bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinically relevant factors for blood‐based Alzheimer biomarker interpretation
Authors: Zetterberg Henrik 
Published: December 2023

AbstractBackgroundBlood‐based biomarkers for Alzheimer disease (AD)‐related processes are moving towards large‐scale clinical implementation at a very rapid pace. Maintaining diagnostic performance when moving from group‐level data in well‐curated clinical cohorts to individual diagnostics in real‐world clinical settings can be challenging. This presentation gives an updated account of clinically relevant factors that may influence AD blood biomarker concentrations in individual patients.MethodsBlood‐based AD biomarker data (amyloid β 42/40 ratio [Aβ42/Aβ40], phosphorylated tau forms [P‐tau], neurofilament light [NfL], and glial fibrillary acidic protein [GFAP]) from human experimental and observational cohort studies were summarized and examined in relation to demographic data, including age, sex, race, ethnicity, body mass index (BMI), as well as kidney and liver function tests, other co‐morbidities, drugs, and food intake.ResultsIn most cohorts, age, creatinine, and BMI were associated with NfL, GFAP, and to a lesser extent p‐tau, but their diagnostic performances were not severely influenced. In general, there were no or only minor effects of common co‐morbidities and medications on AD blood biomarker concentrations. However, individual drugs may have strong effects. For example, a drug affecting microglial activity (minocycline), increased plasma NfL concentration several‐fold, and treatment with a neprilysin inhibitor against heart failure decreased plasma Aβ42/Aβ40 (determined by immunoassay) by ∼30%, i.e., with an effect size greater than what is caused amyloid plaque pathology. Surprisingly, intake of a standardized meal reduced plasma NfL, GFAP, and P‐tau (181 and 231) concentrations by 10‐20% after two hours, which is an effect similar in size to what has been seen in anti‐Aβ antibody trials. Across cohorts and biomarkers, plasma Aβ42/Aβ40 appeared to be the most resistant to these types of confounding factors.ConclusionMoving from group level interpretation in research to individual diagnostics in clinical practice requires special attention to unusual biomarker results and improved knowledge of clinically important confounders. Some of this knowledge will be gained in clinical practice by thoughtful biomarker interpretation and knowledge exchange between clinical and laboratory specialists. Some confounding factors may be assay‐specific. Continued intense collaboration between clinics and laboratories, as well as method comparison and refinement studies, will be highly important.
Tracing the spatial extent of cortical tau over time in Alzheimer’s disease
Authors: St‐Onge Frederic , Binette Alexa Pichet , Chapleau Marianne , Breitner John C.S. , Villeneuve Sylvia 
Published: December 2023

AbstractBackgroundNeuropathological studies defined the paradigm that tau—the pathological hallmark of Alzheimer’s disease (AD)—spreads homogenously across individuals from the medial temporal lobe to the neocortex. This staging system is referred to as Braak stages. However, neuroimaging studies have since highlighted significant inter‐regional and inter‐individual differences in tau spreading patterns. We investigated the spatial extent of cortical tau over time in the amnestic AD spectrum.MethodWe included 195 amyloid‐positive ADNI participants that had at least two tau‐PET scans (90 cognitively unimpaired [CU], 66 with mild cognitive impairment [MCI], 39 with AD dementia; average follow‐up 2.6 years). We derived regional thresholds of tau positivity for 64 cortical regions and the amygdalae using Gaussian mixture modeling and applied them to all tau scans. The same approach was used to obtain thresholds for composite regions corresponding to the Braak stages. For each region, we calculated the rate of change in the amount (i.e., standardized uptake value ratio [SUVR] change) of tau pathology and the annual change in the positivity status (i.e., spatial extent change). These rates were compared between diagnostic groups using linear mixed models.ResultAcross diagnostic groups, change in tau positivity followed Braak staging; over 90% of participants positive at follow‐up either progressed or were already positive on a previous Braak stage at baseline (Fig‐1AI) and greater SUVR change was observed in temporal regions (Fig‐1B). However, across the brain, there was heterogeneity between individual patterns of tau positivity progression (Fig‐1AII). This heterogeneity was most striking in MCI patients, where many regions progressed from low to high levels of tau (Fig‐1C). Regional SUVR change did not differ between participants with AD or with MCI (Fig‐2A), but participants with MCI showed the fastest change in regional positivity compared to participants with AD and CU participants. (Fig‐2B)ConclusionWhile tau propagation follows Braak staging, inter‐individual differences can be found by considering a fine‐grained approach of regional progression to positivity. Furthermore, participants with MCI have the highest number of regions becoming abnormal annually. Our research pushes the importance of considering the entire brain when studying change in tau pathology, particularly before AD diagnosis.
Identifying the metabolomics signatures of genetic variants identified for Alzheimer’s disease
Authors: Mustafa Rima , Pinto Rui , Elliott Paul , Tzoulaki Ioanna , Dehghan Abbas 
Published: December 2023

AbstractBackgroundIntegrating genomics and metabolomics data in humans has the potential to unravel mechanistic insights about and look for evidence of metabolite causality in complex disorders.MethodWe conducted metabolome‐wide association studies (MWAS) on Alzheimer’s disease (AD) associated loci using ultraperformance liquid chromatography–mass spectrometry (UPLC‐MS) in two cohorts of the Airwave Study (1). Expanding our previous study focusing on ABCA7 (2), current MWAS investigated genetic variants in all other loci based on the largest and most recent GWAS on AD (3) to identify metabolic features associated with AD. We performed genome‐wide association studies in the Airwave Study (N = 3,708) to obtain genetic instruments of those features to run Mendelian randomisation (MR) and colocalization analyses.ResultOur MWAS identified 104 features associated with AD loci at metabolome‐wide significance level. MR analysis was conducted on 29 out of 104 features with at least three genetic instruments, showing the potentially causal effects of four metabolic features associated with rs1800978 (ABCA1) and rs587709 (LILRB2). Our in‐house annotation pipeline mapped those features as sphingomyelin (SM)(18:1/20:1), putative sphingolipid, and N‐Acylphosphatidylethanolamines (NAPE). We conducted pairwise colocalisation and HyPrColoc analysis, supporting evidence of common causal variants between SM(18:1/20:1), putative sphingolipid, and NAPE with AD (posterior probability of shared causal variant >0.8).ConclusionThis analysis has broadened our insight into the metabolic signatures of AD, with further study needed to dissect the underlying molecular mechanisms.
Mechanisms of sepsis‐induced inflammation in the aging brain
Authors: Bastarache Julie A , Lee Han Noo Ri , Harrison Fiona E. 
Published: December 2023

AbstractBackgroundSepsis affects millions worldwide with adults over the age of 65 at particularly high risk. Up to 70% of sepsis patients develop delirium and the severity and length of delirium are strong predictors of acquisition of Alzheimer’s Disease and Related Dementias (AD, ADRD). We hypothesize that older adults and those at risk for AD have augmented neuroinflammation during sepsis that correlates development of delirium and persistence of long‐term cognitive impairment.MethodMale and female wild‐type (young‐3 months and aged‐18 months) and 4 month old Tau P301S transgenic AD mice were used to test the effects of polymicrobial sepsis on markers of neuroimflammation and behavior. Sepsis was induced by intraperitoneal injection of a slurry of cecal contents. Plasma and brain were collected from 8 hours to 7 days post infection for measurement of pro‐inflammatory cytokines (IL‐6, CXCL‐1, TNF‐a) and markers of neuroinflammation (GFAP, IBA1 and s100B) using a combination of protein quantification, multiplex and immunohistochemical approaches. Behavior, including measures of locomotor activity, motor learning (rotarod) and cognition (Y‐maze, nest building) were tested up to 7 days post infection.ResultSepsis increases plasma markers of acute neuroinflammation between 8 and 48 hours that resolves by 7 days. Despite this, mice who have recovered from sepsis have persistent microglial activation in the hippocampus at least 7 days later suggesting prolonged damage. Some recovered mice also have persistent deficits in behavioral tasks including activity and nest building despite appearing healthy and fully recovered. Older WT mice are more susceptible to sepsis as measured by severity of illness (Figure) and mortality and mice genetically predisposed to AD have greater deficits in behavioral measures compared to their WT counterparts following infection.ConclusionSepsis is accompanied acutely by marked neuroinflammation and chronically by microglial activation and behavior deficits. Older age and presence of even early stages of AD‐relevant pathology augment these deficits. Persistent microglial activation may underlie this pathology and prime the aged brain to develop an ADRD‐like syndrome.
Experimental Validation of Bioinformatically Prioritized Therapeutic Hypotheses and Targets for Alzheimer’s Disease
Authors: Cary Gregory A. , Wiley Jesse C , Li Qianjin , Nwakamma Richard , Du Yuhong , Zoeller Elizabeth , Duong Duc M. , Fu Haian , Seyfried Nicholas T , Levey Allan I. , Betarbet Ranjita , Carter Gregory W , Center The Emory‐Sage‐SGC TREAT‐AD 
Published: December 2023

AbstractBackgroundThe complex etiology of Alzheimer’s disease (AD) challenges therapeutic development efforts by obscuring which altered biological processes are optimal candidates for intervention. We have created a workflow to prioritize molecular targets based on signatures of AD risk from patient data and assemble candidate targets into functional groupings from which we can articulate sets of hypotheses. Prioritized data‐derived hypotheses to date include mitochondrial dysfunction and chronic neuroinflammation. We present an approach to rapidly assess whether the hypothesized driver genes affect the predicted biological outcomes in the appropriate cellular contexts.MethodImmortalized mouse BV2 cells were used as a microglial surrogate. To test the candidate hypotheses in an AD‐relevant context, we examined both wild‐type BV2 cells and cells where Psen2 expression has been stably knocked down. To perturb the nominated target genes, each cell line was transfected with one of a panel of 29 siRNAs targeting the genes or a control siRNA prior to phenotypic assessment. We tested mitochondrial function using both MitoTracker TMRM staining and the AlamarBlue assay. For immune function, we tested phagocytic activity using pHrodo Green Zymosan Bioparticles and the transcriptional output from NF‐kappaB using a luminescent reporter. Finally we measured proteomic differences between the siRNA treated cells and control cells to assess the impact of each perturbation on the expression of protein sets targeted by the hypotheses.ResultOf the targets screened, 28% are found to exhibit mitochondrial phenotypes in both assays and 38% are found to exhibit immune phenotypes in both assays. Hits from the immune assays are generally more specific to the immune hypothesis targets (70%) whereas the hits from the mitochondrial assays are more evenly divided between both hypothesis areas (50%). Examining the proteomic results highlights the pathways that are altered by each perturbation and we align these with patient data to identify perturbations that affect the targeted pathways.ConclusionWe have established a platform to rapidly assess biologically‐informed and interpretable hypotheses and targets derived from large‐scale data resources for disease relevance. The targets validated by these experiments will be prioritized for further resource development within the TREAT‐AD consortium.
Dual PET imaging of microtubules and synaptic density in a mouse model of Alzheimer’s Disease
Authors: Damuka Naresh , Bansode Avinash , Krizan Ivan , Gollepalli Krishna Kumar , Miller Mack , Bhoopal Bhuvanachandra , Whitlow Christopher T. , Lockhart Samuel N. , Craft Suzanne , Sai Kiran K Solingapuram 
Published: December 2023

AbstractBackgroundWhile microtubule (MT)‐destabilization and synaptic loss hallmark AD pathological events, no study has systematically quantified their in vivo levels in the same brain. Any therapeutic intervention relying on MT destabilization and synaptic vesicle protein (SV2A) levels will benefit from a dual PET imaging strategy, providing target engagement, dosing, and occupancy studies for new drugs. Here, we report MT destabilization and synaptic density imaging results using [11C]MPC‐6827 and [18F]UCB‐H respectively in the same transgenic (TG) and wild‐type (WT) APP/PS1 mice.MethodMale APP/PS1 TG and WT mice (12‐14 mo, 20± 2g, n = 8/group) underwent 30‐min dynamic brain microPET/CT imaging with [11C]MPC‐6827 (0.2±0.02 mCi, iv tail). Four hours later, the same animals underwent another 30‐min brain PET/CT with [18F]UCB‐H (0.2±0.01 mCi, iv tail). A sub‐set of TG and WT mice (n = 4/group) were used to measure ex vivo destabilized MTs and SV2A levels using western blot to confirm MT destabilization and synaptic loss. Whole‐brain standard uptake values (SUVs) were calculated from co‐registered PET‐CT using PMOD. Ex vivo post‐PET biodistribution studies were performed, with percent injected dose‐pe‐ gram (%ID/g) calculated. 48h post‐biodistribution, in vitro autoradiography studies were performed on frozen brain samples from the same animals with [11C]MPC‐6827 and [18F]UCBH; regional uptake was quantified using phosphor‐stimulated luminescence.Result[11C]MPC‐6827 and [18F]UCBH were produced in high (>97±2%) radiochemical purities (n = 20 productions) and specific activities (∼3980±100 mCi/µmol), decay‐corrected to end‐of‐synthesis. Western blot analysis confirmed high destabilized MTs, and low SV2A levels in TG vs. WT. SUV analysis (Fig. 1) showed 56% higher [11C]MPC‐6827 and 66% lower [18F]UCB‐H in vivo brain uptake in TG compared to WT (**p = 0.0032). %ID/g analysis showed 58% higher [11C]MPC‐6827 and 61% lower [18F]UCB‐H ex vivo brain radioactive uptake in TG vs WT (*p = 0.04). Importantly, autoradiography demonstrated 44% higher [11C]MPC‐6827 and 34% lower [18F]UCB‐H in vitro uptake in cortical and hippocampal regions of TG vs. WT (*p = 0.05).ConclusionTG APP/PS1 mice demonstrated higher [11C]MPC‐6827 and lower [18F]UCB‐H brain uptake compared to WT littermates. In vivo PET, ex vivo biodistribution, and in vitro autoradiography data corroborated each other. Preliminary [11C]MPC‐6827 and [18F]UCB‐H PET evaluations showed negative correlations (*r = ‐0.778), suggesting MT destabilization and synaptic loss happen concurrently.
The RESIST Study: Do TNF Inhibitors Protect Against Cognitive Decline in Rheumatoid Arthritis Patients With Mild Cognitive Impairment?
Authors: Marr Calum , McDowell Bethany , Holmes Clive , Edwards Christopher J , Cardwell Christopher , McHenry Michelle , Meenagh Gary , McGuinness Bernadette 
Published: December 2023

AbstractBackgroundRheumatoid arthritis (RA) is an autoimmune disease characterised by chronic inflammation in the joint synovium. Considering growing research interest into the role that systemic inflammation might play in the pathogenesis of Alzheimer’s disease (AD), studying cognitive decline in RA patients can provide important insights into the potential effects of inflammation on cognitive health. Furthermore, evidence suggests that biological drugs used to treat RA, specifically TNF inhibitors (TNFi), may protect against AD progression by reducing systemic inflammation. The rheumatoid arthritis medication and memory study (RESIST) is a multicentre longitudinal observational study which aims to compare rates of cognitive decline in adults with both RA and mild cognitive impairment who are on either a conventional synthetic disease modifying anti‐rheumatic drug (csDMARD) or a TNFi.Method251 participants were recruited (160 on csDMARDs, 91 on TNFis). Participants completed assessments at six‐month intervals for eighteen months. The primary outcome was performance on the Free and Cued Selective Reminding Test (FCSRT). It was hypothesised that the rate of decline in FCSRT score would be lower among participants taking TNFis.ResultBetween‐groups ANCOVA was conducted to compare mean FCSRT scores at 12/18 months, adjusting for baseline score, age, disease activity, pain, wellbeing, depressive symptoms and physical function. Results showed that neither group declined in FCSRT free recall score on average over the 18 month follow‐up period, and that there was no significant difference between groups at 12 (mean difference = 0.59, 95% CI = ‐1.54, 2.72) or 18 months (mean difference = 1.24, 95% CI = ‐0.99, 3.47).ConclusionThe absence of decline in FCSRT performance in either group was unexpected. These findings raise the possibility that both csDMARDs and TNFis may protect against cognitive decline However, a major limitation of the study was attrition due to the COVID‐19 pandemic, which may have influenced results – those who experienced a greater degree of cognitive decline may have been more likely to withdraw from the study. Additional planned analyses will examine the potential moderating effect of APOE genotype, and the relationship between peripheral serum C reactive protein, cytokine levels and cognitive outcomes.
Effects of cerebrovascular disease on tau progression and cognitive decline in Alzheimer’s disease
Authors: Dewenter Anna , Steward Anna , Dehsarvi Amir , Biel Davina , Roemer Sebastian Niclas , Wanger Fabian , Franzmeier Nicolai 
Published: December 2023

AbstractBackgroundRecent post‐mortem studies suggest that cerebrovascular disease contributes to Alzheimer’s disease (AD) pathophysiology and clinical progression. In particular, cerebral amyloid angiopathy is highly common in AD and has been linked to faster cognitive decline. Yet, in‐vivo evidence on the contribution of cerebrovascular disease to pathobiological and/or clinical AD progression is rare. Thus, we assessed in‐vivo, whether i) higher cerebrovascular burden is associated with accelerated progression of primary AD pathology and ii) whether cerebrovascular burden synergistically accelerates AD‐related cognitive decline.MethodWe included n = 256 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) across the AD spectrum with longitudinal 18F‐flortaucipir tau‐PET (follow‐up∼2.30±1.32 years), 18F‐florbetapir or 18F‐florbetaben Aβ‐PET transformed to centiloid (Aβ–: n = 85 Cognitively normal (CN); Aβ+: n = 83 CN, n = 57 Mild Cognitive Impairment, n = 31 Dementia). We focused on global white matter hyperintensity (WMH) volume adjusted to intracranial volume and microhemorrhage (MCH) count as well‐established cerebrovascular disease markers. Cognition was probed through the AD Assessment Scale Cognition 13‐item scale (ADAS‐13). Subject‐specific annual changes in tau‐PET and cognition were calculated via linear mixed models, including random slope and intercept. To enhance reproducibility of our findings, statistical analyses were pre‐specified at AsPredicted.org. All statistical models were controlled for age, sex and APOE.ResultUsing linear regression, we found no main effect of cerebrovascular disease markers on baseline amyloid‐PET or tau‐PET (ps>0.05). Further, higher cerebrovascular burden was not associated with faster Aβ‐related tau‐PET SUVR increase (Fig. 1A+B). In contrast, higher cerebrovascular burden was associated with accelerated cognitive decline. Specifically, interaction models revealed that a higher MCH count was associated with faster cognitive decline at higher tau levels (Fig. 1C), while higher white matter hyperintensity burden was associated with faster cognitive decline at lower tau levels (Fig. 1D).ConclusionWe found no effect of cerebrovascular disease on primary AD pathology. In contrast, cerebrovascular disease was linked to accelerated tau‐associated cognitive decline. This suggests that cerebrovascular disease may not modulate pathobiological AD trajectories but rather add synergistically to AD symptom severity. This has important therapeutic implications, as treating cerebrovascular disease in addition to primary AD pathology (e.g. amyloid) may yield largest clinical efficacy.
ASSOCIATION BETWEEN ALZHEIMER DISEASE AND CANCER: A POSTMORTEM CROSS‐SECTIONAL STUDY IN BRAZIL
Authors: Veitzman Fernanda , Leite Renata Elaine Paraizo , Grinberg Lea T. , Paes Vitor Ribeiro , Pasqualucci Carlos Augusto , Jacob‐Filho Wilson , Nitrini Ricardo , Suemoto Claudia Kimie 
Published: December 2023

AbstractBackgroundA biological mechanism in cancer promotion may have a protective role against AD1. Although disparities between the clinical and the anatomopathological postmortem diagnoses related to the etiology of dementia and cancer were described2, most previous studies were based only on the clinical diagnoses for both diseases. Therefore, we aimed to investigate the association between AD and cancer in a large autopsy study from a racially diverse sample.MethodThis cross‐sectional study analyzed data with postmortem brain tissue from participants over 55 years of age from the Biobank for Aging Studies. Data from the full‐body autopsy reports and a Functional Clinical Questionnaire (FCQ) applied to an informant were used to determine the presence of cancer. The association between AD and cancer was investigated using logistic and linear models adjusted for sociodemographic and clinical variables and APOE allele 4.Result689 subjects were included (mean age 74.2 ± 10.8 years old, 47.5% women, 68% White) (Table 1). 18% of the sample had cancer. The frequencies of cancer types and neuropathological post‐mortem diagnoses are shown in Figure 1. Cancer was not associated with AD (OR = 0.56, 95% CI = 0.21;1.39), or CERAD neuritic plaque score [ b = 0.057, 95% CI = ‐0.31; 0.41], but was associated with lower Braak neurofibrillary tangle staging (b = ‐0.49, 95% CI = ‐0.98; ‐0.03] (Table 2).ConclusionIn a large autopsy study, we found an association between cancer and Braak neurofibrillary tangle staging, which is in accordance with previous research suggesting a protective role of cancer in AD risk3.1. Ospina‐Romero M, Glymour MM, Hayes‐Larson E, Mayeda ER, Graff RE, Brenowitz WD, Ackley SF, Witte JS, Kobayashi LC. Association Between Alzheimer Disease and Cancer With Evaluation of Study Biases: A Systematic Review and Metaanalysis. JAMA Netw Open. 2020 Nov 2;3(11):e2025515.2. Landefeld CS, Chren MM, Myers A, et al. Diagnostic yield of the autopsy in a university hospital and a community hospital. The New England Journal of Medicine. 1988 May;318(19):1249‐1254.3. Nakamura M, Kaneko S, Dickson DW, Kusaka H. Aberrant Accumulation of BRCA1 in Alzheimer Disease and Other Tauopathies. J Neuropathol Exp Neurol. 2020 Jan 1;79(1):22‐33.