bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing Prototype Immunoassays for Plasma GFAP on the LUMIPULSE Platform
Authors: Nojima Hisashi
Published: January 2025

Background

There is increasing evidence that the pathogenesis of Alzheimer’s disease (AD) involves various immunological responses. Indeed, astrocyte reactivity or astrocytosis is a pathological process that is commonly found surrounding amyloid‐β plaques in the brains of AD patients. Although the exact role of astrocytosis is still unrevealed, monitoring astrocyte activity using biomarkers leads to a better understanding of the underlying mechanism of AD pathogenesis. Glial fibrillary acidic protein (GFAP) is commonly used as a reactive astrocyte biomarker following injury or stress in the central nervous system. Here, we developed an assay for plasma GFAP on the LUMIPULSE G platform, and evaluated the preliminary performance.

Method

The LUMIPULSE G System is a fully automated chemiluminescent enzyme immunoassay (CLEIA) platform that processes samples in ready‐to‐use immunoreaction cartridges within 30 minutes. The assay employs a pair of in‐house developed monoclonal antibodies to detect GFAP. Analytical assay characteristics including sensitivity, precision and correlation between paired serum and plasma samples were assessed. The analytical studies comprised a series of buffer, EDTA plasma and serum samples, each tested in multiple replicates. Preliminary clinical performance was investigated using a small set of commercially‐ available samples.

Result

All tested analytical parameters met our acceptance criteria. Healthy control samples from a young age group exhibited results above the limit of quantification (LoQ). The LoQ was determined based on the assessment of low concentrated plasma GFAP samples. Imprecision was less than 10% CV for buffer‐based as well as plasma samples. There was a statistically significant correlation between plasma and serum GFAP levels (r = 0.99, p <0.0001). ROC curve analysis showed the greatest AUC for plasma GFAP to distingish AD patients from healthy controls.

Conclusion

This preliminary evaluation of the Lumipulse G GFAP Plasma prototype assay showed promising results with regards to high sensitivity, low variability, and clinical utility. Further studies with well‐characterised and diverse cohorts are needed to validate the assay’s clinical performance.
Lewy‐related pathology in the Tampere Sudden Death Study
Authors: Kok Eloise H , Paetau Anders , Martiskainen Mika , Lyytikäinen Leo‐Pekka , Lehtimäki Terho , Karhunen Pekka , Myllykangas Liisa
Published: January 2025

Background

When treatments against neurodegenerative diseases eventuate, the most successful time point to administer therapies will be the early stages, most likely before symptoms begin to show. Previous studies have found alpha‐synuclein pathology (Lewy‐related pathology; LRP) in asymptomatic individuals aged 62 years and above, with ranges from 8 to 17%.

Method

We performed immunohistochemical staining with the 5G4 antibody against alpha‐synuclein on brain tissue samples from the Tampere Sudden Death Study – a collection of forensic autopsies on individuals that lived outside hospital institutions in Tampere and the surrounding regions, Finland. Representative paraffin‐embedded tissue regions of brainstem (substantia nigra/pons) were available from 562 cases, ranging in age from 16 to 95 years, with a majority of men (74% vs 145 women). Hippocampal regions were available in 476 cases (87% of those with brainstem available). (Kok et al. 2024)

Result

Alpha‐synuclein pathology was seen in 46 individuals with varying severity. Of the 46 cases positive for alpha‐synuclein pathology, the youngest (42y female) had clinical records of parkinsonism and neuropathologically determined as multiple system atrophy (MSA). An additional 3 cases also showed MSA‐type glial cytoplasmic inclusions, without clinical history. 42 subjects showed Lewy‐related pathology (LRP) in the brainstem. The youngest case with LRP was 54 years with no reported neurodegenerative issues (see Figure). One positive brainstem case was missing the hippocampal region, but otherwise 25 (61%) also had LRP in hippocampal regions. Surprisingly, 9% of those aged 50 years or older had LRP, with a clear preference for males (31 vs 11 females) and increasing incidence with age.

Conclusion

This is the first investigation of a non‐hospitalised population across the adult life span showing the prevalence of LRP in individuals aged as young as their 50’s, suggesting LRP starts much earlier than previously thought and is more common than expected in middle age. The present study has the strength of a large number of younger cases, although may over represent drug abuse and psychiatric issue patients, as well as the obviously higher number of males.
Why We Forget: Memory Encoding in the Aging Brain
Authors: Beason‐Held Lori L , Shafer Andrea T , Calcagno Nicole , Cooper Jasmine , Kitner‐Triolo Melissa , Resnick Susan M.
Published: January 2025

Background

To further understand the neural basis of memory failure in the older brain, we examined the medial temporal lobe (MTL) memory system in 297 cognitively normal participants (mean age = 74.46 (4.95 SD)) from the Baltimore Longitudinal Study of Aging (BLSA).

Methods

Participants performed a face‐scene associative memory encoding task, where they saw a series of scenes with a face at the bottom during fMRI scanning. To help them remember, they were asked whether they thought the face was a good match for the place in the background. An hour after scanning, they were asked to indicate which of two faces was shown before with each place. Brain activation and functional connectivity patterns were examined during encoding trials they later remembered, trials they later forgot, and for encoding success (remembered–forgotten trials).

Results

Brain activation patterns involved regions along the occipitotemporal visual pathway and included the hippocampus (HC), entorhinal cortex (ENT), and parahippocampal gyrus (PHG) for both remembered and forgotten stimuli. In contrast, connectivity differed between remembered and forgotten trials. Remembered encoding was associated with greater connectivity between HC, ENT, and PHG seed regions, and most cortical regions along the occipitotemporal visual pathway. This connectivity pattern was absent for forgotten items. Participant good/bad match perception of the face‐scene pairs during encoding showed bad matches were more frequently forgotten. Task reaction times were also slower for bad matches.

Conclusions

Taken together, this suggests that forgetting may be linked to disruption of the medial temporal lobe networks of the brain, and to whether the features of a visual stimulus are perceived as discordant or mismatched.

This work was supported by the Intramural Research Program of the NIH, National Institute on Aging.
A pilot study evaluating the feasibility, safety, and efficacy of transcranial photobiomodulation (tPBM) for the treatment of mild cognitive impairment (MCI): preliminary findings
Authors: Rashidi‐Ranjbar Neda , Churchill Nathan W. , Schneider Raphael , Schweizer Tom A. , Fischer Corinne E.
Published: January 2025

Background

Mild Cognitive Impairment (MCI) serves as a precursor to Alzheimer’s dementia (AD). Recent research underscores the relationship between mitochondrial dysfunction and amyloid beta accumulation, underscoring the prospect of targeting mitochondrial function for intervention. Consequently, our study aimed to explore the efficacy of transcranial photobiomodulation (tPBM), a novel non‐invasive technique utilizing near‐infrared light to activate mitochondrial cytochrome C oxidase receptors, thereby enhancing cellular energy in individuals with MCI.

Methods

Fifteen MCI patients were randomly allocated to either active or sham groups (8 active, 7 sham), with both groups receiving indistinguishable active and sham tPBM devices. Over a span of 6 weeks, participants underwent daily home‐based tPBM sessions. Pre‐ and post‐treatment assessments included a comprehensive battery of tests, encompassing the Trail Making Test (TMT B & A), Mini‐Mental State Examination (MMSE), Proton Magnetic Resonance Spectroscopy (H‐MRS) of the posterior cingulate cortex, structural MRI, resting‐state functional MRI (rsfMRI), and blood analyses.

Results

In the active treatment group compared to the sham group, significant findings (p<0.05) emerged including: 1) faster executive functioning (reduced TMT B completion time), and a promising trend of enhanced MMSE and TMT B/A scores. 2) H‐MRS analysis revealed a decreased ratio of N‐acetyl aspartate to creatine (NAA/Cr), indicating improved neuronal health. 3) Structural MRI showed increased volume of the right thalamus. 4) Functional connectivity analysis using rs‐fMRI data unveiled higher change in the default mode network (DMN) and limbic network, as well as between DMN and executive control network (ECN). 5) Blood tests showcased decreases in isoleucine, methionine, and sarcosine levels—markers linked to AD and amyloid plaque formation—while displaying increases in butyrate, L‐carnitine, and L‐arginine levels—markers indicative of improved mitochondrial function. Furthermore, a notable trend towards decreased levels of tau protein was observed.

Conclusions

Our preliminary findings suggest a potential therapeutic benefit of tPBM in MCI, possibly through the augmentation of mitochondrial function. However, extending the treatment duration may yield further improvements in cognition. Parameters such as NAA/Cr ratios via H‐MRS, DMN functional connectivity via rs‐fMRI, and blood metabolites may serve as objective indicators of response to tPBM treatment. Nevertheless, conclusive determinations require a larger sample size.
Efficacy monitoring using amyloid and tau PET imaging in Down syndrome populations
Authors: Christian Bradley T. , Zammit Matthew D
Published: January 2025

Background

The triplication of the chromosome containing the gene for APP production conveys a very high risk for people with Down syndrome to develop Alzheimer’s disease by their fifth decade of life.

Method

The Alzheimer’s Biomarker Consortium ‐ Down Syndrome study has tracked the trajectory of PET‐measured amyloid and tau burden in the brains of individuals with Down Syndrome (>25 yrs of age) to carefully characterize their relationship with AD‐related cognitive decline.

Result

Compared to sporadic AD in the neurotypical population, there is a carefully characterized accelerated time course between the emergence of these neuropathologies and the presentation of MCI and clinical dementia in the Down syndrome population.

Conclusion

Clinical drug trials for the treatment and prevention of AD in Down syndrome are now being launched that use these biomarker data to inform and optimize study design. This presentation will discuss the time course of amyloid and tau within the context of treatment strategies for the removal or prevention of accumulation of AD neuropathology in Down syndrome.
SiteRx AI‐Enabled Clinical Intelligence Platform Delivers Superior Amyloid PET Conversion in Early Alzheimer’s Disease (AD) Trial
Authors: Beck Erin , Perilli Frank , Stalder Michael
Published: January 2025

Background

Accurate participant selection is pivotal for the success of Alzheimer’s Disease (AD) clinical trials, particularly in studies requiring confirmation of amyloid plaque presence via PET scans. SiteRx’s AI platform, InclusionAI, enabled 2.7x higher amyloid PET pass rates1 compared to other sources, delivering a significant enrollment contribution to an ongoing Phase 1 study in Early AD (the “Study”).

Method

SiteRx democratizes access to clinical research via the largest neuro focused real world data network in the US. The SiteRx AI‐enabled process leverages structured and unstructured data from longitudinal health records and relevant data against trial inclusion/exclusion criteria to match candidates to trials. The SiteRx platform captures clinical insights and detailed recruitment funnel conversion across screening activities, including amyloid PET. This research compares outcomes between the SiteRx platform and all other study recruitment sources, including site databases and central advertising campaigns.

Result

SiteRx patients demonstrated an amyloid PET pass rate of 64%, significantly exceeding the 23% pass rate from other sources—a testament to the predictive power of SiteRx AI‐enabled clinical intelligence. This effectiveness translated to savings of approximately $16,200 per patient in PET scan costs, amounting to over $3 million for the patients screened to date. Additionally, 85% of SiteRx’s PET‐eligible patients progressed to randomization, reflecting a higher readiness and suitability for trial participation compared to 66% from all other sources. The cumulative benefits of SiteRx have contributed more than a full Study cohort of randomizations.

Conclusion

SiteRx InclusionAI platform underscores a scalable and economically potent approach to AD clinical research recruitment. Access to longitudinal medical records and other relevant data such as previous brain imaging, cognitive inventory exams (e.g. MMSE, MoCA), current medications, documented ICD codes and formal AD diagnoses drive superior amyloid PET pass rates. This data showcases how targeted, data‐driven recruitment strategies can profoundly impact AD recruitment quality, efficiency and speed for clinical trial sponsors.
Brain health in Diabetic Seniors: Understanding the Dementia dynamics
Authors: Singh Ambica , Dey Aparajit Ballav , Dwarakanathan Vignesh
Published: January 2025

Background

In a landscape where both cognitive decline and diabetes are on the ascent globally, an increasingly pertinent question emerges: what interconnections exist between dementia and diabetes in older individuals? Cognitive impairment is a decline in mental abilities that affects memory, attention, reasoning, and other cognitive functions leading to dementia. Diabetes is associated with an increased risk of cognitive impairment and dementia, as well as vascular complications that damage the brain. Several studies have shown that type 2 diabetes and hypertension can impair blood‐brain barrier integrity, cerebral circulation, glucose metabolism, inflammation, oxidative stress, and amyloid‐beta production in the brain. Here, we endeavor to find any correlation between stages of cognitive decline and diabetes in the elderly for better insight and enhanced geriatric care.

Method

In this comparative cross‐sectional study, patients aged 60 years and beyond were recruited from Memory Clinic, Department of Geriatric Medicine, AIIMS, New Delhi. Based on Addenbrooke’s Cognitive Examination‐III (ACE‐III) scoring for cognition, patients with cognitive decline were divided into 3 categories: Subjective Cognitive Impairment (SCI), Mild Cognitive Impairment (MCI) and Major Neurocognitive Disorder (MNCD). 20 patients in each category were taken against 20 controls. Diabetic status was self‐reported and as per their HbA1c levels.

Result

Significant cognitive decline was found in patients with type 2 diabetes with a p‐value of 0.02. As against controls, the association was found highest in MCI group, while SCI had the lowest percentage of diabetics. ACE‐III scores were significantly affected in diabetics. The most affected domain was fluency (p‐value 0.03) followed by memory (p‐value 0.12).

Conclusion

This study shows a clear correlation between cognitive decline and diabetic status in older patients. This work has translational value and clinical utility in the future.
Sex differences in the association between pathology and subjective cognitive complaints in the early stages of Alzheimer’s disease
Authors: Boutin Sophie , Brambati Simona Maria
Published: January 2025

Background

In the preclinical phase of Alzheimer’s disease (AD), individuals deemed at risk exhibit cerebral beta‐amyloid (Aβ) proteins without cognitive impairment, whereas those in the mild cognitive impairment stage display cognitive deficits. Subjective cognitive complaints, or perceived cognitive alterations by the individual without objective decline, emerge during these phases and may correlate with Aβ levels. The assessment of cognitive complaints could thus help identify those vulnerable to AD. Despite increasing interest in the role of biological sex in AD manifestation, it remains less clear in its early stages.

Method

A total of 418 cognitively healthy older subjects and 424 subjects in the mild cognitive impairment stage from the Alzheimer’s Disease Neuroimaging Initiative cohort with PET‐Aβ levels above and below the 1.11 threshold were included in the study. Using ANOVA models, we examined sex differences in cognitive complaints in different domains, i.e., memory, language, attention, organization, planning, visuospatial, assessed using the Everyday Cognition questionnaire. We also tested, using general linear models, whether sex moderated the association between Aβ levels and the severity of complaints in the same groups. Finally, we realized separate logistic regressions in men and women to determine whether the types of cognitive complaints that can predict Aβ positivity vary between sexes at different stages of the disease. In all models, we controlled for age, years of education, and depression and anxiety symptoms.

Results

Although there were no sex differences in complaint types, there was a significant correlation between higher Aβ levels and exacerbated visuospatial and language complaints in both cognitively healthy men and women. Interestingly, this association with visuospatial complaints was stronger in men compared to women. At the stage of mild cognitive impairment only, specific memory, language, and organization complaints predicted Aβ positivity exclusively in women.

Conclusion

These findings suggest that subjective cognitive complaints could be good indicators of increased risk of AD because of their association with one of its biomarkers. Biological sex also seems to exert distinct impacts on AD’s clinical manifestation at different stages of the disease. This shows the importance of considering individual differences to adapt AD diagnosis and personalize early interventions.
MRI and PET findings with long‐term gantenerumab treatment: results from the DIAN‐TU trial
Authors: Benzinger Tammie L.S. , Gordon Brian A. , McCullough Austin A. , Hornbeck Russ C. , Flores Shaney , Koeppe Robert A. , Jack Clifford R. , Li Yan , McDade Eric , Llibre‐Guerra Jorge J. , Clifford David B. , Mills Susan , Santacruz Anna , Wang Guoqiao , Supnet‐Bell Charlene , Ibanez Laura , Klein Gregory , Baudler Monika , Doody Rachelle S. , Kerchner Geoffrey A. , Atri Alireza , Bateman Randall J. ,   The DIAN‐TU Study Team
Published: January 2025

Background

Anti‐amyloid monoclonal antibody therapies for AD have documented plaque removal on amyloid PET scans. We evaluate the findings for amyloid PET, tau PET, FDG PET and volumetric MRI over the course the open label extension (OLE) for the DIAN‐TU gantenerumab treatment, compared to the last imaging obtained prior to the OLE (to evaluate for potential rebound effects) and in comparison to longitudinal imaging in the DIAN Observational study.

Method

This double‐blind, phase 2/3 trial (2012‐2019), followed by open‐label extension (OLE), investigated varying gantenerumab doses up to 1500 mg SQ q2 weeks [NCT NCT01760005]. We report long‐term amyloid‐plaque removal by PET and findings for metabolic FDG PET and tau PET, and additionally changes of atrophy on volumetric MRI. Imaging measures were secondary outcome analyses. Comparison is made between the treatment cohort and controls (DB placebo participants who didn’t enter OLE, plus external controls from the DIAN OBS). Estimated years to onset was included as a covariate. The gap period of ∼1 year is specifically analyzed to estimate any “rebound” effect on amyloid or tau accumulation or neurodegeneration. Volumetric MRI measures include hippocampal volumes, lateral ventricular volumes, and white matter hyperintensities.

Result

In participants who were asymptomatic at baseline and treated with gantenerumab (n = 53), amyloid‐plaque removal measured by PIB‐PET in Centiloids was dose‐dependent. Few participants had reached completely negative levels (below 24). No statistical significance was found for FDG PET, tau PET, or volumetric MRI, including hippocampal volumes. Impact of the gap period of ∼1 year (gap in treatment) on the rate of amyloid accumulation compared to the rate of accumulation predicted in observational studies of this cohort is under evaluation, as are the other imaging measures.

Conclusion

While no overall effect was observed in the total group for non‐amyloid measures, results suggest dose dependent clearance of amyloid plaque in asymptomatic DIAD mutation carriers following long‐term, high‐dose gantenerumab. The potential “rebound effect” of elevated amyloid accumulation for participants for whom there was a significant gap in therapy between the trial and the OLE is under evaluation and will be presented, as will the variables for FDG PET, tau PET, and volumetric MRI.
Comparison of Relative Change with Effect Size Metrics in Alzheimer’s Disease Anti‐amyloid Clinical Trials
Authors: Goldberg Terry E. , Lee Seonjoo , Devanand Davangere , Schneider Lon S. S.
Published: January 2025

Background

Percent slowing of decline is frequently used as a metric of outcome in Alzheimer’s disease (AD) clinical trials, but it may be misleading. Our objective was to determine whether percent slowing of decline or Cohen’s d is the more valid and informative measure of efficacy.

Method

Outcome measures of interest were percent slowing of decline; Cohen’s d effect size, and number‐needed‐to‐treat (NNT). Data from a graphic were used to model the inter‐relationships among Cohen’s d, placebo decline in raw score units, and percent slowing of decline with active treatment. NNTs were computed based on different magnitudes of d. Last, we tabulated recent AD anti‐amyloid clinical trials that reported percent slowing and for which we computed their respective d’s and NNTs.

Result

We demonstrated that d and percent slowing were independent. While percent slowing of decline was dependent on placebo decline and did not include variance in its computation, d was dependent on both group mean difference and pooled standard deviation. We next showed that d was a critical determinant of NNT, such that NNT was uniformly smaller when d was larger. In recent AD associated trials including those focused on anti‐amyloid biologics (aducanumab, lecanemab, gantenerumab, and donanemab), d’s were below 0.23 and thus small, while percent slowing was in the 12%‐27% range and NNTs ranged from 14‐34.

Conclusion

Standardized effect size is a more meaningful outcome than percent slowing of decline because it determines group overlap, which can directly influence NNT computations, and yield information on the likelihood of minimum clinically important differences. In AD, greater use of effect sizes, NNTs, rather than relative percent slowing, will improve the ability to interpret clinical trial results and evaluate the clinical meaningfulness of statistically significant results.
Large‐scale proteomic and genomic analysis identify plasma proteins influencing human brain structure and Alzheimer’s disease risk
Authors: Ayubcha Cyrus , Sun Benjamin B , Ge Tian , Chen Chia‐Yen
Published: January 2025

Background

Recent advances in proteomics technology enable us to comprehensively examine the impact of the proteome on Alzheimer’s disease (AD) and intermediate phenotypes, such as brain imaging measures. Here, by leveraging large‐scale proteomic, brain imaging, and AD genome‐wide association studies (GWAS), we performed Mendelian randomization (MR) and colocalization analysis to investigate the impact of plasma protein levels on brain imaging measures and the link between plasma protein levels, brain imaging, and AD.

Method

We leverage the protein quantitative trait loci (pQTL) datasets from the UK Biobank Pharma Proteomics Project (UKB‐PPP; 2,625 proteins by Olink assay) and deCODE genetics (Ferkingstad et al. 2021; 4,472 proteins by SomaLogic assay). UKB‐PPP and the deCODE study represent the largest plasma proteomics GWAS to date based on two different proteomics platforms, where the total sample sizes are over 30,000 for each. For the brain imaging and AD genetic datasets, we used the brain imaging GWAS from UKB (453 T1 MRI and DTI imaging; Smith et al. 2021), and AD GWAS from Bellenguez et al. 2022.

Result

After extensive data processing and quality control, we performed two‐sample MR and identified significant associations in 170 protein‐DTI imaging pairs and 38 protein‐MRI pairs for 60 unique proteins from UKB‐PPP and 41 unique proteins from deCODE. Colocalization analysis further prioritized proteins related to AD implicated in previous studies. We further extended the association between plasma protein and brain imaging to AD by performing MR and colocalization analyses using pQTL and AD GWAS. As an example, we showed that plasma progranulin (P28799) level showed a significant effect on AD risk (P = 6.79×10−12), while supported by associations between plasma progranulin level and caudate volumes (right and left T1 DTI, P = 8.41×10−6).

Conclusion

In summary, we presented the largest to date study for the impact of plasma protein levels on brain imaging measures and a novel approach to identify biomarkers for AD. Overall, the integration of large‐scale MRI, proteomics, AD phenotype, and genome‐wide data holds great promise for enhancing our understanding of AD, and ultimately facilitates biomarker discovery and therapeutic development.
Blood‐based Proteomic Profiling for the Progression of Cognitive Decline, Neuropsychiatric Symptomatology, and Neuroimaging Outcomes within an Asian Memory Clinic Cohort
Authors: Sim Ming Ann , Choi Hyung Won , Cai Yuan , Richards Arthur Mark , Chen Christopher
Published: January 2025

Background

The prognostic performance of plasma proteomics for longitudinal changes in (i)cognition (ii)neuropsychiatric symptomatology and (iii)neuroimaging outcomes within South East Asia, where prevalence of cerebrovascular disease is high, remains un‐investigated.

Methods

A prospective cohort of Singaporean memory clinic attendees was followed‐up for 4 years. Annual neurocognitive and neuropsychiatric assessments were performed alongside 2‐yearly brain magnetic resonance imaging (MRI) scans. Incident cognitive decline was defined as a Clinical Dementia Rating Scale Sum‐of‐Boxes (CDR‐SB) ≥3 increment from baseline. Significant neuropsychiatric symptomatology progression was defined by a Neuropsychiatric Inventory score increment of ≥4 from baseline.

Neuroimaging outcomes evaluated included (i)rates of progression of cerebral small vessel disease (white matter hyperintensity volume) and (ii)hippocampal atrophy on 2‐yearly MRI scans.

1536 plasma proteins (encapsulating all major biological pathways including neurological, immune‐oncological, cardiovascular and inflammatory pathways) were profiled at baseline using the Olink Explore 1536 platform. Their associations with cognitive, neuropsychiatric and MRI outcomes were subsequently evaluated in multivariable regression models, with correction for false‐discovery rate.

Results

Of 528 subjects (mean age 72.83±7.81years, 43.8% male, 57.9% cerebrovascular disease, 22.4% NCI, 40.3% CIND, 37.3% dementia), the incidence of cognitive decline was 31.6% (167/528). Among 245 proteins significantly associated with cognitive decline, GFAP and NEFL were the most powerfully prognostic (Fig. 1).

The incidence of significant progression of neuropsychiatric symptomatology was 55.68% (294/528). Among 310 proteins significantly associated with the progression of neuropsychiatric symptoms, NEFL and DCBLD2 were the most prognostic (Fig. 1).

NEFL and TNFRSF11B were the most significantly dysregulated proteins for cerebral small vessel disease progression, while GFAP and NEFL significantly associated with rate of hippocampal atrophy. These top proteins also significantly associated with the rates of domain‐specific decline in 4 or more cognitive domains assessed over 4 years (Fig. 2).

The top two gene ontology biological pathways identified from all data on significantly dysregulated proteins, were (i)cell adhesion and (ii)signal transduction, in both clinical entities (Fig. 3).

Conclusion

Our findings, upon interrogation of a biobank from a well‐annotated cohort, identifies late‐stage protein biomarkers and biological pathways for a suite of longitudinal cognitive, neuropsychiatric and neuroimaging outcomes. These biomarkers warrant further validation and mechanistic elucidation as potential therapeutic targets.
Effects of APOE e4 and Neuropathological Diagnoses on Neuropsychiatric Symptoms: Mediation Analyses and Likely Causation in an Integrated NACC Database
Authors: Goldberg Terry E. , Kim Hyun , Devanand Davangere , Lee Seonjoo
Published: January 2025

Background

Our goal in this study was to identify paths from APOE e4 to neurobehaviors itemized on a neuropsychiatric inventory that involved neuropathologies associated with e4 (amyloid, tau, cerebral amyloid angiopathy, and Lewy bodies) or cognition mediators (memory or global cognitive status), as well as direct paths from e4 to cognition or neurobehaviors.

Method

A total of 1199 cases with available neurobehavioral, cognition and neuropathological data were included. We then conducted a series of causal mediation analyses in R in which e4 always served as the independent variable and Neuropsychiatric Inventory (NPI) neurobehavioral items, when included in the mediation, the outcome. Neuropathologies or cognition served as mediators.

Result

Multiple significant indirect paths from e4 through neuropathologies to neurobehaviors were identified. More refined analyses indicated that neuritic plaques and Braak stage, but not extent of diffuse amyloid plaques, drove the findings. A significant direct effect of e4 to memory was also identified. Additionally, Lewy body disease, when treated as an exposure, had a direct effect on hallucinations in keeping with known features of the disease.

Conclusion

We found strong evidence for partial mediation of NPI symptoms by cognition, suggesting that cognitive limitations that may have influenced understanding (or misunderstanding) the environment with impacts on maladaptive behavior. In addition, neuritic amyloid plaque levels and Braak stage, but not diffuse amyloid plaque extent, were key in NPI mediated associations suggesting the possibility that synaptic failure play an important role in multiple neurobehavioral symptoms in dementia, including psychosis. Last, we found strong evidence that e4 may have direct effects on cognition when we used verbal episodic memory as an outcome, suggesting that medial temporal regions that support memory may be sensitive to non‐amyloidogenic and non‐tau related pathophysiological processes.
Evaluation of serum level of seven Sirtuins in Alzheimer’s Disease patients: Biomarker based on the Translational Research
Authors: Singh Abhinay Kumar , Pradhan Rashmita , Chatterjee Prasun , Dey Sharmistha
Published: January 2025

Background

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. Dysfunction of mitochondria and oxidative stress are known to aggravate the disease pathology. Sirtuins, NAD‐dependent deacetylases, have a well‐defined role in this pathway and thus can serve as a potential biomarker for the early detection of the disease.

Method

This study evaluated the level of serum Sirtuins (SIRT1–SIRT7) in three study groups: AD, mild cognitive impairment (MCI) and geriatric control (GC) by the label free surface plasmon resonance (SPR) technology and was further validated by the Western blot experiment. ROC analysis was performed to differentiate the study group based on the concentration of serum SIRT proteins.

Result

Out of seven Sirtuins, serum level of SIRT1, SIRT3 and SIRT6 (mean ± SD) were significantly decreased in AD (1.65 ± 0.56, 3.15 ± 0.28, 3.36 ± 0.32 ng/μl), compared to MCI (2.17 ± 0.39, 3.60 ± 0.51, 3.73 ± 0.48 ng/μl) and GC (2.84 ± 0.47, 4.55 ± 0.48, 4.65 ± 0.55 ng/μl). ROC analysis showed the cut‐off value with high sensitivity and specificity for cognitive impairment (AD and MCI). The concentration declined significantly with the disease progression. No specific difference was observed in the case of other SIRTs between the study groups.

Conclusion

This study for the first time reports the concentration of all seven Sirtuins in serum of AD and MCI patients and reveals an inverse relationship between serum level of SIRT1, SIRT3 and SIRT6 and AD. The cut‐off values with sensitivity and specificity shows the clinical relevance of SIRT3 and SIRT6 as serum protein markers for AD.
Human‐specific α7nAChR‐dependent adaptation to mechanical properties of the extracellular environment
Authors: Szombathy Anna Marie , Ihnatovych Ivanna , Dorn Ryu , Nimmer Erik , Heo Yuna , Bae Yongho , Szigeti Kinga
Published: January 2025

Background

CHRFAM7A is a human‐restricted gene associated with neuropsychiatric and neurodegenerative disorders. The translated CHRFAM7A protein incorporates into the α7 nicotinic acetylcholine receptor (α7nAChR) leading to a hypomorphic receptor. Mechanistic insight from isogenic iPSC derived neuronal and mononuclear cells demonstrated that CHRFAM7A affects Ca2+ signaling and activates small GTPase Rac1 leading to an actin cytoskeleton gain of function. Fundamental differences in tissue stiffness in human and rodent brain are emerging as a translational gap. Since the actin cytoskeleton is a driver of adaptation to tissue stiffness, we explored the role of CHRFAM7A in mechanobiology.

Method

Neuronal progenitors and monocytes were differentiated from isogenic iPSCs (null and CHRFAM7A knock‐in (KI)). Polyacrylamide hydrogels corresponding to Young’s modulus 2 kPa (soft) and 5 kPa (stiff) were used to model the mechanical properties of the tissue environment. Actin immunofluorescent morphological analysis and atomic force microscopy (AFM) were utilized to characterize cellular adaptation.

Result

AFM demonstrated intracellular stiffness adaptation to the soft and stiff environment in CHRFAM7A KI neuronal progenitors and monocytes. In CHRFAM7A KI neuronal progenitors, growth cone (GC) morphology adapted to the stiffness by reinforcing lamellipodia and maintaining directionality. In null MGE progenitors filopodia remained the actin structure in both the soft and stiff environment resulting in GC curvature in the stiff hydrogel. Polarization pattern favored the bipolar morphology in both the neuronal and monocytic lineage of CHRFAM7A KI cells in the stiff environment, while null cells retained the multipolar pattern. Cell polarity correlated with small GTPase activity: in null MGE progenitors, multipolar morphology is associated with high RhoA activity in the stiff environment. In contrast, CHRFAM7A KI MGE progenitors adapted to stiffness by activating both CDC42 and Rac1.

Conclusion

Human specific CHRFAM7A facilitates adaptation to matrix stiffness in both the neuronal and mononuclear lineage, bridging the gap between rodent and human brain stiffness and holding implications for physiological and pathological conditions. Human‐restricted CHRFAM7A needs to be taken into account to overcome the translational gap in drug development for neurodegenerative and neuroinflammatory diseases.
A Thematic Analysis of the Patient Centered Outcomes Research Institute’s (PCORI) Stakeholder Identified ADRD Research Priorities
Authors: Philips Joanna , Audley John , Akinbami Yewande , Majid Tabassum , Arora Neeraj , Penuela‐Wermers Sarah
Published: January 2025

Background

National and international organizations, including the United Nations, Center for Disease Control, Agency for Healthcare Research and Quality, and the US Surgeon General’s Office have highlighted the need for a comprehensive approach to caring for the growing number of older adults in the U.S. Furthermore, advancements in both non‐pharmacological and pharmacological treatments for Alzheimer’s Disease and Related Dementias (ADRD), coupled with the CMS initiative on improving dementia care management (GUIDE), have intensified national attention on the needs of older adults living with ADRD. Acknowledging this convergence of factors and with the input of stakeholders, PCORI identified “Promoting the Health of Older Adults” as one of 12 topic themes for future research. As the leading funder of Clinical Comparative Effective Research (CER), PCORI has invested $88 million to support 15 CER studies focused on ADRD and 10 awards on engagement related initiatives to advance ADRD research interests.

Method

To further identify funding gaps and understand CER priority areas related to ADRD, we conducted in‐depth analyses of PCORI’s ADRD portfolio and of discussions on ADRD with diverse stakeholder partners (i.e. patients, clinicians, researchers, nursing organizations, payers, advocacy groups). An analysis of 24 ADRD‐related stakeholder convenings using open‐ended unstructured interview questions was done and common themes of priority CER areas were identified.

Result

The thematic analysis revealed three ADRD CER priority areas related to: (1) Sensory impairment in ADRD patients, (2) Coordination of healthcare services and (3) Support for caregivers of ADRD patients. Moreover, stakeholders identified the need for interventions that address health inequities in underserved populations affected by ADRD and innovative approaches to navigating a fragmented health care system highlighted by the COVID‐19 pandemic.

Conclusion

Evaluation of PCORI’s ADRD portfolio and engagement discussions provide important insights on current critical evidence gaps and real‐world decisional dilemmas. The engagement discussions illuminate priority areas for research that will holistically address those impacted by ADRD at the patient, caregiver, health system, and community level. These insights reveal a need for research that will focus on underserved older adults and their caregivers, as well as optimizing the coordination and integration of care for this population.
Decrowding Expansion Pathology for Visualization of Herpes Simplex Virus Type 1 and Tau Interaction in Alzheimer’s Disease
Authors: Araya Katherine , Valdes Pablo , Taglialatela Giulio
Published: January 2025

Background

Chronically reactivating Herpes Simplex Virus Type 1 (HSV1) infection has been shown to produce key molecular and behavioral markers of Alzheimer’s disease (AD). Most notably, the accumulation of neurotoxic tau isoforms, neurofibrillary tangles (NFTs), and Amyloid‐beta plaques. Our study takes a unique approach to the systematic characterization of HSV1 biomarkers within the brain. We introduce the novel application of decrowding expansion pathology (dExPath) for immunofluorescent studies, a technique that sheds new light on the interactions between HSV1 proteins and tau. This innovative use of dExPath provides a visualization of HSV1 protein in the context of AD pathology, offering a fresh perspective on the hypothesized interactions between HSV1 proteins and Tau.

Method

We aim to overcome the limitations of traditional imaging protocols, which are often hindered by spatial resolution and tissue density. To achieve this, we utilize dExPath, a technique that physically expands hippocampal tissue fourfold in an isotropic manner. This approach reveals disease biomarkers that are not visible with conventional staining techniques, allowing us to visualize HSV1 protein within AD clinical hippocampal specimens. Through this, we seek to establish a new understanding of the role of viral factors in the development of AD pathology.

Result

Our research has yielded a significant breakthrough. We have successfully identified viral proteins within clinical AD hippocampal specimens using dExPath, a feat that was not possible with traditional immunofluorescent staining techniques.

Conclusion

The findings of our research offer significant implications for the understanding of Alzheimer’s disease. By opening new avenues for therapeutic intervention targeting the interaction between HSV1 protein and tau, we provide potential insights into the disease’s etiology and potential treatment strategies. This could potentially lead to groundbreaking advancements in the treatment of Alzheimer’s disease.
Synergism across neurodegenerative diseases using biological definitions
Authors: Poston Kathleen L.
Published: January 2025

The ability to define neurodegenerative diseases of aging based of biology rather than clinically defined syndromic presentations follows from biomarker development and reflects underlying pathology in living people. The NIA‐AA Research Framework (Jack et al 2018 Alzheimers Dement) proposed the biological definition for Alzheimer’s disease (AD) and sought to provide a common language to identify and stage research participants, who were not cognitively impaired but had abnormal AD biomarkers; it has been revised. The biological classification of Huntington’s disease (Tabrizi et al 2022 Lancet Neurology) included a biological research definition with an integrated staging system, centered on biological, clinical, and functional assessments. Simuni et al (2024 Lancet Neurology) proposed the Neuronal Synuclein Disease (NDS) biological definition, also with integrated staging system, encompassing anyone with biomarker evidence of predominantly neuronal alpha‐synuclein pathology, including people with Parkinson’s disease, dementia with Lewy bodies, or related clinical phenotypes, based on the seed amplification assay biomarker. A key paradigm shift central across these neurodegenerative diseases is diagnosis is not based on the clinical manifestations, but rather disease occurs and can be diagnosed regardless of specific, or in some cases without any, clinical signs or symptoms. It’s recognized these disease processes begin before the onset of symptoms, possibly decades before. Thus, these biological definitions translate this long‐touted recognition into actional research frameworks. There are numerous implications for such a paradigm shift. For one, this allows people to enroll in clinical studies and in clinical trials before the manifestation of classic clinical syndromes, and is likely the only way to test potential therapies for indications that prevent clinical symptoms in people with underlying disease. Further, by separating the syndrome from biology, these definitions recognize that syndromic presentations are not always specific for the underlying pathology, addressing the ongoing challenge of clinical heterogeneity in trials. Another implication of these biological definitions is the co‐occurrence of multiple pathologies, a long under‐recognized entity, can be prospectively studied in living people across the entire clinical spectrum from asymptomatic to severe functional impairment. As these biological definitions iterate upon newly obtainable and validated biomarker data from observational cohorts a more complete molecular characterization of neurodegeneration in aging, independent of syndromic classification, can begin to emerge.
A novel culprit in glucose hypometabolism in Alzheimer’s disease
Authors: Penalva Ylauna , Hernandez Marina Ruelas , Cinkornpumin Jessica , Kaartinen Mari , Pastor William , Munter Lisa
Published: January 2025

Background

Alzheimer’s disease is characterized by early decreases in cerebral glucose metabolism which are linked to reduced glucose transporter 1 (GLUT1) expression at the blood‐brain barrier (BBB). Another key disease hallmark is the abundance of Aβ peptides as plaques in the brain which arise from the processing of the amyloid precursor protein (APP). Autosomal dominant inherited mutations causatively link APP itself to AD, rendering it imperative to fully understand APP’s physiological functions to define the underlying biology of AD. Previous studies in APP knockout (KO) mice implicate APP in metabolic processes such as mitochondrial function and insulin action. However, GLUT1 regulation as well as glucose metabolism at the BBB has yet to be investigated.

Method

We use APP KO mouse embryonic fibroblasts (MEFs), mouse primary cerebral endothelial cells, and vessels enriched from mouse brains to study GLUT1 physiology. RNAseq data was collected in MEFs to determine transcriptional changes underlying studied phenotypes.

Result

Seahorse analysis of APP KO MEFs revealed a 50% decrease in glycolytic activity and 75% decrease in mitochondrial respiration as compared to control. Glucose uptake was also significantly decreased in the absence of APP. These metabolic defects were underlined by a 2‐fold decrease in GLUT1 total expression and a 5‐fold decrease in GLUT1 cell surface levels. The investigation of signaling pathways responsible for GLUT1 upregulation showed that PI3K/Akt/mTORC pathway was downregulated in APP KO MEFs as compared to control. Primary cerebral endothelial cells and vessels recapitulated the decrease in GLUT1 expression as well as decreased activation of the PI3K/Akt/mTORC pathway, suggesting a completely novel role for APP in cerebral glucose metabolism. Analysis of RNAseq data collected in MEFs for pathways regulating glucose metabolism revealed widespread changes in extracellular matrix gene expression.

Conclusion

Our findings posit APP as a major regulator of GLUT1 expression and glucose metabolism. This new perspective on APP is crucial for AD therapy as novel approaches could be developed to target decreased cerebral glucose metabolism.
Detecting Major Depressive Disorder from EEG Signals as a Biomarker for Alzheimer’s Disease
Authors: Orimaye Sylvester O , Smith Jeremy , Colado Guy , Tong Sunvy , Jager Tomas
Published: January 2025

Background

Major Depressive Disorder (MDD) is a complex and multifaceted condition. Traditional screening methods may not capture the full spectrum of symptoms, causing delayed diagnoses or misdiagnoses. Further, MDD is highly prevalent among patients with mild cognitive impairment (MCI), which may then progress to Alzheimer’s disease (AD). Research suggests that MDD among patients with MCI substantially accelerates cognitive decline many years before the onset of AD. We show that a machine learning model can aid MDD diagnoses as a potential biomarker of AD.

Method

Since MDD is associated with changes in prefrontal brain activity, we used electroencephalogram (EEG) signals from this brain region to train a two‐class multi‐layer perceptron (MLP) neural network model that discriminates between MDD patients and healthy controls. The MLP parameters include the lbfgs solver, three hidden layers, 1000 max iterations, alpha of 1e‐6, a relu function, tolerance level of 1e‐3, and a learning rate of 0.1. We used the Multi‐Modal Open Dataset for Mental Disorder Analysis (MODMA) data, which contains three EEG channels, including Fp1, Fp2, and Fpz locations. We extracted predictive features from each channel by transforming the raw EEG signals to train our model. Our features included the EEG signal’s maximum, mean, standard deviation, skewness, kurtosis, and mean absolute Fast Fourier Transform extended with multiple imputed data on the original 50 patients. This led to 1550 observations at 775 per MDD or control. Training and testing data was split using a ratio of 0.70 to 0.30, and experiments were performed using the Scikit‐learn Python library.

Result

The experimental results indicate that the selected three‐channel EEG features can distinguish between MDD and healthy control subjects. The classification accuracy score was 76.8%, and the area under the curve (AUC) score was 85.3% (CI: 83.4% to 87.2%).

Conclusion

We have demonstrated the effectiveness of using EEG signals to detect MDD in patients. The potential applications of our findings are the ability to aid in early medical diagnosis and serve as probable biomarkers of MCI and AD. Additional research is warranted to investigate more predictive features from the EEG signals.