bluuebunny/crossref_metadata_2025 huggingface dataset:
A Graph‐Theoretic Approach for fMRI Time‐Series Classification into Healthy and MCI
Authors: Acharya Ameiy , Sinha Neelam
Published: January 2025

Background

Mild Cognitive Impairment (MCI), a transitional stage between healthy aging and Alzheimer's disease, offers a critical intervention window (Vega and Newhouse, 2014). Diagnosing MCI proves challenging due to subtle neurodegenerative changes. Our study employs graph representations of fMRI time‐series, emphasizing connectivity between brain regions (Stam and Reijneveld, 2007). Utilizing the Dosenbach‐160 ROI atlas and extracting eigenvalues and eigenvectors, we apply machine learning for classification.

Method

Each subject contributes fMRI data from six networks, with each network comprising 187 timestamps and varying numbers of Regions of Interest (ROIs). For every network of each subject, we segment the timestamps into 11‐time interval batches, generating 17 graphs to encapsulate the subject's representation within a network. The principle guiding our approach is that similar eigenvalues reflect similar graphs. Construction of partial correlation graphs involves deriving precision matrices, where ROIs become graph nodes, and partial correlations form edge weights. Transforming these graphs into adjacency, degree, and Laplacian matrices, we further apply eigen‐decomposition on the Laplacian matrix to extract eigenvalues and eigenvectors. The eigenvectors corresponding to the largest absolute eigenvalue serve as features for SVM and Logistic Regression classification.

Result

In our balanced dataset of 100 subjects (50 healthy, 50 MCI) sourced from publicly available ADNI database, SVM achieves accuracies of 80.39% (DMN), 76.86% (Cerebellum), 85.69% (Cingulo‐opercular), 76.27% (Fronto‐parietal), 72.94% (Occipital), and 90.20% (Sensorimotor). Logistic Regression yields accuracies ranging from 71.18% to 86.27%. Notably, the Sensorimotor, Cingulo‐Opercular and DMN networks display distinctive connectivity alterations in MCI, reflecting the versatility and generalizability as well as the medical correctness of our approach. These findings underscore the method's robust ability to discern intricate brain connectivity patterns and contribute to potential clinical relevance for early neurodegenerative disorder diagnosis and intervention

Conclusion

Our study showcases the effectiveness of a graph‐theoretic approach in capturing the intricate connectivity dynamics of fMRI time‐series data across multiple networks. By representing each subject within a network through graphs, we unveil the subtleties of MCI pathology. The derived insights not only contribute to enhanced diagnostic precision but also shed light on the intricate relationships within brain networks.
Planning Ahead with Care: A Randomized Clinical Trial of a Video Intervention to Improve Caregiver Knowledge of Severe Dementia and Medical Care Decisions
Authors: Brandt Katherine , Quimby Megan , Wong Bonnie , Quintiliani Lisa M. , Marchesano Amy , Goldstein Alexa , Celaj Gent , Howe Inola , Krahn Erin , O’Chander Raseeka , Krivensky Samantha , Paasche‐Orlow Michael K. , Volandes Angelo , Dickerson Brad C
Published: January 2025

Background

Caregivers of individuals living with dementia frequently make medical decisions for care recipients, often without a clear understanding of those needs. Educational tools are needed to guide caregivers about when and how to raise the topic of advance care planning (ACP).

Method

Caregivers of individuals living with dementia (N = 130) were randomized into control (N = 64) (ACP verbal educational script) or intervention (N = 66) (ACP verbal educational script and video) groups. Both groups completed online surveys and participated in online interviews. The educational intervention was performed at baseline with pre‐ and post‐intervention assessments. Baseline, three‐ and six‐month interviews assessed severe dementia and medical care knowledge quantitatively (true/false questions) and qualitatively (open‐ended questions). Decisional conflict (Decisional Conflict Scale) and decisions for comfort care (open‐ended questions) were also examined.

Result

Across the entire sample, severe dementia and medical care knowledge increased immediately after the educational intervention. Although the groups did not differ in severe dementia or medical care knowledge (all p values n.s.), the video intervention group demonstrated increased confidence in knowledge about both topics (p<0.05). Post‐intervention, participants’ confidence in severe dementia knowledge and medical care knowledge were higher in the video intervention group vs. control group (p<0.05). Chi‐square analysis indicated that decision for comfort care did not differ between groups (p>0.196). There was no difference between groups in total decisional conflict score or in any of the 5 subscores, pre‐ or post‐intervention (all p values n.s.). However, across all participants there was a decrease in total decisional conflict score and in each subscore pre‐ to post‐intervention (all p values < .001).

Conclusion

Caregivers of individuals living with dementia benefit from education about the stage of severe dementia and medical care decisions that may need to be made. Analysis is ongoing for three‐ and six‐month follow‐up sessions.
Automated word class and person usage metrics as markers of Alzheimer’s and frontotemporal dementia
Authors: da Cunha Pamela Lopes , Ruiz Fabian , Ferrante Franco Javier , Sterpin Lucas , Ibañez Agustin , Slachevsky Andrea , Matallana Diana , Martinez Angela , Hesse Eugenia , Garcia Adolfo M
Published: January 2025

Background

Dementia impacts the way individuals perceive and describe everyday events. Alzheimer's disease (AD) notably affects processing of entities manifested by nouns, while behavioral variant frontotemporal dementia (bvFTD) often presents a detached, third‐person perspective. Yet, the potential of natural language processing tools (NLP) to detect these variations in spontaneous speech remains explored. To tackle this gap, we analyzed both patterns via automated discourse‐level metrics in individuals with AD and bvFTD, contrasting them with healthy controls (HCs).

Methods

Persons with AD (n = 21), bvFTD (n = 21), as well as HCs (n = 21), narrated a typical day of their lives. We analyzed the frequency of nouns and verbs, along with first‐ or third‐person usage, via part‐of‐speech and morphological tagging, respectively. Inferential statistics and machine learning were used to examine whether these features were useful for discriminating patients from HCs at both the group and the subject level. We further evaluated whether such features correlated with cognitive symptom severity, as captured through the Montreal Cognitive Assessment (MoCA).

Results

Compared with HCs, AD (but not bvFTD) patients exhibited a lower proportion of nouns, without differences in verb ratio. Conversely, persons with bvFTD (but not those with AD) had a greater proportion of third‐person markers and a reduced proportion of first‐person markers. Machine learning analyses showed that these features robustly identified individuals within each group (AUCs = 0.75). No linguistic feature was significantly correlated with MoCA scores in either patient group.

Conclusions

Spontaneous daily narratives offer distinct markers for AD and bvFTD, detectable through automated analysis. Focusing on specific linguistic attributes relevant to each type of dementia not only aids in understanding but also enhances diagnosis and tracking of these conditions. Overall, our findings attest to the relevance of NLP tools as a viable, cost‐effective means to identify scalable dementia markers.
Comparing overall medical costs of operative versus nonoperative treatment for femoral neck fractures among Alzheimer’s disease patients: a retrospective cohort study
Authors: Yang Yijiong
Published: January 2025

Background

Addressing femoral neck fractures resulting from ground‐level falls in older adults with Alzheimer’s disease (AD) involves a personalized treatment plan, leading to a substantial economic burden on the healthcare system. The debate surrounding the advantages and disadvantages of surgical interventions versus non‐operative approaches for femoral neck fractures in older individuals with AD remains a topic of active discussion.

Method

In this retrospective cohort study, the total medical expenses associated with operative and non‐operative therapies were compared while adjusting for patients' demographics and baseline health conditions. The study included Optum beneficiaries diagnosed with Alzheimer’s disease (AD) who filed an initial claim for femoral neck fracture between January 1, 2012, and December 31, 2017. Generalized linear regression with a gamma distribution and log link was performed to compare the adjusted overall medical costs between treatment groups controlling for patients’ demographic characteristics (age, gender, race, residential region), insurance type, and baseline health status.

Result

A total of 4,157 AD patients with femoral neck fracture was identified. This included 1,508 cases undergoing internal fixation, 2,334 cases of arthroplasty surgery, and 315 cases of non‐operative treatment. Among them, 59.8% were female (n = 2,487), and the median age was 81 years. The adjusted average total medical costs for arthroplasty and internal fixation were $207,392 and $170,210, which were higher than average total cost for non‐operative group (mean = $63,041). Arthroplasty treatments exhibited overall medical costs 2.56 times higher (95% CI: 2.288 – 2.875) than those of non‐operative treatment, while internal fixation’s overall costs were 2.33 times higher (95% CI: 2.067 – 2.628) than non‐operative treatment. Comorbidities such as history of fall, sarcopenia/muscle weakness, abnormal weight loss, depression, and fatigue had a significant influence on the overall medical cost. Patients with history of fall had an estimated 1.22 times higher medical cost compared with those without history of fall.

Conclusion

The operative treatment groups exhibited higher overall medical costs. The overall costs encompassed not only the direct medical costs associated with surgery but also post‐surgery rehabilitation expenses in nursing homes or home health settings.
Amyloid burden and APOE modify sex differences in estimated meta‐temporal region tau onset age
Authors: Heston Margo B. , Cody Karly , Teague Jordan P , Chavez Elena Ruiz De , Morse Jacob , Deming Yuetiva , Engelman Corinne D. , Chappell Richard J , Langhough Rebecca E. , Gleason Carey E. , Clark Lindsay R. , Zuelsdorff Megan L. , Betthauser Tobey J.
Published: January 2025

Background

Recent advances in Alzheimer’s disease (AD) temporal biomarker modeling have revealed considerable heterogeneity in age at amyloid onset, and recently we and others identified sex and APOE differences in tau onset age and subsequent dementia development. Here we assessed whether amyloid burden, APOE‐ε4 dose, and sex interact to predict estimated T+ onset age (ETOA).

Methods

Alzheimer’s Disease Neuroimaging Initiative participants (N=911, Table 1) underwent serial PET imaging to quantify global cortical amyloid ([18F]Florbetapir SUVR50‐70, [18F]Florbetaben SUVR90‐110) and meta‐temporal tau ([18F]Flortaucipir SUVR80‐100) burden. Cortical amyloid SUVRs were harmonized using linear transformation to Centiloids (CL). Sampled iterative local approximation (SILA) was used to model ETOA and, separately, to estimate amyloid CL burden at ETOA. Kaplan‐Meier survival curves and Cox regression were used to test CL*APOE‐ε4*sex interaction effects on ETOA. Event time was ETOA for T+ individuals and age at last tau PET scan (right censored) for T‐ individuals who could become T+.

Results

We observed a significant CL*APOE‐ε4*sex interaction on ETOA (p=0.013, Table 2). APOE‐ε4 was associated with earlier ETOA in a dose‐dependent manner and effects were greater in females compared to males. ETOA differences between sexes and across APOE‐ε4 were attenuated at higher amyloid burden, largely due to the increased presence of T+ across all APOE‐ε4 statuses and both sexes (Figure 1). Main effects also revealed that higher cortical amyloid burden at ETOA was associated with earlier ETOA and greater T+ risk, as was greater APOE‐ε4 dose (Table 2).

Conclusions

These results suggest that amyloid burden, APOE‐ε4, and sex may influence when temporal tau deposition becomes abnormal. Smaller sample size among APOE‐ε4 carriers, and especially ε4 homozygotes, limits the estimates in this cohort. Future extensions of this work will expand to a multicohort sample, to attempt replication of these findings and to investigate how these factors and their interaction predict time from amyloid and tau onset to dementia.
Capacity for Alzheimer’s Disease confirmatory testing in the US ‐ current situation and simulations for future increase
Authors: Roth Sophie , Yan Jessie T. , Patru Maria‐Magdalena , Mattke Soeren , Ortsäter Gustaf , Gustavsson Anders
Published: January 2025

Background

Recent advances in Alzheimer’s Disease (AD) disease modifying therapies (DMTs) emphasize the need of an early, timely and accurate diagnosis to initiate treatment and improve patient outcomes. Clinicians must confirm amyloid pathology through cerebrospinal fluid (CSF) testing or amyloid positron emission tomography (PET) scan to qualify patients. As a result, the demand for confirmatory CSF or imaging biomarker testing is predicted to rise significantly.

Method

We developed a model to analyze diagnostic capacity for patients with mild cognitive impairment (MCI) seeking care in the US. We assessed amyloid PET and CSF testing from a payer’s perspective over 5 years. It was assumed that CSF testing is constrained by the number of lumbar puncture procedures rather than laboratory capacity. Of all currently available PET capacity per year, about 5% is used for AD diagnosis; this is assumed to increase approximately 7% per year. We compare four scenarios: 1) currently observed CSF (about 3.5%) and amyloid PET (< 1%) usage based on Medicare data; 2) increasing CSF use to meet the increasing demand for confirmatory testing, while PET remains as in scenario 1; 3) 100% amyloid PET 4) 100% CSF usage.

Result

Current usage of CSF and amyloid PET testing (scenario 1) cannot meet the increasing demand for AD confirmatory testing: Assuming 50% of patients with MCI seek care annually, there would be an excess demand of about 10 times in year 1. Increasing CSF usage in scenario 2 would lead to timely diagnosis of up to 55% of beta amyloid positive patients in 5 years, of which 45% is attributed to CSF testing and the remaining to PET use. The more extreme scenarios 3 and 4 of 100% use of either PET or CSF, result in <1% patients and 12.6% patients being diagnosed in year 1, respectively.

Conclusion

Increasing CSF use and capacity could meet the demand for confirmatory testing the quickest, reduce wait times and increase the number of timely diagnosed patients, especially during the time where more amyloid PET capacity is being instituted. Efforts to increase CSF usage and capacity could positively impact patient outcomes.
Association of metabolic syndrome with brain imaging and cognitive function in UK Biobank
Authors: Qureshi Danial , Topiwala Anya G , Al‐Abid Md Shehab Uddin , Allen Naomi , Kuzma Elzbieta , Littlejohns Thomas J
Published: January 2025

Background

Metabolic syndrome (MetS) has been previously associated with an increased risk of developing dementia. Exploring links between MetS, neuroimaging and cognitive function measures can offer insights into whether MetS adversely affects brain health prior to dementia onset. We sought to examine the association of MetS with brain structure and cognition.

Methods

Participants were selected from the UK Biobank multi‐modal imaging study (2014‐ongoing). MetS was defined as the presence of ≥3 of the following components: elevated waist circumference, triglycerides, blood pressure, HbA1c, or reduced HDL‐cholesterol. Neuroimaging outcomes included total brain, grey/white matter, white matter hyperintensity (WMH) and hippocampal volume from T1/T2‐weighted magnetic resonance imaging (MRI), and cognitive tests measuring executive function, reasoning, memory, and processing speed. Cross‐sectional associations were assessed using linear regression adjusted for age, sex, ethnicity, education, socioeconomic status, household income, smoking status, alcohol intake, physical activity, APOE‐ε4 carrier status, and assessment centre. Neuroimaging analyses were further adjusted for imaging‐related confounders (head size, head position, head motion).

Results

Among 32,864 dementia‐free participants, 9,484 (29%) had MetS. MetS was significantly associated with lower total brain volume (β:‐0.06, 95%CI: ‐0.08, ‐0.04), grey matter volume (β: ‐0.09, 95%CI: ‐0.11, ‐0.07), hippocampal volume (left = β: ‐0.02, 95%CI: ‐0.05, ‐0.00; right = β: ‐0.03, 95%CI: ‐0.05, 0.00), and greater WMH volume (β: 0.10, 95%CI: 0.08, 0.12). MetS participants performed significantly worse on cognitive tests of working memory (β: ‐0.11, 95%CI: ‐0.14, ‐0.08), verbal declarative memory (β: ‐0.10, 95%CI: ‐0.12, ‐0.07), processing speed (β: ‐0.09, 95%CI: ‐0.12, ‐0.06), verbal and numerical reasoning (β: ‐0.06, 95%CI: ‐0.08, ‐0.03), executive function (β: 0.05, 95%CI: 0.02, 0.07), and non‐verbal reasoning (β: ‐0.04, 95%CI: ‐0.06, ‐0.01). We observed dose‐response relationships, with an increasing number of MetS components being associated with lower brain volume, greater WMH volume, and poorer cognitive function across all tests.

Conclusion

MetS was associated with lower brain volume, greater vascular pathology, and poorer performance across multiple domains of cognitive function. These findings demonstrate that MetS is related to poorer brain health in dementia‐free individuals and could represent a novel risk factor for future development of dementia.
A Feasibility Study of Brain‐WISE: A Group‐Based, Person‐Centered Dementia Risk Reduction Program
Authors: Cohen Matthew L. , Van Buren Kimberly , Myers Mindy J , Ellison James M , Martens Christopher R. , Lanzi Alyssa M
Published: January 2025

Background

Reducing risk of dementia requires a person to have accessible information about health and risk factors, person‐centered health goals, and self‐efficacy. Here, we test the feasibility of a new risk reduction program called Brain Wellness Information, Support, and Empowerment (Brain‐WISE). Its unique features are that it (1) is aligned with a theoretical model of behavior change, (2) is relatively brief (six 90‐min sessions), (3) is conducted with groups of people who have pre‐existing community; (4) includes individual and group activities and person‐centered health goals; and (5) is conducted with speech‐language therapists.

Methods

We conducted two waves of a single‐arm pilot study with 49 older adults (aged 64‐93) to iteratively refine the program and evaluate its feasibility (adherence, acceptability, and pilot efficacy). Each of the six treatment sessions included a group lecture on brain health topics interspersed with individual and group activities. Brain health topics included (1) normal and abnormal cognitive aging and management of chronic conditions; (2) physical activity; (3) MIND Diet; (4) hearing, cognitive, and social health; (5) preventative use of cognitive aids and strategies; and (6) stress management and sleep. Adherence was measured with attendance. Acceptability was measured with bespoke questionnaires. Patient‐reported outcome measures were administered before and 1 week after treatment to assess changes in intermediate psychological outcomes (e.g., self‐efficacy) and ultimate behavioral outcomes (e.g., physical activity).

Results

Between Waves 1 and 2 we modified lecture content and activity materials, and selected different outcome measures. Attendance in Waves 1 and 2 was 97% and 93.4%, respectively. In each domain of acceptability (lecture content, lecture delivery, and activities), session‐specific mean responses on a 5‐point scale ranged from 4.1 to 4.7. In Waves 1 and 2, 92.3% and 90% of participants agreed or strongly agreed that the program was worthwhile. After Wave 2, pre‐post dementia knowledge increased, MIND diet scores improved, exercise increased, and perceived barriers to lifestyle change decreased. Self‐efficacy did not change.

Conclusions

The Brain‐WISE program is a feasible dementia risk reduction program for community‐dwelling older adults. Based on these findings, a full‐scale RCT to evaluate its efficacy is warranted.
Disentangling Molecular Links Underlying the Heart‐to‐Brain Connection in Older Adults
Authors: VandeBunte Anna M. , Saloner Rowan , Paolillo Emily W. , Ehrenberg Alexander J. , Cadwallader Claire J. , Chen Coty , Wyss‐Coray Tony , Rojas Julio C. , Chan Brandon , Lago Argentina Lario , Bennett David A. , Kramer Joel H. , Casaletto Kaitlin B.
Published: January 2025

Background

Cardiovascular disease (CVD) is among the strongest modifiable risk factors for dementia. However, vascular health is multifaceted, and its neurobiological underpinnings are unclear. A recent study (Williams et al. 2022) leveraged blood proteomics and machine learning to identify a novel group of 27 proteins that robustly predicted 4‐year likelihood of myocardial infarction, stroke, heart failure, or death. We examined whether these CVD‐related blood proteins also relate to brain health outcomes in older adults across three study cohorts.

Method

Discovery cohort included 84 older adults from the UCSF Memory and Aging Center (57% female; 79% clinically normal; 21% mild cognitive impairment [MCI] due to Alzheimer’s disease [AD]) with plasma assayed for the 27 CVD‐related proteins (SomaScan) and plasma neurofilament light (NfL, Simoa). Participants completed brain MRI and neuropsychological evaluations. Separate regression models related each CVD protein to each brain health outcome (NfL, total gray matter volume, global cognition), adjusting for age, sex, BMI, and TIV and education, as appropriate. CVD proteins that reached significance in the discovery cohort were validated in an independent in‐vivo cohort with plasma SomaScan and all three brain outcomes (Stanford ADRC; n=40, 25% AD) and an autopsy cohort with brain tissue protein quantification (Selected Reaction Monitoring) and cognitive data (Rush ADC; n=1103, 40% AD) via parallel regression models.

Result

In the discovery cohort, three CVD‐related plasma protein levels individually associated with global cognition (JAM2, PTPRJ, NCAM1, ps<0.03) and four proteins associated with plasma NfL (PTPRJ, GOLM1, SPON1, LRP11, ps<0.02). Only ADAMTS13 associated with total gray matter volume (p<0.01). In validation analyses, higher abundance of plasma SPON1 related to higher plasma NfL (β=0.38, p=0.02 [Stanford]), and higher abundance of SPON1 in brain tissue related to poorer cognition (β=‐0.13, p<0.0001 [Rush]). Brain tissue SPON1 also significantly differed across clinical diagnostic groups (normal≤ AD/MCI<AD dementia; f=4.71, p=0.0009).

Conclusion

We demonstrate overlap in proteins associated with CVD risk and brain aging. Cross‐validation analyses in plasma and postmortem brain tissue highlight increased SPON1 as a robust predictor of worse neurobehavioral outcomes. SPON1 is an extracellular matrix protein involved in both smooth muscle and nervous tissue growth, and may represent a common link between heart health and brain health.
Subjects treated with expanded non‐genetically modified autologous Natural Killer cells (SNK01) show improved changes in CSF α‐synuclein and in cognitive function
Authors: Gil Clemente Humberto Zúñiga , Gallo Blanca Isaura Acosta , Díaz Rufino Menchaca , Amescua Cesar Alejandro , Hong Sean , Hui Lucia , Lee Hank , Chang Paul , Betito Katia , Song Paul Y
Published: January 2025

Background

Accumulating evidence suggests that the presynaptic protein α‐synuclein (α‐syn), is involved in the pathophysiology of AD and elevated in the cerebrospinal fluid (CSF). The role of Natural Killer (NK) cells of the innate immune system in AD has largely been overlooked. In a murine model, depletion of NK cells augmented the accumulation of pathological α‐syn. Human NK cells have been shown to efficiently internalize and degrade α‐syn aggregates via the endosomal/lysosomal pathway. This has been proposed as a protective mechanism of NK cells against α‐synucleinopathy by removing harmful α‐syn aggregates from the patient’s brain. Our in vitro studies have shown that SNK01, an enhanced autologous non‐genetically modified NK cell product, is able to effectively internalize and degrade α‐syn aggregates.

Method

In this Phase 1 study, SNK01 was administered IV every three weeks for a total of 4 treatments using a 3+3 dose escalation design (1, 2 and 4×109 cells) in subjects with either mild, moderate, or severe AD (Median MMSE of 14). Cognitive assessments and CSF α‐syn analyses were performed at baseline and at 1 and 12 weeks after the final dose. The primary endpoint was safety and secondary endpoints included changes in cognitive assessments and biomarker levels.

Result

Eleven subjects (5 males and 6 females) were enrolled and 10 were evaluable. Median age was 79 years (56 to 85 years). No treatment related adverse events were observed. Despite 70% of subjects being treated at relatively low doses of SNK01, 90% of all evaluable subjects had either stable or improved (±0.1) composite ADCOMS scores at week 11 (one‐week after the final dose), and 60% of subjects (6/10) had a decrease in CSF α‐syn compared to baseline values. In the 5/6 subjects where data was available, these levels continued through week 22 for α‐syn. One additional subject had a decrease in CSF α‐syn compared to baseline values at week 22. At week 11, the decreases in α‐syn corresponded to stable/decrease in ADCOMS in 5/6 subjects.

Conclusion

SNK01 was safe and well tolerated. SNK01 appears to have clinical activity in AD while also reducing α‐syn protein levels in the CSF.
Incidence and Prevalence of Early Onset Dementia in Finland
Authors: Solje Eino , Aaltonen Mikko , Aho Kalle , Heikkinen Sami , Kivisild Ave , Lehtonen Adolfina , Leppänen Laura , Rinnankoski Iina , Soppela Helmi , Tervonen Laura , Haapasalo Annakaisa , Remes Anne , Hartikainen Päivi , Katisko Kasper , Krüger Johanna
Published: January 2025

Background

Early onset dementia (EOD) forms distinct economic, societal, and human burdens on patients, their families, the healthcare system, and society, differing from those associated with late onset dementia. However, epidemiological data on EOD, characterized by onset before the age of 65, is notably scarce.

Method

Our objective was to assess the incidence of all‐cause progressive Early Onset Dementia (EOD) and its subtypes from January 2010 to December 31, 2021 in two specified regions in Finland (Northern Ostrobothnia and Northern Savonia). All visits at the dementia outpatient clinics were manually reviewed during that period. In addition, prevalence of EOD and its subtypes were calculated on December 31, 2021 with 335,376 inhabitants in Northern Ostrobothnia and 186,592 in Northern Savonia.

Result

In the population aged 30‐64 years, crude incidence was 20.5/100 000 persons at risk/year based on 711 new cases from January 2010 to December 31, 2021. The prevalence of EOD was 128.9/100 000 in the age group of 30‐64 years. Amnestic Alzheimer’s disease (48.1%) and behavioural variant frontotemporal dementia (13.1%) were the most frequent subtypes.

Conclusion

EOD represents a significant group of neurological disorders leading to early loss of work capacity, dependence of external assistance, and eventually to premature death. The outcomes of this study aim to assist authorities and healthcare professionals in organizing effective diagnostics and improved care tailored to the specific needs of EOD patients.
Cardiopulmonary coupling measures of sleep stability and risk of cognitive impairment in community‐based older men
Authors: Milton Sasha , Sun Haoqi , Stone Katie L , Yaffe Kristine , Westover Brandon , Thomas Robert J , Leng Yue
Published: January 2025

Background

Poor sleep health is associated with cognitive impairment (CI) in older adults. The cardiopulmonary coupling (CPC) sleep spectrogram, which estimates the sleep state modulated synchronization between heart rate variability and respiration, is an increasingly recognized measure of sleep stability. However, little is known about the longitudinal association between CPC measures of sleep stability and risk of incident CI.

Method

Our sample comprised 2628 men (mean [SD] age = 76.0 [5.3] years, all aged ≥65 years) without CI who had their sleep assessed using polysomnography at baseline (2003‐05) and were followed until 2016 for incident CI as part of the Osteoporotic Fractures in Men (MrOS) study. Electrocardiogram (ECG)‐derived CPC metrics included the percentage of sleep time spent with high frequency coupling (HFC%, 0.1‐0.4Hz, stable sleep), low frequency coupling (LFC%, 0.01‐0.1Hz, unstable sleep), and very low frequency coupling (VLFC%, <0.01Hz, an estimation of rapid eye movement sleep and wakefulness). Incident CI (encoded as a binary variable) was defined as self‐reported dementia diagnosis, dementia medication use, Modified Mini‐Mental State Examination (3MS) score <80, or a decline in 3MS score from baseline to any visit of ≥1.5 standard deviations below the mean. Multivariable logistic regression was used to assess the associations between tertiles of CPC metrics and incident CI.

Result

A total of 419 men developed CI during a mean follow‐up of 10.8 years. After adjustment for covariates including demographics, lifestyle, comorbidities, medication use, and cognition at baseline, men in the middle tertile of HFC% were less likely to develop CI than men in the lowest tertile [OR (95% CI) = 0.73 (0.56,0.96)], while those in the highest tertile of HFC% had similar odds of incident CI [OR (95% CI) = 1.12 (0.87,1.45)] compared with the lowest tertile. Further adjustment for apnea‐hypopnea index (AHI) and use of continuous positive airway pressure (CPAP) did not appreciably alter these results. Neither LFC% nor VLFC% was associated with incident CI.

Conclusion

Older men with intermediate levels of stable sleep had the lowest risk of developing CI over 11 years. Further research is needed to understand the mechanisms linking CPC measures of sleep stability to cognitive aging.
Gendered association between life‐course social mobility and cognitive function among middle‐aged and older adults in India
Authors: Ko Soohyeon , Kim Rockli
Published: January 2025

Background

In rapidly developing countries like India, individuals undergo fluctuations in social status throughout their lives. However, there have been few investigations of the link between life course socioeconomic status and cognitive function in late middle age, particularly regarding whether upward and downward mobility exert symmetric effects. Furthermore, limited attention has been directed toward understanding gender heterogeneity within this association.

Method

This study utilized data from the Longitudinal Aging Study in India 2017‐2018, including 61,257 individuals aged 45 years or above. Based on financial status of family during childhood and monthly per capita expenditure in later life, life course social mobility was classified as “consistently high,” “upward mobility,” downward mobility,” and “consistently low.” Cognitive function was evaluated using the composite cognitive index across five domains (memory, orientation, arithmetic function, executive function, and object naming). Multivariable regression and interaction analysis were employed for estimating associations, with a focus on gender differences.

Result

Participants, with a mean age of 60.13 years, consisted of 45.93% men and 54.07% women. Overall, compared to those who maintained consistently high status, individuals remaining consistently low were associated with the lowest cognitive function (b = ‐1.48, 95% CI = ‐1.60, ‐1.35), followed by those undergoing downward mobility (b = ‐0.86, 95% CI = ‐0.98, ‐0.74) and upward mobility (b = ‐0.76, 95% CI = ‐0.87, ‐0.64). Significantly, the difference between upward and downward mobility varied by gender (p = 0.016). Among men, upward and downward mobility had asymmetric associations, with upward mobility being associated with a higher cognitive function than downward mobility (b = 0.30, 95% CI = 0.11, 0.49), whereas no significant difference was found for women (b = ‐0.03, 95% CI = ‐0.21, 0.16).

Conclusion

This study revealed notable disparities in cognitive function based on life course socioeconomic status. Furthermore, the association of upward and downward mobility on cognitive function exhibited gender‐specific differences. While for men, childhood disadvantage in cognitive function could be offset by upward mobility in adulthood, women experiencing low status at either temporal point in childhood or adulthood displayed lower cognitive function. These findings underscore the importance of tailored interventions, considering life trajectories of social status and gender, to address cognitive health disparities in rapidly evolving economies like India.
The role of imaging in outcomes and safety monitoring for preclinical intervention studies
Authors: Rafii Michael , Vemuri Prashanthi
Published: January 2025

Recent breakthrough findings in clinical trials on amyloid‐lowering therapies have led to the approval of these drugs for the treatment of amyloid‐ positive elderly individuals who show symptoms of mild cognitive impairment and mild dementia. The next frontier is the testing the efficacy of treatments for secondary prevention of AD dementia. Phase III trials in asymptomatic AD are already under way, raising a host of novel questions on the sequelae of trial participation such as the emotional and social repercussions of biomarker disclosure, understanding the risk of side effects and eventually weighing the risk‐benefit ratio of amyloid‐lowering treatment. In this session jointly organized by the Neuroimaging and Partnering with Research Participants PIAs, I will focus on the participants’ perspective on the role of imaging in outcomes and safety monitoring of preclinical interventional studies. I will outline the importance of a partnership between the study team and participants in the design and conduct of study procedures to ensure that they are both efficient and ethical.
Supporting Participants in Preclinical Alzheimer’s Trials: Experience from a Research Participant Advisory Board and the A4 Study
Authors: Walter Sarah , Morales Guadalupe , Shaffer‐Bacareza Elizabeth , Karlawish Jason , Grill Joshua D , Donohue Michael C. , Cohen Paula , Aisen Paul S. S , Sperling Reisa A ,   The A4 Study Team
Published: January 2025

Preclinical Alzheimer’s disease (AD) trials can involve multiple years of follow‐up and burdensome procedures for older individuals. Optimizing the design and conduct of these trials requires input from participants and their families. Since 2020, the Alzheimer’s Clinical Trials Consortium (ACTC) Research Participant Advisory Board has provided input on study attributes including: participant and study partner compensation, consent language, and result communication tools. A key recommendation from the advisory board is to design studies with the option to learn individual research results. Participants find results personally meaningful, even when the clinical relevance of results has not been established. After release of topline study results, A4 research sites were provided reports that included treatment arm assignment and individual research results (cognitive scores, amyloid PET tertile, and Clinical Dementia Rating scale results). Research sites were provided guidance on communicating research results in a training webinar. A survey was subsequently sent to all A4 sites to understand what methods were used to communicate results and support participants. The 42 sites that completed the survey reported sharing results with 445 participants, or 65% of participants active at the end of the study. Participants expressed interest in taking part in other studies and, where eligible, were referred. Those with worsening cognition and function were referred for clinical evaluation and care. Some A4 participants told sites that they expected “something tangible” and “more than a one‐hour meeting” after the many years of participation. The A4 sites that hosted ‘thank you’ events to discuss study‐level results, with separate one‐on‐one sessions to discuss individual results shared these were appreciated by participants. The active involvement of the diverse ACTC Participant Advisory Board has benefited the design of preclinical AD studies. The A4 experience demonstrates that it is feasible to share individual research results, and that a majority of participants will opt to learn. Greater involvement of the Advisory Board at the earliest stages of study design and planning will maximize impact of their feedback, and help researchers move toward the goal of optimized, inclusive trials.
Pharmacological Evaluation of Withanolide A for Anti‐Alzheimer’s Effects: Inhibition of Mitochondrial Permeability Transition Pore (mPTP)
Authors: Sharma Lalit , Gupta Yogesh
Published: January 2025

Background

Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline, neuroinflammation, and mitochondrial dysfunction. In Alzheimer’s, abnormal Mitochondrial Permeability Transition Pore (mPTP) activity may contribute to mitochondrial dysfunction and neuronal damage. Withanolide A, a naturally occurring compound derived from Withania somnifera, have shown potential neuroprotective effects in various neurological disorders. This study aimed to investigate the anti‐Alzheimer’s effects of Withanolide A and explore their mechanism of action through the inhibition of mPTP.

Method

In our study, we employed both in vitro and in vivo AD models to assess the impact of Withanolide A on cognitive function, amyloid‐beta (Aβ) pathology, and mitochondrial function. The in‐vivo study was carried out on Swiss albino mice. The intracerebroventricular injection of the Aß (1‐42) peptide into the ventricular system of the mouse brain was employed for the induction of the AD. Cognitive function was evaluated through a battery of behavioural tests like Morris water maze, Y maze, and open field test while amyloid‐beta (Aβ) pathology was quantified using immunohistochemical analyses. Mitochondrial function was meticulously characterized through measurements of membrane potential, reactive oxygen species (ROS) production, and adenosine triphosphate (ATP) levels.

Result

Our results demonstrated that Withanolide A significantly improved cognitive performance in AD behavioural mouse models, accompanied by a reduction in Aβ deposition. Importantly, Withanolide A exhibited a potent inhibitory effect on mPTP opening, thereby preserving mitochondrial membrane potential and attenuating ROS production. Further, ATP levels were sustained, indicative of improved mitochondrial bioenergetics. Subsequent exploration of molecular mechanisms elucidated the downregulation of pro‐inflammatory cytokines and upregulation of neurotrophic factors following Withanolide A treatment. These findings suggest a direct link between the anti‐Alzheimer’s effects of Withanolide A and their modulation of mitochondrial function through mPTP inhibition. These results highlight the multifaceted neuroprotective mechanisms employed by Withanolide A in mitigating AD pathology.

Conclusion

Our study provides compelling evidence for the potential of Withanolide A as a therapeutic intervention for AD. The observed inhibition of mPTP, coupled with improvements in cognitive function and mitigation of Aβ pathology, positions Withanolide A as a promising candidates for further research in the pursuit of effective treatments for AD.
Gait speed as a surrogate marker of change in cognitive function derived from multimodal lifestyle intervention: J‐MINT study
Authors: Fujita Kosuke , Sugimoto Taiki , Matsumoto Nanae , Uchida Kazuaki , Kuroda Yujiro , Arai Hidenori , Sakurai Takashi ,   J‐MINT study group
Published: January 2025

Background

The effectiveness of multimodal lifestyle interventions to prevent dementia is being validated. Since a relatively long period (∼2 years) is required for manifesting an impact on cognitive function, the exploration of an alternative marker that exhibits changes within a comparatively brief duration, thereby prognosticating future alterations in cognitive function, is needed. The decline in gait function is associated with cognitive impairment and is also a predictor of future cognitive decline. This study examined whether gait speed can be used as a surrogate marker for change in cognitive function derived from multimodal lifestyle interventions.

Method

Data from a multi‐center, open‐label, randomized controlled trial in Japan (J‐MINT study) are utilized. Community‐dwelling older adults with mild cognitive impairment, aged 65 to 85 years, were enrolled in the J‐MINT study. The intervention group received 18 months of a multimodal lifestyle intervention (exercise, nutrition, cognitive stimulation, and vascular risk management), while the control group received only health information. Cognitive function was measured with a global composite score using eight neuropsychological tests. All variables were measured at baseline, 6, 12, and 18 months. Multiple regression analysis was performed for each of the allocation groups to investigate the association between the change in 18‐month cognitive function and the change in gait speed at 6 or 12 months from baseline.

Result

Among 378 participants analyzed (baseline age, 74.2±4.8 years; 50% of male; gait speed of 1.25±0.24 m/s), 194 were the intervention group. Significant gait speed improvement was observed in the intervention group at 12 months when comparing the control groups (least square mean = 0.033). Multiple regression analysis revealed a significant association between changes in gait speed and cognitive function only in the intervention group (gait speed change in baseline to 6M, β = 0.452, p = 0.016; baseline to 12M, β = 0.387, p = 0.042).

Conclusion

Short‐term changes in gait speed following multimodal interventions may serve as valuable surrogate markers, predicting of subsequent long‐term (approximately 18 months later) alterations in cognitive function. This suggests the potential of gait speed as an early indicator of intervention efficacy in preventing cognitive decline.
Proteomic markers of Alzheimer's disease and related dementia risk in individuals with a history of depression
Authors: Diniz Breno S , Chen Zhiduo , Kuchel George A , Fortinski Richard , Kuo Chia‐Ling
Published: January 2025

Background

History of depression is one of the most significant, and potentially modifiable risk factors for Alzheimer’s disease and related dementia (ADRD). However, there is limited evidence on the underlying biological mechanisms that link the history of depression to the higher risk of ADRD. This study aimed to evaluate the proteomic markers associated with the higher risk of ADRD.

Method

We used the UK Biobank (UKB study) to address the study aim. Our sample consisted of 42,807 individuals (3,615 with a history of depression in the baseline assessment) who had plasma proteomic data available. We evaluate the proteomic predictors of the risk of ADRD among individuals with a history of depression using Cox Proportional regression and random forest analysis. The total follow‐up time was 13 years from the baseline analysis. We used the Benjamin‐Hochberg method to control for a false discovery rate.

Result

A small panel of 6 proteins was significantly associated with an increased risk of progressing to ADRD upon follow‐up after controlling for age, educational level, medical comorbidity, and APOE genotype (GFAP, NFL, PSG1, GET3, HPGDS, and VGF; FDR adjusted p‐value <0.05). The predictive power of this proteomic panel was moderate, with C‐statistics = 0.79. Random forest machine learning analysis yielded similar results as the Cox regression analysis.

Conclusion

This study indicates that the risk of ADRD among individuals with a history of depression is partially mediated by abnormal astroglial activation, axonal dysfunction, and neurodegeneration. Other biological mediators of risk also involve abnormalities in synaptic plastic, cell growth, peroxisomal lipid metabolism, and oxidative stress control. Our results point to novel putative mechanisms to develop interventions to mitigate the risk of ADRD among individuals with a history of depression.
Time spent in an impaired glucose state across the midlife and early late adulthood cognitive function: Study of Women’s Health Across the Nation
Authors: Leis Aleda M. , Karvonen‐Gutierrez Carrie A. , Thurston Rebecca C , Khoudary Samar R. El , Derby Carol A.
Published: January 2025

Background

Over 30 million Americans have diabetes, with 9 million likely undiagnosed. Diabetes is associated with cognitive decline and risk for Alzheimer’s disease and related dementia (ADRD). The lifetime impact of diabetes and prediabetes on cognition may be cumulative. We examined whether time spent in an impaired glucose state during midlife was associated with worse cognitive function in early older adulthood.

Method

The Study of Women’s Health Across the Nation (SWAN) is a longitudinal multi‐center cohort of women followed from 42‐52 years. This cross‐sectional analysis includes 1336 women with cognitive testing at Visit 15, baseline fasting blood glucose measures, cognitive testing at Visit 7, and no history of myocardial infarction or stroke. Percentage of visits with an impaired glucose state (IGS; fasting glucose >100µg/mL), or diabetic state (DS; fasting glucose >126µg/mL), were considered, categorized as <25%, 25%‐<50%, 50%‐<75%, and ≥75%. Visit 15 outcomes included working memory (Digit Span Backwards (DSB) test), immediate and delayed memory recall (East Boston Memory Test (EBMT‐I and EBMT‐D)) and processing speed (Symbol Digit Modalities (SDMT) test). Separate linear regression models were constructed examining cumulative time in IGS or DS with each outcome at Visit 15, adjusting for Visit 15 covariates: race/ethnicity, education, BMI, age, physical activity, history of antidiabetic medication, number of visits with glucose, prior cognitive function score at Visit 7, and hormone therapy. SDMT models were adjusted for self‐reported overall quality of vision.

Result

Women were mean age 65 years (SD:2.7) (Table 1) and 50% were non‐Hispanic White. The majority spent <25% of their visits in IGS or DS, and few spent ≥75% time in IGS or DS (6.7% and 0.9%, respectively). IGS was not associated with cognitive outcomes (Table 2). However, those with ≥75% time in DS had a 4.5 unit (95%CI:‐8.8,‐0.2;p = 0.040) lower SDMT score compared to those with <25% time in DS.

Conclusion

While mild glucose impairment over midlife was not related to cognitive function in early older adulthood, prolonged diabetic‐level glucose was associated with worse processing speed in early older adulthood, suggesting the importance of diabetes screening and optimizing glucose control during midlife to preserve cognitive function at older ages.