bluuebunny/crossref_metadata_2025 huggingface dataset:
Data driven subtyping of individuals on the Alzheimer’s continuum using cortical microstructure from diffusion MRI
Authors: Javid Shayan , Zhu Alyssa H , Gari Iyad Ba , Jahanshad Neda , Nir Talia M
Published: January 2025

Background

Alzheimer’s disease (AD)‐related pathologic changes in the brain begin years before MRI‐detected atrophy and the onset of cognitive decline. Diffusion MRI (dMRI) can quantify microstructural alterations in brain tissue, and may be more sensitive to pathologic processes than standard MRI volumetric biomarkers. As AD is a heterogeneous disease, previous studies have used post‐mortem, structural MRI, and PET measures to subtype individuals by areas of the brain affected, identifying distinct patterns of degeneration and decline. Subtyping individuals using non‐invasive dMRI microstructural alterations, which likely occur before volumetric atrophy, may provide complementary assessments of possible trajectories of decline. We pool two datasets to subtype individuals using a data‐driven approach, and determine whether there are subtype differences in cognitive impairment, and more invasively derived metrics (PET and CSF derived assessments of beta‐amyloid (Aβ) plaques or tau tangles).

Method

T1w and dMRI data were processed for 484 ADNI3 and 188 OASIS3 participants (Figure 1A). FreeSurfer was used to segment cortical lobes and subcortical structures; thickness or average MD was calculated in each. T1w and dMRI measures were harmonized across imaging protocols using ComBat. We used SuStaIn (Young 2018) to subtype individuals based on regional dMRI‐derived mean diffusivity (MD) and separately, based on cortical thickness and subcortical volume. We determined how derived subtypes relate to PET or CSF AB and tau levels, and cognitive scores using mixed effects regressions, covarying for age, sex, MRI scanning protocol, and diagnosis.

Result

SuStaIn identified three subtypes for both T1w and MD data. When analyzing MD‐derived subtypes, significant pairwise differences between all subtypes were found for cognitive scores and tau PET. Progression and CSF tau was significant when comparing typical AD with the less altered MD subtypes. T1w‐derived subtypes differed significantly in cognitive scores but not tau measures. There were no significant associations with Aβ.

Conclusion

SuStaIn identified T1w and MD subtypes that reflect previously suggested subtypes, such as typical AD and minimal atrophy AD. Our findings comparing dMRI‐derived subtypes indicate that MD may be sensitive to tau aggregation. Future studies will evaluate staging, include a finer cortical parcellation, and data from additional studies to ensure generalizability of findings.
In Vivo Characterization of Neuroinflammation Using a Folate Receptor Targeted Nanoparticle Platform in a Mouse Model of SARS‐CoV‐2 Infection and Alzheimer’s Disease
Authors: Parekh Parag A , Badachhape Andrew A , Bonilla Lauren , Kneubehl Alexander R , Menon Renuka , Clinton Jennifer L , Bhandari Prajwal , Bhavane Rohan , Admane Prasad , Srivastava Mayank , Ronca Shannon E , Tanifum Eric , Annapragada Ananth , Ghaghada Ketan
Published: January 2025

Background

Clinical studies in COVID‐19 patients have demonstrated evidence of neuroinflammation in patients infected with SARS‐CoV‐2. In this pre‐clinical work, we investigate neuroinflammation in vivo in a mouse model of Alzheimer’s disease (AD) that exhibits both amyloid and tau pathology, the 3xTg‐AD mice crossed with K18 hAce2 and infected with SARS‐CoV‐2 using a folate receptor‐targeted nanoprobe for molecular MRI (mMRI) followed by ex vivo histopathology.

Method

In vivo studies with SARS‐CoV‐2 were performed in an animal biosafety level 3 (ABSL3) facility. 3xTg transgenic mice, a model of amyloid and tau pathology, were bred with k18‐hACE2 transgenic mice to generate double transgenic k18‐hACE2/3xTg transgenic mice that express hACE2 receptors (critical for viral infection) and develop amyloid and tau pathology. 11–14‐month‐old transgenic k18‐hACE2/3xTg mice (n=6) were infected with 103 PFU of SARS‐CoV‐2 Delta variant and underwent mMRI studies 10 days post‐infection. Age‐matched non‐infected k18‐hACE2/3xTg mice (n=6) were used as controls. All mice underwent pre‐contrast and post‐contrast T1‐weighted MRI (T1w‐MRI). Post‐contrast T1w‐MRI was performed 4 days after systemic administration of a high T1 relaxivity folate targeted liposomal‐Gd contrast agent. Signal changes between pre‐contrast and post‐contrast MRI were determined in target regions of the brain. Animals were euthanized after final imaging session for microscopic analysis of the brain.

Result

Non‐infected K18‐hACE2/3xTg mice showed relatively low brain signal enhancement in post‐contrast MRI (3.3 %) consistent with the absence of frank neuroinflammation. In contrast, K18‐hACE2/3xTg transgenic mice infected with SARS‐CoV‐2 demonstrated significantly higher brain signal enhancement (+10.9%) in post‐contrast T1w‐MRI compared to pre‐contrast MRI (Figure 1) suggesting infection‐induced neuroinflammation. Signal enhancement was seen in cortical and hippocampal regions of the brain. Microscopic analysis of mice brain sections depicting the hippocampus region show the folate nanoparticles in the vicinity of amyloid deposits. Quantitative analysis shows increasing amyloid deposition in infected mice. Activated microglia in infected mice staining is also observed at higher levels.

Conclusion

Data suggests that the hybrid hACE2‐3xTg‐AD mice exhibit neuroinflammation and increased amyloid deposition following SARS‐CoV2 infection indicating acceleration of AD pathology in these mice.
Process and metrics surrounding disclosure of genetic and biomarker results in the Duke University/University of North Carolina Alzheimer’s Disease Research Center (Duke/UNC ADRC) cohort
Authors: Mayan Inbal , Whitson Heather , Roth Heidi L , Johnson Kim G
Published: January 2025

Background

Increasingly, research participants in Alzheimer’s studies are seeking disclosure of research results. However, there are no guidelines for result disclosure and specifically, few studies report on their biomarker disclosure procedure. The Duke/UNC ADRC seeks to disclose research results to participants in a standardized fashion with high participant satisfaction.

Method

The Duke/UNC ADRC cohort consists of participants aged 25‐80. Uniform Data Set (UDS) neuropsychological testing, MRI, APOE testing, CSF biomarkers including amyloid beta 42/40 (abeta 42/40), phospho tau (p‐tau) and total tau (t‐tau) are measured in the initial visits. A formal consensus panel confers a clinical and pathological diagnosis based on review of UDS and biomarker results. Participants receive their results during a telehealth appointment. With a standard slide presentation, the clinician educates participants about risk factors, biomarker significance and methods of clinical diagnosis. The clinician presents each participant’s unique results of APOE testing, CSF testing including amyloid and tau and consensus panel diagnosis. The conversation lasts about 25 minutes on average and participants are sent a survey through REDCap that consists of 5 questions. The post‐results survey, which takes 1‐2 minutes to complete, assesses anxiety levels, participant satisfaction and gives participants an option to seek more information.

Result

Results were given to 50 participants. The post results survey completion rate was over 70% with 35 participants completing the survey. 94% (33/35) of participants were pleased with the decision to receive the results and reported the information helpful. Anxiety levels declined after receiving the results. While 46% (16/35) of participants reported medium/high level of anxiety before receiving results, only 17% (6/35) reported medium/high level of anxiety after receiving results.

Conclusion

We show high participant satisfaction and low anxiety levels when receiving genetic and biomarker results. The process we developed shows promise to disclose biomarker information to participants in a standardized fashion, while providing education and sought after information about genetic and biomarker status.
Diffusion Basis Spectrum Imaging in Midlife Obesity: Associations with Abdominal Adipose Tissue
Authors: Dolatshahi Mahsa , Commean Paul K. , Rahmani Farzaneh , Nguyen Caitlyn , Lloyd LaKisha , Kasani Sara Hosseinzadeh , Mittendorfer Bettina , Sirlin Claude , Song Sheng‐Kwei , Benzinger Tammie L.S. , Ippolito Joseph E. , Morris John C. , Raji Cyrus A.
Published: January 2025

Background

Obesity and abdominal adiposity in midlife are shown to increase the risk of Alzheimer disease. However, it is not clear whether midlife adiposity is associated with increased neuroinflammation. We aimed to investigate the associations of obesity, BMI of 30 kg/m2 or higher, and abdominal visceral and subcutaneous adipose tissue (VAT and SAT) with brain histology, using diffusion basis spectrum imaging (DBSI) analysis;

Method

In total, 54 cognitively normal middle‐aged subjects (50.46±6.19 years, male: 21 (38.9%), obesity: 32 (59.3 %), BMI: 32.18±6.99 kg/m2) underwent brain and abdominal 3T MRI. Abdominal VAT and SAT were semi‐automatically segmented using VOXel Analysis Suite (Voxa). A DBSI scheme with a total of 98 diffusion samplings was acquired followed by movement and eddy current correction and brain tissue extraction in FSL. DBSI maps including fractional anisotropy (FA, overall integrity), axial diffusivity (AD, axonal injury), radial diffusivity (RD, myelin loss), restricted fraction (RF, inflammation cellularity), hindered fraction (HF, extracellular edema), and fiber fraction (FF, axonal density) were generated using in‐house software scripted in MATLAB. DBSI‐derived maps were processed using a tract‐based spatial statistics (TBSS) pipeline for whole‐brain white matter voxel‐wise analyses. Using the Randomize tool from FSL, the difference between obese vs. non‐obese, high‐VAT vs. low‐VAT, and high‐SAT vs. low‐SAT groups were investigated for each DBSI‐derived skeleton, with age and sex as covariates, and a threshold of 0.05 for false‐discovery rate. The sex differences were further investigated;

Result

Lower FF and AD and higher RF in widespread white matter areas were observed in the obese vs. non‐obese group, and in the high‐SAT vs. low‐SAT group. Lower AD and higher RF were observed for the high‐VAT vs. low‐VAT group. All of these differences were only significant in females, not males, but higher RF in obese vs. non‐obese was observed both in males and females;

Conclusion

Our data support lower axonal density and fiber integrity, as well as higher inflammation cellularity in cognitively normal, middle‐aged obese individuals, and those with high VAT and high SAT, especially in females. Overall, our data suggest the differential role of visceral and subcutaneous abdominal fat in promoting neuroinflammation and axonal damage.
The Environment Matters: Perspectives on Using the Physical Environment in a Skilled Nursing Facility for Clients with Dementia
Authors: DiGrado Jennie L
Published: January 2025

Occupational therapists (OTs) are among the health care professionals who assist individuals with neurocognitive disorders (NCDs) to engage in self‐care and leisure activities in a skilled nursing facility (SNF) environment. OTs use various environmental modifications to help individuals with NCDs engage in various activities (Jensen & Padilla, 2017). Strong evidence has been found to support occupational therapy recommendations and interventions in adapting the physical environment to support person centered care (Gitlin et al., 2010; Jensen & Padilla, 2017; Zimmerman et al., 2013). This session aims to share findings from a qualitative case study regarding the perspective of OTs and how they use the built physical environment to help individuals with NCDs is a SNF engage in self‐care and leisure related activities. Recommendations from this study include nonpharmacological‐based intervention strategies that incorporate the use of the built environment in a SNF to improve the quality of life for clients with a NCD.
Tear proteomic signature associated with mild cognitive impairment and dementia: an exploratory analysis
Authors: Yuan Changzheng , Shen Jie , Huang Yuhui , Wu Minyu , Zheng Yan , Guo Tiannan , Xu Xin
Published: January 2025

Background

Tear samples were low‐invasive to access and may reflect changes in the brain. We performed an exploratory proteomic analysis using tear samples to identify proteomic signature and potential pathways that may be associated with mild cognitive impairment (MCI) and dementia.

Method

We performed a matched case‐control study using tear samples collected from community‐dwelling older adults, comprising 13 dementia, as well as 34 MCI and 34 age‐, sex‐, educational‐matched normal cognition (NC) controls (age: 73.3 ± 7.1 years; female: 68.4%). The disease staging has been distinguished by clinical dementia rating (CDR). PulseDIA‐based (gas phase fractionation‐assisted data‐independent acquisition mass spectrometry) proteomics analysis was performed. Logistic regression models were used to identify differential proteins when comparing dementia versus NC and conditional logistic regression models were used when comparing MCI versus NC. Identified differential proteins were used to perform enrichment analysis. Lasso regression models were utilized to select protein biomarkers for dementia prediction.

Result

A total of 70 tear proteins were found to be significantly associated with dementia and demonstrated same directions in relation to MCI. In particular, 37 proteins were positively related to dementia, with OR ranging from 3.79 (KLHDC4) to 71.91 (GLO1); 33 proteins were inversely related to dementia, with OR ranging from 0.27 (ABCC2) to 0.03 (COPS7B). The 3 strongest pathways identified by the protein‐protein interaction enrichment analysis were central nervous system neuron development, Eukaryotic Translation Termination, and amide biosynthetic process. In addition, incorporating 13 protein biomarkers to the traditional risk factors‐based model significantly improved the predictive ability of dementia (AUC from 0.813 to 0.971, P = 0.032).

Conclusion

Differential tear proteins between dementia and normal cognition were identified in this exploratory analysis, which may contribute to discovering novel and low‐invasive biomarkers of dementia.
Investigating the role of gut microbiome in alcohol consumption‐associated alterations to cognitive function and biomarkers of Alzheimer’s disease and related dementias
Authors: Peter Darby , Heston Margo B. , Jonaitis Erin M. , Chin Nathaniel A. , Johnson Sterling C. , Asthana Sanjay , Carlsson Cynthia M. , Knight Rob , Kaddurah‐Daouk Rima , Blennow Kaj , Zetterberg Henrik , Rey Federico E. , Bendlin Barbara B.
Published: January 2025

Background

Heavy alcohol consumption is associated with increased risk for Alzheimer’s disease and related dementias (ADRD), with mixed evidence suggesting a dose‐dependent nonlinear effect of alcohol on ADRD. Potential mechanisms by which alcohol may promote or attenuate brain pathology need further exploration. Although chronic alcohol consumption associates with gut microbiome alterations, it remains unclear whether microbial alterations mediate alcohol‐associated neurodegeneration and cognitive decline. Here we investigated whether the gut microbiome mediates alcohol consumption effects on cognitive function and biomarkers of neurodegeneration, glial activation, and AD.

Method

Cognitively unimpaired adults (n=178, Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center; Table 1) underwent neuropsychological evaluation, provided stool samples, and reported average daily alcohol consumption via questionnaire; a subset also underwent lumbar puncture (n=86). Fecal microbiome composition was characterized using 16S rRNA sequencing. A QIIME2/Phyloseq pipeline was used to complete denoising, feature classification, filtration of rare taxa and rarefaction to even sampling depth. Cerebrospinal fluid (CSF) biomarkers were quantified using the NeuroToolKit panel of robust prototype assays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Multiple regression tested for associations between alcohol consumption and global cognitive function indicated by Preclinical Alzheimer’s Cognitive Composite (PACC3) scores (Donahue et al, 2014; Jonaitis et al, 2019), in addition to associations with CSF biomarkers. Non‐parametric methods tested associations between alcohol consumption and phylogenetic diversity as well as bacterial community structure.

Result

A nonsignificant quadratic trend was observed between alcohol consumption and PACC3 scores (Figure 1). No significant associations were observed between alcohol and CSF biomarkers (Table 2). When testing associations between alcohol and gut microbiome independent from CSF and cognitive outcomes, no significant association was observed between alcohol consumption and phylogenetic diversity, nor was alcohol associated with significant alterations to bacterial community structure.

Conclusion

Associations between alcohol consumption and cognition as well as CSF biomarkers were expected to be partially mediated by gut microbial alterations, but few relationships were observed, apart from a nonlinear trend between alcohol and PACC3. Of note, few individuals reported heavy alcohol use, which may have limited power to detect effects in this sample.
Investigating long‐term, progressive cerebral microvascular alterations in late‐onset Alzheimer's disease using APOE4 transgenic mice
Authors: Lee Jang‐Hoon
Published: January 2025

Background

Recent studies show apolipoprotein E4 (APOE4), the strongest known genetic risk factor for late‐onset Alzheimer’s disease, is associated with vascular dysfunctions such as blood‐brain barrier breakdown, in both animal models and humans. However, there is a lack of understanding on how vascular alterations progress with age in APOE4.

Method

Human APOE4 (m/f, n=10 per group) and APOE3 targeted replacement mice (m, n=10) were used to investigate temporal dynamics of long‐term, progressive cerebral microvascular alterations in APOE4. we acquired a set of imaging data including optical coherence tomography (OCT) angiogram and doppler OCT to quantify relative changes in pial and penetrating vessels with age (starting at 13 weeks of age (WOA) and repeated every 4 weeks until 57 WOA). For assessing cognitive function, novel object location test (NOL) was used and performed every 4 weeks starting from 17 WOA.

Result

We compared the rate of change with age (RCA) values between the groups to find the effects of APOE4 and female. In pial vessel diameter, both APOE4‐m and APOE4‐f groups showed vessel diameter decreasing with age at a rate of 2.7 and 3.1% per month, respectively. In contrast, the control group (APOE3‐m) exhibited a slight increase in vessel diameter at a rate of 1.0% per month. When compared between groups based on RCA values, the age of significance (AOS) for the effect of APOE4 was 28 WOA. Adding the effect of female with APOE4, the result showed an earlier AOS of 26 WOA. In penetrating vessels (diameter/flow change in arterioles/venules), a similar trend was observed with both APOE4 groups exhibits more rapid decreasing RCAs and earlier AOS (27 WOA as earliest) than APOE3. More importantly, these AOS values were much faster than cognitive decline (51 WOA).

Conclusion

We found vascular alterations in both pial and penetrating vessels occurred earlier than cognitive decline, being generally greater and earlier in female APOE4 than male APOE4 mice. This female effect in APOE4, although the underlying mechanisms behind such finding is beyond the scope of this study, could still provide valuable insights on understanding vascular dysfunction in sex‐dependent manner.
Investigating the Validity of Digital Biomarkers in the Preclinical Screening of Cognitive Normal, Amyloid‐β‐ MCI and Amyloid‐β+ MCI
Authors: Kim Whani , Kim Jin Sung , Ko Hyun Jeong , Yun Byung Hun , Kim Yuyoung , Kim Dong Han , Kwon Ui Jun , Lim Sang Kwon , Kim Bo Ri , Lee Jee Hang , Kim Geon Ha , Kim Jinwoo
Published: January 2025

Background

Amyloid‐β is widely known as a substantial biomarker in the diagnosis of Alzheimer’s disease. However, detection of amyloid‐β through neuroimaging techniques requires huge amounts of resources. There is a growing demand to detect these pathologies based on digital biomarkers. This study primarily aimed to examine the validity of a mobile‐based tool for assessment of cognitive impairment (mACI) in the prediction of cognitive normal (CN), amyloid‐β negative MCI (Aβ‐MCI), and amyloid‐β positive MCI (Aβ+MCI).

Methods

We recruited 102 participants from Gwangju Alzheimer’s and Related Dementia (GARD) cohort containing K‐MMSE v2, SNSB v2, MRI, PET‐CT, and clinical diagnosis data. 48 participants, who were still in the process of receiving a clinical diagnosis, were excluded. We then collected mACI data, which examined nine cognitive functions proposed in Kim et al. (2023), resulting in 54 participants’ full dataset. Medical doctors labeled the participants into CN (n = 27), Aβ‐MCI (n = 14), and Aβ+MCI (n = 13). We subsequently analyzed the data using machine learning (ML) techniques to see whether the mACI is a successful tool for preclinical screening between them.

Results

We built a predictive model to classify the participants into CN, Aβ‐MCI and Aβ+MCI using the Catboost ML algorithm. To see the result, we performed Recursive Subtest Elimination Cross Validation (RSECV). In doing so, we measured the delta‐AUC indicating the degree of contribution of the eliminated subtest in the preclinical screening of CN, Aβ‐MCI and Aβ+MCI. As shown in Table 1, there are clearly distinctive sets of subtests when screening the participants into CN, Aβ‐MCI and Aβ+MCI. Specifically, the subtest in relation to working memory is likely to be crucial in classifying CN and MCI, and the additional subtest related to executive function plays an important role in classifying Aβ+MCI and others.

Conclusion

In this study, we found that mACI was able to successfully classify CN, Aβ‐MCI and Aβ+MCI. Our work serves as foundational work to reduce screening time and expenses to identify amyloid‐β accumulation using a mobile‐based application.
Cerebral Blood Flow in Midlife Obesity: Associations with Visceral and Subcutaneous Abdominal Adipose Tissue
Authors: Dolatshahi Mahsa , Commean Paul K. , Dai Weiying , Nguyen Caitlyn , Lloyd LaKisha , Kasani Sara Hosseinzadeh , Sirlin Claude , Mittendorfer Bettina , Benzinger Tammie L.S. , Ippolito Joseph E. , Morris John C. , Raji Cyrus A.
Published: January 2025

Background

Obesity and higher adiposity in midlife are recognized as contributors to Alzheimer disease (AD). Neurodegeneration in AD is at least partly mediated by vascular compromise and brain hypoperfusion. In this study, we aimed to investigate the associations between BMI and abdominal visceral and subcutaneous adipose tissue (VAT, SAT) and brain cerebral blood flow (CBF) in cognitively normal midlife individuals.

Method

A total of 66 middle‐aged cognitively normal adults (age: 49.86±5.99 years, females: 66.7%, obesity (BMI of 30 kg/m2 or higher): 51.5 %, BMI: 31.72±6.96 kg/m2) underwent abdominal and brain MRI. Using an in‐house Matlab program, abdominal VAT and SAT were automatically segmented followed by manual editing. A 3D Pseudo‐Continuous Arterial Spin Labeling (pCASL) sequence, with a single post‐labeling delay of 2.025 s, was used for assessing CBF. SPM12 was used to generate ASL absolute CBF (aCBF) maps with a single compartment model, co‐registered to the gray matter segmentations, and normalized to MNI space, followed by spatial smoothing. Using AAL3 atlas and Matlab, region of interest masks were created for amygdala, hippocampus, posterior cingulate, precuneus, parahippocampal, medial orbitofrontal, and middle temporal cortices and applied to absolute CBF (aCBF) maps. The aCBF differences between the obese vs. non‐obese, high‐VAT vs. low‐VAT, and high‐SAT vs. low‐SAT was assessed, with age and sex as covariates. Also, BMI, VAT, and SAT as separate predictor variables, with age and sex as covariates, were used for voxel‐wise analysis.

Result

There was a lower whole‐brain aCBF in the high‐VAT (p=0.004) group and obese (p=0.005) individuals, more prominently in the left middle temporal lobe (p=0.002). No significant difference was observed in global and regional aCBF in the high‐SAT vs. low‐SAT groups. Voxel‐wise analyses showed significantly lower aCBF in association with BMI in temporal, occipital, and frontal lobe clusters after false discovery rate correction.

Conclusion

Obesity and increased visceral abdominal fat are associated with a lower cerebral blood flow, with a more prominent decrease in the middle temporal cortex, as an AD‐signature area, in cognitively normal midlife individuals. These findings highlight the role of obesity, especially visceral obesity, in brain hypoperfusion and potentially Alzheimer disease risk, as early as midlife.
Wearable Frontal EEG for Screening Cognitive Impairment
Authors: Ryoo Nayoung , Kim SangYun , Lee Young Gyu , Chae Yongwook
Published: January 2025

Background

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by progressive cognitive decline. Early detection of AD is essential for timely intervention and treatment. The objective of this study is to explore the potential usefulness of virtual reality (VR) tasks combined with frontal EEG recordings for early detection of cognitive impairment in individuals with SCD (subject cognitive decline), MCI (mild cognitive impairment), and AD (Alzheimer's disease). We aimed to analyze the results and compared them with those of a control group with normal cognition.

Method

Resting‐state EEG was recorded in the awake‐resting state with closed eyes, and task‐induced EEG recordings were obtained during VR tasks from 108 participants. The participants included those with SCD, MCI, and AD, and they were compared with 18 subjects with normal cognition. Alpha reactivity was determined by measuring the decrease in relative alpha power over frontal electrodes.

Result

This study observed a significant decrease in alpha reactivity in the order of SCD, MCI, and AD compared to the control group with normal cognition in EEG recordings (P‐value < 0.05). Additionally, the decibel power ratio of the EEG recorded during cognitive tasks exhibited a reversed order of decrease compared to the resting state across the same diagnostic groups.

Conclusion

This study shows that when performing cognitive tasks with a virtual reality (VR) device on the forehead, distinct features for Alzheimer's disease are observed compared to the healthy control group. While larger and longer‐term studies are necessary, these findings suggest that cost‐effective digital biomarkers using measurable EEG could be valuable for early Alzheimer's diagnosis.
Bone morphogenetic protein levels relate to osteoarthritis and neurobehavioral outcomes in cognitively unimpaired older adults
Authors: Diaz Valentina E. , Paolillo Emily W. , Chen Coty , VandeBunte Anna M. , Cadwallader Claire J. , Schurman Charles A. , Schiling Birgit , Miller Bruce L. , Kramer Joel H. , Casaletto Kaitlin B. , Saloner Rowan
Published: January 2025

Background

Osteoarthritis (OA) is a degenerative disorder of bone aging and risk factor for cognitive decline. Bone morphogenetic proteins (BMPs) are growth factor proteins that regulate skeletal and neural development, and circulating BMPs may mediate molecular cross‐talk between bone and brain. The present study examined plasma BMP levels in relation to OA and neurobehavioral outcomes in cognitively unimpaired (CU) older adults.

Methods

Participants included 65 CU adults (mean age= 76.45, 60% female) enrolled in the UCSF Brain Aging Network for Cognitive Health (BrANCH) study who underwent cross‐sectional neurological examination, neuropsychological testing, and blood draw. Participants were classified as OA (n=31) or control (CTL; n=34) based on clinician exam (UDS Medical Conditions). Plasma was assayed for 11 different BMPs via SomaScan v4.1. Composite z‐scores were calculated for cognitive domains of memory and executive functioning. Mood symptoms were quantified with the 30‐item Geriatric Depression Scale (GDS). ANCOVA compared BMP concentrations between OA and CTL, adjusting for age and sex. Separate multiple linear regressions examined the relationship between OA‐associated BMPs and neurobehavioral outcomes across the entire sample (cognitive z‐scores, GDS total score), adjusting for age, sex, and education.

Results

OA and CTL groups did not significantly differ on demographics or neurobehavioral outcomes (ps>0.10). Five BMPs were differentially abundant (ps<.05) between OA and CTL (lower in OA: BMP5, BMP7, BMP10, BMP6; higher in OA: BMP4). In neurobehavioral models, lower BMP6 and higher BMP4 levels related to worse executive functioning (BMP6: β=0.27, p=.03; BMP4: β=‐0.28, p=.02) and higher GDS scores (BMP6: β=‐0.33, p=.02; BMP4: β=0.34, p=.01). Higher BMP10 also related to lower GDS scores (β=‐0.31, p=.02). No associations were observed between BMPs and memory z‐scores (ps>0.05).

Conclusion

In a cohort of CU older adults, OA related to differential plasma abundance of BMPs. In turn, circulating BMP levels, specifically BMP4, BMP6, and BMP10, were associated with executive function and depressive symptoms. These data help provide a molecular link connecting skeletal disorders of aging (e.g., OA) to adverse neurobehavioral outcomes. Given the diverse immunovascular, metabolic, and growth regulatory functions of BMPs, additional mechanistic work is needed to identify the precise pathways by which systemic BMPs interact with the central nervous system.
The long term effect of a multidimensional comprehensive cognitive intervention training program in cognitive impairments: a longitudinal study in China
Authors: Yang Feng , Li Yatian , Zhou Zhixing , Wang Ruihan , Cai Hanlin , Xia Huanhuan , Chen Qin
Published: January 2025

Background

Older adults with cognitive impairments will benefit from multicomponent interventions include cognitive training, exercise, and lifestyle modifications. Many digital therapeutic products predominantly focus on computerized cognitive training, lacking effective approaches to other crucial interventions. This study aimed to investigate the long term effects of multidimensional comprehensive cognitive intervention training program – Brain and Body Rehab Training (BBRT), which integrates multidomain cognitive training with physical‐cognitive training and multidimensional lifestyle interventions on cognitive performance in participants with cognitive impairment after a 8‐month follow‐up.

Method

All participants (n = 351) were allocated into the cognitive unimpaired (CU) group and cognitive impaired (CI) group. Participants were evaluated by cognitive and performance test batteries before, 4 months and 8 months after the interventions. In both groups, an individualized training program is assigned consisting of completing four to five daily tasks, including cognitive training, physical‐cognitive training, lifestyle interventions, chronic disease/diet/sleep/emotion management, and traditional Chinese medicine non‐pharmacological interventions among others. The intervention duration ranges 15‐25 minutes per day, and task difficulty is dynamically adjusted based on individual task performance and periodic cognitive assessments. Participants were asked to take the intervention 3‐4 times per week for 8 months. The statistic analysis were using mixed‐effect regression model.

Results

After the 4 months intervention, a significant improvement on the cognitive performance was observed in the CI group compared to the CU group (p<0.001), and the improvement persistent after 8 month follow‐up (p<0.001). The change of cognitive performance were associated with frequency of training repetition and whole time of the intervention.

Conclusions

The BBRT program significantly improved the cognitive function in cognitively impaired participants after 4 months training and had a persistent effect after 8 months. The convenient home‐based multidimensional interventions provides an long term effects for the cognitive impaired participants.
Data‐driven progression patterns of Aβ, tau, α‐synuclein and vascular pathology in a clinical population
Authors: Mastenbroek Sophie E. , Collij Lyduine E. , Vogel Jacob W. , Young Alexandra L. , Strandberg Olof , Smith Ruben , Palmqvist Sebastian , Mattsson‐Carlgren Niklas , Barkhof Frederik , Ossenkoppele Rik , Hansson Oskar
Published: January 2025

Background

With the development of disease modifying therapies targeting specific pathologies, accurate in vivo biomarkers have become increasingly important for disease classification. Recently, tests for neuronal α‐synuclein (Lewy body) pathology have become available, complementing pre‐existing tests for Alzheimer’s disease (AD) pathology (Aβ and tau fluid and PET biomarkers) and vascular disease (MRI). Here, we aimed to identify and characterize data‐driven pathology‐based subtypes using these biomarkers.

Method

We included 1677 subjects from a prospective memory clinic cohort (BioFINDER‐2; age[mean±SD]=68.5±12.1; female=50.3%) ranging from cognitively unimpaired (CU) to dementia and including a variety of clinical diagnoses. We applied the data‐driven Event‐Based Subtype and Stage Inference (SuStaIn) model to dichotomized biomarkers of Aβ‐pathology (CSF‐Aβ), tau pathology (tau‐PET), neuronal α‐synuclein pathology (CSF‐α‐synuclein seeding aggregation assay) and vascular burden (MRI white matter lesions) to determine whether different biomarker sequences emerge within a clinical cohort based on the presence of different brain pathologies. Further, regional atrophy patterns (MRI) were included in the models.

Results

Four disease‐trajectories best explained the data; 998 subjects with a confident assignment (mean probability=70%) were classified as “AD” (44.0%), “Mixed AD and Vascular” (15.9%), “Vascular” (22.9%), or “α‐synuclein” (17.2%) based on early‐stage pathology (Figure 1). 579 subjects were not classified and grouped as “No subtype” (mainly biomarker‐negative). The “Vascular” trajectory demonstrated early‐stage central and global atrophy, while “α‐synuclein” exhibited atrophy in late stages (Figure 1). Subjects in “Vascular” had higher levels of vascular risk factors and were more often APOE‐ε2 carriers. Subjects in “Vascular” and “α‐synuclein” were older and more frequently male, while those in “AD” and “Mixed” more frequently had a dementia diagnosis and APOE‐ε4 carriership (Table 1). Compared to unclassifiable subjects, “AD”, “Mixed”, and “α‐synuclein” showed faster widespread longitudinal Aβ accumulation and “AD” and “Mixed” demonstrated faster widespread longitudinal tau accumulation. “AD” and “Mixed” declined faster in global cognition over time compared to “Vascular” and “α‐synuclein” and “Mixed” and “α‐synuclein” in attention compared to “Vascular” (Figure 2).

Conclusion

In a heterogenous clinical population, we identified four common pathology‐based disease trajectories resembling established clinico‐pathological relationships. Future analyses will compare disease‐patterns on longitudinal biomarkers. Disease classification might contribute to personalized medicine approaches in trial and clinical settings.
Blood‐based biomarkers of systemic inflammation, metabolic function, and vascular injury are elevated in patients with rapid progressive neurodegenerative disease
Authors: Kuchenbecker Lindsey A , Tipton Philip W , Brier Matthew R , Satyadev Nihal , Piura Yoav D , Dunham S Richard , O'Bryant Sid E. , Graff‐Radford Neill R , Day Gregory S
Published: January 2025

Background

Patients with rapid progressive Alzheimer disease and related dementias (rpAD/ADRD) develop dementia within 1 year or incapacitation within 2 years of symptom onset. We previously showed that selected CSF biomarkers of neuronal injury (NfL, VILIP‐1), AD neuropathology (p‐tau181), and neuroinflammation (GFAP, MCP‐1, sTREM2) measured at presentation associated with etiologic diagnoses and reliably differentiated patients with treatment‐responsive causes of rapid progressive dementia. However, no differences were identified between CSF biomarkers in patients with rapid and typical progressive forms of AD/ADRD, leaving key questions unanswered concerning the mechanisms that drive rpAD/ADRD. Blood‐based biomarkers may inform the systemic factors that contribute to rpAD/ADRD, including the systemic inflammation, metabolic function, and vascular injury.

Methods

Biomarkers of systemic inflammation (Eotaxin‐3, IFN‐γ, IL‐1b, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, IL‐12p70, IL‐13, TARC, TNF‐α), metabolic function (A2M, B2M, FABP‐3, FVII, I‐309, IL‐18, PPY, TNC, TPO), and vascular injury (CRP, SAA, sICAM‐1, sVCAM‐1) were measured in plasma obtained at presentation from patients with rpAD/ADRD (n=29) and age‐ and sex‐ similar participants with typical progressive AD/ADRD (n=39) enrolled in prospective studies of memory and aging at Mayo Clinic in Florida. Biomarker measures were completed at the University of North Texas Institute for Translational Research using Meso Scale Discovery multiplexed assays. Biomarker concentrations were compared between groups using univariate analyses; potential predictors (p<0.05) were further evaluated via step‐wise multivariate logistic regression.

Results

Markers of vascular injury (SAA, CRP, sICAM‐1), metabolic function (I‐309, TPO), and systemic inflammation (Eotaxin‐3, TARC, TNF‐α) were increased in patients with rapid versus typical progressive AD/ADRD (p<0.05). Eotaxin‐3, I‐309, and SAA were independently associated with rpAD/ADRD in multivariable model after controlling for age and sex. The overall model correctly characterized 86.8% of patients, with an area under the curve of 0.864 (95%CI: 0.777‐0.950; p<0.001).

Conclusion

Blood‐based biomarkers of systemic inflammation, metabolic function, and vascular injury were elevated at presentation in patients with rapid vs typical AD/ADRD. These findings may provide additional insights into the mechanisms that drive rpAD/ADRD. Longitudinal measures from larger cohorts are needed to decipher the relationship between candidate biomarkers and rpAD/ADRD.
Navigating the Challenges of Community Supports Services: A Focus Group for Black Family Caregivers
Authors: Johnson Florence U
Published: January 2025

This qualitative study highlights the challenges faced by Black family caregivers who provide personal care to dementia patients without remuneration or training. Caring for a person with dementia can be stressful and negatively impact the caregiver’s health. Black family caregivers are particularly vulnerable to stress‐related mental health issues. Community support services (CSS) such as support groups, help‐seeking, respite, and dementia training can help address these issues. CSS can also help delay or avoid institutionalization and keep the person living with dementia and their community‐dwelling caregivers safe in their homes.

The study used the RaDAR method to analyze and develop themes from the focus group interviews of six participants. The focus group participants validated the hypothesis that Black caregivers are less likely to use CSS, particularly respite and support groups. Financial constraints and lack of free time were reported as the main barriers to support groups and respite use.

The study concludes that CSS can help address the mental health issues of Black family caregivers. However, financial constraints and lack of free time are significant barriers to CSS use. The study recommends that CSS providers consider offering flexible and affordable services that cater to the needs of Black family caregivers. The study also recommends that policymakers consider providing financial support to CSS providers to enable them to offer affordable services to Black family caregivers.
I struggle watching her diminish: Caregivers experiences of caring for loved ones with Alzheimer’s
Authors: Kamau Lucy Wambui , Bosire Edna N , Blackmon Karen , Udeh‐Momoh Chi , Nesic‐Taylor Olivera , Sokhi Dilraj , Mbugua Sylvia , Narayan Vaibhav , Merali Zul
Published: January 2025

Background

Alzheimer’s disease is a neurodegenerative disease that affects patients’ ability to perform activities of daily living thus requiring assistance from their loved ones. The progressive nature of the disease unravels new and continuous challenges for the caregivers posing a huge burden on caregiving. However, there is little research in Sub‐ Saharan African countries including Kenya, on caregiver’s experiences managing patients with Alzheimer’s disease. We conducted an ethnographic study at the Aga Khan University Hospital (AKUH) to understand caregivers’ experiences and practices caring for patients with Alzheimer’s disease.

Methods

We purposively recruited 30 caregivers who have been managing patients with Alzheimer’s disease from the Neurology clinic at AKUH. We conducted semi‐structured in‐ depth interviews in English or Swahili, which lasted for about 60 minutes to completion. Interviews were audio‐recorded, transcribed, and analyzed thematically with the aid of Nvivo‐12 software.

Results

Key themes identified from data included: (a) Caregiver knowledge and skills in managing patients (b) Caregiving burden (emotional, psychological, physical, financial) (c) dealing with patient’s changing personality, moods, and loss of self‐identity (d) fulfilment and privilege taking care of loved ones (e) navigating through self‐chores and caregiving roles. Overall, most caregivers lacked knowledge and skills for managing patients with Alzheimer’s. Given the limited resources, awareness and support of Alzheimer’s in Kenya, we found that caregivers carried the burden of taking care of their loved ones with some reporting mental health issues related to caregiving burden. In addition, lack of skills and training on how to manage patients’ changing personalities and patients’ loss of identity left many caregivers frustrated and worn out. Despite the challenges, caregivers had a sense of fulfilment taking care of their loved ones.

Conclusion

Caregivers of Alzheimer’s disease in Kenya require support from healthcare providers and other stakeholders in terms of trainings and capacity building skills to enable them to provide optimal care for the patients. They also require psychosocial support to maintain a healthy balance between their daily life activities and those of caregiving.
The impact of caregiver tele‐health support and education intervention on the relationship between caregiver grief and quality‐of‐life
Authors: Gothard Sarah , Mooney Aimee , Tupper Emily , Lindauer Allison
Published: January 2025

Background

Current research around caregiving for person’s with dementia (PWD) has historically emphasized caregiver burden. This leaves a gap of knowledge around other contributors to caregiving’s long‐term effects, including grief. The current analysis explores the relationship between caregiver grief and quality‐of‐life.

Method

The Tele‐STELLA study is a multi‐component, telehealth‐based intervention that teaches caregivers strategies to manage upsetting behaviors related to dementia in 8 weekly, 1‐hour sessions with professionals. The caregivers in this analysis (n = 138) cared for a family member with moderate to late‐stage dementia. A multilinear analysis was used to explore the relationship between grief and quality‐of‐life for 138 caregivers of PWD. Caregivers were women (73.2%) and white (87.0%), with 82.6% reporting financial security. On average, caregivers were engaged in their roles for 4.64 years (SD 3.69); 87.0% of the PWDs were in the moderate stage of dementia. Pre and post questionnaires queried caregivers about frequency of problematic behaviors and their reactions to the behaviors, grief, and household quality‐of‐life.

Result

Of the 138 caregivers who started the 8‐week intervention, 98 (71%) completed both pre/post self‐reported data. Scatterplot visualization demonstrated a linear negative relationship between grief/quality‐of‐life at both pre and post intervention timepoints. Controlling for sex and care recipient dementia severity, a multilinear regression was performed and showed, at alpha 0.05, a significant negative relationship between quality‐of‐life and grief (p‐value: 0.00, B1: ‐0.17) at the pre‐intervention timepoint. Post‐intervention analysis of the same model showed the magnitude of the B1 coefficient of grief changed to ‐0.22 and an increased significance (p‐value: 0.00).

Conclusion

This analysis found that grief in dementia caregiving had a strong negative relationship with quality‐of‐life and that this relationship became stronger after intervention. This may be due to caregivers’ increased awareness of grief, or to the progressive nature of dementia over the 8‐week intervention period, but still highlights grief’s impact on caregiver quality‐of‐life. Future longitudinal studies will be necessary to evaluate if grief can serve as a predictor of quality‐of‐life and long‐term health outcomes for caregivers, and how best to leverage that knowledge for interventions in this population.
Management of Cognitive and Autonomic Symptoms in LBD
Authors: Scharre Douglas W.
Published: January 2025

Support for the management of cognitive and autonomic features of Lewy body dementia (LBD) is offered in detail in this presentation. The US Based Diamond Lewy Cognitive Symptoms management document presents the unique cognitive profile of LBD with general principles for addressing these features along with detailed guidance in the use of cholinesterase inhibitors and Memantine. The US Based Diamond Lewy Autonomic Symptoms management document addresses the management of common autonomic symptoms including urinary dysfunction, male sexual dysfunction, excessive sweating, constipation, sialorrhea, gastroparesis and orthostatic hypotension in LBD.
Plasma p217+tau accurately discriminates Intermediate or Advanced Alzheimer's Disease biological PET stages
Authors: Feizpour Azadeh , Dore Vincent , Krishnadas Natasha , Bourgeat Pierrick , Doecke James D. , Saad Ziad S. , Triana‐Baltzer Gallen , Laws Simon M. , Shishegar Rosita , Huang Kun , Fowler Christopher J , Ward Larry , Masters Colin L , Fripp Jurgen , Kolb Hartmuth C. , Villemagne Victor L , Rowe Christopher C.
Published: January 2025

Background

Plasma phospho‐tau biomarkers, such as p217+tau, excel at identifying Alzheimer’s Disease (AD) neuropathology. However, questions remain regarding their capacity to inform AD biological PET stages at group level and maintain the same precision at individual patient level.

Method

Participants included 248 cognitively unimpaired (CU) and 227 cognitively impaired (CI) individuals, with Janssen plasma p217+tau Simoa® assay, 18F‐NAV4694 Aβ PET (A) and 18F‐MK6240 tau PET (T) data. Biological PET stages were defined based on the draft NIA‐AA Revised Criteria (July 2023): Initial (A+T‐), Early (A+TMTL+), Intermediate (A+TMOD+), and Advanced (A+THIGH+). We used thresholds for A+ of 25 Centiloid and for THIGH of 80 Centaur (2.68 SUVRtemporo‐parietal). Adding an A‐T‐ stage for comparison, we assessed the performance of p217+tau in discriminating between these stages at the group level using Receiver Operating Characteristic (ROC) analysis and at the individual level using logistic regression.

Result

Plasma p217+tau concentrations increased across the stages, with significant differences between them, except for the Initial and Early stages. Screening for Advanced (vs. lower stages), combined Intermediate/Advanced (vs. lower stages), or all stages (vs. A‐T‐), p217+tau showed good group‐level discriminations (AUC 0.91, 0.92 and 0.92; CI only: AUC 0.83, 0.89, 0.93, respectively). At the individual level, the likelihood of PET stage vs. p217+tau level showed good discrimination of A‐T‐ vs any A+ stage and of combined Intermediate/Advanced disease stage vs lower stages in the CI.

Conclusion

In addition to accurately screening for A+ individuals, plasma p217+tau shows promise for separating persons with either Intermediate or Advanced stage AD from those at a lower stage, providing prognostic information and informing better selection for trials and disease modifying therapies.