex, education, APOE4 status, a medical history of diabetes, stroke and depression and a family history of dementia. The UKB‐DRS demonstrated good discrimination accuracy in both the test set (AUC [95% ] = 0.79 [0.77, 0.82]) and external dataset (AUC [95% CI] = 0.83 [0.79,0.87]). Additionally, the UKB‐DRS outperformed all other risk scores (the DRS had the next best AUC [95% CI]: UKB = 0.77 [0.74, 0.8]; WHII = 0.77 [0.73, 0.81]).

Conclusion

This study contributes a novel dementia risk score that may be used to guide primary prevention strategies.
Matrix metalloproteinase‐10 as a novel biomarker of neurodegeneration in Alzheimer’s disease
Authors: Trombetta Bianca A. , Kivisäkk Pia , Carlyle Becky C. , Arnold Steven E.
Published: December 2021

Background

Alzheimer's disease (AD) is driven by cycles of protein misfolding, inflammation, and neurovascular and metabolic dysfunction. Although cerebrospinal fluid (CSF) tau and Amyloid‐β (Aβ) levels are strong indicators of AD pathology, they are inadequate for measuring disease progression or drug response. We investigated a collection of biomarkers that may represent active pathways in AD to identify novel targets for the diagnosis, staging, and pathophysiological profiling of AD.

Method

Immunoassays (MesoScale Discovery, Quanterix) were used to measure a targeted selection of over 20 biomarkers in a well‐characterized cohort of 240 paired CSF and plasma samples obtained from the Penn ADCC and Center for Neurodegenerative Disease Research. The cohort was comprised of individuals with diverse diagnoses, including mild cognitive impairment (MCI), AD, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and cognitively unimpaired controls (CU‐N). Statistical modeling of AD severity, associations between biofluids, and differential diagnosis were performed. Regressions were adjusted for covariates, including age and sex.

Result

CSF MMP‐10, FABP‐3, NfL, and YKL‐40 were significantly elevated in AD compared to CU‐N (p<0.005). MMP‐10, a regulator of blood‐brain barrier integrity, correlated significantly with CSF tau (p<0.005). The established neurodegeneration biomarkers FABP‐3 and NfL correlated significantly (p< 0.05) with CSF AD biomarkers. The neuroinflammatory marker YKL‐40 correlated significantly with CSF tau and ptau‐181 in both CSF and plasma (p<0.05). Linear regression identified a significant correlation between CSF and plasma MMP‐10 in CU‐N (p<0.005) and AD (p<0.005), but not in MCI. CSF MMP‐10 could distinguish CU‐N (AUC: 0.90), MCI (AUC: 0.71), and ALS (AUC: 0.78) from AD. Addition of FABP‐3, NfL, YKL‐40, and MMP‐10 to a logistic model increased classification accuracy between AD and CU‐N in both CSF (AUC: 0.99) and plasma (AUC: 0.788).

Conclusion

Development of a broad biomarker panel may help clarify the interrelated pathophysiologies active in AD onset and progression. Here we highlight MMP‐10 as a novel biomarker that could provide insight on underlying vascular pathology contributing to AD pathogenesis. MMPs have also been implicated in Aβ‐induced proinflammatory response and tau aggregation. Further studies are warranted to assess the physiological significance of MMP‐10 in AD and its mechanistic role in neurodegeneration.
Hypertension, brain training and cognition in the healthy adults aged over 50 years: An online longitudinal study
Authors: Velayudhan Latha , French Thomas , Ugochukwu Aghaji , Corbett Anne , Brooker Helen , Aarsland Dag , Ballard Clive , Proitsi Petroula
Published: December 2021

Background

There have been no studies that investigate if cognitive tasks that have been proven to delay the progress of cognitive decline confound the relationship between Hypertension (HT) and cognitive function. We aimed to investigate whether brain training has a modifying effect on the relationship between HT and cognitive decline.

Method

Participants were from Platform for Research Online to Investigate Cognition and Genetics in Ageing (PROTECT), a longitudinal online study which collected information on demographic, medical and cognitive function annually, who underwent brain training intervention (BT) delivered online throughout the year; participants could choose to undertake it as many times as they wanted or not at all. Digit span, Paired associates, Self‐ordered search and verbal reasoning tests were used to test cognitive functions. Regression models was done to assess influence of hypertension and BT on cognition at follow up and whether the frequency of BT had a modifying effect on the relationship between hypertension and cognitive function from baseline to one year.

Results

5726 participants over the age of 50 participated in BT with mean age 61.9 (±7.05) and 77% women. 1448 (25%) participants with HT had lower scores on all the 4 cognitive measures after adjusting for BT and potential confounders, although only the association with Digit Span test was significant (beta=‐0.031 p=0.03). After testing for interactions, there was an association of HT with verbal reasoning score change for those with BT (beta=‐0.097, p=0.048). There was also an interaction between BT frequency (higher number of attempts) and HT for paired associate learning (interaction beta=‐0.118, p=0.008), whereby frequency of BT was associated with positive change (improvement) only in individuals without HT (beta=0.121, p<0.001), whereas no association was observed in individuals with HT (p>0.05).

Conclusions

HT was associated with lower cognition and also seems to modify the association of BT with cognition. There was improvement of all 4 cognition with increasing number of BT attempts irrespective of HT status, and improvement in Paired Associate scores over one year for participants without HT, implying a potential beneficial role for BT. However, this needs to be validated in larger and longitudinal studies.
Myelin integrity in older adults with vascular cognitive impairment: Implications for mobility performance
Authors: Silva Narlon Cassio Boa Sorte , Dao Elizabeth , Liu‐Ambrose Teresa
Published: December 2021

Background

In individuals prone to white matter pathology, such as older adults with vascular cognitive impairment (VCI), myelin loss could contribute to mobility impairment. Using myelin water fraction (MWF), an in‐vivo technique to quantify myelin content in the brain, we investigated whether myelin content is associated with mobility performance in older adults with VCI.

Method

We analyzed cross‐sectional data from thirty‐two subjects with MRI‐evidence of subcortical ischemic VCI who underwent 3T MRI scanning protocol at the UBC MRI Research Centre (mean [SD], age = 73.8 [5.4], MoCA score = 21.3 [3.8], 65.8% female). The protocol consisted of a standard T1‐weighted contrast for acquisition of high‐resolution structural data, and a gradient and spin echo contrast (GRASE) for acquisition of MWF data. Gait speed (meters/second) collected via a 4‐meter walking test was used as a measure of mobility performance. Following a preprocessing pipeline using the FMRIB Software Library, MWF data were computed for the whole‐brain white matter, and fifteen specific white matter structures of interest. The T1‐weighted images were processed with FreeSurfer to determine estimated intracranial volume (eICV). Hierarchical regression models adjusting for eICV and MoCA were conducted to determine whether lower MWF is associated with slower gait speed.

Result

In models adjusting for eICV only, lower MWF in the superior longitudinal fasciculus was associated with slower gait speed (unstandardized B [95% CI] = 3.287 [0.052 to 6.523], R2 Change = 0.130, p = 0.047). Adjusting for MoCA scores attenuated this relationship (unstandardized B = 3.055 [‐0.155 to 6.265], R2 Change = 0.111, p = 0.061).

Conclusion

To our knowledge, this is the first study to investigate whether in‐vivo lower myelin content is linked to poor mobility in this population. Our findings suggest that poor myelin integrity in specific white matter tracts of the brain may be linked to decline in mobility performance in older adults with VCI. Understanding the mechanisms by which VCI leads to mobility impairment is the first step towards developing strategies to prevent downstream unwanted health outcomes such as falls, hospitalizations, and loss of independence.
Safety, feasibility, and adherence of a daily, in‐home gamma sensory stimulation therapy with the Cognito Sensory Stimulation System in Alzheimer’s subjects
Authors: Williams Martin , Cimenser Aylin , Hempel Evan , Cotter Colleen , Shukla Mohinish , Jiang Kevin , Zhang Annie , Mrozak Holly , Konisky Alexandra , Kwan Kim , Hajos Mihaly , Malchano Zach
Published: December 2021

Background

Non‐invasive, visual and auditory gamma (40 Hz) sensory stimulation demonstrates clearance of β‐amyloid plaques and tau tangles, and cognition improvement in preclinical AD models (Iaccarino, 2016, Martorell, 2019). A home‐use gamma sensory stimulation device (Cognito Therapeutics, Inc., Cambridge, MA) was developed to evoke gamma oscillations in humans. The long‐term safety and feasibility of this approach has not been previously evaluated in AD subjects.

Method

Overture is a prospective 6‐month treatment study in mild‐to‐moderate AD of the Cognito device. Subjects were randomized 2:1, treatment:sham. All subjects underwent in‐clinic EEG to confirm gamma entrainment and calibrate the device. Therapy was self‐administered daily during 1‐hour sessions at home with adherence logged by device. Safety assessments included adverse event (AE) monitoring, MRIs, and physical exams. Subjects and caregivers participated in multiple in‐depth interviews to assess the feasibility of this novel therapy. Subjects had the option to enter a 12‐month extension.

Result

In total, 20,562 treatment sessions have been completed by 74 subjects in the Main and Extension period. Overall rates of AEs during the Main and Extension study periods were roughly equivalent between groups (Active: 2.5/subject, Sham: 2.9/subject). There were no unexpected serious treatment emergent adverse events. Review of MR imaging data by neuroradiology demonstrated stable findings from baseline to follow‐up and absence of ARIA in all subjects. Adherence data showed that Sham participants had a final mean adherence of 95.9%±9.0%, while treatment participants had a final mean adherence of 90.2%±13.3%, and the difference was not significant in an independent‐samples, two‐tailed t‐test (p=0.14). Participants easily adopted and adhered to daily self‐administered therapy, with 60% of enrolled participants choosing to continue into the extension.

Conclusion

The interim results of the study demonstrate that long‐term, daily, self‐administered, home‐use of gamma sensory stimulation is both safe and well tolerated in mild‐to‐moderate AD subjects.