bluuebunny/crossref_metadata_2025_split huggingface dataset:
First‐in‐human [18F]D2‐Deprenyl‐PET imaging and GFAP evaluation as biomarkers of reactive astrogliosis in neurodegenerative diseases
Authors: Katzdobler Sabrina , Vogler Letizia , Eckenweber Florian , Nübling Georg , Palleis Carla , Lindner Simon , Fietzek Urban , Nuscher Brigitte , Mueller Andre , Koglin Norman , Stephens Andrew W , Haass Christian , Brendel Matthias , Levin Johannes 
Published: December 2022

AbstractBackgroundNeuroinflammation is a process occurring in neurodegenerative diseases, such as Alzheimer’s Disease (AD) and parkinsonian syndromes. In light of emerging disease modifying trials, objective biomarkers are urgently needed. Here, we target reactive astrogliosis for biomarker development in a pilot cohort of Multiple System Atrophy (MSA), in which key pathology and associated neuroinflammation are regionally more restricted than in AD, but more pronounced than in Parkinson’s Disease (PD). We combine glial fibrillary acidic protein (GFAP) as fluid‐based biomarker with [18F]D2‐Deprenyl‐(DED)‐PET imaging, a novel PET tracer targeting MAO‐B, for comprehensive characterization of reactive astrogliosis in this model disease.MethodGFAP levels were analyzed in plasma samples of 23 MSA and 22 PD patients, as well as in CSF samples of 14 MSA and 14 PD patients. In a subset of patients (4 MSA‐P, 7 MSA‐C and 3 PD), first‐in‐human [18F]DED‐PET imaging was performed. Fluid‐based and PET‐imaging biomarker levels were cross‐sectionally compared, followed by correlation to clinical disease severity as indicated by UMSARS (Unified Multiple System Atrophy Rating Scale) and MDS‐UPDRS (MDS Unified Parkinson’s Disease Rating Scale). Correlation between fluid‐based biomarkers and PET imaging signals was performed. Two additional patients were on rasagiline treatment and proved target engagement of [18F]DED‐PET imaging.Result[18F]DED‐PET imaging showed significantly higher SUVr signals in various regions of MSA when compared to PD. Signal increases were seen in phenotype‐specific target regions with higher putaminal tracer binding in MSA‐P and higher cerebellar tracer binding in MSA‐C patients (Fig. 1). Decreased [18F]DED‐PET tracer signal was detected in patients on rasagiline treatment, indicating sufficient blocking (Fig. 2). While CSF and plasma GFAP levels did not differ between MSA and PD, GFAP levels in both biofluids correlated with disease severity in MSA (p < 0.05), but not in PD.ConclusionWe present first‐in‐human data on a novel PET tracer to detect reactive astrogliosis in MSA. While [18F]DED‐PET imaging identifies disease‐ and entity‐specific regional astrogliosis, fluid biomarkers representing the overall level of astrogliosis appear to reflect clinical disease burden. Translation of these biomarkers into other neurodegenerative diseases, such as AD, should be pursued.
Longitudinal hippocampal atrophy is associated with cognitive decline independently of amyloid and tau in neocortex
Authors: Hanseeuw Bernard , Jacobs Heidi I.L. , Schultz Aaron P , Buckley Rachel F. , Properzi Michael J , Becker Alex , Farrell Michelle E. , Sanchez Justin S , Papp Kathryn V. , Yang Hyun‐Sik , Chhatwal Jasmeer P. , Price Julie C , Fakhri Georges El , Rentz Dorene M. , Sperling Reisa A. , Johnson Keith A. 
Published: December 2022

AbstractBackgroundHippocampal volume (HV) atrophy is a well‐known biomarker of cognitive impairment. However, it is not specific for Alzheimer’s disease (AD). To disentangle the contributions of AD and other neuropathologies to cognitive decline, we investigated the longitudinal associations between HV and cognition, adjusting for Aβ and tau in participants from the Harvard Aging Brain Study who were clinically normal (CN) at inclusion.MethodsSerial MRI (HV [1.3‐7.0y], PiB‐PET (Aβ, [1.9‐8.5y]), Flortaucipir‐PET (tau, [0.8‐6.0y]), and the Preclinical Alzheimer Cognitive Composite (PACC, [3.0‐8.8y]) were observed over an average five‐year follow‐up in 128 CN participants, including ten who progressed to symptomatic AD during the study. Longitudinal HVs were processed using Freesurfer v.6 and adjusted for intracranial volume. PiB was measured in a neocortical aggregate, Flortaucipir in inferior temporal (IT) and entorhinal cortex (EC). PET data were expressed as PVC‐SUVr scaled to subcortical white matter. We predicted cognition and imaging data over time with random intercept and slope in linear mixed‐models and extracted PACC, PiB, FTP, and HV slopes for each subject. Baseline imaging and slope data were entered in age‐adjusted linear regressions to evaluate their associations with PACC slope.ResultsWithout covariate, faster HV atrophy was correlated with faster PACC decline (Fig.1, R2=0.28, p<0.0001). Adjusting for age, the correlation was reduced, but significant (R2=0.20, p<0.0001, Table 2). Entering all predictors into sequential regression models, we observed that HV atrophy was associated with PACC decline independently of PiB and Tau (Table 3, model‐D). HV atrophy was explained by EC Tau, but not by PiB or IT Tau (model‐C, Fig.2). When comparing all biomarkers, HV slope uniquely accounted for 10% of the variance in PACC decline. IT Tau explained most of the association between EC Tau, PiB, and PACC. Altogether, 45% of the variance in PACC decline was explained by longitudinal changes in imaging biomarkers.ConclusionsIn older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of amyloid and tau, suggesting that non‐AD neuropathologies (TDP43, vascular) contribute to hippocampal‐mediated cognitive decline. Serial HV measures, in addition to AD‐specific biomarkers, may help evaluate the contribution of non‐AD pathologies that cannot be measured in‐vivo but are important for cognition.
Current diagnostic pathways for Alzheimer's Disease ‐ A comparison of six countries
Authors: Carboni Margherita , Suridjan Ivonne , Yan Jessie , Roth Sophie 
Published: December 2022

AbstractBackgroundDiagnostic pathways from cognitive impairment (CI) to Alzheimer’s disease (AD) are complex and vary geographically. This study aimed to quantify and compare the current diagnostic pathways in six countries.MethodsA real‐world, cross‐sectional survey of 1,694 health care professionals (HCPs) was conducted in six countries (US, China, UK, France, Germany and Spain) from October to November 2021. HCPs provided data for 6,744 patients including patient demographics, presenting symptoms, and diagnostic tests and procedures. Descriptive analyses were conducted for all patients and further stratified by countries and HCP types (primary care physicians (PCP) versus specialists (geriatricians, neurologists and psychiatrists)).ResultsMost common presenting symptoms included problems with memory (89.9%), physical/behavioral (87.1%), executive functioning (72.2%) and language (71.4%). 42.1% of patients were presenting to HCPs the first time for their symptoms.96.0% of patients with data on diagnostic tests by country and specialty (n=6,525), underwent clinical and 95.5% cognitive tests, including tests at scheduled follow‐up visits. Mini‐Mental State Examination (MMSE) was the most frequently used cognitive test (n=5,141). About half the patients (n=3,329) received blood‐tests, mainly to rule out other causes of CI (n=2,687) (Table 1).Diagnostic test use varied by country and specialty. In China, cognitive tests, especially MMSE, were more commonly used by specialists (81.9%) than PCPs (41.6%). In the UK blood tests were more commonly used by PCPs (62.5%) than specialists (46.2%).ConclusionDiagnostic pathways varied largely by country and specialty. This study is relevant to populate diagnostic pathways, fill data gaps and advance patient care in AD by supporting future evidence generation, especially when new treatment options arrive.
A pilot study to investigate postural sway and saccadic eye movements comprehensively for MCI classification
Authors: Imaoka Yu , Hauri Laura , Flury Andri , de Bruin Eling Douwe 
Published: December 2022

AbstractBackgroundWhile single assessment of postural sway or saccadic eye movements is potentially useful for dementia screening at clinical settings [1, 2], multimodal assessment of the two movements could improve the screening accuracy [3‐5]. We have developed a novel comprehensive assessment system of posture and saccades, with integrated additional cognitive tasks of visuospatial memory and spatial orientation. We hypothesised that the new system would improve the classification of mild cognitive impairment (MCI).Method23 older adults joined the experiment and were split into two group based on the score of Montreal Cognitive Assessment (MoCA) [6]: 20 healthy older adults (HA) (70.35±4.93 years, 11 men / 9 women) and 3 older adults with MCI (74.7±4.04 years, 1 man / 2 women). The assessment system consists of stabilometer (GP‐5000, ANIMA Corporation, Japan) and a head‐mounted display virtual reality (VR) technology (VIVE Pro Eye, HTC Corporation, Taiwan). We measured postural sway and pro‐ or anti‐saccadic eye movements simultaneously in each of three different VR environments: #1) no additional cognitive task, #2) with visuospatial memory task, and #3) with spatial orientation task. We compared the parameters of saccades and postural sway between HA and MCI groups.ResultHA group achieved the MoCA score of 27.2±1.64, while MCI group scored 20.3±2.08 (P=0.006). Our analysis did not find significant differences between the two groups in all parameters. However, we observed moderate effect on standard deviation of centre of pressure in medio‐lateral direction in two test conditions: 1) the condition with pro‐saccade and visuospatial memory tasks (P=0.14; effect size = 0.32) and 2) the condition with anti‐saccade and spatial orientation tasks (P=0.09; effect size = 0.36).ConclusionModerate effect was observed on postural sway behaviours in the two test conditions. Since these conditions theoretically activate wider areas of the brain, our comprehensive assessment approach could be useful for dementia screening. Future research requires more sample size of MCI population for further analysis.
Exploratory evaluation of 18F‐MK‐6240 tau PET positivity in TANGO phase 2 clinical trial of gosuranemab (BIIB092) in Mild Cognitive Impairment and mild Alzheimer’s disease
Authors: Racine Annie M , Collins Jessica A. , DuBois Jonathan M , Seibyl John , Kong Jessica , Li Yumeng , O'Gorman John , Makaretz Sara J. , Jones Stephanie , Graham Danielle , Rajagovindan Raj , Shulman Melanie , Haeberlein Samantha Budd 
Published: December 2022

AbstractBackgroundTANGO was a randomized, placebo‐controlled, phase 2 study evaluating gosuranemab, an investigational anti‐tau antibody, for potential treatment of mild cognitive impairment (MCI) due to Alzheimer’s disease and mild Alzheimer’s disease. We explored the feasibility and validity of assessing 18F‐MK‐6240 tau PET positivity in post hoc exploratory analyses, to inform evaluation of treatment effect in future clinical trials.MethodTANGO enrolled 654 individuals aged 50‐80 years, diagnosed with MCI due to Alzheimer’s disease or mild Alzheimer’s disease, positive for amyloid pathology. 357 participants enrolled in an optional 18F‐MK‐6240 tau PET substudy. Two expert neuroradiologists read each baseline scan as visually tau positive (Tau+) or negative (Tau‐); discrepant cases were resolved by consensus. Exploratory regional SUVR quantitative thresholds (>2 standard deviations from the mean) were derived on an external 18F‐MK‐6240 sample of N=103 elderly, cognitively unimpaired, amyloid negative adults. TANGO baseline tau PET scans were classified as quantitatively Tau+ if SUVR was above a threshold in composite regions for Braak I‐II (SUVR >1.22) and/or Braak III‐IV (SUVR > 1.29). Baseline demographics and clinical characteristics were compared between the Tau+ and Tau‐ groups and concordance between the two tau positivity approaches (visual read vs. quantitative SUVR thresholds) was assessed.Results85%‐90% of the TANGO tau PET substudy population was Tau+ at baseline using quantitative or visual read approaches, respectively. Interrater agreement for the two visual readers was high (97%). Agreement between the visual read and quantitative methods was also high (93%). Tau+ and Tau‐ groups overlapped in their baseline clinical and demographic characteristics, but the Tau+ group trended toward indicators of more advanced disease at baseline (e.g. worse clinical scores).ConclusionsBased on this study of patients diagnosed with MCI due to AD and mild Alzheimer’s disease, patients who are amyloid positive also have a high probability of having tau pathology as measured by either visual read or quantitative assessment. These exploratory analyses suggest the criteria for 18F‐MK‐6240 tau PET positivity using either visual read or SUVR quantitative thresholds are feasible and valid and provides opportunities to incorporate evaluation of 18F‐MK‐6240 tau positivity into clinical trials.
VIVIAD, A Phase 2b Study Investigating Varoglutamstat in Patients with MCI and Mild AD: Dose Selection and Interim Safety Results
Authors: Weber Frank , Fuchs Katharina , Schaeffer Michael , Bihlet Asger Reinstrup , Alexandersen Peter , Axelsen Tobias Melton , Scheltens Philip , Vijverberg Everard G.B. 
Published: December 2022

AbstractBackgroundVaroglutamstat (PQ912), a small molecule glutaminyl cyclase (QPCT) inhibitor, reduces the brain levels of pyroglutamate‐3‐Aβ (N3pE‐Aβ), a toxic Aβ variant shown to play a pivotal role in the development and progression of Alzheimer’s disease (AD). Encouraging results reported in a prior Phase 2a study (NCT02389413) led to the initiation of a state‐of‐the‐art Phase 2b trial investigating multiple cognitive, safety and biomarker endpoints.MethodsVIVIAD (NCT04498650) is a multicentre randomized, placebo‐controlled, double‐blind, parallel group dose finding Phase 2b study in patients with cognitive impairment (MCI) and mild AD. Objectives are to evaluate the longterm efficacy (primary endpoint Cogstate NTB), safety and tolerability of oral varoglutamstat. The study will recruit 250 patients. The first 90 patients are randomised 1:1:1 (600 mg twice daily, (BID) or 300 mg BID varoglutamstat or placebo BID). An independent DSMB will unblind safety results after 90 patients have completed 24 weeks of treatment in June 2022 and decide on the varoglutamstat dose to be carried forward. The data remain blinded outside the DSMB. After the DSMB decision, all patients will be randomised 1:1 between the final dose of varoglutamstat and placebo and continue treatment up to 48‐96 weeks dependent on study entry date.ResultsThe study is currently enrolling patients in 22 AD study centers in 5 European countries (160 patients are randomised as of April 25, 2022). The safety data providing the base for the DSMB dose decision, the DSMB decision itself and the baseline characteristics of the patients enrolled into the trial so far will be reported at AAIC.ConclusionThe state‐of‐the art Phase 2b study VIVIAD is designed to yield important results in early AD for varoglutamstat, the first small molecule and only project in clinical development selectively targeting the de novo production of neurotoxic N3pE‐Aβ. The DSMB decision represents an important milestone within the Phase 2b study as it will recommend the dose of varoglutamstat considered to be safe for being carried forward to the study completion.
Free water imaging in healthy brain aging and first signs of brain pathology
Authors: Berger Martin , Pirpamer Lukas , Hofer Edith , Ropele Stefan , Pasternak Ofer , Enzinger Christian , Schmidt Reinhold , Koini Marisa 
Published: December 2022

AbstractBackgroundBrain aging is associated with cerebral small vessel disease (SVD). Recently, it was suggested that SVD is mainly driven by increases of extracellular free water (FW). The aim of the present study was to examine the association of FW, conventional and FW‐corrected diffusion tensor imaging (DTI) parameters (fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD)) with aging. The second aim was to determine if differences in FW and DTI parameters exist between individuals with first signs of pathology and healthy elderly controls regarding metrics that are not associated with age.MethodWe examined 87 healthy elderly (age: M = 66.34, SD = 9.82) and 87 individuals with first signs of cerebral pathology (age: M = 68.14, SD = 9.18) of the Austrian Stroke Prevention Family Study. Individuals with first signs of cerebral pathology were defined as having WMH score >1, presence of lacunes and/or microbleeds. FW in global normal appearing white matter (NAWM) as well as conventional and FW‐corrected DTI parameters were used in correlation analyses to assess their association with age. ANOVA adjusted for multiple comparison was used to determine the differences in FW and FW‐corrected DTI metrics between individuals with initial signs of SVD and healthy controls.ResultFW in NAWM as well as non‐FW‐corrected DTI were significantly associated with age in the total sample and both stratified groups (range of |r|: 0.24‐0.49). No correlation between FW‐corrected DTI measures and age were found. Differences between individuals with and without first signs of pathology were only identified for FW in NAWM.ConclusionThe association between uncorrected conventional DTI parameters and age is mainly driven by the amount of FW, calling for caution when interpreting uncorrected DTI scores. In contrast, FW appears to be a sensitive marker at very early, clinically silent, signs of SVD.
Functional Interpretation of Alzheimer’s Disease Genetic Risk and Systematic Gene Prioritization
Authors: Küçükali Fahri , Sleegers Kristel ,   EADB
Published: December 2022

AbstractBackgroundGenome‐wide association studies (GWAS) of Alzheimer’s disease (AD) risk identified over 100 genome‐wide significant susceptibility loci in the past 15 years, but remaining challenges include resolving the mechanism of action of how these associations functionally contribute to AD risk and prioritizing the candidate risk genes in the complex risk loci. To address these, we have recently developed a systematic gene prioritization pipeline that nominated highly likely candidate risk genes within the majority of 42 new loci identified by our recent AD GWAS meta‐analysis. In this subsequent work, we investigated the complete landscape of AD risk‐associated molecular phenotypes and further extended our analyses to known AD risk loci and subthreshold significant loci.MethodWe investigated downstream effects of AD‐associated variants on molecular phenotypes (e.g. gene expression, splicing, methylation, protein expression, histone modifications) through molecular quantitative trait loci (QTL) catalogues measured in disease‐relevant tissues and cells. We queried the lead variants in these QTL catalogues and performed genetic colocalization analyses (coloc) & transcriptome/methylome/proteome‐wide association studies (TWAS/EWAS/PWAS) using the EADB stage I meta‐analysis GWAS on 85,934 cases and 401,577 controls. Evidence for candidate genes in new, known, and subthreshold loci were assessed by the gene prioritization pipeline that was updated with new analyses. Moreover, we investigated AD‐associated cryptic splicing events using Nanopore sequencing.ResultOur results implicated >140 protein‐coding genes with AD risk in 42 new loci, >275 in 34 known loci, and over >65 in 31 subthreshold loci. Within MINDY2 known locus, evidence from multiple QTL‐GWAS integration domains confirmed ADAM10 as a prioritized gene. Moreover, we obtained first QTL‐based evidences for candidate genes within previously‐unresolved new risk loci such as RASGEF1C. In a subthreshold locus, fine‐mapped expression TWAS associations were observed for SNX31 (a member of sorting nexins together with SNX1 in novel loci) consistently across multiple brain expression reference panels, implicating genetic upregulation of SNX31 with increased AD risk. Furthermore, we could confirm AD‐associated novel splicing events within prioritized genes such as DOC2A.
ConclusionOur comprehensive study effectively and systematically prioritized AD risk genes and aided functional interpretation of AD GWAS by contributing to better understanding of genetically‐associated molecular mechanisms underlying AD risk.
Second‐generation fully automated Elecsys cerebrospinal fluid immunoassays demonstrate high precision, reproducibility, and sample stability suitable for clinical use to aid Alzheimer’s disease diagnosis
Authors: Rutz Sandra , Manuilova Ekaterina , Müller‐Hübner Laura , Grimmer Timo , Powers Jennifer , Christenson Robert H. , Karpova Maria , Winter Carla , Teunissen Charlotte E. 
Published: December 2022

AbstractBackgroundBeta‐amyloid(1–42) (Abeta42) and phosphorylated tau 181 (pTau) cerebrospinal fluid (CSF) biomarker analysis is recommended alongside cognitive evaluation to aid Alzheimer’s disease (AD) diagnosis. For clinical use, CSF biomarker assays should demonstrate high precision/reproducibility and sample stability. This study evaluated precision, reproducibility, and sample stability of second‐generation fully automated Elecsys® CSF immunoassays.MethodFrozen/pooled CSF and PreciControl samples were analyzed using Elecsys β‐Amyloid(1–42) CSF II/Phospho‐Tau (181P) CSF immunoassays on cobas e 601 (Roche Diagnostics International Ltd). pTau/Abeta42 ratios were calculated. Precision was evaluated at one site per Clinical and Laboratory Standards Institute (CLSI) EP02‐A3 (two runs/day in duplicate over 21 days; n=84). Reproducibility was determined per CLSI EP05‐A3 over five days using a single lot across three sites (site‐to‐site)/three lots at one site (lot‐to‐lot). Coefficients of variation (CVs)/standard deviations (SDs) for repeatability/intermediate precision/reproducibility were calculated using variance component analysis. Sample stability was determined from fresh CSF, collected per manufacturer's instructions. Baseline measurements were taken <6 hours after lumbar puncture and follow‐up measurements (from stored aliquots) at defined intervals for ≤8 days at room temperature (RT; 25°C; n=13), ≤15 days at 6°C (n=14), and ≤13 weeks at ‐20°C (n=25). Storage stability was determined from percent recoveries/ordinary linear regression.ResultRepeatability CVs were <2.4% and <1.9% for Abeta42 and pTau immunoassays, respectively, and <2.4% for pTau/Abeta42 ratio. Intermediate precision CVs were <3.3% and <3.7% for Abeta42 and pTau immunoassays, respectively, and <3.9% for pTau/Abeta42 ratio. Site‐to‐site reproducibility CVs were <5.1% and <3.6% for Abeta42 and pTau immunoassays, respectively, and <6.5% for pTau/Abeta42 ratio (Table 1). For the Abeta42 immunoassay, lot‐to‐lot reproducibility CVs were <5.4%, except for one sample pool (mean concentration: 322 pg/mL; SD: 34.1 pg/mL; Table 2). Lot‐to‐lot reproducibility CVs were <3.6% for the pTau immunoassay and <6.0% for pTau/Abeta42 ratio. At maximum sample storage duration (8 days at RT/15 days at 2−8°C), median recoveries of 95%/98% were observed for Abeta42 and 97%/99% for pTau immunoassays. Stability assessment at ‐20°C is ongoing.ConclusionThe Elecsys immunoassays demonstrated high precision/reproducibility, supporting clinical use in AD diagnosis. Conservative recommendations for sample storage are 5 days at RT/14 days at 2−8°C.