bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endpoints and outcomes: the challenge of biomarker choice for VCI trials
Authors: Winder Zachary , Sudduth Tiffany L , Patel Ela , Anderson Sonya , Neltner Janna , Bahrani Ahmed Ali , Abner Erin L , Nelson Peter T , Jicha Gregory A , Wilcock Donna M 
Published: December 2022

AbstractBackgroundClinical trials for Alzheimer’s disease (AD) have been significantly enhanced by the development of a suite of biomarkers ranging from PET and MRI modalities to CSF and now, plasma. Such biomarkers have refined trials by enabling the specific inclusion of participants with the targeted pathology. Clinical trials for vascular cognitive impairment and dementia (VCID) will require similar development and validation of biomarkers to be used for inclusion, stratification, target engagement, and efficacy in trials.MethodsWe have explored fluid biomarkers for VCID using two longitudinal cohorts: UK‐ADRC and MarkVCID. Using the Quanterix Simoa assays, we have examined) neurodegenerative (NfL), inflammatory (GFAP, IL1b, TNFa, IL6, IL10), and angiogenic (PlGF, VEGF‐A, MMP9) biomarkers in plasma. We examined associations of these plasma biomarkers with disease phenotypes: white matter hyperintensities (WMH) and cerebrovascular reactivity (CVR) on MRI, learning and memory assessments, and neuropathologic hallmarks including amyloid plaques, tangles, amyloid angiopathy (CAA), brain arteriolosclerosis and microinfarcts.ResultsIn association with WMH, a presumed neuroimaging indicator of small vessel disease, we found that PlGF and WMH were positively correlated. Further, higher plasma GFAP was significantly associated with decreased CVR. For cognition, PlGF was associated with decreased attention and processing speed as assessed by Trail Making Test‐A; anti‐inflammatory cytokine IL10 was positively correlated with performance on verbal memory and verbal fluency. As has been shown previously, we observed that plasma NfL was negatively associated verbal fluency. Finally, when examining cerebrovascular pathologies, we found PlGF was positively associated with CAA, while GFAP was positively associated with chronic small vessel pathology like microinfarcts; IL8, an endothelial‐derived cytokine, was positively associated with more severe brain arteriolosclerosis.ConclusionA number of candidate plasma biomarkers have been identified for potential use in clinical trials for VCID and these warrant further validation and characterization. While angiogenic markers like PlGF were associated with WMH, small vessel pathology may be more strongly associated with inflammation as indicated by GFAP and IL8. Verbal memory and fluency may be negatively affected by inflammation, and NfL remains a robust biomarker for cognitive test performance.
Mitochondrial dysfunction in models of Progressive Supranuclear Palsy
Authors: Troutwine Benjamin R , Lysaker Colton R , Strope Taylor A. , Swerdlow Russell H , Wilkins Heather M 
Published: December 2022

AbstractBackgroundProgressive Supranuclear Palsy (PSP) is a rare neurodegenerative disease hallmarked by tau pathology in both neurons and astrocytes. Familial forms of PSP are caused by mutations affecting tau (MAPT) while risk factors for sporadic PSP are largely unknown. Mitochondrial function declines during aging and mitochondrial dysfunction is observed in PSP. Generation of reactive oxygen species and mitochondrial dysfunction are thought to directly contribute to the production of tau deposits. Here we interrogated mitochondrial function in astrocytes and neurons derived from induced pluripotent stem cell models of sporadic and familial PSP.MethodsInduced pluripotent stem cells were obtained from healthy controls, patients with sporadic PSP, and PSP patients carrying a MAPT A152T mutation. iPSCs were differentiated into neurons and astrocytes following StemCell Technologies protocols. Mitochondrial function was assessed using the Seahorse XFe96 analyzer. Fluorescent stains were used to determine mitochondrial mass, mitochondrial membrane potential, mitophagy levels, mitochondrial turnover, and mitochondrial calcium levels.ResultsNeurons derived from sporadic PSP and A152T tau patients had decreased mitochondrial respiration, increased mitochondrial superoxide, and increased mitochondrial mass. Astrocytes derived from sporadic PSP patients had increased mitophagy, mitochondrial turnover, mitochondrial calcium, and mitochondrial superoxide. Complex I and Complex IV activity were increased in sporadic PSP derived astrocytes, but in A152T tau astrocytes we observed decreased Complex I activity.ConclusionNeurons and astrocytes derived from PSP patients show changes in mitochondrial function. Alterations are cell type specific and differ between sporadic and familial PSP models. We are working to determine how this contributes to tau pathology.
Keep Your Brain HAP‐B: Group Psychoeducation to Promote Behaviors which Support Healthy Brain Aging
Authors: Trittschuh Emily H , Shryock Sarah Kelly , Hirschhorn Elizabeth W , Verstaen Alice 
Published: December 2022

AbstractPositive health behaviors can promote brain health with age. We developed a novel health education and implementation group for older Veterans called the “Healthy Aging Project: Brain” also known as HAP‐B. We had these primary goals: provide psychoeducation, focus on ‘what matters’, improve awareness of health behaviors, and promote behavioral change through individualized goal‐setting, monitoring, and support. The scientific literature + needs assessment‐based content addresses 4 key areas: physical activity, sleep improvement, cognitive stimulation, and social interaction. Each of the 6 “classes” are 90 minutes long. Pre‐pandemic n=37 Veterans across 6 groups participated. To mitigate health risk exposure and reach Veterans for whom travel is a barrier, we have adapted the group to a virtual format with n=18 participants across 3 virtual groups (another group is ongoing, n=6). This QA/QI project collects optional pre/post self‐report measures which target satisfaction with the group, depressive symptoms, sleep quality, social support, and subjective well‐being. Additions along the way include in‐session self‐ratings for targeted goal behavior adherence and a pre/post self‐efficacy questionnaire. Our population tends to be predominantly male and White. Results and qualitative findings are promising. The group has successfully been run in 3 outpatient in‐person settings: Mental Health Services, Geriatrics Memory Health Clinic, and Primary Care Mental Health Integration. In‐person results suggest a significant decline in report of depressive symptoms. Lessons learned for implementation for both the in‐person and virtual formats will be shared, as well as analyses on associations between self‐efficacy and satisfaction with life over time. Future directions include ongoing data collection to increase power, continued efforts to increase participant diversity, and direct comparison of in‐person vs virtual formats. We will also present our initiated adaptation for flexible use in long‐term care facilities and among those with cognitive impairments.
A Visual Interpretation Algorithm for Assessing Brain Tauopathy with [18F]MK6240 Positron Emission Tomography
Authors: DuBois Jonathan M , Seibyl John , Racine Annie M , Collins Jessica A. , Martarello Laurent , Salinas Cristian A 
Published: December 2022

AbstractBackgroundIn vivo characterization of pathologic deposition of tau protein in the human brain by PET imaging is a promising tool in drug development trials in Alzheimer’s disease (AD). [18F]MK‐6240 is a radiotracer with high selectivity and sub‐nanomolar affinity for neurofibrillary tangles. Here, we developed a visual assessment that provides a binary outcome for tau deposition, as well as a semi‐quantitative metric of the extent of regional tau deposition in the brain.MethodData included 214 subjects (AD, HC, MCI, and other disorders) who underwent [18F]MK‐6240 PET scans, which were used to generate 70‐90 min static images. Half of the subjects were reviewed by an expert nuclear medicine physician blind to participants’ diagnosis to identify common patterns of brain uptake. Based on this review, a visual read method was developed for testing in a separate cohort of 102 subjects, which included two additional independent readers. Visual read outcomes were compared with quantitative ROI analysis.ResultReaders demonstrated a high level of concordance for binary regional outcome, with all three‐reader in agreement on 74.3% of scans with a Fleiss’s k=0.912. Readers showed excellent intra‐reader reproducibility, with two readers attaining 10/10 self‐agreement and one reader attaining 9/10 agreement. Relative to clinical diagnosis, readers showed a sensitivity of 76‐81% and specificity of 91‐92%. Mean cortical SUVr was higher in read positive (2.17/0.91) than to negative (1.02/0.18) scans.ConclusionWe developed a read algorithm permitting both binary determination and the regional extent of abnormal tau. These cross‐sectional results demonstrate feasibility, which might allow for further evaluation of progressive tau changes in AD.
Cohort effects in mild to moderate AD trials: an empirical assessment utilizing data from the Alzheimer’s disease cooperative study
Authors: Birnbaum Adam , Gillen Daniel L. , Grill Joshua 
Published: December 2022

AbstractBackgroundHeterogeneity in patient populations can impact clinical trial conclusions and generalizability. Long recruitment windows may exacerbate this in Alzheimer’s disease (AD) trials, which often recruit over extended periods.MethodWe used data from 8 Alzheimer’s Disease Cooperative Study (ADCS) clinical trials (DHA, Homocysteine, Huperzine, Intravenous Immunoglobulin, Resveratrol, Valproate, NSAIDs, and FYN Kinase inhibitor) in patients with mild to moderate AD to investigate cohort effects by time‐of‐trial‐enrollment.For each participant, we assigned a study‐ and site‐specific enrollment time defined as the number of days between a patient’s screening and the first screening visit at the site. We used study‐ and site‐specific time origins to account for calendar time differences between studies and, within a study, differences in site times to activation.To investigate differences in baseline characteristics, we split our sample into tertiles by enrollment time and compared sex, race and ethnicity, age, years of education, and baseline scores on the Alzheimer’s Disease Assessment Scale ‐ Cognitive Subscale (ADAS‐Cog).To assess cohort effects on trial outcomes, we used the 12‐month within‐subject change in ADAS‐Cog. We regressed the 12‐month change in ADAS‐Cog on a patient’s enrollment time while controlling for their baseline score and demographic information and allowing for clustering between patients in the same study.ResultGroups were demographically similar at baseline across enrollment tertiles. We found a significant difference in 12‐month change in ADAS‐Cog for patients with different enrollment times: later enrolled patients had an expected 12‐month change in ADAS‐Cog 0.146 points higher than similar patients who enrolled one quarter (91.2 days) earlier (95% CI: 0.082‐0.210). This magnitude of difference was roughly on par with an additional year of education. We also found a negative relationship with age, with older patients tending to experience a smaller 12‐month decline.ConclusionIn these 8 trials, we found minimal evidence of cohort effects that would meaningfully change study generalizability or treatment effect. Future analyses will account for the overall pace of accrual in the trials and assess for potential differential effects in fast vs. slow‐accruing studies.
Deep Sleep Time Measured by Wearable Device Associated with Amyloid Burden in the Elderly with Subjective Cognitive Decline.
Authors: Park Kee Hyung , Yang Dong Won , Hong Yun Jeong , Kim Ahro , Ho SeongHee , Jeong Jee Hyang , Kim SangYun , Choi Seong Hye , Han SeungHyun 
Published: December 2022

AbstractBackgroundFactors other than age and genetics may influence the development of Alzheimer’s disease. In particularly, there is growing evidence that sleep disturbances are associated with increased β‐amyloid burden. We investigated the association between sleep characteristics measured with a wearable device and β‐amyloid burden in the elderly diagnosed with subjective cognitive decline.MethodWe conducted a cross‐sectional study in 76 elderly people over 60 years of age with subjective cognitive decline determined by detailed neuropsychological tests. β‐amyloid burden was determined by F18‐florbetaben positron emission(PET) using two methods. Firstly, visual rating of BAPL (Brain amyloid plaque load) score was used to determine β‐amyloid positivity. Secondly, the SUVR (standardized uptake value ratio) values were used for the quantitative evaluation of β‐amyloid deposition. Sleep characteristics including total sleep time, number of awakenings during sleep, REM sleep time, deep sleep time, and light sleep time were measured using a wearable device. In addition, we investigated the association between β‐amyloid burden and age, ApoE4 genotype, MMSE, and PSQI.ResultOf the 76 subjects included in the analyses, 64.5% were women. The subjects were 70.7 (±6.09) years of age at the beginning of the study. Fifteen subjects were positive and 61 were negative on F18‐florbetaben PET. The average SUVR value was 1.27 (±0.220). In particular, we found that deep sleep time was significantly higher in the β‐amyloid‐negative group (49.5±13.1 minutes) than in the positive group (39.4±13.1 minutes). (p‐value 0.009)ConclusionAccording to our analysis, a decrease in deep sleep time appears to be associated with amyloid deposition. This is consistent with recent evidence that sleep disturbances may be associated with increased β‐amyloid burden. A large‐scale prospective study is needed to clarify the causal relationships between deep sleep and amyloid deposition.
Soluble TAM receptor biomarkers: Neuroprotection in AD neuroinflammation?"
Authors: Brosseron Frederic , Maass Anne , Kleineidam Luca , Ravichandran Kishore Aravind , Peters Oliver , Priller Josef , Schneider Anja , Fließbach Klaus , Wiltfang Jens , Duzel Emrah , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Teunissen Charlotte E. , Synofzik Matthis , Wagner Michael , Jessen Frank , Ramirez Alfredo , Ruiz Agustin , Heneka Michael T. 
Published: December 2022

AbstractBackgroundWhile neuroinflammation is reckoned as a pathological hallmark of AD, research on suitable biomarkers is still ongoing. Here, we report on findings from the DZNE DELCODE, Fundacío ACE and other cohorts demonstrating distinct inflammatory biomarker profiles in CSF and serum. Intriguingly, within these profiles, soluble TAM receptor markers are elevated in neurodegeneration but still relate to protection of cognition and brain structure.MethodWe investigated a panel of 20 experimental biomarkers utilizing customized immunoassays in CSF and serum samples of DELCODE and other cohorts with a total of >1000 subjects, including healthy controls, subjective cognitive decline, mild cognitive impairment, AD relatives and AD patients. Data were analyzed in relation to clinical and biomarker‐based staging as well as cognitive and structural imaging composite scores, adjusted for covariates such as age.ResultVarious inflammatory markers, when measured in CSF, were found to correlate to tau isoforms and other neurodegeneration markers and to be elevated in pre‐dementia stage subjects with already pathological tau levels. Among these, soluble TAM receptors sAXL and sTyro3 were related to preserved cognition and brain structure. In serum, inflammatory markers displayed different interrelations, with individual proteins in serum showing no or modest correlation to their CSF counterparts or other AD biomarkers. Noteworthy, serum soluble AXL increased only in AD subjects and related to decreased structure and function.ConclusionNeurodegeneration in AD is accompanied by a pattern of elevated inflammatory CSF biomarkers. These proteins likely represent cellular responses to neuronal damage and are evident already at pre‐dementia stages of disease. Within this response, upregulation of TAM receptors in the brain could serve to regulate neuroinflammation and promote cellular survival, with receptor turnover resulting in elevated CSF levels. Noteworthy, blood signatures of the same biomarkers, though not without significance, show different patterns of relations towards disease features, likely reflecting distinct peripheral cellular origins and biological functions of the respective proteins. These findings point towards TAM signalling as potential target for future therapeutic intervention, especially in subjects with pre‐dementia neurodegeneration phenotypes. As such, CSF soluble TAM levels might provide promising readout biomarkers.
Midlife plasma proteome‐wide analysis identifies peripheral immune networks associated with 25‐year dementia risk
Authors: Walker Keenan A , Chen Jingsha , Shi Liu , Yang Yunju , Fornage Myriam , Zhou Linda , Schlosser Pascal , Surapaneni Aditya , Grams Morgan E , Duggan Michael R , Peng Zhongsheng , Gomez Gabriela , Tin Adrienne , Hoogeveen Ron C , Sullivan Kevin J , Ganz Peter , Lindbohm Joni V , Kivimaki Mika , Nevado‐Holgado Alejo J , Buckley Noel , Gottesman Rebecca F , Mosley Thomas H , Boerwinkle Eric , Ballantyne Christie M , Coresh Josef 
Published: December 2022

AbstractBackgroundA diverse set of biological processes have been implicated in the pathophysiology of Alzheimer’s disease (AD) and related dementias. However, there is limited understanding of the biological pathways mechanistically relevant in the earliest phase of disease and a lack of protein biomarkers available to capture the biological systems involved.MethodTo discover early biomarkers and further understand on a molecular level the systemic factors that may promote neurodegeneration, we used a large‐scale proteomic platform to relate 4,877 plasma proteins measured in middle‐aged adults to dementia risk over a 25‐year period (n=10,981; 1,874 incident dementia cases) in the Atherosclerosis Risk in Communities (ARIC) study (Figure 1). Dementia‐associated proteins were related to 20‐year cognitive decline in the Whitehall II study, and to AD risk and CSF biomarkers European Medical Information Framework‐AD study.ResultProteome‐wide association study in ARIC discovered 32 midlife dementia‐associated plasma proteins, the majority of which were involved in either immune function, proteostasis/autophagy, or extracellular matrix organization (Figure 2). We replicated the relationship between candidate proteins and neurocognitive outcomes in multiple independent cohorts and demonstrated a relationship between dementia‐associated plasma proteins and cerebrospinal fluid markers of Aß42, p‐tau181, neurodegeneration, and neuroinflammation (Figure 3). Using network analysis, we identified 19 co‐expressed protein modules, 4 of which were strongly associated with either short‐term and long‐term dementia risk (Figure 4). Pathway analyses conducted for the dementia‐associated protein modules suggested dysregulation of specific immune pathways (e.g., JAK‐STAT signaling, Toll‐like receptor activation) and disrupted proteostasis/autophagy and extracellular matrix organization during midlife ∼20 years before dementia onset, and abnormal coagulation/complement signaling ∼10 years before dementia onset (Figure 5). We used two‐sample Mendelian randomization to identify which midlife plasma proteins and protein networks may play a mechanistic role in Alzheimer’s disease, and demonstrated that many of the dementia‐associated proteins may play a causal role in systemic inflammatory and autoimmune diseases associated with heightened AD/dementia risk.ConclusionThis work sheds light on the complexity of the systemic immune response in the decades preceding dementia onset and highlights multiple potential biomarkers and therapeutic targets for early AD.
Diagnostic and Prognostic Performance of the Modified Lumipulse pTau 181 Assay in Plasma for Alzheimer’s Disease
Authors: Wilson Edward N. , Young Christina B , Benitez Javier A. Ramos , Vandijck Manu , Swarovski Michelle S. , Shahid Marian , Corso Nicole , Kennedy Gabriel , Trelle Alexandra N , Channappa Divya , Belnap Malia , Lind Betty , Bastard Nathalie Le , Quinn Joseph F , Nairn Angus C , Kerchner Geoffrey A. , Sha Sharon , Wagner Anthony D , Henderson Victor , Longo Frank M. , Wyss‐Coray Tony , Poston Kathleen L , Mormino Elizabeth C. , Andreasson Katrin I. 
Published: December 2022

AbstractBackgroundRecent advances demonstrate utility in blood‐based phosphorylated tau (pTau) as a diagnostic biomarker for Alzheimer’s disease (AD). While several platforms show high diagnostic and prognostic performance, most assays rely on antibody combinations that require long tau peptides for their detection. The Lumipulse G Plasma pTau 181 assay (Fujirebio) instead uses an antibody combination targeting epitopes proximal to Thr181 and therefore can detect shorter tau peptides. This allows for a wider array of expressed plasma pTau 181 peptides to be measured.MethodPlasma pTau 181 was measured in three cohorts using the modified Lumipulse G Plasma pTau 181 assay: cohort 1 included 269 cognitively unimpaired (CU), 109 mild cognitively impaired (MCI), and 80 AD participants from the Stanford Alzheimer’s Disease Research Center (ADRC); cohort 2 included 192 CU from the Stanford Aging and Memory Study (SAMS); and cohort 3 a third, independent plasma cohort from the Yale University ADRC included 20 CU and 20 AD participants. Outcome measures included discriminative accuracy of the modified assay for clinical AD diagnosis, association with amyloid and tau pathology determined using CSF biomarkers or positron emission tomography (PET), and ability to predict longitudinal cognitive change.ResultPlasma pTau 181 showed robust clinical performance in differentiating AD from CU participants in cohort 1 (AUC = 0.934) and cohort 3 (AUC = 0.845). In cohort 1, the analyte associated with CSF pTau 181 (β=+0.543 and P<0.001), CSF Aβ42/Aβ40 ratio (β=‐0.349 and P<0.001), and amyloid‐PET global SUVRs (β=+0.494 and P<0.001). Associations between plasma P‐tau181 with CSF and PET biomarkers were significant when examined in Aβ+ and Aβ‐ groups separately. Plasma pTau181 was also found to associate with inferior temporal tau‐PET in the subset of CU in cohort 2 (N=35, β=+0.393 and P=0.016). Finally, in cohort 1 baseline plasma pTau 181 predicted change in MoCA over 2‐year follow‐up, controlling for clinical diagnosis, age, sex, and education (β=‐0.211 and P=0.009).ConclusionThe results across these 3 participant cohorts revealed the modified Lumipulse G pTau 181 assay discriminates AD pathology in clinical and preclinical AD, strongly associates with CSF and PET imaging in Aβ+ and Aβ‐ participants and predicts longitudinal cognitive decline.