bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms by which varicella zoster virus contributes to Alzheimer’s disease pathologies
Authors: Nagel Maria A. , Bubak Andrew N. , Mueller Niklaus H. , Niemeyer Christy S. , Mahalingam Ravi
Published: January 2025

Background

Varicella zoster virus (VZV) reactivation, manifesting as herpes zoster, increases dementia risk. Herein, we review the literature supporting the biological plausibility of VZV contributing to AD pathologies and examine the unique ability of VZV to induce amylin that has been found in blood vessels and parenchyma of AD patients.

Method

We conducted a literature review on VZV and dementia to elucidate a potential model for how VZV reactivation intersects with AD. Further, we cloned the human amylin promoter into a luciferase reporter plasmid that was transfected into primary human brain vascular adventitial fibroblasts. Cells were then infected with multiple strains of VZV (Gilden, vOka) and HSV‐1 (McKrae, Kos) or transfected with plasmids expressing individual VZV or HSV‐1 proteins. Luciferase activity was subsequently measured.

Result

After reactivation, VZV has been shown to infect cerebral arteries, produce a similar spectrum of cerebrovascular disease (VZV vasculopathy) similar to that seen in AD, and cause long‐lasting cognitive impairment. Importantly, we found VZV‐infected primary human brain vascular adventitial fibroblasts (HBVAFs) contain intracellular amyloidogenic peptides seen in AD plaques (amyloid‐beta (Ab)‐42, amylin) and amyloid; RNA sequencing showed enrichment of pathways of amyloidosis/AD, with upstream regulators amyloid precursor protein (APP), apolipoprotein E, microtubule‐associated protein tau, presenilin 1, and amylin (IAPP). VZV vasculopathy patient cerebrospinal fluid (CSF) is amyloidogenic, has elevated amyloid and amylin (correlating with anti‐VZV antibody titers), and decreased Ab‐40 that is seen in cerebral amyloid angiopathy (CAA). VZV antigen/DNA co‐localized with amyloid‐containing arteries in select CAA cases. Finally, we found that VZV infection, but not HSV‐1 infection, induces luciferase activity from the amylin promoter and identified a specific immediate early VZV protein that was sufficient to activate the amylin promoter.

Conclusion

Our studies support the notion that VZV may contribute to AD progression, in part through infection of cerebral arteries, that leads to amylin expression and amyloid deposition. This VZV vasculopathy likely accounts for a subset, if not all, CAA seen in AD brains and is consistent with a previous study linking VZV to vascular dementia.
Advancing a Digital Health Ethics Framework for AD/ADRD
Authors: Largent Emily A. , Karlawish Jason , Wexler Anna
Published: January 2025

Background

“Digital health” is a broad term that encompasses a heterogeneous set of scientific concepts and technologies. While digital health tools have the potential to contribute to better health and health care for individuals and communities, they also pose ethical challenges – particularly in the context of Alzheimer’s Disease and Alzheimer’s Disease and Related Dementias (AD/ADRD). There is no single established ethical framework, however, to aid individuals in evaluating the ethical dimensions of digital health tools in the context of AD/ADRD. To advance the development of an ethical framework, we draw on our experiences with the Penn Artificial Intelligence and Technology (PennAITech) Collaboratory for Healthy Aging, which assists in the identification, development, and dissemination of innovative technologies and artificial intelligence methods to support older adults, including those with AD/ADRD in their home environment.

Methods

We employed two primary methods to assist with the development of our framework. First, we reflected on consultations with product developers that we conducted in our roles as leads of the PennAITech Ethics and Policy Core. The Core seeks to identify and address real‐world ethical, regulatory, and policy issues that arise at the intersection of aging, AI, and digital health through consultations. Second, we reviewed the relevant clinical, scientific, ethics, law, and policy literature to identify and characterize enduring and emerging issues.

Results

We will present our framework for digital health ethics in the context of AD/ADRD and use real world examples to identify and characterize a core set of ethical considerations that cut across many types of digital health tools. These include: assessing and addressing bias; considering risk‐benefit tradeoffs; protecting user privacy; considering environmental impact; measuring value along technical, clinical, usability, and cost dimensions; educating users; and promoting equitable access. For each issue, we also identify potential means of addressing these challenges.

Conclusion

Widespread adoption of digital health tools has the potential to improve health and health care for individuals, caregivers, and communities affected by AD/ADRD, but realizing this potential requires anticipating and addressing ethical challenges.
Assessment of the brain metabolome following innate immunity stimulation in a non‐human primate model of sporadic CAA
Authors: Patel Akash G , Soliman Muhammad T , Ficaro Lia , Nehete Bharti P , Karimi Sohail , Wang Fengzhu , Kim Hakyoung , Williams Lawrence E , Nehete Pramod N , Jones Drew R. , Wisniewski Thomas , Scholtzova Henrieta
Published: January 2025

Background

Non‐human primates (NHP) serve as an important bridge for testing therapeutic agents that have been previously shown to be effective in transgenic mouse models. Our earlier published data using an NHP model of sporadic AD‐related pathology that develops abundant cerebral amyloid angiopathy (CAA), squirrel monkeys (SQMs), indicates that chronic treatment with TLR9 agonist, class B CpG ODN, safely ameliorates CAA while promoting cognitive benefits. In the present study, we intended to delineate alterations in brain metabolome induced by chronic CpG ODN administration in order to provide further insight into CpG ODN immunomodulatory capabilities.

Method

Global metabolomics analysis by HILIC‐LC‐MS was performed on frontal cortex tissue dissected from geriatric SQMs one month after the final CpG ODN or Vehicle (saline) injection. Tandem spectral (MS2) data was searched against the NIST/METLIN libraries for compound identification. Metabolite peak intensities were used for differential metabolite expression (p<0.05) and pathway analysis was performed using Metaboanalyst 5.0.

Result

Differential metabolomics analyses revealed 151 putatively identified metabolites that were significantly altered in the brains of CpG ODN‐treated SQMs. Amino acids were the largest group of metabolites altered, with decreased levels in the CpG ODN group compared to the saline controls. ROC analyses identified several metabolites strongly associated with CpG ODN treatment, including amino acids such as proline and branched chain amino acids valine, leucine, and isoleucine. Furthermore, trimethylamine N‐oxide, a gut microbiome‐derived metabolite previously implicated in AD, was the most downregulated metabolite in the brains of CpG ODN monkeys relative to saline controls. Enrichment analysis identified significantly altered pathways including: “Aminoacyl‐tRNA biosynthesis”, “Valine, leucine and isoleucine biosynthesis”, and “Arginine biosynthesis.”

Conclusion

Overall, the brain metabolome in an NHP model of naturally occurring CAA pathology was assessed for the first time. We observed decreased levels of several AD‐associated metabolites. These findings further develop our novel concept of immunomodulation in order to provide essential preclinical evidence for CpG ODN use as an effective drug for AD.
Key issues in recruitment for minority aging research in humanitarian settings
Authors: Pirela‐Mavarez Rosa P. , Xu Chun , Terwilliger Joseph D. , Garza Noe , Reyes Roberto , Oropeza Omar , Manusov Eron Grant , Maestre Cristian A. , Alliey‐Rodriguez Ney , Mejia‐Arango Silvia , Melgarejo Jesus D , Parker Cynthia De La Garza‐ , de Erausquin Gabriel A. , Gil Mario , Escobar Romeo , Patel Neela K. , Seshadri Sudha , Maestre Gladys E.
Published: January 2025

Background

The increasing number of natural disasters and wars will result in complex emergencies affecting how individuals age. Additionally, the continued complex crises in certain areas of the globe exacerbates risks for chronic health conditions and poverty. Implementing ethical and community‐engaged research in these complex humanitarian settings requires tailored approaches. The South Texas Alzheimer’s Disease Research Center and the Rio Grande Valley Alzheimer’s Disease Resource Center for Minority Aging Research have adopted the humanitarian lens perspective deployed in the Maracaibo Aging Study in Venezuela to promote the recruitment and retention of older adults and their care partners in the Texas/Mexico border. Our objective is to identify and share key issues in recruitment for aging research in a complex humanitarian setting.

Method

Listening sessions, focus groups, and interviews were carried out to understand barriers, facilitators, beliefs, and preferences of older adults, care partners of people living with dementia, promotoras/community health workers, family physicians, and community‐based organizations to understand their expectations better. Elements of the humanitarian framework and capacity building were informed by the qualitative data and guidance from a senior coalition.

Result

Located in the Texas/Mexico border, the Rio Grande Valley constitutes one of the most impoverished areas in the nation. Competing needs, lack of incentives for participation in research, and fear associated with increasing health care costs were the most frequently cited barriers among residents. We decided to implement several aspects of humanitarian work that were related to efficient research and as a response to community expectations. Advocacy for integrating services into primary and community care was supported through staff training, task‐sharing, and establishing referral and follow‐up mechanisms. Diversifying the research workforce with bilingual and multicultural junior investigators and promotoras further addressed the cultural fluidity. As a result, a research registry of over 400 individuals was built, and more than 400 have participated in different aging studies.

Conclusion

Humanitarian settings in high‐income and low‐and middle‐income countries share many implementation needs, including scaling up efforts and tackling multiple challenges simultaneously. Community‐engaged aging research in humanitarian settings requires consideration and assessment of evidence‐based planning and execution and impact evaluation.
Ola Mau I Ka Hula: An Intervention Approach Strategy
Authors: Antonio Ke'alohilani Worthington
Published: January 2025

The prevalence of Alzheimer’s disease and related dementias (ADRD) is rising in Hawai`i, where it is projected that 10% of people aged 65+ will be diagnosed with ADRD by 2025. Nationwide, Native Hawaiians and Pacific Islanders (NHPIs) are more likely to have early‐onset ADRD than Whites, Asians, and African Americans. Contributing factors to this are that NHPIs have a higher prevalence of hypertension, obesity, diabetes, and dyslipidemia than other US racial and ethnic groups, which increase the likelihood of ADRD.

Ola Mau I Ka Hula is an intervention program being implemented by the Natives Engaged in Alzheimerʻs Research (NEAR): IKE Kupuna Project. This program is the successor to Ola Hou I Ka Hula, the intervention program for the KāHOLO Project that focused on cardiovascular risk factors in Native Hawaiian populations. This culturally‐grounded approach centers on the use of hula and lifestyle interventions to mitigate the vascular risk factors that increase the risk for mild cognitive impairment (MCI) and subjective cognitive impariment (SCI), and subsequently also ADRD. Factors such as socialization, physical activity, and learning a language are known to improve risk for ADRD. By design, hula targets multiple risk factors for ADRD and incorporates these risk reducers with a cultural twist.

This approach focuses on building on previous clinical trials and interweaving those interventions, which includes the PILI Lifestyle Program (PLP) and the KāHOLO Project. The melding the culturally‐informed components of traditional hula classes, lifestyle intervention classwork, and cultural classes teaching traditional crafts and knowledge. Community members and hula experts were consulted to adapt and strengthen the intervention strategy and the various curriculum components. The intervention was further adjusted depending on each partnering communityʻs available resources in order to ensure the sustainability of the program.
Stories of Trauma and Strength Among Aging Vietnamese Americans: Qualitative Findings from the Vietnamese Insights into Cognitive Aging Program
Authors: Vu Uyen TM , Farias Sarah Tomaszewski , Hinton Ladson , Park Van Ta , Tiet Quyen Q , Whitmer Rachel A. , Meyer Oanh L.
Published: January 2025

Background

Previous research demonstrates that stress and trauma are associated with poor health and increased dementia risk, but this is mostly based on studies of non‐Hispanic Whites. This descriptive analysis delineated the war‐related adversity and trauma in participants of the Vietnamese Insights into Cognitive Aging Program (VIP) study, a new cohort of cognitive aging in Vietnamese individuals in Northern California.

Method

VIP is a longitudinal study of 548 Vietnamese Americans aged 65+ years living in Northern California who are seen annually at either research site for three years. During visit 1, a short (15‐20 minutes) semi‐structured interview was conducted with all consented participants about their life and experiences in Vietnam and their immigration to the United States. Using the early life trauma data collected at visit 1 at the Sacramento site, we calculated a total trauma exposure count for all 274 participants and selected out individuals with the highest self‐reported traumas (i.e., top one‐third, see Table 1 for listing of traumas and Table 2 for the frequency distribution of total traumas). We then pulled out the interview data for participants who had consented to be audio‐recorded, whose recordings were of good quality, and whose interviews had been transcribed verbatim. A total of 35 interviews were included in this analysis. Six transcripts were coded independently by two authors until agreement was reached. A codebook was developed, and the remaining transcripts coded and analyzed by the lead author.

Result

The 35 participants had a mean age of 73 years (SD = 5.57). Most were male (71.4%). Forty percent finished high school; 34% had at least a primary school education, and 26% had at least some college. We found six major themes: (1) being imprisoned, (2) challenges after being released, (3) escaping Vietnam, (4) witnessing trauma, (5) experiences of loss, and (6) gratitude and grit (see Table 3).

Conclusion

Results from this study reveal traumatic events 35 individuals in the VIP at the Sacramento site were exposed to as well as their perseverance. Findings provide potential to explain the relationship between trauma/adversity and cognition and dementia risk that will be explored in future VIP research.
Personal risk perceptions for Alzheimer’s disease and dementia among older adults may not be grounded in knowledge
Authors: Jacova Claudia , Robertson Frank , Gehling Jacklyn , Marx Hannah , Dhaliwal Ravneet K. , Harris Steven
Published: January 2025

Background

Public interest in brain health has reached unprecedented levels, yet research on AD/dementia literacy has continued to reveal gaps and misconceptions, especially among those with lower education. The public’s knowledge has often been characterized as particularly weak around AD/dementia risk factors. Here we were interested in whether personal risk perceptions among dementia‐free community‐dwelling older adults are evidence‐based. We investigated whether risk endorsement was associated with the expected personal characteristics, for example increased endorsement of age‐related risk with older age or of diabetes‐related risk with poorer health.

Method

We recruited 279 community‐dwelling participants aged ≥60 years, free of neurocognitive diagnoses, and located within the United States (M age = 73.8, range 60‐96; M education (years) = 14.9, range 10‐20; 52% women). Participants completed an online survey through Qualtrics’ research panel teams where they indicated the factor/s (select all that apply) that contributed to their own risk for AD/dementia including demographic and modifiable factors. They also rated their general health on a 5‐point scale (excellent = 1 to bad = 5). We regressed endorsement (Y/N) of each risk factor on age, education, gender, and self‐rated health. We also summed endorsed risk factors and regressed this overall risk count on the four predictors.

Result

Risk factors, from most to least endorsed, were age = 75.6%, physical inactivity = 34.4%; high blood pressure = 26.2%, smoking = 14.7%, diabetes = 14.0%, gender = 11.8%, and education = 5.4%. Overall risk count averaged M = 1.8 (range 0‐7) and self‐rated health averaged M = 2.2 (range 1‐4). Age, gender, and education did not predict endorsement of any risk factor, whereas lower self‐rated health predicted a higher likelihood of endorsing diabetes (OR = 1.6, CI 1.1 = 2.6) but not of any other risk factor. None of the predictors were associated with overall risk count. We examined the contribution of education further by including an education by age interaction term but found no significant relationships in these models either.

Conclusion

We found that across educational groups, perceptions of personal risk for AD/dementia appear to be insufficiently grounded in knowledge. Our findings align with previous research highlighting the inadequacy of knowledge around AD/dementia risk factors and risk reduction among older adults. Future health education initiatives should specifically promote a nuanced understanding of risk factors.
Joint modelling of longitudinal AD cognitive markers and incident MCI/dementia quantifies the longitudinal cognitive—AD risk relationship
Authors: Aslanyan Vahan , Ortega Nancy E , Mack Wendy J , Pa Judy
Published: January 2025

Background

Randomized clinical trials for AD increasingly use composite continuous cognitive endpoints to establish efficacy. While these endpoints provide necessary research and clinical evidence, they do not inform the potential impact on incident MCI/AD. Similarly, studies designed with disease progression as an endpoint fail to incorporate within‐person longitudinal cognitive and functional changes in assessment of disease risk, often relying on baseline measures only, or explore cognitive and functional performance change in separate analyses, independent of conversion. This study incorporates longitudinal change in cognition (measured by Preclinical Alzheimer’s Cognitive Composite (PACC)) and dementia severity (measured by Clinical Dementia Rating—sum of boxes (CDR‐SB)) to measure how longitudinal changes in cognition and function may relate to the risk of disease progression.

Method

Participants were selected from the Harvard Aging Brain Study, a longitudinal study collecting demographic, neuropsychological, and APOE genotyping outcomes. Longitudinal changes in CDR‐SB and PACC score were modelled jointly with conversion to MCI/dementia. All models were adjusted for baseline age, sex, education, and APOE‐e4 carrier status.

Result

287 participants (27 conversions to MCI/dementia, 59.1% women, baseline age = 73.7 years (SD = 6.2), 27.6% APOE‐e4+, education = 15.8 years (SD = 3.09)) collectively had 1511 observations over a median follow‐up of 2.2 years (range 0‐8.7 years).

After adjusting for covariates, PACC score changed by ‐0.016/year (95%CI:(‐0.032, 0.000)) and was associated with hazard ratio (HR) = 1.0405 for progression (95%CI:(1.029,1.054). Survival analysis with baseline PACC score underestimated the association of PACC score and conversion (HR = 1.028 per ‐0.016 between‐individual difference in PACC score, 95% CI: (1.02,1.036)).

Similarly, within‐individual CDR‐SB changed by 0.025/year (95%CI:(0.015,0.035)). This change corresponded to HR = 1.081 for progression (95%CI:(1.053,1.111)). Survival analysis with baseline CDR‐SB underestimated the association of CDR‐SB and rate of conversion to MCI/AD (HR = 1.057 per 0.025 between individual difference CDR‐SB, 95%CI:(1.042,1.073)).

Conclusion

This study shows the joint effect of within‐individual longitudinal modelling of cognitive and functional performance with incident MCI/dementia. We show that modeling the baseline value only in analyses underestimates the association between cognition or function and risk of incident cognitive impairment. We conclude that longitudinal monitoring and assessment of cognition and function may result in more accurate estimates for risk. Future studies will pursue joint models that include fluid and imaging biomarkers.
Potential Eligibility for Disease Modifying Therapies Among Individuals Referred to A Tertiary Care Memory Clinic in Calgary, Alberta, Canada: Implications for AD Biomarker Testing
Authors: Thomas Gavin , Smith Eric E. , Ismail Zahinoor , Kirkham Julia G , Roach Pamela , Goodarzi Zahra , Chowdhury Mohammad Z I , Seitz Dallas
Published: January 2025

Background

Potential disease modifying therapies (DMT) for Alzheimer’s disease (AD) may become available in Canada although it is unclear what percentage of people presenting to tertiary care memory programs may require beta‐amyloid testing be eligible for these treatments. We evaluated eligibility for potential DMTs among individuals in the Prospective Registry for Persons with Memory Symptoms (PROMPT) dementia research registry, comprising patients seen in a tertiary care cognitive clinic in Calgary, Alberta, Canada, based on cognitive criteria, medical history, and potential diagnosis of AD on clinical criteria.

Method

We analyzed all individuals included in the PROMPT registry from July 2010 to May 2023 who were diagnosed with either mild cognitive impairment (MCI) or possible or probable dementia at their baseline assessment. AD biomarker testing is not routinely available in this clinic. The characteristics of PROMPT participants were then compared to the inclusion criteria used in recent trials of three DMTs. The proportions of individuals in the PROMPT registry who were potentially eligible for DMTs were then determined.

Result

Of the 1,901 individuals in the PROMPT registry, 1,119 were diagnosed with MCI or dementia at their baseline visit (mean age 75 years and 54% male). Among the group with MCI or dementia, 86% (965) were diagnosed with either MCI or AD. Of the individuals diagnosed with MCI or AD, 55‐80% met cognitive test score eligibility for different DMTs at their initial clinic visit. Potential medical contraindications to treatment with DMTs were present in 27% of this sample. Of all individuals referred to the tertiary care cognitive disorders clinic diagnosed with MCI or AD, approximately 40‐58% could potentially be eligible for DMTs based on their initial clinic assessment. Of all individuals in the PROMPT dementia registry, between 20‐29% could potentially be candidates for DMTs pending neuroimaging and biomarker confirmation of eligibility.

Conclusion

A high proportion of memory clinic referrals are diagnosed with MCI or AD and are potentially eligible for DMTs and would require beta‐amyloid biomarker testing for eligibility confirmation. This information will help better define resource requirements for implementing AD DMTs should these become available in Canada.
Impact of Type 2 Diabetes and Hypertension on Cognition: A Propensity Score‐Matched Analysis in Mexican Americans from San Antonio
Authors: Lopez‐Alvarenga Juan C , Almeida Marcio A , Cavazos José E. , Mahaney Michael C , Maestre Gladys E. , Glahn David C , Duggirala Ravindranath , Blangero John
Published: January 2025

Background

Observational studies have reported cognitive domain alterations in individuals with Type 2 diabetes mellitus (T2D), affecting cognitive domains of information‐processing speed, memory, attention, and executive function. Epidemiological observational studies have shown an association between higher blood pressure [HBP], low processing speed, short‐term memory and learning, and delayed recall. Within the US Hispanic/Latino population, specifically Mexican Americans, cognition remains insufficiently studied. This preliminary analysis aims to discern the impact of T2D and hypertension on cognition, employing propensity score matching to mitigate confounders.

Method

A dataset with 650 participants without dementia (mean age 50 ± 12.6 years, BMI 29.1 ± 6.6, 63% females) from the Mexican American Family Study Cohort from low economic strata was analyzed. The effects of T2D and HBP were evaluated using propensity score matching, specifically employing nearest‐neighbor matching under a logistic model. Coefficients (95% confidence intervals) and p‐values were reported.

Result

Among the participants, 9% had T2D, 6% had HBP, and 2% had both conditions. Adjusting for sex, age, and BMI, the presence of T2D impacted face memory delay [b = 1.3 (0.1, 2.5) p = 0.032] and Continuous Performance Test (CPT) hits [b = 45.9 (24.7, 67.1) p<0.001]. Hypertension influenced California Verbal Learning Test (CVLT) learning [b = ‐11.1 (‐15.1, ‐7.4) p<0.001], CVLT recognition [b = ‐3.2 (‐6.1, ‐0.3) p = 0.03], and CPT hits [b = ‐31.1 (‐64.4, 2.3) p = 0.068)—Figure 1 CVLT score on T2D and HBP status.

Conclusion

This preliminary study underscores the heightened risk of hypertension and T2D impacting cognitive function among Mexican Americans. Variations in cognitive measurements based on T2D or hypertension were observed, emphasizing the need for specific cognitive screening tools tailored to the prevalence of chronic conditions in this susceptible population.
The Bristol Brain Health Clinic
Authors: Butters Anneka F , Archer Hilary , Farouk Hannah , Coulthard Elizabeth
Published: January 2025

Background

Currently, most clinical services focus on dementia diagnosis rather than prevention, despite evidence showing benefits of preventative interventions. People often present with memory problems before having dementia, or when in the early stages and are motivated to adopt preventive lifestyle strategies to slow decline. To address gaps in clinical services we set up the Bristol Brain Health Clinic (BHC) in 2017. Here we present a clinic evaluation of diagnostic work up, interventions, and patient experience.

Method

Relevant data was extracted from the medical records of patients attending The North Bristol NHS Trust BHC. Descriptive statistics were performed. Evaluation was carried out in line with European Task Force recommendations.

Result

110 patients were seen in clinic between 2017‐ 2023. Mean follow‐up was 2yrs (SD 1.32). All patients had access to diagnostic assessments: neurological examination, neuropsychometry, serological and cerebrospinal fluid testing (CSF). Patients were offered bespoke lifestyle information and research opportunities.

Patient cohort: Mean age was 63 years (SD 11.74). 67% were male. Mean MOCA at baseline was 24 (SD 3.62).

Dementia Risk Factors (prevalence): High blood pressure (49.09%), high cholesterol (47.27%), diabetic (15.45%), prediabetic (13.63%, current smoker (9.90%), ex‐smoker (39.10%), > 14 units of alcohol per week (21.81%), history of heavy drinking (14%), Mean BMI 28.01 (SD 5.85), hearing loss (40%), history of head injury (23.63%), low mood (55.45%), poor sleep quality (64%).

CSF Studies: 38 subjects were tested for biomarkers of neurodegenerative disease. Twenty (52.63%) were positive, 18 (47.37%) were negative.

Diagnoses at Final Review: Mild cognitive Impairment 27.27%, Dementia 20%, Subjective Cognitive Decline 18.91%, Uncertain 33.64%. Aetiologies: Alzheimer’s Disease 22.73%, Functional Cognitive Disorder 14.55%, Vascular 7.27%, Multi‐Factorial 5.45%, Parkinson’s Disease 2.73%, Lewy Body Disease 2.73, Affective Disorders 2.73%, Mixed 1.82%, Other 1.82%, Uncertain Cause 38.18%.

Discharge: 37.14% of the cohort were discharged with stable/resolved symptoms.

Patient Feedback: 84.21% ‘Extremely Likely’ to recommend our service. 92.31% felt possibly better able to cope with symptoms.

Conclusion

Our population had a high prevalence of dementia risk factors and range of diagnoses. Many patients’ symptoms were stable/resolved at follow up. This population merits further investigation and continued early targeting with preventative measures.
Differential Impact of Pulmonary Impairment Type on Cognitive Function
Authors: Mitra Sumedha , Prasad Raghav , Sahadevan Pravin , Sundarakumar Jonas S.
Published: January 2025

Background

Worsening pulmonary health may be independently associated with declining cognitive function. However, the association between specific types of pulmonary impairment with cognitive function is not well understood. The present study aims to determine the differential impact of Chronic Obstructive Pulmonary Disease (COPD) and Preserved Ratio Impaired Spirometry (PRISm) in a rural Indian aging cohort

Method

Data from participants (n = 1223) of the Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) cohort were analyzed. Predictive spirometry equations were derived from a similar population. Lung function was classified as normal, COPD or PRISm, based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and PRISm criteria, respectively. The Hindi Mental State Examination (HMSE) test was used to assess global cognition, while a comprehensive culturally adapted neuropsychological battery, COGNITO, was used to assess cognitive performance across five domains (visuospatial abilities, language comprehension, attention, memory and executive function). Multivariable regression models, adjusted for confounders (Table 1), were used to determine associations between spirometry parameters and cognitive performance.

Result

We found that PRISm, in comparison to normal lung function, had a significant negative association with the composite COGNITO score (β(95% CI) = ‐0.11 (‐0.18, ‐0.03), p = 0.003) as well as individual domain‐wise scores: attention (β(95%CI) = ‐0.12 (‐0.22,‐0.01), p = 0.02), memory (β(95%CI) = ‐0.12 (‐0.24,‐0.01), p = 0.02) and executive functions (β(95%CI) = ‐0.15 (‐0.28,‐0.02), p = 0.02) (Table 2). No significant associations were noted among between COPD and cognitive test scores.

Forced Vital Capacity (FVC) ratio (FVC/FVC predicted) was significantly associated with HMSE score (β(95%CI) = 0.35 (0.04,0.65), p = 0.02) and the composite COGNITO score (β(95%CI) = 0.14 (0.03,0.24), p = 0.007). However, Forced Expiratory Volume (FEV1) ratio (FEV1/FEV1 predicted) was not significantly associated with HMSE score or the composite COGNITO score.

Conclusion

We observed that PRISm and not COPD was associated with cognitive function, thus suggesting PRISm could be a potential risk factor for dementia (Figure 1). Correlating these findings with brain MRI, could yield findings about their differential impact on brain structure and function.
Impact of physical frailty parameters on the association between sleep quality and multimorbidity
Authors: Chatterjee Priya , Sahadevan Pravin , Pradhan Hitesh , Sundarakumar Jonas S.
Published: January 2025

Background

Previous studies have reported that poor sleep quality is associated with several adverse outcomes including multimorbidity, particularly in the aging population. Another common occurrence in the elderly is frailty. We aim to study the mediating effect of objective physical frailty parameters on the association between sleep quality and multimorbidity in an aging rural Indian population.

Method

We used baseline data (n = 3300) from the ongoing Srinivaspura Aging Neuro Senescence and Cognition (SANSCOG) cohort study, conducted in the rural areas of the state of Karnataka in India. Objective physical frailty parameters included in the study were hand grip strength (HGS), chair stand test (CST), timed up and go (TUG) tests. Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality. Multimorbidity was categorized based on the presence of two or more diagnosed chronic disease conditions (self‐reported/objective measures). Multivariable logistic regression was performed to find out the association between poor sleep quality and multimorbidity. Mediation analyses [using Karlson–Holm–Breen (KHB) method] were performed separately for each of the physical frailty parameters on the association between poor sleep quality and multimorbidity and results were reported as adjusted Odds ratio (a‐OR) and 95% CI. Models were adjusted for age, gender, education, socioeconomic status, current smoking and alcohol consumption status.

Result

A total of 39.09% participants had poor sleep quality (PSQI>5) and 54.12% had multimorbidity. Participants with poor sleep quality had higher odds of being multimorbid [a‐OR: 1.41, 95% CI: 1.21‐1.65]. Among the physical frailty parameters, individuals with higher TUG time had higher odds of having multimorbidity [a‐OR: 1.08, 95% CI: 1.04‐1.11]. People with higher score in the CST had lower odds of being multimorbid [aOR: 0.95, 95% CI: 0.92‐0.97]. Performance in TUG and CST significantly mediated the association between poor sleep quality and multimorbidity, although the mediated effects were small (TUG‐ 5.00% and CST‐ 6.83%). However, no association was found between HGS and multimorbidity.

Conclusion

Our study finds that poor sleep quality is associated with increased risk of multimorbidity and that poor performance in physical frailty parameters mediates this association.
Higher educational attainment linked with accelerated longitudinal tau accumulation in Alzheimer’s disease
Authors: Cai Yue , Zhou Xin , Fang Lili , Liu Lin , Li Anqi , Yang Jie , Sun Pan , He Zhengbo , Yu Xianfeng , Guo Tengfei ,   Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

Background

Previous cross‐sectional studies have extensively documented that higher educational attainment (EA) is associated with lower β‐amyloid (Aβ) plaques and tau tangles in Alzheimer’s disease (AD). However, studies investigating the relationship between EA and longitudinal tau accumulation are strikingly lacking.

Method

We analyzed Aβ‐PET (A), tau‐PET (T), and 3D T1‐MRI images (N) from the ADNI cohort to identify 196 Aβ‐PET positive participants (A+) and 114 cognitively unimpaired participants without evidence of AD pathology and neurodegeneration (A‐/T‐/N‐/CU). A subset of 209 individuals had resting‐state functional MRI data (Rs‐fMRI), and 173 participants had at least one follow‐up tau‐PET. Participants were categorized into High‐Edu and Low‐Edu subgroups based on the median years of education of the whole cohort (16 years). Aβ‐PET SUVR of 18F‐florbetapir (FBP) or 18F‐forbetaben (FBB) were converted to Centiloids. Baseline and follow‐up tau uptakes based on the Schaefer‐200 atlas were compared between High‐Edu and Low‐Edu subgroups. The interaction of education status with baseline Aβ‐Centiloids and entorhinal tau on longitudinal tau accumulation was assessed. The voxel‐wise amplitude of low‐frequency fluctuation (ALFF) and Regional Homogeneity (ReHo) maps calculated from Rs‐fMRI data were compared between High‐Edu and Low‐Edu subgroups, and the impact of ALFF and ReHo alterations on Aβ‐Centiloids and entorhinal tau‐related longitudinal tau accumulation was also examined.

Result

A+ High‐Edu individuals displayed lower baseline tau levels in temporal and parietal lobes but faster tau accumulation in medial and lateral temporal lobes (p<0.05, Figure 1). Moreover, A+ High‐Edu individuals revealed more pronounced positive associations between Aβ‐Centiloids and tau increases in bilateral visual cortices, as well as between entorhinal‐tau and tau increases in inferior parts of temporal pole and middle temporal lobe, compared to Low‐Edu individuals (p<0.05, Figure 2). Voxels with higher ALFF and ReHo in High‐Edu individuals converged in a cluster in the temporal pole, and the higher ReHo of this cluster predicted faster entorhinal tau‐related longitudinal tau accumulation in medial and lateral temporal cortices (p<0.05, Figure 3).

Conclusion

These findings suggest that higher EA is associated with faster tau accumulation in medial and lateral temporal lobes in AD, and the accelerated tau accumulation of these regions may be linked to higher ReHo associated with education.
Mid‐ to late‐life changes in blood‐based biomarkers of Alzheimer’s disease pathology and neurodegeneration and associations with brain amyloid deposition: The ARIC‐PET Study
Authors: Pike James Russell , Lu Yifei , Chen Jinyu , Walker Keenan A. , Sullivan Kevin J. , Griswold Michael E. , Thyagarajan Bharat , Mielke Michelle M. , Lutsey Pamela L. , Wong Dean F. , Knopman David S. , Sharrett A. Richey , Coresh Josef , Mosley Thomas H. , Gottesman Rebecca F. , Palta Priya
Published: January 2025

Background

Blood‐based biomarkers show promise as a noninvasive, inexpensive method for measuring Alzheimer’s disease pathology throughout the lifecourse. However, the predictive and classification accuracy of these biomarkers at different stages of the lifecourse and among diverse, community‐dwelling populations requires further investigation.

Method

Between 2014 and 2015, 329 dementia‐free participants from the Atherosclerosis Risk in Communities Study underwent brain magnetic resonance imaging (MRI) and florbetapir positron emission tomography (PET). Amyloid positivity was defined as a global cortex standardized uptake value ratio greater than 1.2. Stored plasma samples collected in midlife (1993‐95, mean age 58.5 years) and late‐life (2011‐13, mean age 76.2 years) from a subsample of 259 participants were assayed in 2022 using Quanterix SiMoA. The assay quantified amyloid‐β (Aβ)42/40, phosphorylated tau at threonine 181 (p‐Tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Unadjusted and covariate‐adjusted logistic regression models estimated the association between plasma biomarkers from midlife and late‐life and amyloid positivity in late‐life. Unadjusted receiver operating characteristic curves documented the classification accuracy of the plasma biomarkers separately and collectively.

Result

The sample (Table 1) included 151 women (58.1%), 105 Black participants (40.4%), and 136 (52.3%) participants with amyloid positivity. In models adjusted for demographics, lifestyle factors, cardiovascular factors, and the presence of APOE ε4 alleles, assays measured in midlife were not associated with amyloid positivity in late‐life (Table 2). However, late‐life measurements of Aβ42/40, p‐Tau181, and GFAP and change per decade from midlife to late‐life in p‐Tau181 and GFAP were associated with greater odds of amyloid positivity. The greatest classification accuracy (Figure 1) was achieved by using all assays measured in midlife and late‐life (AUC = 0.754), although the accuracy when using only late‐life measures was comparable (AUC = 0.737).

Conclusion

Late‐life plasma biomarkers of Alzheimer's disease neuropathology and astrogliosis were associated with late‐life amyloid positivity, but midlife plasma biomarkers obtained 16 to 20 years earlier did not exhibit a statistically significant association. Additional longitudinal research is needed to determine whether changes in plasma biomarkers measured before an individual is classified as amyloid positive can be used to identify individuals at risk of developing Alzheimer's disease.
The association of Diabetes Mellitus with Amyloid and Tau biomarkers
Authors: Duijkers Stephan , van der Velden Jolien , van Gils Veerle , Oomens Julie Elisabeth , Vos Stephanie J. B. , Ramakers Inez H.G.B. , Visser Pieter Jelle , Jansen Willemijn J. ,   the Amyloid Biomarker Study group
Published: January 2025

Background

As global populations age, both Alzheimer’s Disease (AD) and diabetes mellitus (DM) incidence are projected to increase tremendously over the coming 20‐30 years. Studies have found that having DM is associated with increased risk of developing AD dementia. It remains unclear however whether DM impacts underlying AD pathology. In the current study we investigate associations between DM and profiles of amyloid‐β‐42 (A) and phosphorylated tau‐181 (T) pathology in cerebrospinal fluid (CSF) in participants with normal cognition (NC) and mild cognitive impairment (MCI).

Methods

We included 2890 participants with NC and 1598 participants with MCI from 21 studies of the Amyloid Biomarkers Study. Participants were classified into four AT biomarker profiles: A‐T‐, A+T‐, A+T+ and A‐T+, based on data‐driven or cohort‐specific cutoffs. All participants had data on DM diagnosis (yes/no). Bonferroni corrected chi‐square tests with pair‐wise Z‐tests were performed to compare the observed AT biomarker profile frequency across DM groups. To examine whether age‐related changes in AT biomarker profile frequencies were dependent on DM, an interaction between age and DM was entered into a Markov‐Chain‐Monte‐Carlo generalized linear mixed model.

Results

Table 1 displays sample demographics. Table 2 displays differences between participants with and without DM per AT profile. In both NC and MCI, participants with DM more often had the A‐T+ biomarker profile than participants without DM (NC: 7.6% vs. 13%; MCI: 10.2% vs. 18%; both p<0.05), while frequencies of the A‐T‐, A+T‐ and A+T+ biomarker profiles were similar among DM groups. In both NC and MCI, DM status did not impact the age‐related increase in AT biomarker frequencies (NC p = 0.34; MCI p=0.45) (Figure 1).

Conclusions

These results demonstrate that for both NC and MCI, persons with DM more often have an A‐T+ profile compared to those without diabetes, suggesting that people with DM have an increased risk of isolated tau pathology that may be independent from amyloid pathology. DM did not change frequencies of biomarker profiles across age. These findings warrant further research and could have implications for both diagnostics and clinical trial design.
A MACHINE LEARNING MODEL FOR THE PROGNOSIS OF ALZHEIMER’S DISEASE DEMENTIA AT THE MILD COGNITIVE IMPAIRMENT STAGE USING MITOCHONDRIAL METHYLCYTOSINES AS NOVEL BLOOD‐BASED BIOMARKERS
Authors: Mosquera Jose Luis , Blanch Marta , Fontal Beatriz , Martí Pau , Ferrer Paula , Trapero Carla , Rojo Nuria , Rico Inma , Campdelacreu Jaume , López Joan Bello , Lleo Alberto , Fortea Juan , Martinez‐Lage Pablo , Tort‐Merino Adrià , Sanchez‐Valle Raquel , Cruchaga Carlos , Fowler Christopher J , Laws Simon M. , Mehanian Courosh , Rene‐Ramirez Ramon , Gascon‐Bayarri Jordi , Barrachina Marta
Published: January 2025

Background

Prediction of progression to Alzheimer’s Disease Dementia (ADD) at the Mild Cognitive Impairment (MCI) stage is an unmet medical need.

Mitochondrial dysfunction in Alzheimer’s Disease at the brain and systemic level has been extensively described. Our previous studies showed an altered mtDNA methylation pattern throughout AD progression in human postmortem brains (Blanch et al. 2016). Similar results were found in blood samples from MCI patients (Stoccoro et al. 2022).

ADmit has developed an epigenetic Next‐Generation Sequencing approach for identifying differential mtDNA methylation patterns in blood samples from MCI patients. The methylation measures, along with non‐invasive clinical features, have been integrated into a classification model that predicts the probability of progression to ADD.

Method

A total of 600 subjects were recruited from longitudinal prospective clinical studies: AIBL Consortium (n=248), Hospital Universitari Bellvitge (n=125), CITA‐Alzheimer Foundation (n=75), Hospital Clínic Barcelona (n=79), Knight‐ADRC (n=64), Hospital Sant Pau (n=5), and Hospital General Hospitalet (n=4). The analysis was focused on blood samples from the baseline visit for Cognitively Normal (CN, CDR=0, n=168) and MCI subjects (CDR=0.5, n=432) with a clinical follow‐up between 3 and 16 years. The model classifies the subject as CN, MCI that does not progress to ADD, and MCI that does progress to ADD, using over 200 methylation measures and some clinical variables without including the AbPET scan. An MCI patient was considered progressed to ADD when their CDR shifted to ≥ 1, or there was a ≥ 2‐point deterioration in CDR‐SOB, or ≥ 1‐point deterioration in at least four instrumental daily life activities. The dataset was split in two subsets for training and for testing (80:20). Several methods were explored in previous analyses. Random Forest showed a superior performance through a triply replicated 10‐fold Cross‐Validation and feature selection process.

Result

The predictions on the testing data are: Accuracy=0.832 (CI95% 0.752‐0.894), Kappa=0.711, F1‐score=0.853, Sensitivity=0.951, Specificity=0.707, PPV=0.773, NPV=0.932, and an AUC=0.775.

Conclusion

The present classification model performs accurate classification of ADD at MCI stage up to 14 years before the appearance of clinical signs of dementia and represents a promising minimally‐invasive prognostic tool. This is the first blood‐genomic (mitochondria) prediction model.
Effect of tau on global graph measures from high‐density EEG in preclinical and prodromal stage of Alzheimer disease
Authors: Spruyt Laure , Mlinarič Tjaša , Reinartz Mariska , Hulle Marc Van , Laere Koen Van , Dupont Patrick , Vandenberghe Rik
Published: January 2025

Background

In Alzheimer disease (AD) changes in the small world network have been described, which can be considered as the balance between local connectivity, exhibited with the “clustering coefficient”, and global integration, investigated by “characteristic path length”. With high‐density EEG, we examined the effect of early spread of tau aggregates on these global graph measures.

Method

This study includes 47 participants who underwent a 100‐minute dynamic 18F‐MK6240 PET‐scan and a five‐minutes eyes closed 128‐channel resting‐state EEG. The total group consisted of 24 cognitively normal amyloid‐negative individuals (CN_N), 10 cognitively normal amyloid‐positive individuals (asymptomatic AD) (CN_P) and 13 patients with prodromal AD (Table 1). We calculated in the alpha frequency band the average undirected weighted Phase‐Lag‐Index and used this as weights for the graph and analyzed the global graph measures characteristic path length and clustering coefficient in sensor‐space. For both the whole group as for the constituent subgroups, we examined the Spearman correlation between these global graph measures and tau‐PET load in an a priori defined early‐metaVOI, comprised of the entorhinal and perirhinal cortex, hippocampus, parahippocampus and fusiform cortex. To investigate the difference between tau‐PET load, clustering coefficient and path length in the 3 subgroups, we applied a Kruskal‐Wallis test.

Result

There was a significant correlation of tau‐PET load with the characteristic path length (r=0.33; p=0.03) and also with the global clustering coefficient (r=‐0.39; p=0.007) in the whole group analysis. When considering the asymptomatic AD group separately, there was also a significant correlation of tau‐PET load with the characteristic path length (r=0.77; p=0.01) and with the global clustering coefficient (r=‐0.82; p=0.007). There was no significant correlation within the CN_N subgroup (path length r=‐0.03; p=0.91; clustering coefficient (r=‐0.06; p=0.80)), neither in the prodromal AD subgroup (path length r=‐0.13; p=0.67; clustering coefficient (r=‐0.03; p=0.92)) (Figure 1). There was a significant difference in tau‐PET load between the subgroups CN_N and prodromal AD (p<0.025) and in clustering coefficient and path length between the CN_N and the CN_P group versus the prodromal AD subgroup (p<0.025).

Conclusion

In the asymptomatic stage of AD, focal tau‐PET load in medial temporal cortex is associated with global electrophysiological measures of network disintegration.