bluuebunny/crossref_metadata_2025 huggingface dataset:
Discovery and preclinical development of [18F]ACI‐19626, a first‐in‐class TDP‐43 PET tracer
Authors: Seredenina Tamara
Published: January 2025

Background

Aggregated TDP‐43 is found as the main component of pathological inclusions in amyotrophic lateral sclerosis (ALS), limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), in 50% of patients with frontotemporal dementia (FTD), and is present as co‐pathology in other neurodegenerative diseases, including Alzheimer’s disease (AD). Biofluid or imaging biomarkers of TDP‐43 pathology are currently unavailable. Direct detection of TDP‐43 aggregates holds promise for unraveling the pathobiology of disease and for enabling precision medicine approach via improved diagnosis, patient stratification and assessment of therapeutic efficacy in clinical trials in AD and related diseases.

Methods

Using our Morphomer® small molecule library of brain‐penetrant and beta sheet binding compounds, initial hits were identified using patients’ brain material. Radiobinding and autoradiography assays were used to assess binding affinity and target engagement on brain samples from cases with TDP‐43 proteinopathies, and selectivity over other aggregation‐prone proteins on AD and Parkinson’s disease (PD) tissue. The pharmacokinetics in the brain was studied in mice, followed by evaluation in cynomolgus monkeys to assess brain uptake, distribution and washout for selected 18F‐radiolabeled compounds.

Results

Screening of >500 compounds led to identification of several distinct chemical series that bound pathological TDP‐43 derived from FTLD‐TDP brain samples with nanomolar affinity. Rational drug design and medicinal chemistry optimization enabled the discovery of the TDP‐43 tracer, ACI‐19626. This compound has high affinity binding (low nM Kd) for human brain‐derived aggregated TDP‐43 and can differentiate FTLD‐TDP type A and B patient samples from age‐matched controls. ACI‐19626 displays selectivity for TDP‐43 over Abeta, Tau and alpha‐synuclein aggregates, and no binding to common off‐target proteins, including monoamine oxidase A and B. In monkeys, [18F]ACI‐19626 has a rapid brain uptake and fast and complete washout, a profile suitable for brain PET imaging.

Conclusions

[18F]ACI‐19626 was identified as a potential first‐in‐class TDP‐43 PET tracer and selected for evaluation in a First‐in‐Human study based on its excellent affinity, selectivity and pharmacokinetic properties. [18F]ACI‐19626 has the potential to detect and monitor the progression of TDP‐43 pathology in brains of living patients with TDP‐43 proteinopathies such as ALS, FTLD‐TDP, AD and LATE, enabling precision medicine approach and combination therapies.
Limbic predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is associated with lower volume in gray and white matter of the temporal and frontal lobes and basal ganglia: A deformation‐based brain morphometry study
Authors: Tazwar Mahir , Evia Arnold M , Ridwan Abdur Raquib , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos
Published: January 2025

Background

Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is common in older adults and has been associated with substantial cognitive impairment. However, the association of LATE‐NC with brain morphometry has not been thoroughly investigated. In this work, we examined the association of LATE‐NC with brain morphometric anomalies using deformation‐based morphometry (DBM) in a large community cohort of older adults that came to autopsy (N=897).

Method

Cerebral hemispheres were acquired from 897 deceased older adults participating in Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Clinical Core. Hemispheres were imaged ex‐vivo on 3T MRI scanners, which was followed by detailed neuropathologic examination. The participant scans were non‐linearly registered to an ex‐vivo template, and the resulting deformation fields were used to calculate the logarithm of the Jacobian determinant in each voxel (LogJ maps).

Voxel‐wise linear regression was used to test the association between deformations shown in the LogJ maps and LATE‐NC stages, controlling for other age‐related neuropathologies (Alzheimer’s disease, Lewy bodies, arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, gross and microscopic infarcts), age at death, sex, education, postmortem intervals, and scanners. To identify the earliest LATE‐NC stage exhibiting morphometric abnormalities, LogJ values were compared between LATE‐NC stages 1–5 and stage 0. Statistical significance was set at p<0.05.

Result

Voxel‐wise analysis revealed an independent association of LATE‐NC with significantly lower volume in both gray and white matter regions within the temporal and frontal lobes and basal ganglia (p<0.05), including amygdala, hippocampus, entorhinal, parahippocampal, temporal pole, inferior temporal, middle temporal, fusiform, medial orbitofrontal, lateral orbitofrontal, insula, accumbens, and putamen cortices. Groupwise comparison of LogJ values revealed significant morphometric anomalies in small temporal lobe areas in stages 1–2, more temporal lobe as well as basal ganglia tissue in stage 3, and finally also included frontal lobe areas in stages 4–5.

Conclusion

The morphometric anomalies were detected as early as LATE‐NC stage 1, suggesting that MRI is sensitive to the early stages of the disease. This pattern is consistent with the known pathological distribution of LATE‐NC in the brain and may potentially be used in the development of a marker of this devastating neuropathology.
Understanding Family Caregiver Experience and Satisfaction with Nursing Home Care: A Conceptual Model
Authors: Piersol Catherine V , Martinez Jenny , Chew Felicia M , Leland Natalie E
Published: January 2025

Background

Family caregivers are challenged to manage the progressive cognitive decline and behavioral symptoms of Alzheimer’s disease and related dementias, which often trigger nursing home placement. Research has addressed the effect of nursing home placement on family caregivers; however, their perceptions about care are less understood. We sought to examine the experiences of family caregivers with the objective of developing a conceptual model to explain the complex nature of family caregiver experience.

Methods

We will describe our qualitative study that utilized the grounded theory method. Purposive sampling was used to recruit family caregivers from a sample of 23 nursing homes in the United States enrolled in a larger pragmatic trial. Caregivers participated in one‐on‐one, in‐depth interviews with trained research assistants. An iterative, three‐step data coding process was employed to analyze the interview transcripts.

Results

Study participants (N = 30) were primarily female (90%), White (86.6%), and ranged from age 29 to 84. This presentation will characterize seven emerging themes that interrelate to create a conceptual model. One theme, “Family caregiver satisfaction with care” emerged as the core concept, with the other six themes serving as contributing intrinsic and extrinsic factors that interrelate and impact family caregiver perception of satisfaction. The contributing factors are (1) family caregiver interactions with nursing home staff, (2) staff management of resident behavioral symptoms; (3) nursing home context; (4) family caregiver knowledge of dementias; (5) family caregiver strain; and (6) the resident experience. Family caregivers experience each contributor simultaneously and in differing patterns, depending on the care situation. We will display our conceptual model and discuss how the interactions between contributing factors affect family caregiver satisfaction across a dynamic continuum from low to high satisfaction.

Conclusion

Our conceptual model offers a mechanism for understanding the factors important to family caregivers of nursing home residents with dementia, prompting their action and reaction to care situations and staff interactions. The model reflects the importance caregivers place on staff knowledge about dementia and their use of appropriate care approaches. Understanding how satisfaction with care is perceived by family caregivers may encourage collaboration between families and staff.
Digital Interventions in Neuro‐Rehabilitation: Gotcha! app‐based therapy for proper name anomia in people with dementia
Authors: Badalova Aygun
Published: January 2025

Background

Proper name anomia is a common experience that can become amplified in patients with a diagnosis of dementia (PWD). The Gotcha! app aims to provide practice‐based therapy for PWD to relearn the names of key people in their lives. It has been developed using the principles of errorless learning and spaced retrieval, which have previously been shown to improve the remembering the familiar people’s names and benefit the relationship between the PWD and their loved ones. (Clare et al, 1999, 2000, 2003).

Methods

Gotcha! is a digital confrontation naming therapy app which enables patients to train one face per day by using photos of the person whose name is to be trained. We employed a single‐case experimental design with weekly testing of free‐naming in both six‐week blocks (pre therapy and therapy). During the therapy, a novel speech verifier is used to provide real‐time feedback (Barbera et al. 2020). Two analyses method is used to investigate the behavioural data: 1) within‐subject non‐parametric analysis using Tau‐U metric (Parker et al. 2011); 2) a parametric group analysis using an ANOVA.

Results

The trial is ongoing. Results from the first 20 subjects show:

1) Tau‐U. 80% showed a positive trend with better naming during the training phase with 8/20 reaching statistical significance.

2) ANOVA demonstrated a significant effect at the group level of training>baseline phase, F (1,19) = 13.18, p = 0.01

Conclusion

App‐based proper name anomia retraining works for the majority of PWD in our trial thus far. Being able to freely recall and produce the name of a relative or loved one has a big impact on people’s lives.
Effects of technology‐based cognitive and exercise interventions on cognitive function in persons with mild cognitive impairment: A systematic review, network meta‐analysis, and meta regression
Authors: Ye Yifan , Zhang Lifeng
Published: January 2025

Background

Technology has been increasingly integrated into controlling the decline of cognitive function for persons with mild cognitive impairment (MCI). It is unclear whether technology‐based cognitive and exercise interventions could generate synergistic benefits and what components would optimize this effect.

Methods

In this study, we searched MEDLINE, Web of Science, Scopus, Embase and APA PsycInfo from inception to Nov 4, 2023. We included randomized controlled trails that evaluated the effects of technology‐based cognitive and exercise interventions on cognitive function for persons with MCI. Our primary outcome was global cognition. Outcomes were summarized in narrative synthesis and combined using meta‐analysis. Pairwise meta‐analysis and network meta‐analysis were sequentially performed to identify the effects of each category of interventions and their comparative intervention effectiveness, respectively. Meta‐regression was performed to examine any influence of study design and participants’ characteristics on the intervention effectiveness. This systematic review protocol was registered in PROSPERO (CRD 42023486359).

Findings

A total of 28 studies with 1633 participants were included. The results of pairwise meta‐analyses indicated that technology‐based cognitive and exercise interventions were superior to active/passive controls in global cognition, cognitive shifting, proceeding speed, working memory, delayed recall, and category fluency (p<0.05). The results of network meta‐analyses indicated that the optimal components were cognitive stimulation combined with mind‐body exercise in improving global cognition (SUCRA: 77.0%, SMD 0.85, 95%CI ‐0.17 to 1.87) and cognitive shifting (SUCRA: 92.4%, SMD 1.57, 95%CI 0.88 to 2.25), while cognitive training combined with mind‐body exercise were the most beneficial in developing proceeding speed (SUCRA: 88.5%, SMD 0.68, 95%CI 0.14 to 1.22). Meta‐regression further suggested that the effects of the tested interventions were independent of the various factors relating to study design and participants’ characteristics.

Interpretation

Technology‐based cognitive and exercise interventions can be effective in improving global cognition and core subdomains of cognition in persons with MCI. This review highlights the more superior effects of technology‐based cognitive stimulation combined with mind‐body exercise in improving global cognition.
Dual Perspectives
Authors: Ard Tyler , Pappas Ioannis
Published: January 2025

“Dual Perspectives” integrates multiple MRI scans, creating a nuanced synthesis of grey matter and diffusion‐based regional connections. This rendering holds particular significance in the realm of Alzheimer’s and dementia research by offering a comprehensive examination of data crucial for understanding these complex neurodegenerative conditions.

The inclusion of grey matter provides a detailed insight into the structural composition of the brain. Grey matter, comprised of neuronal cell bodies and dendrites, is fundamental to cognitive functions. High‐resolution grey matter imaging allows researchers to discern intricate structural alterations, contributing critical information about the anatomical changes associated with Alzheimer’s and dementia.

Simultaneously, the image delves into the realm of diffusion‐based regional connections, derived from the movement of water molecules within the brain’s white matter pathways. Given the pivotal role these pathways play in transmitting signals between different brain regions, understanding diffusion‐based connections becomes essential in unraveling the intricacies of Alzheimer’s and dementia.

The split harmonization of grey matter and diffusion‐based perspectives within this work offer a holistic view into the structural mediums of these neurodegenerative disorders. Overall, “Dual Perspectives” presents a lens into the intricacies of the brain, creating an artistic representation of neuroimaging‐derived data that is indispensable for advancing research in the field.
Bridging Academia and Community to Educate and Support Care Partners of People Living with Dementia
Authors: Webster Claire , Gauthier Serge , Rosa‐Neto Pedro , Morais José A
Published: January 2025

Background

Universities can play a very important role in providing post‐diagnosis dementia education and support to the community. The McGill University Dementia Education Program was founded in 2017 by Claire Webster, a former care partner and dementia care consultant with this aim. Mrs. Webster had no affiliation with the university prior to beginning the program other than being an annual guest lecturer on the topic of caregiving and dementia. Frustrated by the healthcare system, Mrs. Webster approached the university with an idea to introduce an innovative program centered on patient/care partner education using a multi‐disciplinary approach.

Methods

The program offers a comprehensive range of free resources and cutting‐edge teaching and learning techniques, including simulation to educate and support persons living with dementia, family and informal care partners, healthcare professionals, medical students and the public at large; a dementia companion guide available in 10 different languages with many more currently in translation; over 100 educational webinars and podcasts known as “McGill Cares”; virtual support groups for care partners; 14 bilingual video capsules demonstrating leisure and recreational activities and an online education program currently under development for care partners.

McGill University has fully embraced the “person/patient centered care approach” into its medical curriculum by making in mandatory for all first‐year medical students to attend Claire Webster’s lecture on “Navigating the Journey of Caring for a Person Living with Dementia”.

Results

Within only 5 years of its inception, the McGill University Dementia Education Program has received international recognition. The Academic and Medical Directors of the program (authors of this abstract) were selected by Alzheimer’s Disease International to write the 2021 and 2022 World Alzheimer’s Reports on the inter‐related topics of diagnosis and post‐diagnosis management. In 2023, Claire Webster was appointed to the Government of Canada’s Ministerial Advisory Board on Dementia.

Conclusion

Universities can play a critical support role, bridging academia and community to provide service to society. They can institute community outreach programs that leverage the wealth of expertise within their institution, and they can integrate caregiver awareness and education into their medical school curriculum.
Young‐Onset Dementia and Career Development ♥ An Artsract
Authors: Allen Rachel Louise
Published: January 2025

My PhD research is about Young‐Onset Dementia and Career Development, focusing on women’s experiences.

This artwork or abstract (‘artstract’) represents how the research has developed to date. Understanding of career is informed by Super’s (1980) Life‐Span, Life‐Space approach to career development, which can be understood flexibly to incorporate diverse experiences (including those of women and those living with a dementia diagnosis during working age).

The sunshine, represented here as a ball of yarn (because yarn can be useful but can also unravel), represents the life stages of the approach, with the rainbow stripes below reflecting the Life Rainbow (Super, 1980). The woman’s face in silhouette (so the whole self cannot be seen) is decorated with painted flowers, building to a 3D representation around the brain and senses. This reflects the new beginnings and opportunities that can arise when living with dementia. However, several layers of paint, fabric and magazine collage are not visible because dementia can erode memories and abilities that the person can no longer utilise.

The ’mess’ of collage and materials mixed with the simpler pencil lines represents the complexity of career. Whereas once this could be considered perhaps as linear, relating only to paid work and progression, this research conceptualises career more as life and work. When a woman is diagnosed with young‐onset dementia, this could impact several life stages and multiple roles in her life. She may be employed or retired, a carer for children, grandchildren or aging parents, and active in her community. Dementia is a condition with stigma, and this artstract challenges stereotypical assumptions and representations of dementia as something that only affects older people, or that those living with dementia do not have a career or that career cannot continue whilst living with a diagnosis. The bright colours were chosen to reflect the Life Rainbow (Super, 1980) and emphasise the experience of hope whilst living with a diagnosis.

Super, Donald (1980) A Life‐Span, Life‐Space Approach to Career Development, Journal of Vocational Development 1980 Vol. 16 Pages 282‐298
Assessing the Influence of Modifiable and Non‐modifiable risk factors on Cognitive and Biomarker Trajectories in Preclinical Alzheimer's Disease: Establishing a Longitudinal Model for Brain Health
Authors: Maffei Luciana
Published: January 2025

Background

The pathogenesis of Alzheimer’s disease (AD) begins 15‐20 years before the onset of clinical symptoms, often referred to as the preclinical stage of AD. It is crucial to understand why some individuals develop AD and although biological, psychological, and social factors have been established, their influence in the very early stages of disease trajectories is somewhat unclear. Longitudinal studies are key to understanding how and when these risk factors determine brain health as well as the risk for developing AD later in life.

Method

This study will extract data from multiple DPUK and non‐DPUK longitudinal datasets containing lifestyle, psychological, environmental, social, and biological data from individuals as young as 18. The study will assess the relationship between a diverse range of biopsychosocial risk factors in the preclinical stage of AD and conduct machine learning statistical analyses to determine which and when these factors interact with biomarker activity contribute to disease risk.

Results

Results are expected to demonstrate a significant interaction between biopsychosocial risk factors and longitudinal biomarker activity in participants <55. Results are also expected to identify the age of biomarker change along with key predictors of initial disease trajectory.

Conclusion

Results from these longitudinal datasets may help with more accurate and earlier prediction tools across various populations and provide rationale to incorporate less understood psychosocial factors into these tools. The analysis will also inform the significance of modifiable factors so individuals can undertake their own preventative methods to reduce AD risk. The study may also have important implications for clinical trial design and promote healthy ageing.
Blood DNA methylation biomarkers for cognitive decline in older adults with type 2 diabetes
Authors: Manzali Sigalit , Ravona‐Springer Ramit , Jacob‐Hirsch Jasmine , Heymann Anthony , Beeri Michal S , Greenbaum Lior
Published: January 2025

Background

Type 2 diabetes (T2D) is a recognized risk factor for dementia. This study aimed to pinpoint blood DNA methylation biomarkers for cognitive decline in older adults with T2D by comparing those who developed dementia with those who remained cognitively normal during follow‐up

Method

Illumina Infinium MethylationEPIC microarray was used for the initial 24 couples and Infinium HumanMethylationEPIC microarray version 2.0 for the subsequent 8 couples. Beta and p‐values were calculated using Partek genomic suite and SeSAMe for the respective microarray versions. Human CpG annotation manifests for both versions were utilized, and quantile normalization (Partek genomic suite) facilitated comparisons across different arrays. Functional analysis employed Ingenuity IPA.

Result

The analysis covered 128 samples (32 converters and 32 matched non‐converters) at baseline and a 36‐month follow‐up. Methylation levels significantly differed between converters and non‐converters, with 950 sites altered in converters versus 25 in non‐converters (FDR corrected p value ≤0.05) during follow‐up. To identify potential biomarkers, methylation changes unique to baseline were examined. Of the 249,490 shared methylation sites, 526 were differentially methylated between converters and non‐converters at baseline (p‐value ≤0.05, fold change ≥1.5). Notably, 293 sites were altered solely at baseline, while 233 showed differential methylation at both baseline and 36‐months follow‐up. Among the 169 genes related to the 293 sites altered only at baseline, Ingenuity IPA analysis identified 29 genes linked to neurodegeneration and cognitive impairment (17%) and 38 genes associated with inflammation (22%). Another set of interest included 137 genes related to the 233 sites differentiating converters from non‐converters at both time points, with some genes implicated in neurotransmitter secretion and regulation of neuron differentiation.

Conclusion

These initial findings indicate significant blood methylation changes early in cognitive decline among older adults with T2D. These alterations, if validated in additional cohorts, could serve as biomarkers for T2D‐related cognitive decline.
Plasma amyloid‐β40/42 ratio can distinguish co‐morbid Alzheimer’s disease pathology in patients with Lewy body disease
Authors: Shinohara Moeko , Murakami Hidetomo , Sakashita Yasuhiro , Mori Yukiko , Komatsu Junji , Muramatsu Daiki , Hikishima Sadao , Ono Kenjiro
Published: January 2025

Background

Although comorbidity with Alzheimer’s disease (AD) is not uncommon in Lewy body disease (LBD), no blood biomarkers which can identify AD pathology in LBD have ever been established.

Objectives

To investigate if plasma amyloid‐β (Aβ) biomarkers can distinguish AD comorbidity in LBD patients.

Methods

We examined plasma Aβ40, and Aβ42 in 15 patients with Aβ negative LBD, 10 with Aβ positive LBD, and 37 with AD. In addition, patients underwent amyloid‐positron emission tomography imaging (11C Pittsburgh compound‐B) or cerebrospinal fluid Aβ42 test.

Results

The plasma Aβ40/Aβ42 ratio was significantly decreased in patients with Aβ+ LBD compared with those with Aβ‐ LBD (p = 0.037) and could accurately classify the two diseases (area under the curve, 0.727).

Conclusions

Plasma Aβ40/Aβ42 ratio might be a useful marker for comorbid AD pathology in LBD.
RWD insights into the use, safety and effectiveness of novel treatments
Authors: Iwata Atsushi
Published: January 2025

In Japan, the regulatory authority approved the drug in September 2023, and on December 20, it became available for prescription country‐wide under the health insurance system. However, there are strict patient, physician, and facility requirements for the prescription of Lecanemab, and various problems are anticipated in its future implementation and widespread use in society.

Lecanemab is the first anti‐Aβ antibody in Japan, and even dementia specialists do not have sufficient knowledge and experience in its introduction, evaluation of efficacy, and evaluation and handling of side effects. In particular, it is important to establish a smooth flow of referrals from primary care physicians to specialized medical institutions and the sharing of correct awareness of the drug in order to expand the range of this drug’s use.

In addition, the Japanese government has instructed Eisai to conduct a post‐marketing surveillance of all patients in order to properly evaluate the efficacy and adverse effects of the drug. Therefore, various data will be obtained within this framework, but since some ADL scales and raw imaging data will not be collected, a registry is planned to be started by academia to supplement Eisai’s database. As a pilot study, we have established an electronic data collection system (EDC) and a mechanism for registering data to an imaging database, and named it REGI‐ALZ (Real‐world Evidence Generating Initiative for ALZheimer’s isease). In Japan, APOE genetic testing can only be done for research purposes because there is no approved in vitro diagnostic test for APOE. Therefore, RFEGI‐ALZ was designed to allow data collection for the purpose of measuring APOE. We hope that this system will serve as a reference for the registry of academia that will be established in the future.
SomaScan plasma proteomics of cSVD
Authors: Gomez Gabriela T. , Shi Liu , Fohner Alison E , Chen Jingsha , Yang Yunju , Fornage Myriam , Duggan Michael R , Peng Zhongsheng , Daya Gulzar , Tin Adrienne , Schlosser Pascal , Longstreth W.T. , Kalani Rizwan , Sharma Malveeka , Psaty Bruce M. , Nevado‐Holgado Alejo J , Buckley Noel , Gottesman Rebecca F. , Lutsey Pamela L. , Jack Clifford R. , Sullivan Kevin J , Mosley Thomas H. , Hughes Timothy M. , Coresh Josef , Walker Keenan A. , Coresh Josef
Published: January 2025

Background

Cerebral small vessel disease (cSVD), as defined by neuroimaging characteristics such as white matter hyperintensities (WMHs), cerebral microhemorrhages (CMHs), and lacunar infarcts, is highly prevalent and has been associated with dementia risk and other clinical sequelae. Although risk factors for cSVD have been identified, little is known about the biological processes and molecular mediators that influence cSVD development and progression.

Methods

Within the Atherosclerosis Risk in Communities (ARIC) study, we used SomaScan Multiplexed Proteomic technology to relate 4,877 plasma proteins to concurrently measured MRI‐defined cSVD characteristics, including WMHs, CMHs, and lacunar infarcts, in late‐life (n=1508; mean age: 76). Candidate protein associations with WMH volume were replicated in the Cardiovascular Health Study (n=765; mean age: 73) and Baltimore Longitudinal Study of Aging (n=902; mean age: 66). Cohort‐specific effect estimates were pooled using a fixed‐effect, inverse variance weighted meta‐analysis. Within 4228 non‐demented older adults in ARIC, we examined the association of WMH‐associated proteins with eight‐year dementia risk (641 incident dementia cases) using multivariate Cox proportional hazard models. All multivariate regression models were adjusted for demographic, kidney function, and cardiovascular risk variables.

Results

This proteome‐wide analysis of older adults identified 13 WMH‐associated plasma proteins involved in synaptic function, endothelial integrity, and angiogenesis (Figures 1a, 2a). Nine of these proteins replicated in one or more external cohort (Figures 1b, 2b) and two proteins, oligodendrocyte myelin glycoprotein (OMG) and neuronal pentraxin receptor (NPTXR), remained associated with late‐life WMH volume when measured nearly two decades earlier during midlife (Figures 1c, 2c). Eight of the 13 WMH‐associated proteins were associated with lacunar infarcts, 6 with subcortical CMHs, and 4 with lobar CMHs (Figures 1d, 2d). Although none of the genes coding for WMH‐associated proteins have been nominated by WMH GWAS, 7 of these genes have been previously linked to cardiometabolic traits known to influence cSVD, such as blood pressure and cholesterol (Figures 1e, 2e). Finally, 11 candidate proteins were associated with incident dementia, underscoring their clinical relevance (Figures 1f, 2f).

Conclusions

This large‐scale proteomic analysis within longitudinal community‐based samples identified several plasma proteins, including OMG and NPTXR, as top candidate biomarkers for elevated WMH volume and its clinical manifestations.
Differences in protein expression in Alzheimer’s disease patients based on risk factors for amyloid‐related imaging abnormalities
Authors: Oosthoek Marlies , Vermunt Lisa , Blujdea Elena Raluca , in 't Veld Sjors G.J.G. , van der Flier Wiesje M. , Barkhof Frederik , del Campo Marta , Avilés Martín Pucheu , Visser Allerdien , Schut Martijn C. , Vijverberg Everard G.B. , Teunissen Charlotte
Published: January 2025

Background

The exact mechanism underlying amyloid‐related imaging abnormalities (ARIA) is unknown. Several factors explain ARIA risk, including the presence of microbleeds, APOE4 carriership, and very low Aβ42 levels. The cerebrospinal fluid (CSF) proteome reflects ongoing mechanisms and, thereby, provides an accessible fluid to refine risk of ARIA development. In this explorative study, we aimed to determine how the CSF proteome relates to the ARIA risk profile and identify potential biomarkers for ARIA risk.

Method

We included AD dementia patients who were Aβ42/tTau ratio positive (n=156; median age: 67 IQR:60‐72, 38% F, median MMSE‐score: 19.8 IQR:17‐24). We dichotomized all risk factors: microbleeds were divided in 0 (M‐, n=123) or >0 (M+, n=33), APOE4 status was divided in carriers (APOE4+, n=96) and non‐carriers (APOE4‐, n=60), CSF Aβ42 levels were separated based on the median (Low and High). We also defined a high and low risk profile: patients with M+APOE4+AL (n=13) and M‐APOE4‐AH (n=23). CSF proteomics were performed using antibody‐based proteomics (Olink), and we selected 288 proteins previously shown to be related to AD (del Campo et al., 2022). With linear regression analysis (with age and sex corrections), we compared protein levels per risk group.

Result

We identified 20 proteins that were differentially expressed in M+ versus M‐, 7 proteins in APOE4+ versus APOE4‐, 3 proteins in Aβ42L versus Aβ42H, and 49 proteins in M+APOE4+AL to M‐APOE4‐AH. The top proteins include EGFR, CRTAC1, AXL, CNTN1, and TIMP4. Overall, almost all proteins were downregulated in the ARIA risk group and most proteins were not overlapping between risk groups.

Conclusion

These results show that there are differences based on the ARIA risk profile. The differentiating proteins could provide extra information on the ongoing biological processes that increase ARIA risk and in the future aid to refine ARIA risk. Potentially, these results could aid in the development of a new biomarker for ARIA risk. Future analysis focus on further understanding the proteins involved and validating the findings.
Use of Design Thinking to Develop Approaches to Collect and Use Person‐Centered Dementia Care Measures in Low‐Resource Long‐Term Care Settings
Authors: Corazzini Kirsten , Lepore Michael , Kusmaul Nancy , Wang Jing , Rataj Alison , Kim Yoon Chung , Murray Briana , Davie Laura , McConnell Eleanor S , Holmes Sarah D
Published: January 2025

Background

Low‐resource residential long‐term care (LTC) settings, including settings located in medically underserved and health professional shortage communities, have fewer environmental resources to support high‐quality, robust data collection and use of measures to support person‐centered dementia care (PCC). Further, such settings are more likely to serve older adults from populations that have experienced historic harms related to misuse of personal data, including low‐income and minoritized populations. Design thinking engages community‐members to understand a problem from the end‐user’s perspective (empathize and define), brainstorm new solutions (ideate), and develop proposed solutions (prototype and test). This study describes the development of user‐design workshops to co‐develop, with residents living with dementia (RLWD), their family members and care staff, a person‐centered measurement collection and data sharing infrastructure in low‐resource residential dementia care settings.

Methods

The overall approach is a multi‐method, community‐based, participatory research study with design thinking principles. Stakeholders in each of four low‐resource LTC settings provided in depth perspectives on collecting and sharing data about RLWD to support PCC. Results from qualitative thematic analysis informed the development of user‐design workshops to co‐design feasible and acceptable data collection and use protocols.

Results

Residents, relatives, and staff community members (N = 68 participants) were recruited from 4 low‐resource residential LTC settings (N = 2 rural, 2 urban settings). Journey maps were developed to capture community‐member perspectives by drawing upon themes in each of four key areas: identifying information for care; accessing information for care; sharing information for care; and prioritizing information for care. Journey maps provided the structure to develop co‐design workshop protocols to re‐engage community‐members to empathize, define, ideate, and prototype acceptable and feasible data collection and data sharing protocols of PCC measures.

Conclusion

Findings from this study capture multiple facilitators and barriers to robust data collection and use protocols in resource‐constrained LTC environments. However, findings also demonstrate the potential for user‐centered design approaches to generate novel solutions in ways that honor the perspectives of RLWD, their family members, and the staff who care for them. Ultimately, such approaches contribute to the growth of inclusive research infrastructure to grow capacity for high quality, person‐centered dementia care.
Classification of Patients with Dementia with Lewy Bodies by Event‐related Oscillations
Authors: Güntekin Bahar , Duygun Rümeysa , Bölükbaş Burcu , Kuloğlu Hikmet Buse , Yemeniciler İrem , Yirikogullari Harun , Helvacı‐Yılmaz Nesrin , Hanoğlu Lutfu
Published: January 2025

Background

In the EEG research of Alzheimer's Disease (AD) and other diseases belonging to dementia, the literature is rapidly growing to indicate biomarkers specific to the type of dementia. The literature showed firm conclusions that decreasing event‐related delta and theta responses could be a biomarker showing cognitive decline (Güntekin et al. 2022). However, event‐related EEG biomarkers of Lewy Body with dementia (DLB) were not studied well. The present study aims to differentiate the event‐related oscillations between DLB patients with healthy controls during cognitive paradigms.

Method

19 DLB patients and aged‐matched 20 healthy controls (HC) were included in the study. 32‐channel EEG was recorded during the visual oddball paradigm. Event‐related power spectrum and phase‐locking were analyzed for the delta (0,5‐3,5 Hz), theta (4‐7 Hz), alpha (8‐13 Hz), beta (15‐28 Hz), and gamma (28‐48 Hz) frequency bands. The statistical analyses were run with repeated measures of ANOVA.

Result

DLB patients had decreased event‐related delta and theta power and phase‐locking compared to HC (p<0.001; p<0.001). There is no differentiation in event‐related alpha, beta, and gamma power between DLB patients and HC controls. The phase locking factor could differentiate better between healthy controls and DLB patients in the higher frequency bands. Event‐related alpha (p=0.002), beta(p=0.001), and gamma (p=0.010) phase locking of DLB patients were decreased in DLB patients compared to HC.

Conclusion

The present study showed that, like other types of dementia, DLB patients had reduced delta and theta power and phase locking compared to HC. The event‐related phase locking factor in all frequency bands was more effective in differentiating DLB than HC and could be used a biomarker. Furthermore, the phase locking factor in delta, theta, alpha, beta, and gamma frequency bands could be used with machine learning approaches to classify HC and DLB.
The Impact of Diet on AD Biomarkers in a Community‐Based Sample
Authors: Okafor Amarachukwu , Vartak Ambika , Johnson Aubrey S. , Guzmán Diana S. , Smith Anna C. , Houlihan Hannah M. , Heuer Lauren B. , Rentería Miguel Arce , Turney Indira C. , Mayeux Richard , Brickman Adam M. , Manly Jennifer J. , Gu Yian , Lao Patrick J.
Published: January 2025

Background

Greater adherence to the Mediterranean Diet (MeDi) is associated with lower risk for cardiovascular disease, slower cognitive decline, and reduced risk for Alzheimer’s Disease (AD). However, its association with AD biomarkers is not well known. We hypothesized that greater MeDi adherence is associated with reduced amyloid and tau PET burden in a community‐based sample of older adults in Northern Manhattan.

Methods

Participants from the Washington Heights/Inwood Columbia Aging Project (WHICAP) completed the Willet Food Frequency questionnaire (FFQ) at study baseline. A subset completed one (n=161 participants; age=81±6 years, 20% Hispanic, 50% Black, 65% women, education=13±4 years) or two timepoints of amyloid PET (FBB, n=19; follow‐up time=6.4±1.9), as well as one timepoint of tau PET (MK‐6240, n=17). PET scans were 8.6±4.6 years after the FFQ. We evaluated the impact of MeDi adherence on subsequent baseline amyloid and tau burden, quantified as SUVR or positivity (SUVR>1.25 for amyloid or SUVR>1.81 for tau), as well as the annualized percent change in amyloid burden over time, accounting for age, sex, race and ethnicity, education, caloric intake, and time between the FFQ and PET scan.

Results

Fifty‐eight (36%) participants were amyloid positive and 7 (41%) were tau positive in early Braak regions at their first timepoint, and 2 (8%) individuals converted from amyloid negative to amyloid positive at their second timepoint. Greater MeDi adherence was not associated with amyloid burden (‐0.02 [‐0.04, 0.004], p=0.11) but was marginally associated with a lower likelihood of amyloid positivity (‐0.21 [‐0.44, 0.0009], p=0.055). Greater MeDi adherence was not associated with tau burden (0.003 [‐0.13, 0.13], p=0.97) or the likelihood of tau positivity (‐0.66 [‐1.9, 0.63], p=0.3). MeDi adherence was not associated with the change in amyloid burden over time (‐0.19 [‐1.5, 1.1], p=0.8).

Conclusion

Greater MeDi adherence was associated with a reduced likelihood of subsequent amyloid positivity, suggesting diet may play a role in amyloid‐related AD risk. Replication in larger studies is needed. Further attention should be placed on the individual components of the MeDi adherence score (e.g. fish, vegetables) and their differential consumption and effects across racial and ethnic groups.
Evaluating brain age using functional connectivity in autosomal dominant Alzheimer disease
Authors: Macharia Kiana Angela , Gordon Brian A. , Wisch Julie K. , Metcalf Nicholas V , Roman June , Benzinger Tammie L.S. , Cruchaga Carlos , Goate Alison M. , Hassenstab Jason J. , Ibanez Laura , Karch Celeste M. , Llibre‐Guerra Jorge J. , Morris John C. , Perrin Richard J. , Renton Alan E. , Supnet Charlene B , Xiong Chengjie ,   Dominantly Inherited Alzheimer Network (DIAN), Bateman Randall J. , McDade Eric , Ances Beau , Millar Peter R
Published: January 2025

Background

Brain‐predicted age estimates are used to quantify an individual's brain age compared to a normative trajectory. We have recently shown that brain age from structural MRI is elevated in autosomal dominant Alzheimer disease (ADAD), a unique sample that allows the study of AD progression independently of age‐related confounds. Resting‐state functional connectivity (FC) may capture a biphasic response to sporadic AD, and thus may complement structural measures of brain aging in ADAD.

Method

We trained a Gaussian Process Regression (GPR) model to predict age from FC in 271 regions of interest in 779 cognitively unimpaired, amyloid‐negative, non‐ADAD participants. We applied the model in a cohort of 256 ADAD mutation carriers (MCs) and 200 familial non‐carrier controls (NCs) from the Dominantly Inherited Alzheimer Network (DIAN). We then assessed whether the brain age gap (FC‐BAG; difference between predicted and actual age) varied based on mutation status, cognitive status, or estimated years until symptom onset (EYO). We also explored its associations with markers of amyloid (PiB PET, CSF amyloid‐β‐42/40), phosphorylated tau (CSF and plasma pTau‐181), neurodegeneration (CSF and plasma neurofilament light (NfL)), and cognition (global neuropsychological composite and CDR®‐sum of boxes).

Result

The model accurately predicted age in the training set (r = 0.77), validation set (r = 0.76), and DIAN NCs (r = 0.82), Figure 1. FC‐BAG was elevated in symptomatic MCs (p < .001), but only marginal elevation was observed in asymptomatic MCs (p = 0.047), Figure 2. In symptomatic MCs, FC‐BAG weakly associated with pTau‐181 in CSF (r = 0.34, p = 0.0046) and plasma (r = 0.26, p = 0.02), but no other associations with AD biomarkers or cognition were observed, Figure 3.

Conclusion

FC‐BAG was elevated in symptomatic ADAD, consistent with recent demonstrations in sporadic AD. However, we did not detect a predicted biphasic response to presymptomatic ADAD pathology. This inconsistency may be driven by differences between AD forms or by low reliability of FC, which may result in low statistical power and inconsistent brain‐behavior relationships. FC‐based BAG offers unique benefits but ultimately does not function as a reliable model for observing advanced aging in preclinical ADAD.
OML‐Combine: Online Machine Learning tool for Combining datasets to increase power and facilitate multi‐centre collaboration on Alzheimer's disease studies
Authors: Christodoulides Chris Dalas , Canovas Rodrigo , Dore Vincent , Doecke James D. , Laws Simon M , Weiner Michael W , Rowe Christopher C. , Villemagne Victor L , Masters Colin L. , Fripp Jurgen , Maruff Paul , Shishegar Rosita
Published: January 2025

Background

Diagnostic and prognostic decisions about Alzheimer’s disease (AD) are more accurate when based on large data sets. We developed and validated a machine learning (ML) data harmonization tool for aggregation of prospective data from neuropsychological tests applied to study AD. The online ML‐combine application (OML‐combine app) allows researchers to utilize the ML‐harmonization method for harmonization of their own data with that from other large available data bases (e.g. AIBL) to enable development of their own neuropsychological models of AD.

Method

The OML‐Combine application implements an established neuropsychological test data harmonization method1 based on non‐parametric multivariate imputation using random forests (missForest)2. Test data not included in a cohort is classified as missing and imputed using known data from the cohort based on information known from other studies1. A web‐based R‐Shiny application was developed to facilitate harmonization of data from different cohorts and visualise outcomes. OML‐combine also calculates percentages of missing values for each test score across the pooled dataset allowing decisions about the validity of harmonized data. OML‐combine also allows harmonization of multiple datasets simultaneously.

Result

The R Shiny package was used to produce an interactive data harmonization tool. Figure 1 displays the interface, showing results from an example harmonization and validation step using simulated data from AIBL (N=1813) and ADNI (N=1945). In the validation tab, users are provided with a figure of the distributions of both raw and harmonized datasets, including predicted test scores and an accuracy measurement for each score. These can be used to validate the outcomes and compare them to known relationships established from the raw data for each dataset.

Conclusion

OML‐Combine facilitates the harmonization of neuropsychological test data from established AD cohort studies. Visualization of predicted test scores and the original data sets can thereby assist with decisions about accuracy of harmonized data and can provide a basis for adjustment of inputs to optimize models. This allows researchers to combine their own data with that from other currently available studies to improve diagnostic and prognostic models of AD.

References:

1doi: 10.1002/alz.044302

2doi:10.1093/bioinformatics/btr597
Blood‐based biomarkers for Alzheimer’s disease among ethnoracial minority samples – a scoping review
Authors: Osse Amanda Leisgang , Nguyen Amy , Moeller Stacey , Cummings Jeffrey L. , Kinney Jefferson W , John Samantha E
Published: January 2025

Background

Approximately 6.7 million Americans, aged 65 and older, are living with Alzheimer’s disease (AD) dementia. Ethnoracial minority populations are at greater risk for AD. Black/African Americans (B/AA) are twice as likely than non‐Hispanic White (NHW) individuals to develop AD, and Hispanic/Latinos (H/L) are 1.5 times as likely. Accurate, timely, and accessible diagnosis of AD is limited. The use of blood‐based biomarkers (BBB) could improve treatment and care among ethnoracial groups at risk.

Method

We performed a scoping review of the literature to summarize the current state of BBB research in B/AA and H/L populations. Searches through three databases (PubMed, APA PsycInfo, and Scopus) yielded 383 and 281 papers for B/AA and H/L populations, respectively. Papers were evaluated through title/abstract, followed by full paper review, and included in the final sample if plasma, serum, or whole blood biomarkers were collected in B/AA and H/L samples with pathological or cognitive evidence of AD etiology.

Results

Overall, 19 B/AA (sample size range N=76‐5,228) and 30 H/L (sample size range N=51–3071) papers published between 1999 and June 1, 2023 met criteria. Publications evaluating ethnoracial minority samples increased over time and particularly in recent years (Figure 1). Studies included samples primarily from the United States, with majority of B/AA studies conducted in the eastern U.S., and majority of H/L studies conducted in Texas (Figure 2). We classified biomarkers into five categories, AD pathologies (amyloid, tau, neurodegeneration [ATN]), cardiovascular, inflammatory, metabolic, and unspecified. Studies evaluating ATN in both H/L and B/AA increased over time, with multiplex assays and Quanterix Simoa the most frequently used methods.

Conclusion

There has been a progressive increase in investigations of BBB for AD across all ethnoracial groups. Consideration of the blood sample measured, demographics of the individuals included, and location of the studies is required. Standardization of methods used and biomarkers evaluated, as well as replication of studies across larger and broader samples are needed to allow reliable conclusions to be drawn. Better understanding of BBB of AD in H/L and B/AA populations would advance the diagnosis and treatment of AD in these at‐risk ethnoracial groups.