bluuebunny/crossref_metadata_2025 huggingface dataset:
[18F]SMBT‐1 PET can visualize the spatial distribution of reactive astrogliosis in patients with neurodegenerative dementias
Authors: Okamura Nobuyuki , Hiraoka Kotaro , Kobayashi Ryota , Tomita Naoki , Ishiki Aiko , Mesfin Berihu , Wu Yingying , Harada Ryuichi , Kikuchi Asuka , Takeda Kazuko , Kikuchi Akio , Furukawa Katsutoshi , Watabe Hiroshi , Mugikura Shunji , Kawakatsu Shinobu , Ishii Kenji , Nihashi Takashi , Kato Takashi , Furumoto Shozo , Tashiro Manabu
Published: January 2025

Background

Reactive astrogliosis refers to functional and morphological changes in astrocytes that occur with neuronal damage in numerous neurological conditions. PET tracers targeting monoamine oxidase B (MAO‐B) are used to visualize reactive astrogliosis in the living brain. [18F]SMBT‐1, a MAO‐B selective PET tracer, was developed by modifying the chemical structure of [18F]THK5351. This study investigates the changes in [18F]SMBT‐1 binding in the brains of patients with Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD).

Method

The study involved 85 subjects, including healthy controls (HCs), subjects with mild cognitive impairment (MCI), patients with AD dementia, and FTLD including behavioral variant frontotemporal dementia (bvFTD) and semantic dementia (SD). To compare the regional standardized uptake value ratio (SUVR) values between disease groups, 30‐minute dynamic scans were conducted 60 minutes after administration of [18F]SMBT‐1. The cerebellar white matter was used as a reference region for calculating the SUVR values. PiB PET or flutemetamol PET was performed to confirm the existence of amyloid‐β pathology in the brain.

Result

[18F]SMBT‐1 binding in the cerebral cortex was elevated in amyloid PET‐positive HC, MCI, and AD patients compared to amyloid PET‐negative subjects. The amount of SMBT‐1 binding in the neocortex correlated with changes in cognitive function of HC and MCI subjects. In addition, a distinct spatial pattern of [18F]SMBT‐1 retention was observed in patients with bvFTD and SD, consistent with areas of brain atrophy in the frontal and temporal lobes.

Conclusion

Distinctive patterns of [18F]SMBT‐1 binding were observed in the neocortex of AD and FTLD, indicating its usefulness for the differential diagnosis of dementia. The study also implies that reactive astrogliosis is present before dementia onset, associated with amyloid‐β accumulation and cognitive decline.
Longitudinal cognitive changes in SCD participants in relation to plasma amyloid status and the potential additive effect of plasma ptau181 levels: A CLoCODE study
Authors: Shao Kai , Hu Xiaochen , Buerger Katharina , Düzel Emrah , Fliessbach Klaus , He Beiqi , Jiang Xueyan , Kleineidam Luca , Laske Christoph , Li Ruixian , Perneczky Robert , Peters Oliver , Priller Josef , Schneider Anja , Spottke Annika , Teipel Stefan , Wang Xuanqian , Wei Min , Wei Yongzhe , Wiltfang Jens , Yang Jie , Yu Xianfeng , Zhang Mingkai , Zhang Liang , Jessen Frank , Wagner Michael , Kuhn Elizabeth , Han Ying ,   DELCODE study group and SILCODE study group
Published: January 2025

Background

Subjective cognitive decline (SCD), in the absence of objective cognitive impairment, may be the first symptomatic manifestation of Alzheimer's disease (AD). Previous studies have suggested that its combination with amyloid‐positivity (Aβ+) may represent stage 2 AD, and is associated with a higher risk of future cognitive decline. Here, we aim to (1) confirm this using the plasma Aβ42/40 ratio, and (2) test whether the addition of plasma phospho‐tau181 (ptau181, a marker of Aβ and tau pathology) could help refine the prediction of future cognitive decline in SCD patients.

Method

We included 290 cognitively unimpaired older adults with SCD from two cohorts included in the ongoing Sino‐German CLoCODE collaborative project (49.3% female, 70.80±6.18y): 31 from SILCODE, and 259 from DELCODE. All participants had available baseline plasma biomarkers (Aβ42/40 ratio and ptau181 using the SIMOA method), and serial assessment of global cognition using a z‐transformed standard composite score over up to 6 years. Linear mixed‐effects models were conducted to confirm the predictive value of plasma Aβ+ for longitudinal cognitive decline in participants with SCD (model 1), and to determine the additive value of plasma ptau181 levels by examining their interaction (model 2), but also its effect in samples stratified by Aβ+/‐ (models 3).

Result

In the combined CLoCODE sample, we found a significant interaction between time and Aβ confirming that Aβ+ SCD (42.1% of CLoCODE SCD patients) had a faster cognitive decline than Aβ‐ SCD patients, who showed test‐repetition improvement (p<0.001). This association remained significant when ptau181 was added to the model (p=0.002). A triple interaction between time, Aβ, and ptau181 was also found (p<0.001), showing that those with a faster cognitive decline were Aβ+ SCD patients with higher baseline ptau181 levels (Figure A). This was also confirmed in stratified analyses, where there was a significant interaction between time and ptau181 levels only in Aβ+ participants (p<0.001; Aβ‐, p=0.72; Figure B). Similar results were obtained in stratified cohort analyses.

Conclusion

Our findings suggest that plasma biomarkers of AD pathology may help to identify SCD patients who will experience future cognitive decline due to AD, and thus require closer follow‐up.
CSF ATN and α‐synuclein co‐pathology in AD, PD, and DLB
Authors: Rizzo Marianna , Teunissen Charlotte , Zetterberg Henrik , Blennow Kaj , Kollmorgen Gwendlyn , Ramia Nancy , Krüger Rejko , Borejko Olga , Aarsland Dag , Hu Michele , Klockgether Thomas , Brockmann Kathrin , Gasser Thomas , Jessen Frank , Spottke Annika , van der Flier Wiesje M. , Lemstra Afina Willemina , Tijms Betty M. , Frisoni Giovanni B. , Hort Jakub , Nedelska Zuzana , Chevalier Claire , Krishnan Rajaraman , Visser Pieter Jelle , Vos Stephanie J. B. ,   the IMI EPND consortium
Published: January 2025

Background

Co‐pathology between Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB) remains poorly understood but is relevant for trial design. We aimed to compare CSF markers of amyloid, tau, and neurodegeneration (ATN) and α‐synuclein between AD, PD, DLB and controls, and investigate the influence of demographical, genetic, and clinical factors on amyloid positivity.

Method

As part of the EPND study, we included 337 individuals with AD, PD, DLB and controls from 6 centers. CSF Aß1‐42, p‐tau181, NfL, and α‐Syn were centrally measured using NeuroToolKit (Roche Diagnostics International Ltd), and clinical data were harmonized. Controls were individuals with normal cognition and normal Aß1‐42. AD was defined as abnormal Aß1‐42 without meeting clinical criteria of DLB or PD. Data were analyzed by general linear models adjusted for age and sex.

Result

38% individuals were female, and mean age was 67 years. 170 individuals had AD, 74 PD, 66 DLB, and 27 were controls (Table 1). AD individuals showed lower Aß1‐42 levels compared to all other groups (Figure 1). DLB individuals had lower Aß1‐42 levels than those with PD, with both groups displaying lower levels than controls. P‐tau181 concentrations were higher in AD relative to DLB and PD (both p<0.001), with DLB showing higher (p=0.013) and PD lower (p=0.007) levels than controls. Relative to controls, α‐Syn levels were lower in AD, DLB and PD (p=0.016, p=0.016, and p=0.019, respectively). NfL levels were higher in AD (p=0.003) and DLB (p=0.009) compared to controls. 80% of DLB and 58% of PD individuals were amyloid‐positive. Compared to amyloid‐negative ones, amyloid‐positive DLB and PD individuals had lower α‐Syn levels (both p<0.001, Figure 2). Amyloid‐positive PD individuals had lower p‐tau181 levels compared to amyloid‐negative ones (p<0.001). No differences were observed between amyloid‐positive and negative DLB and PD individuals regarding NfL levels. Age, sex, APOE‐ε4, MMSE, and MDS‐UPDRS‐III score were not related to amyloid positivity in DLB and PD.

Conclusion

Amyloid pathology is highly prevalent in DLB and PD and associated with lower α‐synuclein levels. α‐Synuclein levels are also decreased in AD. This highlights overlapping pathologies in AD, DLB and PD and has significant implications for clinical trial designs.
Unmasking Invisible Burdens: A Systematic Review on Perceived Discrimination and its Impact on Allostatic Load in Black Individuals
Authors: Harb Alaa , Capuano Ana W. , Barnes Lisa L. , Souza‐Talarico Juliana Nery
Published: January 2025

Background

Prolonged discrimination is psychosocial stressor, influencing mortality rates and contributing to cardiovascular and mental health disorders among Black individuals. Allostatic load (AL), the wear and tear of stress is a biological cumulative risk that links psychosocial stressors to adverse health outcomes. Currently, a consolidate review of evidence underscoring discrimination and AL in Black individuals is not available. The purpose of this review is to synthesize the existing evidence on the association between perceived discrimination and allostatic load (AL) in Black individuals, and to examine whether this relationship may underlie racial health disparities.

Method

We searched six databases (PubMed, CINAHL, EMBASE, PsycINFO, Web of Science, and Scopus) and completed manual searches of published studies to obtain potentially relevant data. Two independent reviewers assessed studies for original research measuring discrimination (i.e., validated scales) and AL (i.e., biomarkers of stress‐target systems) in Black individuals 18 years and older.

Result

This review included 11 studies with a total of 24,087 participants. The majority were Black females between 18‐96 years old, although 3 studies had exclusively Black samples. Perceived discrimination was measured using everyday and lifetime discrimination scales. Allostatic load was assessed via blood biomarkers representing cardiovascular, metabolic, immune, and neuroendocrine systems. Across studies, higher reported discrimination was associated with elevated allostatic load, indicating greater physiological dysregulation. This relationship persisted after adjusting for potential demographic and health confounders. However, findings were mixed regarding the specific biomarkers related to discrimination, and a few studies found no significant association.

Conclusion

The available evidence suggests a correlation between perceived discrimination and heightened allostatic load in Black individuals, which may help explain racial health disparities. However, inconsistencies across studies indicate a need for additional longitudinal research to clarify the relationships between discrimination, physiological stress responses, and health outcomes over time. Elucidating these mediating processes can inform interventions aimed at mitigating the adverse effects of discrimination on minority health.
Case report: A 50 year‐old Down syndrome man exhibiting no Alzheimer’s disease biomarker profile nor cognitive impairment. Experience from the Argentine Initiative for the Study of Down syndrome and Alzheimer’s
Authors: Clas Giulia Solange , Pertierra Lucia , Helou Belén , Tapajoz Fernanda , Guimet Nahuel Magrath , Allegri Ricardo , Marazita Mariela , Romorini Leonardo , Surace Ezequiel Ignacio
Published: January 2025

Background

Down Syndrome (DS) is the most common genetic form of intellectual disability. In recent years, there has been a significant increase in the life expectancy of individuals with DS, currently reaching the age of 60 or over. However, it has been observed that as of age 40, these individuals experience higher risk of developing dementia, and almost all of them exhibit histopathological characteristics of Alzheimer's disease (AD) in their brains.

As part of the first Latin American initiative for the study of Alzheimer’s disease in adults with Down syndrome (IASDA), we recruited a 50‐year‐old participant identified as SD8, who did not exhibit beta‐amyloid brain deposition and showed no signs of cognitive impairment.

Method

The absence of beta‐amyloid brain deposition was determined by positron‐emission tomography (PET) using an amyloid‐binding compound (PiB) and quantification of cerebrospinal fluid biomarkers. To explore the possibility that lack of Aβ deposition could be due to an interstitial deletion of the APP gene, we performed Array‐CGH and MLPA assays. Additionally, an exome analysis was conducted to assess the presence of Alzheimer's protective gene variants. Induced pluripotent stem cells (iPSCs) were generated from SD8 peripheral blood mononuclear cells and subsequently differentiated into neurons. This approach will enable a more in‐depth study to gain further insights into this case.

Result

These investigations revealed that SD8 possessed three copies of the APP gene, thus eliminating the possibility of an interstitial deletion. However, the exome analysis yielded no significant findings.

Conclusion

In summary, in this study we present the strategies employed to delve into the possible mechanisms of SD8 being an AD “escapee” and outline our planned steps for further investigation.
Multi‐cohort analyses link plasma GDF15 with dementia, brain atrophy, and plasma biomarkers
Authors: Blew Cassandra O , Duggan Michael R , Joynes Cassandra M , Gomez Gabriela T , Tian Qu , Pilling Luke C , Chen Jingsha , Rooney Mary R , Schlosser Pascal , Herman Alison B , Tsitsipatis Dimitrios , Fornage Myriam , Gottesman Rebecca F. , Palta Priya , Lu Yifei , Ballantyne Christie M , Griswold Michael E , Coresh Josef , Walker Keenan A.
Published: January 2025

Background

Growth/differentiation factor‐15 (GDF15) has been associated with dementia risk, yet its predictive value across cohorts and sub‐population, as well as its relationship with endophenotypes relevant to dementia, remains unknown.

Methods

Using the Atherosclerosis Risk in Communities (ARIC) study as the discovery cohort, we examined the relationship between plasma GDF15 levels (SomaScan) and risk for incident all‐cause dementia (ACD) in late‐life (N=4,287, 7‐year follow‐up, Mage=75±5) and in midlife (N=11,595, 20‐year follow‐up, Mage=57±6). Utilizing the UK Biobank (UKB; replication cohort), we related plasma GDF15 (Olink) to incident ACD (N=35,673, 14‐year follow‐up, Mage=61±5), vascular dementia (VaD) and Alzheimer’s disease dementia (AD). Finally, we examined the cross‐sectional association of plasma GDF15 (SomaScan) with brain volume (N=994), white matter lesions (N=911), and plasma biomarker levels (Aβ42/40, GFAP, NfL, and pTau‐181) in cognitively normal Baltimore Longitudinal Study of Aging (BLSA) participants. Analyses were stratified by APOEε4 status, cardiometabolic diseases, education, sex, race, and obesity.

Results

Late‐life GDF15 abundance was associated with ACD risk in the full ARIC sample (HR=1.61 per log2 increase; [95% CI: 1.36‐1.90]) and in all but one subgroup – obese individuals (Figure 1A‐B). GDF15 measured during late‐life predicted 7‐year ACD risk with an AUC of 0.63 (AUC for GDF15+Age: 0.71). Midlife GDF15 was also associated with ACD risk in the full ARIC sample (HR=1.55 per log2 increase; [1.32‐1.82]) and in each subgroup (Figure 1C‐D). GDF15 measured during midlife predicted 20‐year ACD risk with an AUC of 0.65 (AUC for GDF15+Age: 0.75). We replicated GDF15’s relationship with ACD risk in the UKB sample and found that GDF15 has a much stronger association with VaD (HR=1.76 per log2 increase; [1.48‐2.10]) compared to AD (HR=1.11; [1.01‐1.23]; Figure 1E). In the BLSA, higher GDF15 was significantly associated with lower total and regional brain volume, a pattern of accelerated structural brain aging (SPARE‐BA), and elevated plasma NfL and pTau181 (Figure 2A‐G).

Conclusions

Plasma GDF15 is associated with incident dementia risk across multiple cohorts, particularly vascular dementia, independent of cardiometabolic diseases and obesity. While our analyses indicate that GDF15 may play a role in dementia risk as early as midlife, GDF15, alone, provided only modest accuracy for dementia prediction.
The Knight Alzheimer Research Imaging dataset: a comprehensive multimodal resource for exploring aging, preclinical, and symptomatic Alzheimer disease pathology
Authors: Hoagey David A. , McKay Nicole S. , Gordon Brian A. , McCullough Austin A. , Schindler Suzanne E. , Xiong Chengjie , Morris John C. , Benzinger Tammie L.S.
Published: January 2025

Background

The Knight Alzheimer Research Imaging (KARI) dataset, a compilation of data from projects conducted at Washington University in St. Louis, represents a comprehensive effort to advance our understanding of Alzheimer disease (AD) through multimodal data collection. The overarching goal is to characterize normal aging and disease progression to contribute insights into the biological changes preceding AD symptom onset.

Methods

The dataset comprises cross‐sectional and longitudinal measures of magnetic resonance imaging (MRI), including T1 and T2‐weighted structural, diffusion, and resting‐state acquisitions, from over 1,600 participants aged 42 to 103 years. Additionally, a subset of participants underwent amyloid (1,100+) and tau (500+) tracer positron emission tomography (PET) acquisitions, along with cognitive, genetic, and cerebrospinal fluid (CSF) biofluid measures.

Results

In addition to raw MRI and PET acquisitions, this dataset also includes processed output that has undergone rigorous quality assessment, anatomical segmentation, and quantification procedures using FreeSurfer, as well as post‐processing quantification of amyloid and tau burden. All data are publicly available in an online repository and can be accessed upon request.

Conclusions

The KARI dataset offers a valuable resource for investigating biomarkers, genetic factors, and imaging data in normal aging, preclinical, and symptomatic Alzheimer’s disease. Expanded use could contribute to the development of early diagnostic tools, treatment strategies, and a deeper understanding of the complexities associated with neurodegenerative diseases.
Correlation of aqueous and plasma levels of phosphorylated tau181 with age and Montreal Cognitive Assessment Scores in individuals undergoing cataract surgery
Authors: Patel Hemal , Robbins Cason B , Wisely C. Ellis , Ma Justin , Singh Pali P , Challa Pratap , Kim Terry , Grewal Dilraj S , Fekrat Sharon
Published: January 2025

Background

Phosphorylated tau (p‐tau) 181 was isolated in aqueous humor and was correlated with other measures that might be consistent with Alzheimer’s disease (AD) including higher plasma p‐tau181 concentrations and lower Montreal Cognitive Assessment (MoCA blind version 7.1) scores.

Method

Blood samples, aqueous humor samples, and MoCA scores were collected from patients at the time of cataract surgery. Plasma p‐tau181 concentrations and aqueous p‐tau181 concentrations were then determined using ultra‐sensitive single‐molecule assay ELISA (SiMoA) technology. Associations were tested between aqueous and plasma concentration levels, aqueous concentration levels and MoCA score, plasma concentration levels and MoCA score, aqueous concentration and age, and plasma concentration and age.

Result

49 eyes of 49 participants were enrolled. In this cohort, average age was 71.2 years, average MoCA score was 19.4/22, average plasma p‐tau181 concentration was 8.3 pg/mL and average aqueous p‐tau181 concentration was 3.2 pg/mL. Plasma p‐tau181 (Spearman’s rank rho=0.457, p= 0.01) and aqueous p‐tau181 (Spearman’s rank rho=0.324, p= 0.048) significantly increased with age. Higher plasma p‐tau181 was significantly associated with higher aqueous p‐tau181 (rho=0.457, p= 0.015). In 43 patients with no history of cognitive impairment, plasma p‐tau181 was negatively but not significantly associated with MoCA scores (rho= ‐0.391, p= 0.065). However, aqueous p‐tau181 was significantly negatively associated with MoCA scores (rho= ‐0.556, p= 0.009) in these patients.

Conclusion

p‐tau181 is measurable in aqueous humor and plasma. Its presence in the aqueous is correlated with its presence in plasma, with increasing age, and is negatively correlated with MoCA scores. Further study in individuals with mild cognitive impairment or AD confirmed by cerebrospinal fluid and volumetric MRI metrics may yield further insight.
Development of a clincally‐viable, single AAV vector for App C‐terminus CRISPR editing
Authors: Aulston Brent D , Parra‐Rivas Leonardo A , Roy Subhojit , Pizzo Donald
Published: January 2025

Background

Our lab has developed a CRISPR‐based, gene‐editing strategy that targets the extreme C‐terminus (C‐term) of APP (amyloid precursor protein) – a gene with a central and indisputable role in AD. We have reported previously that APP C‐terminus CRISPRs effectively attenuate APP β‐cleavage and Alzheimer’s pathology in vivo. Here, we present new data demonstrating the feasibility and efficacy of a clinically‐viable, “all‐in‐one” therapeutic vector that has all the components needed for APP C‐terminus editing (Cas enzyme / gRNAs / regulatory elements) packaged into a single AAV.

Method

APP C‐terminus targeting gRNAs along with a SaCas9 expression cassette were cloned into AAV expression backbones and packaged into AAV‐PHP.eB capsids. Resulting AAVs were injected into APPNL‐G‐F mice and APP C‐terminus editing along with amyloid beta (Aβ) plaque pathology were evaluated.

Result

AAV treated brain tissue showed wide‐spread expression of APP CRISPRs and robust APP C‐terminus editing. Both amyloid plaques and insoluble Aβ were decreased in APP CRISPR treated tissue.

Conclusion

These data demonstrate in vivo feasibility of our approach and advance our long‐term goal of creating a “one‐and‐done”, single injection CRISPR therapeutic for permanent treatment of AD in human patients.
Exploring Class‐II PI3K Inhibition for the treatment of Alzheimer’s Disease: Virtual Screening for PI3KC2A Inhibitors
Authors: Jadala Chetna , Robo Michael T , Richardson Timothy I.
Published: January 2025

Background

Focusing on novel AD treatments, the TREAT‐AD centers offer an array of free research tools, shared via the AD Knowledge Portal in a Target Enablement Package (TEP). This abstract showcases the research conducted by the IUSM‐Purdue TREAT‐AD Center, specifically focusing on Targeting class‐II PI3K’s as a potential breakthrough in AD therapy. Endocytosis within the brain encompasses diverse pathways for internalizing extracellular cargoes and receptors into cells. The prominent routes include clathrin‐mediated endocytosis and phagocytosis. Endocytosis plays a crucial role in processing amyloid precursor protein (APP) leading to abnormal production of Aβ peptides. Recycling endosomes are vital for delivering and eventually releasing Aβ into the brain. Recent research emphasizes the pivotal role of PI3K‐C2α, a class II PI3K member, in regulated endocytosis through its clathrin‐binding domain. Its localization spans clathrin‐coated pits, endocytic vesicles, early endosomes, and the trans‐Golgi network, generating phosphatidylinositol 3‐phosphate (PtdIns(3)P) and/or phosphatidylinositol 3,4‐bisphosphates (PtdIns(3,4)P2) in vivo. Targeting clathrin‐mediated endocytosis by inhibiting PI3K‐C2α, a key regulator in clathrin coated vesicle formation, could be a potential therapeutic strategy against Alzheimer’s disease.

Method

We conducted extensive virtual screenings of vast compound libraries to determine potent small molecules inhibiting PI3K‐C2α. Employing shape‐based screening, and clustering techniques, we identified leading compounds for subsequent in vitro kinase assays. Compounds exhibiting nanomolar activity were selected for further investigation. Leveraging these findings, we conducted Structure‐Activity Relationship (SAR) studies, optimizing analogs to enhance binding affinity and cellular pharmacology.

Result

We have identified novel PI3K‐C2α inhibitors and are in the initial stages of optimization. These compounds exhibit promising target engagement, pending further assessment for biochemical activity and cellular pharmacology. In silico assessments suggest their structures are ideal for CNS drug discovery plans.

Conclusion

Inhibiting PI3K‐C2α stands as a promising therapeutic approach for Alzheimer’s disease. We've discovered unique molecular structures that inhibit the enzyme. Our findings suggest potential probe molecules for validating the target and developing lead compounds for clinical investigations.
Faithful Approaches: Considering Islamic Tenets in ADRD Care for Muslim Women
Authors: Irfan Bilal , Ankouni Ghadeer , Reader Jonathan M , Seraji‐Bozorgzad Navid , Giordani Bruno , Bakulski Kelly M. , Bhaumik Arijit K , Hampstead Benjamin M. , Rahman‐Filipiak Annalise
Published: January 2025

Alzheimer’s disease and related dementias (ADRD) and its associated care pose unique challenges, particularly within minority groups such as Muslim women. This population may face higher rates of ADRD alongside barriers to accessing culturally sensitive care. This abstract emphasizes the crucial role of understanding and integrating Islamic cultural and religious practices into ADRD care. Key aspects include respecting principles of modesty and privacy, critical for women who observe hijab or niqab. There is a great heterogeneity amongst the Muslim population, spanning diverse linguistic and ethnic backgrounds, varied levels of religious observance and influence of cultural norms, and intra‐religious jurisprudential differences. Ensuring cultural sensitivity in telehealth settings, clinician‐patient interactions, and neuropsychological evaluations is paramount. Practical measures, such as providing secluded environments for virtual consultations and using educational materials featuring women in hijabs, can significantly enhance patient comfort and understanding. In clinical settings, it’s important to acknowledge some Muslim women’s preferences for female healthcare providers and minimize clothing modifications. Understanding the role of the mahram and other close family members in providing support and essential information during clinical interactions is crucial. Accommodating cultural norms during cognitive testing and other assessments is also vital for effective care. Advanced care planning for Muslim patients must be mindful of Islamic beliefs around end‐of‐life care and organ donation. The discussion of diagnostic procedures, treatment planning, and caregiving needs to be contextualized within Islamic ethics and family dynamics. Considerations such as Halal‐compliant medications and facilitating religious practices in healthcare settings are important components of patient‐centered care. This abstract highlights the necessity for healthcare providers to adopt culturally sensitive approaches that respect the values, beliefs, and practices of Muslim women with ADRD. It advocates for ongoing research and collaboration between healthcare professionals and Muslim communities to further refine these approaches. By understanding and addressing the specific needs of Muslim women, healthcare providers can offer more effective and empathetic care, thereby improving the quality of life for this underserved population in the realm of dementia care.
Understanding cognitive deficits in memory clinic patients with mixed disease by combining plasma markers and advanced diffusion MRI
Authors: Dewenter Anna , Dehsarvi Amir , Steward Anna , Biel Davina , Pescoller Julia , Zhu Zeyu , Wagner Fabian , Gross Mattes , Nuscher Brigitte , Roemer Sebastian Niclas , Buerger Katharina , Janowitz Daniel , Ewers Michael , Tiedt Steffen , Dichgans Martin , Brendel Matthias , Franzmeier Nicolai
Published: January 2025

Background

Memory clinic patients typically present with Alzheimer’s disease (AD) and cerebral small vessel disease (SVD) to varying degrees. Therefore, it is crucial to determine the etiology of cognitive deficits for facilitating patient‐centered treatment in memory clinics. Plasma biomarkers (ptau217, Glial Fibrillary Acidic Protein [GFAP], Neurofilament light chain [NfL]) and fixel‐based advanced diffusion MRI markers (fiber density, fiber‐bundle cross‐section) show potential towards disentangling AD‐ and SVD‐related brain changes (Dewenter et al., Brain, 2023). However, their predictive power in understanding heterogeneous and SVD/AD‐specific cognitive deficits in memory clinic patients remains incomplete. We assessed i) how plasma‐based and fixel markers explain AD‐typical and SVD‐typical cognitive deficits and ii) their interrelation to uncover disease‐specific mechanisms.

Method

We included n=76 in‐house memory clinic patients with Simoa‐based plasma ptau217, GFAP and NfL assessments, comprehensive neuropsychological testing (CERAD‐plus battery) and 3T MRI. Global white matter hyperintensity (WMH) volume and average skeletonized mean diffusivity (MD) were included as well‐established SVD markers. AD severity was probed through plasma ptau217 and cortical thickness of the pre‐established AD signature ROI. Advanced diffusion MRI was used to assess fiber density and fiber bundle cross‐section of key white matter tracts (Figure 1A).

Result

Using linear regression, increased ptau217, reduced cortical thickness in AD signature ROI and fiber‐bundle cross‐section were highly associated with impaired episodic memory, i.e. a typical AD‐related symptom (Figure 1B, Figure 2A). In contrast, GFAP and NfL increases and reductions in MSMD and fiber density were associated with executive dysfunction, a typical sign of SVD‐related cognitive impairment (Figure 1B, Figure 2A). Additionally, fiber density was associated with GFAP and NfL levels, while fiber bundle‐cross section, a macroscopic marker of tract atrophy, was not associated with any of the plasma markers (Figure 2B).

Conclusion

Ptau217 displayed high sensitivity and specificity for AD‐typical memory impairment, whereas GFAP and NfL were associated with SVD‐typical processing speed and executive impairment. Additionally, fiber density, a pre‐established imaging marker for SVD, was associated with GFAP and NfL. This highlights the effectiveness of these markers in distinguishing and characterizing SVD and AD in memory clinic patients and emphasizes the importance of considering concomitant SVD in patients with elevated GFAP and NfL levels.
Differential effects of sex on hippocampal volume and cortical thickness in a racially and ethnically diverse cohort across the Alzheimer’s disease continuum
Authors: Levine Taylor F , Caldwell Jessica ZK
Published: January 2025

Background

Although substantial literature supports sex differences in Alzheimer’s disease (AD), many research samples comprise predominantly non‐Hispanic white (NHW) participants, limiting generalizability. Work from our group in mainly‐NHW cohorts suggests a female‐specific time‐limited resilience in cortical thickness (CT; Cieri et al., 2022) and possibly hippocampal volume in the presence of amyloid (ADNI: Caldwell et al., 2017; Caldwell et al., 2018; but c.f., BioFINDER: Caldwell et al., 2019). Here, we investigated brain‐based sex differences in a racially and ethnically diverse AD cohort.

Method

We obtained data from the Health and Aging Brain Study‐Health Disparities and included 798 self‐reported NHW, 470 Black American (BA), and 713 Mexican American (MA) participants. We examined sex differences in structural resilience, as defined by stable hippocampal volume (HCV) and cortical thickness (CT; including superior and middle temporal, isthmus and posterior cingulate, precuneus, and inferior parietal) in the presence of AD pathology (plasma Aβ42/Aβ40). We hypothesized that women would show structural resilience when cognitively normal (CN; CDR=0) but not when mildly cognitively impaired (MCI; CDR=.5‐1).

Results

A significant moderation was observed for NHW individuals, such that CN women showed no relationship between HCV and Aβ42/Aβ40, whereas MCI women showed greater atrophy with increasing pathology (Right: p=.027; Left: p=.043). The same pattern was observed in BA men, who showed no relationship between HCV and Aβ42/Aβ40 when CN, but more atrophy with greater pathology when MCI (Right: p=.003; Left: p=.007). CT moderation analyses revealed a similar pattern of structural resilience in BA CN women in the left precuneus (p=.026) and left inferior parietal region (p=.026), and in MA CN men in right middle (p=.038) and left superior temporal regions (p=.028).

Conclusion

As in some prior studies, CN NHW women showed time‐limited HCV resilience in the presence of amyloid; BA women also showed time‐limited CT resilience. Counter to expectations, resilience also was observed in CN BA men (HCV) and CN MA men (CT). Further work is needed to parse complex patterns of resilience and vulnerability across racial and ethnic groups, and to understand causal factors underlying these patterns.
Estimating Alzheimer's Disease Progression Score Using Machine Learning on FreeSurfer‐Derived MRI Gray Matter Volumes
Authors: Sung Junhyoun , Shibata Dean , Chan Kwun Chuen Gary , Shui Lan , Haynor David R.
Published: January 2025

Background

The early diagnosis and monitoring of Alzheimer's disease (AD) presents a significant challenge due to its heterogeneous nature, which includes variability in cognitive symptoms, diagnostic test results, and progression rates. This study aims to enhance the understanding of AD progression by integrating neuroimaging metrics with demographic data using a novel machine learning technique.

Method

We used supervised Variational Autoencoders (VAEs), a generative AI method, to analyze high‐dimensional neuroimaging data for AD progression, incorporating age and gender as covariates. We used two non‐overlapping datasets: 257 samples from ADNI3 and 676 from ADNI2, analyzing 68 cortical and 48 subcortical grey matter volumes extracted from their MRI 3D T1 images. The VAE model aimed to minimize reconstruction error (MSE), Kullback‐Leibler divergence, and classification error, and to estimate latent variables for each subject. A Disease Progression Score (DPS) was calculated by encoding the extracted imaging features into a latent space and projecting test data onto a trajectory curve. The study used stratified sampling for robustness and assessed the model's performance using the area under the ROC curve (AUC), and correlated the mean DPS with cognitive assessment scores by applying Kendall’s Tau.

Result

The VAE model demonstrated excellent discriminative power in classifying AD progression stages, with ROC AUC values near 1, particularly when using all 116 features. Cortical volumes were more predictive than subcortical volumes. The mean DPS showed a statistically significant correlation with cognitive assessments (p<0.01), with Kendall's Tau values of 0.66 for CDR‐SB, ‐0.45 for MMSE, and ‐0.49 for MoCA, indicating its validity as a quantitative biomarker for cognitive decline in AD.

Conclusion

Supervised VAEs can effectively model the progression of Alzheimer’s disease brain atrophy on MRI and could potentially serve as imaging biomarkers in clinical trials. The strong correlation between the DPS and cognitive assessments highlights the potential of supervised VAEs to provide a quantifiable measure of AD severity, which would be useful for clinical assessments and for objectively monitoring disease progression. The study's methodology and findings contribute to computational neuroscience and offer a foundation for future research in early detection and personalized treatment strategies for Alzheimer's disease.
Developing Cryptic ACTL6B as Novel TDP‐43 Loss of Function Biomarker
Authors: Chen Margery JQ , Irwin Katherine E , Chang Koping , Jasin Pei , Braunstein Kerstin E , Sinha Irika , Troncoso Juan C , Ling Jonathan P , Wong Philip C
Published: January 2025

Background

The nuclear clearance and cytoplasmic aggregation of splicing repressor TAR DNA/RNA‐binding protein‐43 (TDP‐43) occur in approximately 50% of Alzheimer’s disease (AD) cases and about 45% of frontotemporal dementia (FTD). However, it is not clear how early such mechanism occurs in AD and FTD as there is no method of detecting TDP‐43 dysregulation in living individuals. Since the loss of nuclear TDP‐43 leads to cryptic exon inclusion, we propose that cryptic exon‐encoded peptides may be detected in patient biofluids as biomarkers of TDP‐43 loss of function.

Method

We developed antibodies against the TDP‐43‐dependent cryptic peptide within actin‐like protein 6B (ACTL6B) and characterized them through protein blot analysis using TDP‐43‐knockdown (KD) SH‐SY5Y neuroblastoma cell lysates. Next we performed immunofluorescent staining of patient brain tissues to determine whether cryptic ACTL6B can be found in patient neurons. We then developed a Meso Scale Discovery (MSD) ELISA using our cryptic ACTL6B antibody.

Result

While the wild‐type (WT) ACTL6B antibody detected an expected band in both WT and KD SH‐SY5Y lysates, the cryptic ACTL6B antibody detected a band in only KD SH‐SY5Y. Using this antibody, we detected cryptic ACTL6B in FTLD and AD, but not control, brain tissues. The cryptic ACTL6B staining colocalizes with neurons that display TDP‐43 nuclear depletion and/or cytoplasmic aggregation. Using transfected SH‐SY5Y cells to overexpress either cryptic or WT ACTL6B, the MDS ELISA was sensitive and specific for cryptic ACTL6B, with 0.5 micrograms of lysate from SH‐SY5Y overexpressing cryptic ACTL6B showing MSD signal 5‐fold higher than 0.5 micrograms of lysate from SH‐SY5Y overexpressing WT ACTL6B (1546 vs. 290 units).

Conclusion

The study provides evidence that our cryptic ACTL6B antibody is sensitive and specific for the ACTL6B cryptic peptide. This antibody could be used to determine TDP‐43 nuclear clearance/loss of function in patient brain tissues, providing a more sensitive approach to detecting TDP‐43 pathology than staining for TDP‐43 cytoplasmic aggregates. In the future, we will use our novel MSD ELISA to test the presence of cryptic ACTL6B in patients’ CSF and blood, which could aid in early‐stage disease detection.
Efficacy of a Muscarinic (M1) Positive Allosteric Modulator, SUVN‐I7016031 in Animal Models of Dementia
Authors: Abraham Renny , Medapati Rajesh Babu , Petlu Surendra , Subramanian Ramkumar , Badange Rajesh Kumar , Bojja Kumar , Shinde Anil , Molgara Parusharamulu , Nirogi Ramakrishna
Published: January 2025

Background

SUVN‐I7016031 is a novel and selective positive allosteric modulator (PAM) of the M1 subtype of the muscarinic acetylcholine receptors (mAChRs). The proposed primary indication for SUVN‐I7016031 is in the treatment of dementia such as Alzheimer’s disease dementia (ADD) and Parkinson’s disease dementia (PDD). In the current research, the pharmacological properties of SUVN‐I7016031 in various types of dementia were investigated.

Method

SUVN‐I7016301 was characterized using a calcium mobilization assay. The binding affinity towards the orthosteric M1 ‐ M5 site was investigated. The effect of SUVN‐I7016031 on neuronal spike rate in coronal hippocampal slice electrophysiology was studied in agonist and PAM modes of testing. The pharmacokinetic properties of SUVN‐I7016031 were studied both in rodent and non‐rodent species. The effect of SUVN‐I7016031 on MK‐801 induced memory deficits in rats using object recognition task (ORT) and on time‐induced social memory deficits in rats using social recognition task (SRT) was studied. The efficacy of SUVN‐I7016031 in a rat model of PDD was investigated. The effects of SUVN‐I7016031 (10‐60 mg/kg, p.o.) on inositol 1 phosphate (IP‐1) levels were studied in rats.

Result

Functionally, SUVN‐I7016031 was found to be a positive allosteric modulator at the M1 receptor with an allosteric potency EC50 of 355 nM. In hippocampal slice electrophysiology studies, the EC50 and EC30 values were ∼527 nM and ∼326 nM, respectively. No significant binding towards the orthosteric site at the muscarinic M1 to M5 receptor was observed. SUVN‐I7016031 showed good oral bioavailability in rats, dogs, and monkeys. SUVN‐I7016031 was found to have brain penetration properties with adequate free fraction. SUVN‐I7016031 reversed delay‐induced memory disruption in adult rats in a SRT and antagonized MK‐801 induced memory disruption in ORT. SUVN‐I7016031 was found to reverse haloperidol induced memory deficits, a rat model of PDD. Treatment with SUVN‐I7016031 produced a significant increase in striatal inositol 1‐phosphate (IP‐1) levels in rats, providing in‐vivo support for the activation of M1 mAChRs by SUVN‐I7016031.

Conclusion

SUVN‐I7016031 is a novel, potent, and selective M1‐PAM that demonstrated pro‐cognitive effects in animal models of PDD and ADD.
Exploration of Neuroanatomical Characteristics Relating to Progression from Preclinical to Prodromal Alzheimer's Disease
Authors: Kim Hak Hyeon , Kwon Min Jeong , Jo Sungman , Park Jieun , Kim Jiwon , Kim Jae Hyoung , Kim Sang Eun , Kim Ki Woong , Han Ji Won
Published: January 2025

Background

To investigate the neuroanatomical characteristics at the whole‐brain level associated with progression from amyloid‐positive preclinical to prodromal Alzheimer’s disease (AD) in relation to amyloid deposition and regional atrophy.

Method

We included 45 participants with amyloid‐positive preclinical AD and 135 participants with prodromal AD matched 1:3 by age, sex, and education, from participants in the Korean Longitudinal Study on Cognitive Aging and Dementia and visitors to the dementia clinic of Seoul National University Bundang Hospital. All participants underwent 18F‐florbetaben positron emission tomography and 3D structural T1‐weighted magnetic resonance imaging. We calculated the standardized uptake value ratios (SUVRs) and volumes in 80 regions of interest (ROIs) using the Desikan‐Killiany‐Tourville atlas and compared them between the preclinical and prodromal AD groups. We used the least absolute selection and shrinkage operator (LASSO) logistic regression model to identify ROIs associated with prodromal AD in relation to amyloid deposition, regional atrophy, and their interaction.

Result

Although global SUVR did not differ between the amyloid‐positive preclinical and prodromal AD groups, the prodromal AD group showed a higher SUVR in the superior parietal cortex, right precuneus cortex, and right supramarginal gyrus. Regional volume differences between the two groups were observed in the overall cortex and subcortical areas, except in the occipital lobe, and the LASSO logistic regression model showed significant associations between prodromal AD and atrophy in the entorhinal cortex, inferior parietal cortex, both amygdalae, and left hippocampus. The mean SUVR in the right superior parietal cortex (beta coefficient = 0.0172) and its interaction with the regional volume (0.0672) were also selected in the LASSO model. The mean SUVR in the right superior parietal cortex was strongly associated with an increased risk of prodromal AD, particularly in participants with lower regional volume.

Conclusion

Compared with amyloid‐positive preclinical AD, patients with prodromal AD showed more regions with significant volume differences than amyloid deposition. Amyloid deposition in the right superior parietal cortex may play a significant role in the progression of prodromal AD, particularly in interaction with its reduced volume.
Associations of late mid‐life lifestyle with brain and cognitive changes in individuals on the AD vs. non‐AD continuum
Authors: Oomens Julie Elisabeth , Cody Karly Alex , Du Lianlian , Jonaitis Erin M. , Studer Rachel L , Artz Caitlin , Wintlend Madilynn , Köhler Sebastian , Visser Pieter Jelle , Vos Stephanie J. B. , Langhough Rebecca E. , Jansen Willemijn J. , Johnson Sterling C.
Published: January 2025

Background

To aid development of prevention strategies, we investigated whether a composite measure of late‐midlife lifestyle health was associated with (1) change in brain tau burden, vascular burden and neurodegeneration and (2) cognitive trajectories when accounting for these brain changes.

Method

We included 324 individuals from the Wisconsin Registry for Alzheimer’s Prevention. Late‐midlife lifestyle was assessed using the Lifestyle for Brain Health (LIBRA) score, encompassing 12 risk‐and protective factors for cognitive decline and dementia. Biomarker outcomes included regional tau PET burden in the entorhinal cortex (EC) and a meta‐temporal composite (MTC; mean(SD) FU time 2.4(0.6) years) as well z‐scores for WMH (FU time 2.6(0.77) years), hippocampal volume and global brain atrophy (HV; GBA; FU time 5.7(3.1) years). Cognitive outcomes included Preclinical Alzheimer’s Cognitive Composite (PACC‐3) and memory and executive domain performance (FU time 6.6(3.5) years; z‐scored). Amyloid status was determined based on global cortical average PiB DVR (cut‐off>1.16). We used linear mixed effect models to examine whether LIBRA modified age‐related tau, WMH, neurodegeneration and cognitive trajectories across amyloid positive and negative participants. Models for cognitive outcomes also accounted for MTC tau burden and GBA and their interactions with age.

Result

Participant characteristics are given in table 1. LIBRA did not modify age‐related biomarker trajectories, independent of amyloid status. Reduced models indicated LIBRA main effects on MTC SUVR and GBA, such that higher late‐midlife LIBRA scores, indicative of worse brain‐lifestyle, were associated with lower (better) MTC SUVR values and higher GBA z‐scores (indicating more atrophy; b=‐0.02, p=0.017 and b=0.05, p=0.018 respectively; Figure 1). LIBRA was differentially associated with executive function trajectories in amyloid positive vs. negative participants (p interaction 0.019; Figure 2) while there was no association of LIBRA with PACC3 or memory trajectories.

Conclusion

Lifestyle health was differentially associated with executive function trajectories, but did not modify age‐related biomarker, PACC3 or memory trajectories. We saw a counterintuitive association of lifestyle health with tau burden, and lifestyle health was associated with GBA. Improving our understanding of the contribution of lifestyle factors to brain and cognitive changes in the pre‐dementia stage will aid the development of prevention strategies.
Performance assessment of novel chemiluminescence immunoassays for the detection of specific biomarkers for Alzheimer’s disease
Authors: Arendt Philipp , Römpler Katharina , Brix Britta , Franco Stephanie , Borchardt‐Lohölter Viola , Schulz Anette , Busse Mandy , Busse Stefan
Published: January 2025

Background

To support diagnosis of Alzheimer’s disease (AD), concentrations of Aβ1‐42, tTau and pTau(181) and the Aβ1‐42/Aβ1‐40 ratio are determined in cerebrospinal fluid (CSF). To increase standardization and comparability between diagnostic laboratories, certified reference material (CRM) is used to evaluate the trueness of novel assays. Due to lack of CRMs for tTau, pTau(181), and Aβ1‐40, comparability may be assessed by comparing assays from different manufacturers. This study compares the performance of novel chemiluminescence immunoassays (ChLIAs) developed by EUROIMMUN with established chemiluminescence assays.

Method

Biomarker concentrations were determined in 110 CSF samples (patients without known diagnosis; mean age 57.2 years, range 11–94 years; 49 female, 60 male, 1 unknown) using the Beta‐Amyloid (1‐42), Beta‐Amyloid (1‐40), Total‐Tau and pTau(181) ChLIAs (all EUROIMMUN) and the corresponding Lumipulse G assays (Fujirebio). The assays were performed according to the manufacturers’ instructions on the fully automated random‐access devices IDS‐i10 (Immunodiagnostic Systems) and LUMIPULSE G 600II analyzer (Fujirebio), respectively. Agreement of results obtained with the two chemiluminescence systems was calculated.

Result

Overall agreement ranged from 89.0% to 97.3%. Agreement for the determination of normal biomarker concentrations was 93.4%–100% and 57.7%–94% for abnormal concentrations. The level of agreement was highest for Aβ1‐42 determination. Pearson’s regression coefficient revealed high correlation of results (R=0.82 to R=0.99 for Aβ1‐42 determination). While concentrations determined using EUROIMMUN assays were generally higher, numerical differences had minor influence on the diagnostic evaluation.

Conclusion

Using the EUROIMMUN ChLIAs, AD‐specific biomarkers can be measured with high precision and stability on fully automated random‐access devices. The highest level of agreement and correlation was found for Aβ1‐42 determination as assays are aligned to the respective CRMs. This indicates the need to introduce CRMs for standardization of tTau, pTau(181), and Aβ1‐40 assays.