bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Physical Activity Interventions on Brain Metabolites : A systematic review and meta‐analysis
Authors: Moon Chooza , Zhang Meina , Tran‐Dong Melanie , Lee Jihye
Published: December 2023

Background

Physical activity is a modifiable behavioral factor that could delay the development of Alzheimer’s disease. Although metabolites detected in the brain correspond to neuronal integrity and neurodegenerative pathologies, we do not clearly understand the effect of physical activity interventions on brain metabolites. The purpose of this systematic review and meta‐analysis was to assess the effect of physical activity on brain metabolites measured by magnetic resonance spectroscopy (MRS).

Methods

A systematic search was performed in PubMed, Embase, Web of Science and CINAHL from database inception to November 2022. Eight studies were integrated into the final systematic review and meta‐analysis.

Results

Among included studies, 5 of the studies were randomized control designs, 1 study was an observational longitudinal study, 1 study was an observational cross‐sectional design, and 1 study was a case‐control design study. These studies involved 312 participants with mean age from 23 to 72. Physical activity interventions included cycling, running, and yoga. We found multiple metabolites are associated with physical activity including Myo‐inositol, choline (Cho), N‐acetyl aspartate (NAA), creatine, glutamate, and glutamine. The brain areas studied in reviewed articles included the hippocampus, frontal, occipital, or thalamus. From the quantitative synthesis, NAA/ Cho was higher in the physical activity group (effect size (ES) = ‐0.30, p = 0.03) than in the control group. However, for NAA (ES = ‐0.22, p = 0.08) and NNA/Cr (ES = 0.03, p = 0.07), the difference between the physical activity group and the control group was not statistically significant.

Conclusion

Evidence shows that there have been attempts to understand the relationship between physical activity and metabolites. The meta‐analysis demonstrates physical activity may affect changes in NAA/Cho. However, caution needs to be accompanied when interpreting the direct association between physical activity and different brain metabolites due to insufficient data, publication bias, and heterogeneity.
Voxel‐by‐Voxel regression analysis identifies association between postmortem TDP‐43 and antemortem fractional anisotropy within white matter fibers connected to the hippocampus
Authors: Heywood Ashley , Stocks Jane K , Schneider Julie A , Bennett David A. A , Arfanakis Konstantinos , Beg Mirza Faisal , Wang Lei
Published: December 2023

Background

TAR DNA‐binding protein 43 (TDP‐43), has been shown to be involved in various neurodegenerative disorders involving axonal damage including ALS, FTLD, and LATE. Studying the relationships between postmortem TDP‐43 and antemortem white matter (WM) structural integrity can allow for a better understanding of the disease, rather than exploring clinical presentations alone.

Methods

In‐vivo diffusion‐weighted images were gathered on a 1.5T scanner from subjects from the Religious Orders Study and the Rush Memory and Aging Project. Images were processed using TORTOISE to calculate fractional anisotropy (FA). We utilized the IIT probabilistic WM atlas to identify voxels containing fibers that originate or terminate in the hippocampus. A semi‐quantitative rating of TDP‐43 severity was assessed in 5 brain regions. We utilized regression models to relate postmortem disease and antemortem FA within each voxel. Coexisting disease including β‐amyloid plaques, tau tangles, and cerebrovascular disease were used as covariates, along with demographic variables.

Results

The 58 subjects were 91.10 (SD = 6.37) years old at death with a median interval from MRI to death of 2.8 years (SD = 1.19). Results revealed a significant negative relationship (p<0.05) between postmortem TDP‐43 and FA within fibers connecting the hippocampus to the parahippocampal and entorhinal cortices, fornix, and lingual gyrus. Preliminary results did not survive multiple comparisons correction.

Conclusions

Our findings indicate that greater TDP‐43 disease burden is associated with lower white matter integrity within regions of the limbic system. These findings suggest the TDP‐43 disease process may contribute to reduced structural connectivity between the hippocampus and related regions, which may impact larger brain networks.
Associations between gray and white matter volumes from ex vivo imaging and Alzheimer’s Disease Neuropathologic Change Score in the ACT autopsy cohort
Authors: Choi Seo‐Eun , Mukherjee Shubhabrata , Hunt David , McKown S. Kris , Latimer Caitlin S , Bogdani Marika , Keene Lisa , Keen Amanda , Kern Katie , Balderas Ashley , Shadle Christina , Howard Kim , Nolan Amber L. , Campos John S , Larson Eric B , Keene C Dirk , Crane Paul K , MacDonald Christine
Published: December 2023

Background

Applications of ex vivo magnetic resonance imaging (MRI) of human brain tissue from autopsy has grown in recent years and can provide useful information that is complementary to data from neuropathological evaluations. We sought to evaluate relationship between gray matter (GM) and white matter (WM) volumes and Alzheimer’s Disease Neuropathologic Change Score (ADNC) in the Adult Changes in Thought (ACT) autopsy cohort.

Method

GM and WM volumetric data for 33 regions of interests (ROIs) were derived using FreeSurfer for each hemisphere. The volumes were separated into GM and WM with data provided from left hemisphere or right hemisphere or from both. We adjusted GM volume for each ROI by taking the ratio of total ROI volume and total GM and WM volume across both hemispheres. We adjusted appropriately for brains where we had data from any one hemisphere and standardized each GM ROI volume. We adjusted and standardized for WM ROI volumes similarly. We ran logistic elastic net to model the relationship between dichotomized ADNC score and GM and WM volumes adjusting for age at death, sex and brain volume. We performed additional analyses to determine if the results from primary analyses were driven by “Not” or “High” level of the ADNC score.

Result

There were 143 brains with Freesurfer data that passed quality control. The mean age of death was 91 and 63% were female (Table 1). Odds ratios (OR) obtained from the elastic net regression are presented in Table 2 and they are visualized in Figure 1. Larger fusiform GM volume (OR = 0.8), frontal pole GM volume (OR = 0.89), and temporal pole GM volume (OR = 0.85) were associated with decreased risk of AD in our primary analyses. Cuneus GM volume (OR = 1.08) and precentral WM volume (OR = 1.13) had an inverse relationship in these models. Follow‐up analyses revealed that the fusiform GM volume (OR = 0.75) was significantly smaller for individuals with “High” ADNC score (Table 2).

Conclusion

Post‐mortem ex vivo imaging may serve a complementary role in autopsy studies. Future efforts will be focused on evaluating relationship between brain volumes and various standard neuropathological variables in larger data sets.
The association of race, sex, and neighborhood disadvantage with baroreflex sensitivity in the U.S. POINTER Neurovascular ancillary study
Authors: McCarron Megan E. , Brinkley Tina E , Leng Xiaoyan , Bailey Margie J , Baker Laura D , Shaltout Hossam A
Published: December 2023

Background

The arterial baroreflex maintains stable blood flow to the brain. Reduced baroreflex sensitivity for modulation of heart rate (BRS) has been observed in patients with Alzheimer’s disease (AD) and mild cognitive impairment and may be impacted by race, ethnicity, sex, and socioeconomic factors such as the Area Deprivation Index (ADI), a validated, neighborhood‐level composite index that incorporates 17 social determinants of health. However, these relationships have not been well described.

Method

This study utilized baseline data from 196 participants enrolled in the U.S. POINTER Neurovascular study, an ancillary to the parent U.S. POINTER multi‐site lifestyle intervention trial that adds assessments of autonomic function and vascular structure and function. BRS was calculated from continuous blood pressure and electrocardiogram recording using the slope of the regression line between changes in systolic blood pressure and RR interval values in the same direction, with higher BRS indicating better autonomic function. ADI scores ranging from 1 to 10 were calculated using 9‐digit zip codes, with 10 indicating the greatest disadvantage. Analysis of variance and linear regression were used to evaluate associations between measures of interest.

Result

The average age of the study population was 67.9 ± 5.4 years, 64 (17%) were males, and 60 (30.6%) identified as people of color (POC). Overall, the mean BRS was 9.2 ± 4.6 ms/mmHg, and the average ADI score was 4.56 ± 2.69 (range: 1 to 10), corresponding to a national ADI percentile of 40.7 ± 26.1 (range: 3 to 100). Less than a quarter of participants (n = 42, 21.4%) had an ADI percentile >67, indicating a moderate to high level of neighborhood disadvantage. White participants had lower BRS compared to POC (8.60 ± 4.49 vs. 10.60 ± 4.61 ms/mmHg, p = 0.0048). In a multiple regression model adjusting for demographics and ADI, sex (p = 0.0283), race and ethnicity (p = 0.0049), and education (p = 0.0196) were significantly associated with BRS, indicating better autonomic function in men, POC, and those with higher education. ADI was not associated with BRS.

Conclusion

Race, ethnicity, and education impact autonomic function. Further investigations are needed to assess the impact of other demographic and socioeconomic factors on neurovascular health.
Assessing the impact of falls on neuropsychiatric symptoms in patients with neurodegenerative disease
Authors: Joghataie Goldin , Dilliott Allison Ann , Frank Andrew R , Lang Anthony E , Roberts Angela C , Troyer Angela , Levine Brian , Arnott Stephen R. , Tan Brian , Fischer Corinne E. , Marras Connie , Kwan Donna , Munoz Douglas , Tang‐Wai David F. , Finger Elizabeth , Rogaeva Ekaterina , Orange Joseph B , Ramirez Joel , Sunderland Kelly M , Zinman Lorne , Binns Malcolm , Borrie Michael , Masellis Mario , Freedman Morris , Montero‐Odasso Manuel , Ozzoude Miracle , Bartha Robert , Swartz Richard H. , Abrahao Agessandro , McIlroy Bill , Strong Michael J. , Tartaglia Carmela
Published: December 2023

Background

Falls are the most common injury faced by older adults and those with neurodegenerative diseases. Falls can result in concussion/mild traumatic brain injury(mTBI). Concussions in older adults or those with neurodegenerative disease can have a significant impact on behavior as post‐concussion symptoms include neuropsychiatric issues. We hypothesized that there is a relationship between past fall and neuropsychiatric symptoms and neuropsychiatric symptom severity.

Methods

We used data on falls and Neuropsychiatric Inventory (NPI) from the Ontario Neurodegenerative Disease Research Initiative dataset for 480 individuals with neurodegenerative diseases (Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, frontotemporal dementia and vascular cognitive impairment). We used the Chi‐squared and Mann‐Whitney tests to compare frequency of NPI symptoms (anxiety, depression, irritability, disinhibition, apathy, delusions, hallucinations, agitation, euphoria, motor‐disturbance, night‐time behaviour, appetite), and total NPI severity and distress, respectively, between patients with and without falls in the past 12 months.

Results

Comparing patients with falls (n = 169; mean‐age = 68.3±9; 36% F) to patients without falls (n = 311; mean‐age = 68.7±7; 32% F), there was a significantly higher frequency of anxiety (Chi‐squared test, X2 (df = 1, N = 480) = 12.859, P‐value = 0.0003); higher median anxiety severity (Mann‐Whitney/Wilcoxon‐test p‐value = 0.0002); and higher median partner anxiety distress (Wilcox test p‐value = 0.0006) in those who had had a previous fall compared to those who had not, even with multiple comparison correction. Depression, apathy, disinhibition, night‐time behaviours, and eating/appetite changes and total NPI severity were significantly worse in those with previous falls but did not survive multiple comparison correction.

Conclusion

We found that anxiety frequency, severity and distress were much higher in patients with neurodegenerative disease who had a fall in the preceding 12 months compared to those without falls. Our study suggests that neuropsychiatric symptoms, especially anxiety are frequent and should be assessed in those with previous falls as they can be a consequence of mild brain injury and may contribute to worsening cognition or behaviors.
Effectiveness of Recruitment Sources in a Multicenter Clinical Trial for Dementia Prevention ‐ rrAD study
Authors: Hall Tristyn , Szabo‐Reed Amanda , Van Sciver Angela R , Truver Bryce , Goff Sara , Sewell Monica , Martin Adriana , Vidoni Eric , Burns Jeffrey M. , Keller Jeffrey N. , Binder Ellen F. , Zhang Rong
Published: December 2023

Background

Exercise and Intensive Vascular Risk Reduction in Preventing Dementia (rrAD Study) was a NIH‐funded multisite, clinical trial. The rrAD Study assesses the effects of aerobic exercise training and intensive pharmacological reduction of vascular risk factors on cognitive performance in older adults at high risk for Alzheimer’s disease (AD). The enrollment goal was 640 participants across the span of two years. We report herein our recruitment and enrollment results of the rrAD Study.

Method

The major inclusion criteria were older adults, age 60‐85, who had family history (FH) of dementia or subjective memory complaints, hypertension, and a sedentary lifestyle. Individuals with dementia and other neurodegenerative diseases, or unstable medical conditions were excluded (NCT02913664). 3,291 potential participants were recruited and 2,747 were phone screened to participate in the rrAD Study. 513 cognitively normal older adults, aged 60 to 85 years with hypertension and increased risk for AD were randomized.

Result

The rrAD Study had a 15.5% recruitment yield of total phone screened individuals to randomization. E‐mail brought in the largest number of phone screen contacts and was the overall most cited recruitment source (20.9%, n = 574, Figure 1), followed by interviews/editorials (18.7%, n = 515), other/unknown source (17.9%, n = 492), and broadcast advertising (11.8%, n = 325). E‐mail and interview/editorials led to greatest number of consented and randomized participants. However, the recruitment sources that were more likely to lead to consent/participation were, professional referral (i.e. physician, 57.1% yield), social media (49.2% yield), and mail/phone from site (45.2% yield).

Conclusion

From this outreach, the utilization of multiple recruitment sources prove to be a dominant factor to meet recruitment and enrollment goals. E‐mail and interview/editorials demonstrate to be the most effective recruitment sources that led to the greatest number of phone screens, consents, and randomizations. In future studies, we might limit the broadcast advertisement effort since it did not lead to a high volume of consents and randomization; this could be due to the limited amount of study information stated on a 60‐second radio advertisement. Whereas, e‐mail and interview/editorials may produce more qualified participants since these sources can provide a wide scope and detailed information about the study.
Communication for Alzheimer’s treatment success in healthcare interventions with education
Authors: Swenson Danielle E , Garfield Lindsey , Carroll Candace
Published: December 2023

Background

The CDC estimates that 5.8 million Americans will be diagnosed with Alzheimer’s disease in 2020, and the number of Alzheimer’s cases is projected to nearly triple to 14 million people by 2060 (Matthews et al., 2019). Alzheimer’s patients frequently have difficulty communicating with healthcare providers resulting in decreased quality of care. Family members of Alzheimer’s patients accompany their loved ones to healthcare appointments, frequently witnessing an escalation of confusion and not possessing the knowledge and tools to aid communication (Thompson et al., 2020). Currently, in assisted living programs for Alzheimer’s patients, family members are not educated on communication strategies when leaving the facility with their loved ones (Brodaty & Donkin, 2009. Therefore the purpose of this project is to develop an Alzheimer’s educational intervention on communication for family members of patients with Alzheimer’s currently living in an assisted living program.

Method

Participants will include family members of Alzheimer’s patients from an assisted living unit at a senior facility in the Midwest United States. A zoom educational presentation will include how family members can assist their loved ones with Alzheimer’s disease during healthcare/dentist visits, and personal trips such as hair salons, and restaurants. Participants will complete pre‐ and post‐test evaluations of their knowledge regarding best communication practices for loved ones with Alzheimer’s and their confidence in their ability to apply these methods

Result

We will assess the impact of this project and its implications as a nurse‐driven education to improve family members' knowledge related to Alzheimer’s communication. This can improve outings and experiences for families, ultimately resulting in improved quality of life for Alzheimer’s patients.

Conclusion

Alzheimer’s disease education is needed for family members to help navigate common appointments and outings such as healthcare/dentist visits, hygienic/hair salon appointments, and restaurants. This education can improve the quality of life for Alzheimer’s patients and their family members.
Multiomics‐based prediction of trajectories of global cognitive functioning in the ADNI cohort
Authors: Laroche Valentin , Reijnders Rick A , Harvey Joshua , Jansen Willemijn J. , Eijssen Lars M.T. , Cavill Rachel , Lunnon Katie , van den Hove Daniel L.A. , Pishva Ehsan
Published: December 2023

Background

Cognitive impairment is the first manifestation of dementia. However, the rate of changes in cognitive function varies between individuals and unraveling heterogeneity in the trajectory of cognitive decline and dementia is crucial for adopting a suitable treatment. In this study, first, we aimed at identifying distinct trajectories of cognitive function, and next we used extensive machine learning approaches on multi‐trait ploygenic scores,CSF proteomics, plasma lipidomics and metabolomics data for classification of the trajectories identified in the initial analysis.

Method

Three‐year trajectories of global cognitive functioning were defined using six longitudinal measurements of the Mini‐Mental State Examination (MMSE) on 640 individuals in the Alzheimer’s disease Neuroimaging Initiative (ADNI) cohort. To compute the trajectories of cognitive function, we applied Latent Class Mixed Modeling adjusted for age, sex, and education. We used multiple machine learning algorithms, including Random Forest, Conditional Random Forest, Generalized Linear Models, and (sparse) Partial Least Square Discriminant Analysis. The best performing models were selected based on a set of prediction performance metrics.

Result

We identified three distinct trajectories of global cognitive function: Stable, Slow decline (SD) and Fast Decline (FD). The Random Forest algorithm performed best in prediction of the Stable versus Decliners (SD + FD), using the combined omics data. (AUC: 0.83 and a Matthews Correlation Coefficient (MCC): 0.59). The model is based on seven molecular features, among which we found lipids belonging to the ceramide pathway which has already been implicated in cognitive impairment and AD.

Conclusion

Defining trajectories of individuals with distinct patterns of cognitive changes over time, paired with omics‐based data, will allow the identification of new biomarkers for early detection of dementia. Additionally, they might unveil novel subtype‐specific molecular pathways which can contribute to more precise drug discovery processes.
Lower Physical Activity Is Associated With Objective But Not Subjective Cognitive Impairment In Older Adults Without Dementia
Authors: Alonzo Matthew , Ringman John M , Schneider Lon S. S. , Braskie Meredith N , Toga Arthur W. , Zlokovic Berislav V , Chui Helena C , Joe Elizabeth B
Published: December 2023

Background

Physical activity has been associated with better performance on cognitive assessments for older adults in both observational and interventional studies. Older adults who exercise the 150 minutes a week recommended by the Physical Activity Guidelines for Americans were also less likely to report subjective cognitive decline on the Behavioral Risk Factor Surveillance System than those with lower levels of physical activity. Potential explanations for a cognitive benefit from exercise include reduction of vascular risk factors, preservation of brain mass and neuronal structural integrity, and promotion of psychological health and self‐efficacy.

Method

Cross‐sectional data on exercise habits, self‐reported memory problems, and cognition were collected for 137 older adults without dementia as part of a larger observational study. Participants were categorized as meeting (3 or more hours a week of physical activity) or not meeting (< 3 hours) physical activity recommendations. We used multivariable logistic regression to evaluate the association between exercise and self‐reported memory problem, and linear regression for association between exercise and total score on the Montreal Cognitive Assessment (MoCA) after adjusting for potential confounders including age, sex, level of education, cognitive status (CDR global score of 0 vs 0.5), and Geriatric Depression Scale score.

Result

Data on baseline exercise was available for 103 cognitively normal older adults and 34 with mild cognitive impairment (MCI). Mean participant age was 66.6 years and 58.4% were female. 48 participants (35%) reported exercising at least 3 hours per week. Participants with at least 3 hours a week of physical activity had significantly higher scores on the MoCA compared with those with less than 3 hours a week (B = 1.22, p = 0.040) after adjusting for age, sex, level of education, cognitive status, and depressive symptoms. There was no association between physical activity and participant‐reported memory symptoms using the same covariates (B = ‐0.50, p = 0.223).

Conclusion

Weekly physical activity levels consistent with current guidelines were associated with better performance on a cognitive assessment in older adults without dementia. Physical activity was not associated with presence or absence of a self‐reported memory problem in this sample.
Identification of novel genetic risk factors for cerebral amyloid angiopathy and characterization of the implicated LINC‐PINT locus
Authors: Atik Merve , Reddy Joseph S. , Nguyen Thuy , Sotelo Katie , Tutor‐New Frederick Q , Carrasquillo Minerva M. , DeTure Michael , Dickson Dennis W. , Allen Mariet , Ertekin‐Taner Nilufer
Published: December 2023

Background

Cerebral amyloid angiopathy (CAA), characterized by the accumulation of amyloid‐beta in the cerebrovasculature, effects blood vessel integrity leading to brain hemorrhages and an accelerated cognitive decline in Alzheimer’s disease (AD) patients. In a previous genome‐wide association study (GWAS) of 853 neuropathologically confirmed AD cases, we identified a LINC‐PINT splice variant that associated with lower CAA levels amongst individuals that did not have a copy of the APOEe4 AD risk allele (Reddy. J et al 2021). In this study, we perform GWAS to identify further genetic risk factors for CAA and AD neuropathology (Braak stage, Thal phase) in additional AD cases, and participants lacking significant AD pathology (non‐AD).

Method

We expanded the original AD cohort (N = 853) with 400 additional AD cases genotyped using the Infinium Omni2.5+Exome array. We also identified 110 AD and 502 non‐AD donors from the Mayo Clinic Brain Bank, with existing CAA scores and genome‐wide genotypes. We performed QC and imputation of these genotypes to TOPMed. We will conduct GWAS in AD only (N = 1,363), non‐AD only, as well as the combined cohort (N = 1,865). We will test imputed variant dosages for association with square root transformed CAA, Braak and Thal, using linear regression in PLINK, adjusting for relevant covariates. We will perform interaction analysis of CAA‐associated variants with APOEe4 and sex; and pursue stratified analyses. Summary statistics will be utilized to perform SNP‐based gene set enrichment analysis to identify biological pathways implicated in CAA.

Result

We expect that the increased power of this expanded dataset will lead to the identification of additional novel genetic risk factors for CAA and AD neuropathology. Genetic interaction analysis with sex and APOEe4 may further elucidate the role of these risk factors. The addition of 1,102 participants will enable assessment of the LINC‐PINT locus for association with CAA in an independent dataset.

Conclusion

We expect this study will provide further insights into the genetic architecture underlying risk for CAA, both in the context of significant AD pathology, and without. Characterization of genetic variants in the context of neuropathology may lead to new avenues of research aimed at identifying biomarkers and therapies to treat CAA, and AD.
Advocating for Change: Lessons Learned from Ontario’s Quest for a Renewed Dementia Strategy
Authors: Fitzgerald Kyle , Paron Shawn
Published: December 2023

Dementia has been labelled a public health priority by the WHO; with prevalence expected to triple over the next 30 years, urgent, whole‐of‐government action is needed to prepare for unprecedented strains on our health, home, and long‐term care systems. This session will focus on the experiences of Ontario, Canada’s largest province, detailing how government, private, and not‐for‐profit stakeholders can collaborate to influence policy.

The effectiveness of policy networks as a tool to create policy change, specifically in the dementia space, will be examined using Ontario as an example. Learning outcomes will include a better understanding of how public institutions make decisions, what guides a policy agenda and how to influence such, how to create a sense of urgency, defining ageing as a problem worthy of public consideration, and evaluating the success of advocacy efforts. Participants will be encouraged to consider networks they can join and/or form in their respective jurisdictions, and how they can contribute personally and/or professionally to advocacy efforts.

Examples of successful advocacy initiatives in Ontario will be examined. These include public campaigns leading up to and during the 2022 Ontario general election; the Roadmap Towards a Renewed Ontario Dementia Strategy (www.alzheimer.ca/on/roadmap); and the Ontario Dementia Care Alliance (https://alzheimer.ca/on/en/take‐action/policy‐advocacy/ontario‐dementia‐care‐alliance).
Dementia with Lewy bodies Drug Therapies in Clinical Trials: 2022
Authors: Abdelnour Carla , Gonzalez Maria Camila , Gibson Lucy L , Poston Kathleen L. , Ballard Clive G , Cummings Jeffrey L. , Aarsland Dag
Published: December 2023

Background

Reviews of randomized clinical trials (RCTs) in Dementia with Lewy bodies (DLB) are essential for informing ongoing research efforts of symptomatic therapies and potentially disease‐modifying therapies (DMTs).

Methods

We performed a Systematic Review of DLB drug development by examining 3 international registries: ClinicalTrials.gov, the European Union Drug Regulating Authorities Clinical Trials Database, and the International Clinical Trials Registry Platform, to identify drugs in trials in DLB. We analyzed recruitment status, the disease stage and diagnostic groups included in clinical trials, number of trials participants and treatment exposure, use of repurposed agents per clinical trial phase, description of outcome measures for primary endpoints, use of biomarkers for inclusion and/or outcome measures, sponsorship, and global distribution.

Results

We found 25 agents in 40 trials assessing symptomatic treatments and disease modifying therapies for DLB: 7 Phase 3, 31 Phase 2, and 2 Phase 1 trials. We found an active pipeline for drug development in DLB, with most ongoing clinical trials in phase 2. We identified a recent trend towards including participants at the prodromal stages, although more than half of active clinical trials will enroll mild to moderate dementia patients. Additionally, repurposed agents are frequently tested representing 65% of clinical trials.

Conclusion

To accelerate DLB drug development there is a need for more clinical trials, increased diagnosis at earlier stages of the disease, disease‐specific outcome measures and biomarkers, as well as augmenting global representation and including more diverse populations.
Tasmanian ISLAND Sleep Study: prodromal neurodegenerative disease (iRBD) is associated with subjective reports of daytime sleepiness and poor sleep quality
Authors: Bramich Samantha , King Anna E , Noyce Alastair J , Bindoff Aidan D , Kuruvilla Maneesh , Naismith Sharon L , Bartlett Larissa , Vickers James C , Alty Jane E
Published: December 2023

Background

Isolated REM sleep behaviour disorder (iRBD) is a prodrome to dementia with Lewy bodies (DLB) and other neurodegenerative disease (NDD) such that over 90% of people with iRBD (pwRBD) will develop a NDD within 10 years of diagnosis. Disrupted sleep and dream‐enactment episodes are frequently observed by bed partners of pwRBD but it is unclear whether pwRBD perceive reduced sleep quality themselves, as previous studies show inconsistent results. This research aims to investigate sleep quality in iRBD and we hypothesise that people with probable iRBD (pwpRBD) will report poorer sleep quality, compared to healthy controls.

Method

Adults aged 50+ years in the Tasmanian ISLAND Sleep Study, Australia, completed the single REM Sleep Behaviour Disorder Screening Question (RBD1Q) and the Pittsburgh Sleep Quality Index (PSQI) online. The PSQI includes a ‘total sleep quality’ score as well as 7 subscales: duration of sleep, sleep disturbance, sleep latency, day dysfunction due to sleepiness, sleep efficiency, overall sleep quality, and need meds to sleep.

Result

2,905 participants were recruited (mean (SD) age 64 (7.7) years; 26% male) and 273 (9.4%) screened positive for pRBD (45% male). In the pRBD group, 66% had poor total sleep quality, compared to 57% of controls (p = 0.001). pRBD was associated with a greater prevalence of sleep disturbance (67% vs 54%) and daytime dysfunction due to sleepiness (24% vs 11%). There was no difference in sleep duration, sleep latency, or sleep efficiency between pRBD and controls.

Conclusion

We found that pwpRBD report more sleep disturbance, daytime sleepiness and overall poorer sleep quality compared to those without pRBD. This suggests that pwpRBD may suffer from greater sleepiness than has previously been reported in the literature and highlights the importance of sleep enquiries in those with suspected prodromal NDD who drive or operate machinery.
The Effect of Socialization on Alzheimer’s Disease
Authors: Khanna Deepesh , Maldonado‐Puebla Ricardo , Raina Parth
Published: December 2023

Background

Age is a risk factor for Alzheimer’s disease, a neurodegenerative disease where beta amyloid plaques accumulate in the brain1. Elderly individuals especially those in nursing homes were burdened by the social isolation during the COVID‐19 pandemic. The purpose of this literature review is to describe the effectiveness of social engagement and how combatting isolation can have a neuroprotective effect in individuals at risk for Alzheimer’s disease.

Method

We conducted a search in PubMed examining articles from 2010 to 2023 that discussed the effect of socialization on Alzheimer’s disease particularly during the COVID‐19 pandemic. Our search terms were “Alzheimer’s Disease + Socialization”, “Social Isolation + Alzheimer’s Disease”, “Alzheimer’s Disease + COVID‐19”, “COVID‐19 + Social Isolation”, “Social Interventions + Alzheimer’s Disease”. Inclusion criteria consisted of patients ages 60 and older with Alzheimer’s disease, mention of social isolation or engagement, and any relationship between COVID‐19 and Alzheimer’s disease. Exclusion criteria were defined as other dementias, non‐social interventions, and the effects of other viruses on Alzheimer’s disease. After the screening process 30 articles were included along with 6 articles that were suitable to the topic.

Result

Of the 36 total articles: 19 articles focused on an intervention involving socialization; 8 articles explored the effect of social isolation during COVID‐19 on patients with Alzheimer’s disease; 5 articles examined social isolation as a risk factor for dementia; and 4 articles discussed the effect of socialization on Alzheimer’s disease. A few studies reported that having a large social network can improve cognition and mood for patients with Alzheimer’s disease. Studies reported that interventions such as volunteering, video calls, group art classes, animal interactions, and others produced positive outcomes in Alzheimer’s patients but not all were statistically significant.

Conclusion

Our review found a consistent association between a socially integrated lifestyle and decreased incidence of early‐onset dementia. Although not all interventions were solely social, the presence of a strong social structure remained at the core of a healthy aging process.

References:

1. Tiwari, S., Atluri, V., Kaushik, A., Yndart, A., & Nair, M. (2019). Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics. International journal of nanomedicine, 14, 5541‐5554. https://doi.org/10.2147/IJN.S200490
Comparing longitudinal impact of LATE and Alzheimer’s neuropathologic changes in the oldest old
Authors: Sajjadi S. Ahmad , Yu Jiaxin , Qian Tianchen , Bukhari Syed A. , Montine Thomas J. , Corrada María M. M. , Kawas Claudia H.
Published: December 2023

Background

Limbic predominant age related TDP‐43 encephalopathy‐neuropathologic change (LATE‐NC) is prevalent in the oldest old and clinically, it mimics Alzheimer’s disease. Our aim was to determine the association between longitudinal change in clinical and neuropsychological measures and the common neurodegenerative diseases in an exclusively oldest‐old cohort to establish features that help distinguish LATE‐NC from Alzheimer disease neuropathologic change (ADNC) during life.

Method

412 participants from The 90+ Study with longitudinal evaluations and autopsy data were studied. We dichotomized the neuropathologic features and considered the following as the criteria for presence: any degree (mild, moderate or severe) of LATE‐NC, cerebral amyloid angiopathy (CAA), arteriolosclerosis, and hippocampal sclerosis; moderate or severe likelihood of ADNC (according to NIA‐AA criteria); limbic, transitional, or neocortical Lewy bodies (LB); two or more microvascular lesions (MVLs); and severe atherosclerosis. Longitudinal scores of Clinical Dementia Rating Sum of the Boxes (CDR‐SB) and 13 neuropsychological tests grouped into 7 cognitive domains were standardized. We studied the longitudinal relationship between CDR‐SB and each of the 7 cognitive domains with the neuropathologic changes using linear mixed effect models that included all neuropathologic changes adjusting for age at death, sex, and education. P‐values were corrected for multiple comparisons.

Result

Table 1 summarizes the characteristics of the participants. LATE‐NC was present in 36% of the cohort and 51% of those who died with dementia. Figure 1 demonstrates the association of pathologic features with CDR‐SB and cognitive outcomes in a model that included all pathologies and was adjusted for multiple comparisons. At time of death, both LATE‐NC and ADNC were associated with worse performance in CDR‐SB, global cognition, memory, language, and orientation. Longitudinally, out of the two diseases, only LATE‐NC was associated with significant decline in CDR‐SB and orientation, and neither were associated with significant longitudinal decline in other cognitive domains including memory.

Conclusion

Our results confirm the high prevalence and important cognitive consequences of LATE‐NC in the oldest old. Remarkable similarity of cognitive signature of LATE‐NC and ADNC highlight the need for biomarkers capable of distinguishing these two consequential diseases of the oldest old.
Rapidly Progressive Dementias: Case series in a South American hospital
Authors: Santajuliana Franco , Berrios Waleska , Deschle Florencia , Caporale Sofia , Pozo Juan , Marroquin Maria Veronica , Grecco Martin , Ayarza Ana , Povedano Guillermo
Published: December 2023

Background

Rapidly Progressive Dementias‐RPDs include patients with cognitive decline that evolve to dementia or death faster than expected within 1 to 2 years, although typically seen progress during weeks to months in the clinical practice.

RPDs constitute 3‐4% of all dementias. It comprises an extensive spectrum of clinical disorders such as immune‐mediated, infectious, metabolic, and prionic diseases, as well as neurodegenerative dementias. So, it remains significant to identify this clinical syndrome and its eventual reversible causes.

We report a case series of patients with RPDs that were admitted to our hospital.

Method

Retrospective study. We selected patients with RPDs assessed during June 2018 and June 2022. We collected: demographic data, time of evolution, comorbidities, radiological and laboratory findings, treatment and response, and mortality.

Result

We included 19 patients with a median age of 74 years, and 52.6% were female (N = 8). The median time of evolution was 2 months. 26.3% (N = 5) patients had a history of oncological disease and 10.5% (N = 2) of psychiatric disorders. Diagnostic work‐up showed abnormalities: 47.4% on MRI (N = 9; 2 cortical diffusion restriction, 1 global cortical atrophy, 1 meningioma, 1 glioma, 1 hydrocephalus, 3 vascular lesions), 10.5% in the laboratory (N = 2; hypothalamic‐pituitary‐thyroid axis alterations), 21.1% epileptic discharges on electroencephalogram (N = 4). Autoimmune panels in CSF and serum were positive for GAD‐65 in one case amongst 8 patients studied (12.5%). We arrived at an etiology in 52.6% (N = 10) of patients: 1 Creutzfeldt‐Jakob disease, 1 hypothyroidism, 1 steroid‐responsive encephalopathy associated with autoimmune thyroiditis‐SREAT, 1 Hakim‐Adams syndrome, 2 brain tumors, 2 neurodegenerative dementias, 3 vascular dementias). 47.4% (N = 9) patients received treatment with IV methylprednisolone, with a good response in 44.4% (N = 4). Mortality was 36.8% (N = 7).

Conclusion

In our case series, we identified 21.1% of patients with potentially reversible etiologies. However, we observed 47.4% of cases without a definitive diagnosis. It could be associated with immune‐mediated entities without a specified antibody at the time of evaluation. We also report a death rate close to that described in the literature.
Target prioritization using human genetics – anchored protein – protein interactions network for Parkinson’s Disease
Authors: Chaurasia Shilpi , Srivastava Gyan P , Xu Dong
Published: December 2023

Background

Advancements in genome‐wide association studies (GWAS) have provided pivotal information about genes that are genetically associated to disease conditions. For example, Parkinson’s Disease GWAS studies and GWAS meta‐analysis has provided many candidate genes representing various pathways associated with Parkinson’s Disease, e.g., Lysosomes, mitochondrial dysfunction, Syn‐aggregation, etc. Amongst them, Leucine‐rich repeat kinase 2 (LRRK2) is one of the strongest candidates for PD therapeutic and many compounds targeting LRRK2 are already under clinical trials. To optimize therapeutic effects, protein interactors of LRRK2 could be targeted. We hypothesized that instead of selecting GWAS candidate itself, e.g., LRRK2, exploring a network of interacting proteins to GWAS candidates could give us better understanding of the genetic link to disease biology and hence better targets for therapeutic success.

Method

We created genetically anchored protein‐protein interaction network for Parkinson’s Disease from genes having strong genetic link to PD (seed genes) and all proteins interacting with any of the seed genes. These networks were uploaded and visualized on our in‐house tool – PDNet, a network‐based visual analytics prototype to analyze the network modules and propose candidates for potential therapeutic target prioritization in PD. Published and internally generated gene expression data is used to identify differentially expressed genes that fit in pathways implicated in PD.

Result

Pathway crosstalk were observed amongst different pathways and hub‐genes were identified that could be potential key drivers of the network in the disease progression and help in understanding the disease pathology. Multiple parameters were computed for the prioritization of the candidate genes, that have the highest score of an indirect genetic link to PD and could be good target for consideration based on other OMICS evidence. The experimental target evaluation of these candidates has narrowed down targets for further screening for drug discovery.

Conclusion

Our GWAS‐based network analysis framework provides a new way of identifying targets that are genetically involved in the disease but doesn’t show strong signal in GWAS analysis.
Nucleus basalis of Meynert degeneration starts in the earliest stages of Alzheimer’s disease: A deformation‐based morphometry analysis
Authors: Shafiee Neda , Dadar Mahsa , Spreng R. Nathan , Collins D Louis
Published: December 2023

Background

One of the earliest pathological events in the course of AD is thought to be the degeneration of cholinergic neurons in the basal forebrain (Grothe et al. 2012). The largest cluster of cholinergic cells within the basal forebrain are found in the Nucleus basalis of Meynert (NbM) (Hampel et al. 2020). Studies show that loss of cholinergic projections due to cholinergic degeneration in NbM, is associated with the decline in cognitive abilities, specifically in memory and attention processing (Mesulam et al. 2013). However, identifying the NbM region on MR images is difficult due to limitations in the resolution and contrast of T1w images.

Method

Data included the baseline MRI scans of 677 amyloid‐positive subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset from ADNI1, 2, and GO. Scan resolution was increased to 0.5 mm isotropic voxel size by super‐sampling (Manjón et al. 2010) before non‐linear registration to an ADNI‐based unbiased template. The resulting deformation fields were used to compute the Jacobian determinant map for each subject as a proxy for local volume. A voxel‐wise linear regression model analysis was performed on Jacobian maps to assess the pattern of volumetric change within an NbM mask according to diagnosis: DBM ∼ 1+Dx+AGE+Dx:AGE+SEX; where DBM are the Jacobian values for subjects, Dx is the categorical variable for disease stage (NC, eMCI, lMCI, AD) and Dx:AGE is an interaction term between diagnosis and age of each subject.

Result

Figure 1 shows the statistically significant differences in local volume, comparing successive disease stages, within the NbM mask, after FDR correction (coronal section, A) NC vs eMCI, B) eMCI vs lMCI, C) lMCI vs AD). As it has been shown here, the Jacobian map (as a proxy for atrophy) becomes more pronounced as the disease advances.

Conclusion

Our results show that NbM degeneration starts as early as the preliminary stages of mild cognitive impairment, and this change accelerates as the disease progresses. This points to MRI‐based measurements of NbM as potential biomarkers for early AD detection and as a marker of disease burden.
The effect of fasting status on Alzheimer’s disease plasma biomarkers AB40, AB42, GFAP, NfL, CD‐14, and YKL‐40
Authors: Vasquez Erin Livia , Kautz Tiffany F , Kivisäkk Pia , Satizabal Claudia L. , Bernal Rebecca , Seshadri Sudha , Cruchaga Carlos , Yiallourou Stephanie , Gonzales Mitzi M. , Himali Jayandra Jung , Pase Matthew P.
Published: December 2023

Background

Prior research has shown that Alzheimer’s disease (AD) blood biomarkers may be altered by fasting status, but this is poorly studied.1 For accurate diagnosis, it is essential to have controlled protocols. To examine the effect of fasting on AD biomarkers, we compared levels of amyloid‐beta (AB) 40, AB‐42, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), YKL‐40, and CD‐14 in fasting and non‐fasting samples.

Method

MarkVCID consortium2 plasma (n = 10) was used to determine the effect of fasting for AB‐40, AB‐42, GFAP, and NfL using the Quanterix Neuro 4‐plex E kit. Blood samples were collected in the morning and again 2‐hours post‐breakfast.

Knight Alzheimer’s disease research center (ADRC) plasma (n = 16) was used to determine the effect of fasting on YKL‐40 (MSD) and CD‐14 (ELISA, R&D system). Blood collections occurred within a 1‐year span.

Biomarker results were normalized as required and paired t‐tests or Wilcoxon signed‐rank tests were used to compare values between fasting and non‐fasting results. ICC was used to correlate fasting and non‐fasting results.

Result

There were significant differences between fasting and non‐fasting levels for NfL (p = 0.0137), GFAP (p = 0.0137), and AB42:40 (p = 0.0020), but no significant changes for AB42 (p = 0.4316) and AB40 (p = 0.1815) (Figure 1). Strong correlations between fasting and non‐fasting results were observed for all four biomarkers (ICC = 0.873‐0.964) (Figure 3).

There was no significant difference between fasting and non‐fasting concentrations for YKL‐40 (p = 0.86) or CD‐14 (p = 0.43) (Figure 2). There was poor correlations between fasting and non‐fasting YKL‐40 (ICC = 0.472) and CD‐14 (ICC = 0.254) (Figure 3). This was not due to the length of time between the two blood draws (YKL‐40, r2 = 0.067; CD‐14, r2 = 0.024) or the collection time of day (YKL‐40, r2 = 0.076; CD‐14, r2 = 0.001) (Figure 1).

Conclusion

Although significant changes in NfL, GFAP, and AB40:42 were observed, these values correlated well, suggesting that fasting might not alter diagnostic categorization. Additionally, while no significant differences were measured for YKL‐40 or CD‐14, there was poor correlation between fasting and non‐fasting values that were not related to the length of time between the draws or the time the draw occurred. We are working to determine the variable(s) responsible for these results.
TSH levels versus impairment of cognitive and affective domains in older adults: A secondary analysis of MHAS
Authors: Pinilla Thalia , Parra Mauren , Salazar Salomon , Borda Miguel Germán
Published: December 2023

Background

TSH levels are associated to symptoms such as bradypsychia, bradylalia, hypoprosexia, decreased learning ability, memory impairment and even depressive symptoms, affecting cognitive domains.

Method

A secondary analysis of National Study of Health and Aging in Mexico (MHAS) from population interviewed in 2012 with TSH levels (1.948) regarding people with (1287) and without (661) congnitive impairment, in comparison to a follow‐up in 2018 (849 people) based on the same cognitive domains and TSH levels.

Result

Cognitive impairments were higher in women than men, specially around 60 years. The most affected impairment was no amnesic unidomain. People included have mostly normal thyroid function, but people with worst THS levels, commit more than one cognitive domain.

Conclusion

TSH levels control reduce the progression of cognitive impairment.