bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing a core outcome set for people living with mild cognitive impairment: Protocol for the MCI Core Outcomes Study
Authors: Gabb Victoria Grace , Woodward Natalie , Harding Sam , McNair Angus , Clayton Julie , Alderman Sophie , Barrett‐Muir Winsome , Richardson Alan , Rudd Sarah , Webb Joseph , Dooley Jemima , Coulthard Elizabeth , Turner Nicholas
Published: January 2025

Background

Core outcome sets (COS) are a set of outcomes which stakeholders agree should be collected and reported as part of a minimum dataset for studies in a clinical population. COS developed collaboratively with patients and other stakeholders encourage researchers to report outcomes which are considered important by affected individuals. COS may reduce heterogeneity of outcome selection allowing for better synthesis across studies (e.g., meta‐analysis) and reduce selective reporting of positive outcomes to support more informed healthcare decisions. There is currently no approved COS for patients with mild cognitive impairment (MCI). Therefore, we are collaborating with patient and public contributors to develop a COS for people with MCI.

Method

The study will involve three stages: 1) an umbrella review, which will provide outcomes from published studies by retrieving articles from systematic and scoping reviews of interventional studies involving people with MCI; 2) interviews with stakeholders with lived experience of MCI (people living with MCI and their partners/relatives) and relevant professional stakeholders (e.g., health and social care professionals or those from relevant charitable organisations or industry) will identify additional outcomes stakeholders consider important; 3) a “long list” of possible outcomes will be curated from Stage 1 and 2 and a two‐round Delphi survey process and consensus meeting(s) will identify the final COS to be recommended.

Result

The study is ongoing. The review is at the data extraction stage. From the first 25 studies, the most common outcome measurement instruments reported so far are all related to cognitive functioning: the Mini‐Mental State Examination (9/25, 36%), Trail Making Test (6/25, 24%), and Verbal Fluency Test (6/25, 24%). Updated results will be available for the conference. Interviews are anticipated to start in mid‐2024 with the COS published in 2025.

Conclusion

A COS for people with MCI will identify outcomes of importance for individuals affected by MCI and improve transparent outcome reporting in interventional research to better support patient care.
Associations of Gait, Cognitive Imparment, Dementia and Obstructive Sleep Apnea inIndividuals with Down Syndrome: Preliminary Findings
Authors: da Conceição Conceição Aline de Souza Gonçalves Gomes , Cecilio Ana Paula Assunção , Sant´Ana Livea Carla Fidalgo Garcêz , Fonseca Luciana , Forlenza Orestes Vicente
Published: January 2025

Background

It is known that atipical aging in DS is related to a high risk of early dementia, with neuropathological charactheristics compatible with Alzheimer´s disease (AD). Changes in functional mobility are expected throughout the aging process, with impairments in motor performance, involving balance and gait. Growing evidence suggests that sleep disruption may also accelerate the progression to symptomatic Alzheimer’s disease (AD) in this population. Therefore, it is mandatory to assess sleep quality and diagnose sleep‐disordered breathing, especially obstructive sleep apnea (OSA), associated with DS, to improve cognition and quality of life, preventing related comorbidities.

Method

We evaluated 66 individuals with DS (≥20 years), divided into 3 groups: stable cognition, prodromal dementia, and Alzheimer’s disease. Each individual was evaluated with the Performance‐Oriented Mobility Assessment (POMA) protocol, Polysomnography, and Cambridge Examination for Mental Disorders of Older People with Down’s Syndrome and Others with Intellectual Disabilities interview adapted for adults with DS (CAMDEX‐DS).

Result

The logistic regression model with the stepwise backward technique, with the initial model including age, gender, body mass index (BMI), degree of intellectual disability, and apnea‐hypopnea index (AHI), showed that gait performance in POMA are independent factors associated with the diagnosis of control and dementia (POMA p < 0.005). All cognitive domains were correlated with OSA, but only orientation had a significant correlation (p‐value 0.268). We did not find a difference in OSA scores among POMA.

Conclusion

The POMA results indicate that those with AD have worse gait performance and a higher risk of falls relative to those with dementia and stable cognition. There was no evidence of correlation between gait speed and OSA, which may have been influenced by the sample size (n:17). Further longitudinal studies with larger samples are needed to confirm our results.
Association of Tau and Amyloid with Representational Similarity in the Amygdala’s Reactivity to Negative and Neutral Stimuli in Individuals at Risk for Alzheimer’s Disease
Authors: Liu Mingtong , Betthauser Tobey J. , Gresham Lauren K. , Schaefer Stacey M.
Published: January 2025

Background

Emotional dysfunction is often observed in older adults at the early stage of Alzheimer’s disease. Individuals at risk for Alzheimer’s disease may show differences in emotional reactivity before they exhibit cognitive decline (Fredericks et al., 2018). It is unclear whether emotional symptoms are associated with brain changes during the development of the disease. In this study, we examined the associations of tau and amyloid burden with representational similarity in the amygdala’s reactivity to negative and neutral stimuli in individuals at risk for Alzheimer’s disease.

Method

Participants are from the Wisconsin Registry for Alzheimer Prevention (n = 81, 69% Female, 6% BIPOC). During the fMRI scans, participants viewed 30 negative, 30 neutral, and 30 positive images followed by a neutral face. Representational similarity analysis was used to calculate the similarity of the amygdala activation pattern to negative images and neutral images. Amyloid and tau burden were measured using the positron emission tomography.

Result

Our results showed that greater tau burden in the entorhinal cortex is significantly related to less neural similarity in right amygdala to negative and neutral stimuli. Individual differences of tau burden in the entorhinal cortex, but not amyloid burden, significantly predict neural similarity in the right amygdala to negative and neutral stimuli when controlling for covariates, such as age, gender, and race. Neural similarity in both left and right amygdala to negative and neutral stimuli is greater in the T− group, compared to the T+ group.

Conclusion

Greater tau burden in the entorhinal cortex predicts less neural similarity in the right amygdala to negative and neutral stimuli, suggesting a greater differentiation of the amygdala’s response with higher tau.
The impact of locus coeruleus degeneration on pair bonding and other Alzheimer’s disease‐relevant phenotypes in monogamous prairie voles
Authors: Kelberman Michael A. , Donaldson Zoe R , Winther Kelly , Franks Emily , Weinshenker David
Published: January 2025

Background

Alzheimer’s disease (AD) fractures social relationships, extending the burden of disease beyond the affected individual and onto caregivers and loved ones. One brain region known to be crucial in regulating social behaviors is the noradrenergic locus coeruleus (LC), a region that becomes dysfunctional as AD progresses. Unfortunately, deficits in social bonding have been relatively understudied in AD, due in part to the limited social behavioral repertoires of mouse and rat models of AD. Here, we used monogamous prairie voles, which display many human‐relevant complex social behaviors, to assess the impact of LC degeneration on social bonding and other AD‐relevant phenotypes.

Methods

Prairie voles (male and female, 3 – 6 months of age) were administered the selective LC neurotoxin DSP4 or saline (i.p., administered twice separated by a week). Voles were paired a week after their last injection and tested on partner preference tests 1, 3, and 7 days post‐pairing, timepoints designed to test for the presence and duration of bond impairment. Animals were then tested on sleep latency (arousal), Y‐maze (working memory), novelty‐suppressed feeding (anxiety‐like phenotypes), and resident intruder (social behavior) tasks to assess other AD‐relevant phenotypes. Vole pairs were then separated and singly housed in separate vivariums. After 4 weeks of isolation, they were re‐tested in the same battery of behavioral tests and in a final partner preference.

Results

DSP4 administration impaired bond formation in male but not female voles, even after 7 days of cohabitation, a striking result as other manipulations that impair bond formation typically delay rather preclude bonding. Further supporting a lack of pair bonding, DSP4 treated males displayed lower levels of aggression in a resident intruder task while still co‐housed with their partner. Meanwhile, partner separation increased anxiety‐like behavior in DSP4‐treated males, suggesting an interaction with a well‐delineated social stressor. Female behavior was unaffected by DSP4 treatment. Confirmation of LC lesions with HPLC and IHC, and behavioral analysis of partner preference after separation are ongoing.

Conclusions

This study shows that LC degeneration may contribute to social behavior abnormalities observed in prodromal AD. It further suggests that LC degeneration may exaggerate behavioral deficits following the loss of a partner.
Social Engagement as a Protective Factor for Cognition in Older Adults: Examining Sex and Race Differences
Authors: Dixon Jasmine S , Amariglio Rebecca E , Howard Marjorie , Sachs Bonnie C. , Snyder Heather M , Espeland Mark A. , Baker Laura D , Papp Kathryn V
Published: January 2025

Background

Social engagement, characterized as frequency of family/friends contact and activities with others, has emerged as a protective factor for Alzheimer’s disease. However, it is unclear how social engagement protects against cognitive decline and whether there are differences across sex and racial groups. Here we determine whether: 1) greater social engagement is associated with better global cognition in older adults at risk for cognitive decline, 2) depressive symptoms and vascular risk are mediators, and 3) the associations vary by sex and race in a cognitively at‐risk but clinically unimpaired sample.

Methods

We analyzed baseline subset data from adults who self‐identified as monoracial Black (n = 340) or White (n = 1,451) participating in the U.S. POINTER clinical trial. Social engagement was measured by a composite of seven items from the modified (for cultural sensitivity) Community Healthy Activities Model Program for Seniors (CHAMPS). Vascular risk was quantified by the Framingham Risk Score and depressive symptoms on the Geriatric Depression Scale (dichotomized). Global cognition was measured using a multi‐domain cognitive composite. Linear regression models examined associations between social engagement and cognition in the whole sample (n = 1,791) and in race‐by‐sex stratified analyses. Mediation models examined vascular risk and depressive symptoms as mediators. All models were adjusted for age, education, and time of enrollment.

Results

Across the whole sample, greater social engagement was associated with better global cognition, fewer depressive symptoms, and less vascular risk. Vascular risk, but not depressive symptoms, was a significant mediator such that greater social engagement was associated with lower vascular risk, and greater vascular risk was associated with poorer global cognition. In race‐by‐sex stratified analyses, greater social engagement was associated with better global cognition only in White women. Greater social engagement was associated with lower depressive symptoms for White women, White men, and Black women but not Black men.

Conclusions

Results suggest that social engagement is a protective factor for global cognition, and against vascular risk and depressive symptoms. Vascular risk may be a modifiable biological mechanism underlying the protective influence of social engagement on cognition for older adults. The CHAMPS data suggest that White women exhibit the greatest benefit from social engagement.
The Huntington’s Disease Integrated Staging System
Authors: Long Jeffrey M ,   Huntington’s Disease Regulatory Science Consortium (HD‐RSC) Work Group
Published: January 2025

The Huntington’s Disease Integrated Staging System (HD‐ISS) comprises a biological research definition of HD and evidence‐based staging centered on prognostic biological, clinical, and functional landmarks. It is the result of a formal consensus process within the Huntington’s Disease Regulatory Science Consortium’s Regulatory Science Forum (RSF), a working group made up of expert representatives from industry and academia. The RSF considered prognostic biomarkers, signs, and symptoms of HD, and performed empirical data analysis. It used observational data to calculate healthy‐control‐based landmark variable cut‐offs for stage classification and to internally validate the framework.

The HD‐ISS starts with Stage 0, which comprises individuals with ≥ 40 CAG repeats in the huntingtin gene (HTT) before detectable indications of disease pathology. HD progression is verified by assessments of underlying pathophysiology (Stage 1), then proceeds to a detectable clinical phenotype (Stage 2) and continues to a decline in function (Stage 3). Operationally, individuals can be classified into Stages 1‐3 based on CAG‐independent thresholds of landmark assessments. Importantly, the HD‐ISS covers the entire disease spectrum starting from birth, and is unconstrained by concepts such as “manifest,” “premanifest,” or “prodromal.”

The HD‐ISS allows the definition of study populations across the entire duration of the disease trajectory, including before clinical motor diagnosis. Clinical trials using the HD‐ISS can be implemented immediately. In HD‐ISS Stages 2 and 3, we have knowledge of how to enrich and what endpoints to measure. Although clinical trials in Stage 1 may require further research, that work is ongoing. While participant populations may also be defined by additional enrichment criteria as determined by the study objectives, we propose that all new clinical studies use the HD‐ISS.
A Biological Definition and Research Integrated Staging System of Neuronal α‐Synuclein Disease: Research Framework
Authors: Simuni Tanya
Published: January 2025

The NSD‐ISS Working Group developed a data‐driven approach to: 1) determine a biologic definition for disease; 2) establish a framework for a disease staging platform. NSD is defined by the presence of pathologic n‐asyn (S) assessed by a validated in vivo biomarker and ultimate presence of dopaminergic neuronal dysfunction (D). This biologic definition is independent of the presence of clinical features, or if present, of the specific clinical syndrome. NSD‐ISS integrates these biological anchors (S and D) and degree of functional impairment caused by motor, cognitive or other non‐motor signs. Individuals in stage 0 and 1 are free of clinical signs and can be diagnosed either by presence of fully penetrant pathogenic variants (G) in SNCA gene (Stage 0), n‐asyn alone (Stage 1A) or in combination with dopaminergic neuronal dysfunction (Stage 1B). Stage 2 is characterized by subtle clinical signs but no functional impairment, with either n‐asyn (S) alone (Stage 2A) or in combination with dopaminergic neuronal dysfunction (Stage 2B). Stages 3‐6 require the presence of both biomarkers and stage‐specific increase in severity of functional impairment. We have developed operational definitions and applied staging to PPMI and two interventional studies cohorts.

Conclusions

The NSD‐ISS provides a comprehensive biologically‐based framework essential to advance biologically‐targeted therapeutic development. The NSD‐ISS is expected to evolve as additional biomarkers emerge. We present the first data‐driven application of the NSD‐ISS, highlighting the heterogeneity of the biological stages in a phenotypically homogeneous cohort.
Sex‐Specific Causal Genes for Alzheimer’s Disease via Proteome‐Wide Association Studies
Authors: Reid Danielle M. , Belloy Michael E.
Published: January 2025

Background

Women are at higher risk of developing Alzheimer’s disease (AD). Sex differences in AD pathobiology and prevalence appear to be partially attributed to genetics, but sex‐stratified genome‐wide association studies (GWAS) of AD have demonstrated a relative paucity of associated variants, which may reflect challenges of limited power. Furthermore, these studies lack information regarding the impact on sex‐specific proteins and pathways relevant to AD, which limits clinical translation and targeted drug development. Sex‐stratified protein quantitative trait locus (pQTL) studies pose to address these limitations. We hypothesized that directly integrating brain pQTL data with the largest to date sex‐stratified AD GWAS would increase power to reveal sex‐specific AD associated genes.

Method

Sex‐stratified GWAS of AD from Belloy et al. 2023 included 410,276 female and 385,813 male non‐Hispanic White individuals of European ancestry. Human brain proteome data with matching genome‐wide data were available from Wingo et al. 2022 (NSubjects = 722) and 2023 (NWomen = 507; NMen = 301). Briefly, genetic variants were associated with proteins through the FUSION package to estimate effects on protein abundance and produce non‐sex‐stratified (NProteins = 2,934) and sex‐stratified protein‐specific variant weights (NProteins = 1,800 for males; NProteins = 2,463 for females). This approach retains only proteins that show significant genetic associations (i.e., protein levels displaying significant heritability). Proteome‐wide association studies (PWAS) were performed via FUSION combining sex‐stratified AD GWAS with non‐sex‐stratified and sex‐stratified protein weights (Figure‐1). Enrichment/pathway analysis for gene and disease ontology was conducted via the DOSE package (R 4.3.3).

Result

Sex‐matched AD PWAS identified 27 and 2 AD causal genes for females and males, respectively. Sex‐stratified AD GWAS integrating non‐stratified protein weights identified 30 causal genes in females and 7 in males. Upon filtering results of both discoveries for sex specificity, 18 female and 2 male AD causal genes were prioritized (Figure‐2). Enrichment/pathway analysis of female‐specific AD causal genes highlighted metabolic‐related health outcomes (Figure‐3).

Conclusion

We performed sex‐stratified PWAS of AD and identified 18 female‐specific AD causal genes, of which 8 strikingly converged onto metabolic disorders as a putative female‐specific AD pathway. These findings increase our understanding of AD pathogenesis and may inform therapeutic target development relevant to sex‐specific precision medicine. Supporting analyses in additional proteogenomic resources are ongoing.
Quantitative multi‐parameter mapping of locus coeruleus in aging and Alzheimer’s disease
Authors: Lenzoni Sabrina , Femminella Grazia Daniela , Loane Clare , Kurt Elif , Duckett Millie , Weiskopf Nikolaus , Callaghan Martina F , Dolan Ray , Howard Robert J , Düzel Emrah , Hämmerer Dorothea
Published: January 2025

Background

The Locus Coeruleus (LC) is prominently affected by neuronal loss in the earliest stages of Alzheimer’s disease (AD). Assessing LC integrity can serve as an important early biomarker for assessing AD progression. Neuromelanin (NM) accumulates in LC neurons and NM imaging has therefore been proposed as a means of imaging the LC. As signal intensity is taken as a proxy for cell density, a quantitative imaging approach of the LC, which is less variable across sites and time is desirable. The present study used a multi‐parameter mapping (MPM) protocol optimized for LC imaging to compare weighted and quantitative maps in healthy younger, healthy older adults and individuals with AD.

Methods

Structural MRI data was acquired in a group of 26 healthy young adults, 26 healthy older adults and 26 individuals with Alzheimer’s disease. Three sets of T1‐weighted, MT‐weighted, and PD‐weighted images yielded quantitative maps (R1, MTsat, PD, and R2*) in each individual within one scan session. Qualitative and quantitative methods were used to assess weighted and quantitative maps for LC imaging across groups.

Results

Qualitatively, LC visibility was higher in weighted images. The LC was also apparent in R1 maps, but less clearly visible in MTsat and R2* maps (Figure 1). LC contrast ratio (with pons as reference), was reduced in Alzheimer’s disease compared to younger adults as detected by MTw scans (p = .001) and to older adults as detected by T1w (p<.001), MTw (p<.001), and PDw scans (p = .007). No group differences were detected in quantitative maps, suggesting less sensitivity to pick up typical LC integrity reductions. PD maps could not be reliably estimated in the modified setup of the MPMs.

Conclusion

Although among the quantitative maps LC was most visible in R1 images, our findings indicate that R1 maps capture the LC signal intensity less well as compared to non‐quantitative LC imaging, as suggested by a qualitative assessment of LC visibility and inability to detect known group differences. Further research should improve sensitivity of quantitative maps for LC assessment by combining sequences capturing different aspects of LC tissue properties.
Elucidating the role of individual mTORC components on neuronal insulin signaling
Authors: Stahl Jack , Joji Aswathy , Khorkova Olga , Volmar Claude‐Henry , Wahlestedt Claes
Published: January 2025

Background

Rapamycin is currently in clinical trials for AD, yet numerous studies have suggested that rapamycin inhibits mTORC2 as well as mTORC1, which could be detrimental for AD pathology. Brain insulin resistance is a known aspect of AD pathology and mTORC2 inhibition reduces AKT phosphorylation, which is a main mediator of cellular insulin signaling, perpetuating insulin resistance and further worsening brain glucose metabolism. Here, we show that rapamycin prevents insulin‐induced AKT phosphorylation in human neurons and explore the differential effects of mTORC1 and mTORC2 on neuronal insulin sensitivity.

Method

Human neuronal cells were treated with 100nM rapamycin for 48 hours prior to collecting cellular protein for western blot analysis of S6 phosphorylation (mTORC1) and AKT phosphorylation (mTORC2). We then sought to specifically inhibit each complex by knocking down Raptor and Rictor, essential components for the formation of mTORC1 and mTORC2, respectively. Cells were transfected with siRNAs targeting Raptor or Rictor for 72 hours prior to collecting cellular protein for western blot analysis. For insulin experiments, cells were stimulated with 100nM insulin in serum‐free media for one hour prior to collecting protein for downstream analysis.

Result

Treatment with 100nM rapamycin for 48 hours drastically decreased phosphorylation of ribosomal protein S6 (mTORC1) by 92% and phosphorylation of AKT (mTORC2) by 95%. While knocking down Rictor decreased mTORC2 activity by 71%, we were surprised to see that knocking down Raptor increased mTORC1 activity 2.1‐fold 72 hours post‐transfection. Treatment with 100nM rapamycin for 48 hours, which inhibits both mTORC1 and mTORC2, decreased total cellular protein and completely blocked insulin‐induced AKT phosphorylation at serine 473.

Conclusion

Rapamycin has inhibitory effects on neuronal insulin signaling by inhibiting mTORC2, which can exacerbate AD pathology and symptoms. Our finding that knocking down Raptor increases mTORC1 activity contradicts the reduction in S6 phosphorylation seen with rapamycin treatment, a well‐established mTORC1 inhibitor, warranting further investigation into the role of individual mTORC components on neuronal metabolism. While mTORC1 inhibition has shown promise as a therapeutic strategy for AD, inhibition of mTORC2 can be detrimental for AD and elucidation of the metabolic role of each complex in the context of AD can guide future mTOR‐related therapeutic strategies.
Redundancy in systematic research of exercise interventions for older adults with cognitive impairment: Is more better?
Authors: Ries Julie D , De Santis Claudia , Ouabicha Kaoutar , Dagne Mahederemariam Bayleyegn , Sood Pallavi , Heyn Patricia C
Published: January 2025

Background

Exercise as an intervention to impact cognition in older adults with mild cognitive impairment and dementia is a well‐studied phenomenon. Recent proliferation of synthesis studies on this topic might be perceived as a positive contribution to the science of exercise as medicine, but research redundancy (defined here as multiple overlapping review studies utilizing the same randomized controlled trials [RCTs]) is not only unnecessary but can be harmful. Redundancy can create research waste and be detrimental to the ability to draw confident conclusions from the evidence. The purposes of this meta‐research are to (1) evaluate redundant representation of RCTs across published meta‐analyses (MAs) on the effects of exercise on older adults with cognitive impairment, and (2) discuss implications for interpretation of the evidence.

Method

This study was borne of a living evidence synthesis project, following standard synthesis methodology including PROSPERO registration, PRISMA guidelines, librarian‐assisted search strategy using multiple databases, and recurrent searches in 2015, 2018, 2020, and 2023.

Result

Thirty‐eight MAs met our inclusion criteria, referencing a total of 692 RCTs. Of the 692 studies cited in the MAs, only 267 (38.6%) are unique studies. One‐hundred‐forty‐nine of those unique studies were cited in only one MA, and 118 were cited in anywhere between 2‐17 different MAs. Thus, 425 (61.4%) of the total 692 RCTs recognized across the 38 MAs were redundant. Categorized by the number of MAs in which a study was represented, 37 RCTs (13.9%) were included in 2 MAs, 48 (18%) were represented in 3‐5 MAs, 26 (9.7%) were in 6‐10 MAs, and 7 of the unique studies (2.6%) were represented in 11‐17 MAs.

Conclusion

The impact of exercise on cognition of older adults with cognitive impairment is an important topic being extensively researched. While replication is a common practice in research, excessive redundancy in research does not provide new contributions and may be wasteful. Additionally, there are negative implications for meaningful interpretation of evidence when there is significant redundancy across publications. Efforts to reduce research waste might include rigorous research protocol registration requirements and the use of artificial intelligence to aid in monitoring protocols and publications.
Head‐to‐head evaluation of leading blood tests for amyloid pathology
Authors: Petersen Kellen K. , Schindler Suzanne E. , Tosun Duygu , Saef Benjamin A. , Shaw Leslie M. , Li Yan , Saad Ziad S. , Triana‐Baltzer Gallen , Baratta Michael , Rosenbaugh Erin G. , Bannon Anthony W. , Potter William Z. ,   the Alzheimer’s Disease Neuroimaging Initiative (ADNI), and the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium Plasma Aβ and Phosphorylated Tau as Predictors of Amyloid and Tau Positivity in Alzheimer’s Disease Project Team
Published: January 2025

Background

Blood tests that accurately determine the presence of amyloid pathology are critically needed. Compared to amyloid PET and CSF tests, blood tests are less expensive, less invasive, more accessible, and highly scalable. The Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium evaluated the accuracies of leading AD blood tests in classifying amyloid PET status.

Method

Assays from C2N Diagnostics (Aβ42, Aβ40, p‐tau217, p‐tau217 ratio [phosphorylated to non‐phosphorylated tau at position 217]), Fujirebio Diagnostics (Aβ42, Aβ40, p‐tau217), ALZPath (p‐tau217), Janssen (p‐tau217), Roche Diagnostics (Aβ42, Aβ40, p‐tau181, GFAP, NfL), and Quanterix (Aβ42, Aβ40, p‐tau181, GFAP, NfL) were run on plasma samples from ADNI participants with corresponding florbetapir‐PET scans. Unadjusted logistic regression models were constructed for each measure or combination of measures from each assay platform. The classification accuracies of the plasma biomarker measures for amyloid PET status (Centiloids>20) were assessed with receiver operating characteristic area under the curve (AUC) analyses and compared using DeLong’s tests.

Result

The cohort included data from 392 individuals with a median age of 78.1 years; 193 (49.2%) were female; 132 (33.7%) were APOE ε4 carriers; 191 (48.7%) were amyloid PET positive; and 192 (49.0%) were cognitively impaired (Clinical Dementia Rating>0), (Table 1). Models with high classification accuracies for amyloid PET status included the C2N p‐tau217 ratio + Aβ42/Aβ40 (AUC 0.929 [95% confidence intervals 0.902‐0.956]) and Fujirebio p‐tau217 + Aβ42/Aβ40 (0.911 [0.882‐0.940]), (Table 2). The AlzPath p‐tau217 (0.885 [0.851‐0.920]), Janssen p‐tau217 (0.882 [0.848‐0.916]), Roche p‐tau181 + Aβ42/Aβ40 + GFAP + NfL (0.873 [0.838‐0.909]), and Quanterix p‐tau181 + Aβ42/Aβ40 + GFAP + NfL (0.808 [0.763‐0.854]) models had lower accuracies than the C2N p‐tau217 ratio + Aβ42/Aβ40 model (p = 0.0006, 0.0006, 0.0006, and <0.0001, respectively), (Figure 1). In 122 individuals with CSF Roche Elecsys p‐tau181/Aβ42 data, the classification accuracy for amyloid PET status was 0.915 (0.864‐0.967).

Conclusion

In this head‐to‐head study, logistic regression models of C2N p‐tau217 ratio + Aβ42/Aβ40 and Fujirebio p‐tau217 + Aβ42/Aβ40 were among the most accurate in classifying amyloid PET status. The classification accuracies of the blood tests for tau PET status, brain atrophy status, and clinical dementia symptoms will also be assessed.
Disruption of Arc‐NMDAR‐p55PIK‐AKT pathway increases Aß42 and Aβ plaque deposition, and reduces CA3 neuron counts in APPswe/PS1∆E9 mouse model
Authors: Gladulich Luis , Cuoco Camila , Worley Paul F
Published: January 2025

Background

Arc is a synaptic immediate early gene that mediates two distinct pathways at excitatory synapses. Canonically, Arc accelerates endocytosis of AMPA receptors by direct binding to TARPgs and endocytic machinery and thereby contributes to mGluR‐LTD. Arc also acts at recently potentiated synapses, where it is phosphorylated by CaMKII and binds NMDAR subunits NR2A and NR2B and recruits the PI3K adaptor p55PIK to assemble a signaling complex that activates AKT and inhibits GSK3β. This Arc‐NMDAR‐p55PIK‐AKT signaling mediates metaplasticity that prevents depotentiation of recently potentiated synapses and is important for memory updating (Arc‐LTP pathway). Arc‐NMDAR‐p55PIK‐AKT signaling contributes significantly to total AKT activity, which is a pro‐growth/pro‐survival signal, and can be selectively disrupted by conditional deletion of p55PIK. The Arc‐LTD pathway has previously been shown to enhance APP processing to generate Aß by recruiting g‐secretase to endosomes. Here, we examine the role of the Arc‐LTP pathway in Aß amyloidosis, and cell viability using the APPswe/PS1∆E9 mouse model.

Method

We bred p55PIK floxed(p55PIKflox/flox) mice with APPswe/PS1∆E9(APP/PS1) mice and Nestin‐Cre to generate APP/PS1+ mice that were also conditional knock‐outs for p55PIK. p55PIKflox/flox; APP/PS1+ mice without Cre were examined as controls. Mice were examined at 6 m. Aβ40/42 were measured via ELISA and IF staining. Cell count was done via NeuN co‐staining. Comparisons used Prism 10 software and student’s T‐test for comparison and considered statistically significant if p<0.05.

Result

Compared to APP/PS1, APP/PS1;p55PIK KO mouse forebrain exhibited roughly two‐fold increase in Aβ42 in both the PBS and formic‐acid soluble fractions and a corresponding increase in both number and size of Aβ plaques. Aß40 levels were not significantly increased. Neuronal cell counts in the hippocampus suggested ∼20% reduction in the CA3 region without changes in other regions.

Conclusion

Preliminary studies suggest a role for Arc‐NMDAR‐p55PIK‐AKT signaling in APP processing. The prominent increase of Aß42 and plaque area are consistent with a role in effective g‐secretase processing of APP while the reduction of CA3 cell counts suggests a role in neuron viability. Arc acting at potentiated synapses appears to have a protective effect. Ongoing studies are examining larger cohorts of both genders at 6m and 12m
Pharmacological reacidification of lysosomes attenuates intraneuronal amyloidosis, early neuron death, and amyloid plaque formation in 5xFAD mice
Authors: Malampati Sandeep , Stavrides Philip , Im Eunju , Goulbourne Chris N. , Mohan Panaiyur S. , Das Bhaskar C. , LEE Ju‐Hyun , Nixon Ralph A. , Stavrides Philip , Im Eunju , Goulbourne Chris N. , Mohan Paniyur S. , Das Bhaskar C. , Lee Ju‐Hyun , Nixon Ralph A.
Published: January 2025

Background

Autophagy‐lysosomal pathway (ALP) dysfunction emerges early in Alzheimer’s disease(AD). In mouse AD models, lysosomal acidification deficits impair ALP in neurons, in some inducing massive autolysosome accumulations, intraneuronal amyloid plaque, and early neuronal death yielding an extracellular amyloid plaque. This distinctive neurodegenerative pattern (PANTHOS) emerges in early‐stage AD and is recapitulated in human late‐onset AD (accompanying poster). Restoring lysosomal acidity via β2‐adrenergic receptor (β2‐AR) activation with Isoproterenol (ISO) reverses ALP dysfunction in PSEN1‐FAD patient fibroblasts.

Method

To reverse autolysosomal acidification deficits in vivo, we engineered 33 derivatives using ISO pharmacophore. Candidate compounds compared to ISO underwent screening in AD model cell lines and PSEN1‐FAD fibroblasts. After toxicity and PK/PD studies in vivo, a lead compound achieving an effective 11.63 micromolar brain concentration was administered IP for 2 or 4 months in 2‐month 5xFAD mice expressing a ratiometric autophagy/pH LC3 probe (5xFAD/TRGL) or in 2‐month 5xFAD versus vehicle‐treated 5xFAD/TRGL or 5xFAD controls respectively. Effective ISO sustained release pellets were implanted SC in the matched cohorts for 2 months. Outcomes were assessed using multiplex immunocytochemistry, computer‐aided ALP and pH analysis, EM, and behavioral tests (fear conditioning, novel object recognition).

Result

Incubating AD cell lines with the lead compound, restoring lysosome pH by acting through β2‐AR mediated, PKA‐dependent pathway, efficiently rescued autophagy. 5xFAD mice treatment with compound or isoproterenol restored neuronal lysosomal acidification and markedly attenuated ALP deficits. Lysosomal re‐acidification strikingly reduced ALP‐related intracellular amyloid/APP‐βCTF/Aβ (PANTHOS) and death of these neurons. Moreover, extracellular plaque burden reduction (>50%) commensurate with reduced neuronal death frequency. Notably, compound induced pH restoration alleviated memory impairments in 5xFAD mice.

Conclusion

These studies establish that lysosomal acidification deficit in the 5xFAD mouse is upstream of, and the likely basis for ALP failure, neuronal death, and amyloid pathology, consistent with the pathological sequence previously documented in multiple mouse AD models. The mechanism of action of β2‐AR activators via correcting PKA‐regulated Cl− and H+ flux in vATPase‐deficient lysosomes as established in PSEN1‐FAD fibroblasts, likely accounts for autolysosome pH correction in 5xFAD neurons. These findings demonstrate the potential of lysosomal remediation as a therapeutic approach for AD. Grant support: NIA P01AG017617, R01AG062376.
Deciphering the Relationship Between Astrocyte Calcium Signaling, Neurovascular Coupling, and Cerebrovascular Function in Alzheimer’s Disease
Authors: Weiss Blaine E. , Gant John C , Lin Ruei‐Lung , Kraner Susan D , Thibault Olivier , Sompol Pradoldej , Norris Christopher M.
Published: January 2025

Background

Astrocytes are a glial cell type responsible for many protective functions in the brain. While they are primarily recognized for regulating synaptic activity, they’re also essential for maintaining the neurovascular unit, and cerebral hyperperfusion during metabolic demand. Calcium signaling has been identified as a regulatory process for these functions. Amyloid Beta deposits (Aβ) are a primary diagnostic marker of Alzheimer’s disease, and are linked to synaptic degeneration, astrocyte reactivity, and cognitive decline. Alzheimer’s disease also frequently presents with vascular damage and hypoperfusion, suggesting impaired astrocyte function. We investigated the impact of amyloid burden on stimulation‐evoked vasoreactivity and astrocyte calcium signaling to determine potential patterns of physiological impairment that may contribute to Alzheimer’s disease pathology.

Methods

Six‐month‐old 5XFAD and littermate control mice were injected with AAV2/5‐Gfa104‐jGCaMP8f into barrel cortex and imaged three weeks later, while awake, using two‐photon microscopy. Neurovascular coupling experiments were conducted using timed air puff stimulation of whiskers, and calcium signals were recorded from activated astrocytes. Calcium transient properties were analyzed over different cellular compartments by custom developed Matlab applications. Vascular tone in response to stimulation was also measured, and correlations calculated with endfeet signaling.

Results

Astrocytes from 5XFAD mice showed a significant reduction in calcium signaling amplitudes, (F(1,53) = 8.735, p = 0.0047, n = 25,32) compared to wild type controls with a significant deficit in female 5XFAD mice. Correlations between other signaling properties such as rise/decay kinetics, and network connectivity were also characterized between the 5XFAD and control mice. Astrocyte endfoot compartments also showed reduced transient amplitudes. (F(1,30) = 3.226, p = 0.033, n = 17,15) Neurovascular coupling in the 5XFAD mice was reduced (F(1,39) = 2.511, p = 0.015, n = 20,19) despite no changes in arteriole elasticity. A correlation between astrocyte calcium signaling and the magnitude of stimulation‐induced vasodilation was observed in wild‐type mice but not in the 5XFAD group.

Conclusion

Amyloid induced pathology impairs the brain’s adaptivity to neuronal stimuli at the neurovascular unit. The uncoupling between vasoreactivity and astrocyte signaling processes implies that amyloid accumulation may render the brain vulnerable to conditions of neuronal hyperexcitability and metabolic dysregulation observed in Alzheimer’s disease.
Exploring Alzheimer’s disease progression through the lens of genetics and sleep disturbances
Authors: Fernandez‐Moguel Leticia , Gobdon Ifrah , Seixas Azizi A , Çöltekin Arzu , Dedic David , Ramos Alberto R
Published: January 2025

Background

T/S ratio represents the average telomere length per genome, and has been previously linked to Alzheimer’s Disease (AD) and biological sex [1], but there is a gap in our understanding of its interactions with sleep patterns. Towards filling this gap, we present a preliminary analysis exploring correlations between age, biological sex, T/S ratio and presence of a sleep disorder for patients with mild cognitive impairment (MCI) and AD against a “cognitively normal” (NL) baseline.

Method

Expanding on our previous work [2] we include the T/S ratio and the biological sex variables from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (n = 1409). We split biological age in decades, and create a binary variable for reported sleep disturbance, i.e., No = 0, Yes = 1, in either Neuropsychiatric Inventory Questionnaire (NPIK) or Obstructive sleep apnea (OSA). We then examine correlations between the studied variables in NL/MCI/AD groups. Table 1(a) shows the sample distribution.

Result

The T/S ratio decreases with increasing age, and it is statistically significantly lower for men than women on average (Figure 1, Table 1(b)), converging around age 90. In the group without sleep disturbances, no significant differences were observed for men, whereas for women, the groups (61‐70, MCI/AD) and (71‐80, NL/MCI) showed significant differences (Figure 2 & Table 1(b)). People with sleep issues exhibit erratic T/S ratio changes and more statistically significant differences depending on the cognitive state of the patient (Figure 2).

Conclusion

The T/S ratio decreases with age, and is lower for males than females. Importantly, the erratic T/S ratio pattern for people with sleep issues, especially in MCI and AD groups, suggest potential new hypotheses on genetics and epigenetics. Further research and refinement of these models may contribute towards early detection and intervention strategies for Alzheimer’s disease.

References

[1] Nudelman, KNH, et al. “Telomere shortening in the Alzheimer’s disease neuroimaging initiative cohort.” Journal of Alzheimer’s disease 71.1 (2019): 33‐43.

[2] Bonfa, A, et al. “Exploring the relationship between sleep disturbances and Alzheimer’s disease using machine learning.” Sleep 46. Supplement_1 (2023): A370‐A370.
Investigating Granulovacuolar Degeneration in Alzheimer’s Disease and Other Tauopathy Models
Authors: Dai Daniel S , Chio Tak Ian , Lee Virginia M.‐Y.
Published: January 2025

Background

Granulovacuolar degeneration (GVD) is a common feature in Alzheimer’s disease (AD) and other tauopathies such as corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Pick’s disease (PiD). Despite its prevalence, much remains unknown about the role of GVD in the pathobiology of these diseases. Morphologically, GVD is characterized by intraneuronal membrane‐bound vacuoles, also known as GVD bodies (GVBs). Previously, it has been observed that in vitro and in vivo mouse models of tauopathy can also induce GVB formation. Nevertheless, the in vivo models in particular remain poorly characterized. Herein, we provide a more systematic characterization of GVD in the in vivo mouse models to better enable elucidation of GVD and its relation to tau pathology and neurodegeneration.

Method

Brain sections were retrieved from various tauopathy mouse models. GVB distribution was characterized via immunohistochemistry using CK1δ as the primary GVB marker. Co‐staining with a phospho‐tau antibody (AT8) confirmed the presence of tau pathology in all of our models.

Results

CK1δ+ GVBs were detected in multiple tauopathy mouse models, including PS19 as well as AD‐tau‐injected wild type, 5xFAD, and 6hTau mice. The level of GVBs differ between mouse models and correlate with the level of tau pathology that was developed in these mice. In particular for the 6hTau mice, where the amount of GVBs was the most robust, temporal characterization of GVB formation shows the most significant increase in the number of GVB+ neurons from 1 to 3 months post‐AD‐tau injection. At the single cell level, the number of CK1δ+ puncta also increased over time. By 3 mpi, GVBs were detected beyond the hippocampus (site of injection) and in the cortical regions where tau pathology was also present. Finally, 6hTau mice injected with CBD‐, PSP‐, and PiD‐tau all developed GVBs, albeit at variable levels that parallel the extent of tau pathology.

Conclusions

GVB development tracks with tau pathology development in our in vivo mouse models. The increase in GVBs within a cell over time suggests that GVBs continue to form as tau pathology matures. This induction of GVBs by tau pathology is irrespective of the different tau strains from different tauopathies.
Plasma CycleGAN: Integrating Blood‐based Biomarkers for Cross‐modality Translation from MRI to PET
Authors: Chen Yanxi , Su Yi , Fu Yu , Chen Kewei , Weidman David , Caselli Richard J. , Reiman Eric M. , Wang Yalin
Published: January 2025

Background

Cross‐modality translation between MRI and PET presents significant challenges due to the distinct mechanisms underlying those modalities. Currently, the leading method for this translation is CycleGAN. Previous studies have proved a strong correlation between BBBMs and brain amyloid status measured by PET. However, the impact of blood‐based biomarkers (BBBMs) on PET image synthesis has not yet been thoroughly evaluated. In this study, we propose Plasma CycleGAN, a generative model based on CycleGAN to synthesize PET images from MRI, while also incorporating BBBMs and other clinical covariates. We show that Plasma CycleGAN outperforms the state‐of‐the‐art CycleGAN for MRI‐to‐PET translation. Our method is the first to integrate BBBMs in a conditional cross modality translation from MRI to PET.

Method

Our model was built on CycleGAN architecture, while the backbone was improved by integrating BBBMs as additional conditions in the input domain. To be specific, we introduce a masked perturbation in the MRI image, whose voxel‐level magnitudes are learnable parameters in the neural network. The dataset we used to evaluate our model is downloaded from the ADNI database. The cohort contains 160 subjects with matching BBBM, T1‐weighted MRI images, amyloid PET, and clinical features, including age, sex, weights, etc. The synthesized PET images are compared with the ground truth PET images for performance evaluation using traditional metrics like structural similarity index (SSIM), peak‐signal‐to‐noise ratio (PSNR) and mean square error (MSE). In addition, the Pearson correlation coefficients (PCCs) of the masked SUVR ratios were calculated.

Result

We evaluated the baseline CycleGAN model using MRI input, as well as combined inputs of MRI+BBBM and other clinical features. Our model achieved an SSIM of 0.72±0.16 and PSNR of 22.8±2.3 in PET image synthesis task using MRI+ Aβ42/40, both yielding the best results among all input combinations. MRI+sex achieved the best result using MSE measurement. PCCs of all experimental results ranged from 0.44 to 0.5.

Conclusion

We introduce Plasma CycleGAN, the first generative model to integrate BBBMs and clinical features in PET image synthesis from MRI images. In PET image synthesis task, our proposed integrated model outperforms the baseline CycleGAN model.