bluuebunny/crossref_metadata_2025_split huggingface dataset:
PhysicOmics: Combining MR physics, proteomics, and transcriptomics to study cerebral aging and neurodegeneration
Authors: Bae Jonghyun , Gong Zhaoyuan , Guo Alex , Laporte John P , Faulkner Mary E , Bouhrara Mustapha 
Published: January 2025

AbstractBackgroundNeuroimaging‐based evidence suggests that changes in cerebral tissue determinants, including axonal density and myelin content, are associated with aging and neurodegenerative diseases. While neuroimaging markers show strong association with physiological changes, direct validation of their specificity remains challenging. Histology provides useful information for validation, however, faces limitations including denaturation of the sample during preparation. However, in the era of omics, validation of neuroimaging markers becomes accessible with dataset from various biological measurements. We provide two examples of validations of our MR physics‐based markers of myelin water fraction (MWF), a surrogate of myelin content, and neurite density index (NDI), a proxy of axonal density, using proteomics and transcriptomics (Figure 1).MethodAssociation between neurofilament light chain (NfL) and NDI:58 participants (age=21‐83yrs.) underwent our multishell diffusion imaging protocol for NDI determination using C‐NODDI. Blood was collected at the time of MRI to quantify the NfL level, a biomarker of axonal integrity, using Simoa assays. The association between NDI and NfL was evaluated using a multiple linear regression analysis.Association between myelin gene expression and MWF:132 subjects (age=22‐94yrs.) underwent our relaxometry protocol for MWF determination using BMC‐mcDESPOT. Further, microarray data were obtained from the Allen Human Brain Atlas, providing gene expression data from 6 healthy donors. Using Pearson correlations, we assessed the association between regional MWF measurements (averaged across participants) and regional gene expressions, with a focus on Myelin Basic Protein (MBP) and transcription factors involved in myelin synthesis.ResultFigure 2 shows strong negative regional correlations between NfL and NDI derived using C‐NODDI. Further, we found strong positive correlations between MWF and genes involved in myelin production (Figure 3).ConclusionGiven the strong correlations between NfL or MBP and NDI or MWF, this work provides evidence of the specificity of these MRI biomarkers of axonal density and myelin content, making C‐NODDI and BMC‐mcDESPOT powerful and relevant MR methods for clinical investigations and trials. While further investigations are still required in the context of neurodegeneration, our work demonstrates the potential of combining MR physics and omics to delve deeper into the neurobiological and molecular mechanisms underlying aging and age‐related diseases.
Long‐Term Impact of Amyloid PET in Memory Clinic Diagnostic Workup: A Matched Cohort Study on Healthcare Costs, Institutionalisation, and Mortality Risk
Authors: van der Veere Pieter J. , Broulíková Hana M. , Hoogland Jeroen , van Harten Argonde C. , van Maurik Ingrid S. , van de Giessen Elsmarieke , Berkhof Johannes , van der Flier Wiesje M. 
Published: January 2025

AbstractBackgroundWe hypothesise that improved diagnostic precision, operationalised by adding amyloid positron emission tomography (PET) to the diagnostic work‐up in a memory clinic, is beneficial for long‐term health and healthcare cost outcomes. We investigated whether a more precise diagnosis influenced institutionalisation and mortality incidence trajectories, and annual healthcare costs over a period up to eight years.MethodBetween October 2014 and December 2016, patients from the Amsterdam Dementia Cohort were offered an amyloid‐PET as part of their diagnostic work‐up. Those who received an amyloid‐PET were propensity‐score matched to participants without a PET, creating two balanced groups containing 442 patients each (Table 1; 64±8yrs, 40%F, 43% dementia). Statistics Netherlands provided healthcare costs for six years, institutionalisation for seven years, and mortality data for eight years of follow‐up. Institutionalisation and mortality incidence were calculated, and mean costs were bootstrapped. Healthcare costs were first evaluated as annual total cost and subsequently disaggregated into the following categories: primary care, hospital‐related care, mental health care, aid products, medication, homecare, and institutionalisation.ResultThe amyloid‐PET and no‐PET groups had distinct institutionalisation and mortality incidence trajectories (Figure 1). The difference in institutionalisation was most pronounced three years after the diagnosis with 11% institutionalisation in the amyloid‐PET group (95% confidence interval [CI]: 8%‐14%, n=50), compared to 20% in the no‐PET group (15%‐25%, n=95, p=0.002). Subsequently, the difference attenuated to 28% (24%‐33%, n=118) vs. 33% (27%‐38%, n=135, p=0.28) after six years. Mortality incidences started to converge after four and merged after six years. Annual healthcare costs were €3968 (CI:1177‐6942, Table 2) lower in the amyloid‐PET group. This difference was mostly attributable to the categories of institutionalisation costs (€‐3361; CI:‐5929 to ‐918) and primary care (€‐99; CI:‐195 to ‐7).ConclusionA more precise diagnosis through an amyloid‐PET positively influenced the incidence trajectories of institutionalisation and mortality, with the largest differences observed in the first three to four year after the diagnosis. Our findings suggest a more precise diagnosis could lead to more efficient and tailored primary care and to postponed institutionalisation. Less time spent in institutional care was also identified as a main driver of lower healthcare costs.
Automated Brain Volumetry Analysis for Differential Diagnosis of Frontotemporal Dementia Subtypes
Authors: Cho Hyeonwoo , Park Mina , Lee Seung Hyun , Jung Wooseok , Kim Dong‐Hee , Kim Jinyoung , Lee Yeha ,   for the Frontotemporal Lobar Degeneration Neuroimaging Initiative*
Published: January 2025

AbstractBackgroundClinical diagnosis of frontotemporal dementia (FTD) can be challenging, requiring an accurate tool dedicated to this diagnostic hurdle. Since FTD exhibits distinct regional atrophy patterns on magnetic resonance imaging (MRI), AI‐aided automated brain volume analysis could enhance the clinical diagnostic assessment of FTD, including the detection of the disease and the classification of subtypes, which encompass behavioral variant (BV), semantic variant (SV), and progressive non‐fluent aphasia (PNFA). In this study, we leverage automated brain volumetry software to approach both FTD detection and the differential diagnosis among its subtypes.MethodA total 258 patients with FTD (BV = 57, SV = 40, PNFA = 34) and 127 Normal Control (NC) were identified from the frontotemporal lobar degeneration neuroimaging initiative (NIFD) data sets with available MRI. We obtained 104 areas of patient’s normalized regional brain volumes using VUNO‐Med DeepBrain. Comparative analyses were conducted to explore differences in regional volume distribution between FTD and NC, as well as among FTD subtype based on their known atrophy patterns. Additionally, regional normative percentiles were utilized as features for classification using the XGBoost algorithm to distinguish FTD vs NC, BV vs SV vs PNFA, and BV vs SV vs PNFA vs NC.ResultIn BV, significant differences in atrophy patterns were observed in the frontal lobe, demonstrating an anterior‐posterior gradient compared to SV, PNFA and NC (P<0.01). SV exhibited left side dominant asymmetric atrophy, particularly in the inferior temporal lobe, compared to BV, PNFA, and NC (P<0.01). Additionally, the inferior horn of the lateral ventricle in SV had higher volume than other subtypes, attributable to atrophy of surrounding brain regions. In contrast, the differences in atrophy patterns for PNFA were statistically less significant when compared to other FTD subtypes. Automated brain volumetry software‐based classifications demonstrated high accuracy of FTD vs NC (Accuracy 95% CI = [0.88, 0.89]), BV vs SV vs PNFA ([0.79, 0.81]), and BV vs SV vs PNFA vs NC ([0.82, 0.83]).ConclusionOur study demonstrates the effectiveness of automated brain volumetry and machine learning in identifying FTD and differentiating frontotemporal dementia subtypes, contributing to an enhanced understanding of subtypes and improved diagnostic precision in neurodegenerative disorders.
Tau Aggregates in Cerebrospinal Fluid: A Promising Biomarker for Neurodegenerative Diseases
Authors: Islam Md Tohidul , Karikari Thomas K , Blennow Kaj 
Published: January 2025

AbstractBackgroundThis research introduces a novel method for quantifying aggregated tau in body fluids, specifically cerebrospinal fluid (CSF), aiming to enhance the diagnosis and monitoring of neurodegenerative diseases, with a focus on Alzheimer's disease (AD).MethodBy combining tau protein amplification with a highly sensitive single‐molecule array (Simoa) immunoassay using an anti‐tau antibody CT19.1 in a homogenous manner, the approach enables precise measurements of tau aggregates in CSF.ResultPreliminary testing involved 40 CSF samples from AD and non‐AD individuals, treated with a recombinant tau amplifier that we innovated in our research facility and subjected to an extended incubation period. Without amplification, the immunoassay showed baseline signals. However, after amplification, the technique not only elevated signals to a detectable range but also differentiated AD CSF from non‐AD samples.ConclusionOur methodology integrates tau amplification with a remarkably sensitive immunoassay detection system, allowing for precise quantification of tau aggregates in CSF. The approach is to adapt into the assay for plasma and serum samples. This expansion of the method's applicability has the potential to revolutionize non‐invasive diagnostic tools for neurodegenerative diseases. This innovation opens a possibility to facilitate the tracking of disease progression and the assessment of treatment responses, thereby making significant contributions to the advancement of clinical research and therapeutic trials. Another important aspect of this approach is the use of the assay antibody CT19.1 which is generated in our facility. This antibody binds to the pathologically significant MTBR region, which is considered the core region that facilitates tau aggregation, which indicates a possibility to explore further as therapeutic intervention.
Associations of load and progression of imaging markers of microvascular lesions and neurodegeneration with odor identification decline: a population‐based study
Authors: Oltra Javier , Kalpouzos Grégoria , Ekström Ingrid , Larsson Maria , Qiu Chengxuan , Laukka Erika J 
Published: January 2025

AbstractBackgroundOlfactory deficits are predictive of cognitive decline and dementia. Previous studies have linked brain magnetic resonance imaging markers of neurodegeneration to olfactory deficits in aging; however, these studies analyzed cross‐sectional data for markers, olfaction, or both. Furthermore, potential cerebrovascular contributions to understanding why olfactory deficits predict dementia remain unexplored. We aimed to examine whether markers of microvascular lesions and neurodegeneration and their progression are associated with the rate of olfactory decline in community‐dwelling older adults.MethodParticipants were 405 individuals (mean age=70.2 years; 60% females) from the Swedish National study on Aging and Care in Kungsholmen (SNAC‐K) who were free from dementia at baseline. We analyzed microvascular lesions (presence of lacunes, white matter hyperintensities volume, global perivascular spaces [PVS] count) and neurodegeneration (lateral ventricular, hippocampal, and total gray matter volumes) markers, available up to 6 years and an olfactory measure (Sniffin’ Sticks odor identification task), available up to 15 years. Additionally, we assessed summary scores for microvascular lesions and neurodegeneration load (range 0–3), accounting for all markers of each category (1 point for its presence or for being in the worst quartile, as appropriate). Data were analyzed with linear mixed‐effects models.ResultAfter adjustment for sociodemographic (age, sex, and education) and extra covariates (smoking status and semantic memory), a higher global PVS count (β =‐0.041; 95% CI, ‐0.077 to ‐0.005) and a high load (≥2 points) of neurodegeneration (β=‐0.112; 95% CI, ‐0.221 to ‐0.002) at baseline were associated with a faster olfactory decline. Longitudinally (n=228), faster accumulation of PVS (β=‐1.812; 95% CI, ‐3.474 to ‐0.150), faster hippocampal atrophy (β=1.348; 95% CI, 0.413 to 2.283), and an increment from low (≤1 point) to high load for microvascular lesions (β=‐0.167; 95% CI, ‐0.327 to ‐0.007) and neurodegeneration (β=‐0.206; 95% CI, ‐0.321 to ‐0.092) were associated with an accelerated olfactory decline.ConclusionBoth microvascular lesions and neurodegeneration are longitudinally associated with olfactory decline in aging. This relationship supports the notion that olfactory deficits could be valuable as an early marker for dementia. More longitudinal studies are needed to untangle the mechanisms in play between cerebral vascular burden, atrophy, and olfaction.
Urine BMP is lowered in frontotemporal dementia due to progranulin mutations
Authors: Tucker Katie , Swift Imogen J , Goldsmith Sophie E , Esteve Aitana Sogorb , Rohrer Jonathan D. 
Published: January 2025

AbstractBackgroundGRN mutations are a common cause of frontotemporal dementia (FTD), with previous studies linking granulin deficiency to reduced bis(monoacylglycerol)phosphate (BMP) levels, which ultimately impairs ganglioside degradation. BMP is involved in the lysosomal functions within cells, as it facilitates the adhesion of hydrolases and activator proteins where the lysosomal membranes meet, therefore a lack of BMP could impact lysosome function and integrity. We hypothesised that urine levels of BMP isoforms will be lower in FTD patients with GRN haploinsufficiency, as a reflection of reduced BMP in neural tissues, when compared to those with FTD caused by C9orf72 expansions and MAPT mutations, or healthy controls. The objective of this study was to investigate changes to urinary phospholipids as potential biomarkers of GRN mutations in FTD.MethodA panel of 3 different di‐22:6 BMP, and 3 di‐18:1 BMP isoforms, as well as total di‐22:6 and di‐18:1 BMP, were measured in urine collected from the UCL GENFI cohort consisting of 36 controls, 11 symptomatic GRN mutation carriers, 11 symptomatic C9orf72 carriers and 12 symptomatic MAPT mutation carriers. A mass spectrometric method was used to quantitate molecular species of BMPs in urine, with results normalised to creatinine. Data analysis was performed in Stata, using an age and sex‐adjusted bootstrapped regression to compare the different symptomatic groups to the controls, with P<0.05 considered statistically significant.ResultGRN mutation carriers showed reduced levels of the 2:2 di‐22:6 BMP isoform (mean=11.9 (standard deviation=7.5)) when compared to controls (17.9 (13.5); p=0.015), with a trend for reduced levels of the 2:2 di‐18:1 BMP isoform also (3.5 (2.1)) for GRN mutation carriers compared with (4.6 (4.2)) for controls, consistent with the idea that mutations in GRN lower levels of BMP. Concentrations of the 2:3 and 3:3 isoforms as well as the total amount were not significantly different between control and mutation groups.ConclusionOur results indicate that GRN mutations cause a reduction in the levels of certain isoforms of BMP in urine. Future studies will be helpful to see if urinary BMP concentrations increase with treatments that restore progranulin levels.
Potentially inappropriate medication use among older adults with cognitive impairment and dementia attending primary care‐based memory clinics
Authors: Sharma Rishabh , Lee Linda , Chang Feng , Patel Tejal 
Published: January 2025

AbstractBackgroundThe use of potentially inappropriate medications (PIMs) in older adults with dementia and/or Mild Cognitive Impairment (MCI) has been associated with increased adverse events, drug‐related problems (DRPs), prolonged hospitalization, risk of falls, and increased length of stay. This study aimed to identify which explicit tool, Beers criteria 2023 or Screening Tool of Older Persons Potentially Inappropriate Prescriptions (STOPP) 2023, identifies more PIM use among older adults with MCI or dementia.MethodsA cross‐sectional study was conducted at a Multispecialty Interprofessional Team‐based (MINT) memory clinic. Patients with MCI or dementia were recruited between Jan and August 2023. Patient medical records were reviewed for PIMs using Beers Criteria 2023 and STOPP criteria 2023. Bivariate logistic regression analysis was employed to identify potential factors associated with the use of PIMs.ResultsOverall, 44 participants were enrolled in the study, with a mean age of 80.2± 6.2 years. Among 44 patients, 36.4% (n = 16) patients had MCI, followed by one‐fifth of patients (n = 9) who had mixed dementia and 11.4% (n = 5) with vascular cognitive impairment. At least one PIM was identified in 47.7% (n = 21) and 27.2% (n = 12) of the study participants based on Beers' and STOPP’s criteria, respectively. Using the Beers criteria, 50 PIMs were found, with an average of 0.9 PIMs for each patient, while a total of 31 PIMs were identified using the STOPP criteria, with an average of 0.6 PIMs per patient. There was a significant association between ≥ 9 number of comorbidities and PIMs as per Beers criteria (OR = 8.4, 95% Confidence interval: 1.27‐ 55.39, P = 0.027). However, no statistically significant association was observed with PIMs as per STOPP criteria.ConclusionThe frequency of PIMs identified using Beers and STOPP criteria highlights the importance of identifying and addressing PIMs in this population. This study adds valuable insights to the progressing comprehension of medication‐related complexities in older adults living with MCI or dementia.
Clinical Profile of AXS‐05 in Treating Alzheimer’s Disease Agitation: Results from the Phase 2/3 Development Program
Authors: Cummings Jeffrey L. , Grossberg George T , Streicher Caroline , Tabuteau Herriot 
Published: January 2025

AbstractBackgroundPatients with Alzheimer’s disease (AD) often experience burdensome neuropsychiatric symptoms, including agitation which occurs in both home and long‐term care (LTC) facilities, and is associated with substantial increases in caregiver burden and LTC placements. AXS‐05 (45‐mg dextromethorphan/105‐mg bupropion), a novel, oral NMDA receptor antagonist and sigma‐1 receptor agonist, approved by the FDA for major depressive disorder, is being investigated for treatment of AD agitation (ADA). AXS‐05 has been evaluated in 2 randomized, double‐blind studies: Phase 2 ADVANCE‐1 (NCT03226522); Phase 3 ACCORD (NCT04797715).MethodADVANCE‐1/ACCORD enrolled patients (65‐90 y) with a diagnosis of probable AD using 2011 NIA‐AA diagnostic criteria. ADVANCE‐1 evaluated the acute effects of AXS‐05 on improving ADA. Patients were randomized 1:1:1 for 5 weeks (AXS‐05 or bupropion [105‐mg] or matching placebo). Primary endpoint: change from baseline in the Cohen‐Mansfield Agitation Inventory (CMAI) total score. ACCORD evaluated the effects of AXS‐05 in preventing ADA relapse using a randomized discontinuation design; it comprised an open‐label period (OLP; ≤9 weeks) until response was sustained (≥4 consecutive weeks). In the double‐blind period (DBP), patients were randomized 1:1 (AXS‐05/placebo) for up to 26 weeks in the DBP or until relapse. Primary endpoint: time‐to‐relapse.ResultADVANCE‐1 comprised 357 patients in the modified intent‐to‐treat population: AXS‐05 (n = 152) bupropion (n = 49), placebo (n = 156) (mean baseline CMAI total scores = 60.7, 66.1, 59.4, respectively). At Week 5, AXS‐05 significantly reduced CMAI total score by 15.4 points vs bupropion (10.0 points; P<.001) and placebo (11.5 points; P = .010). In ADVANCE‐1, common adverse events (AEs; ≥3%) included somnolence (8.2%), dizziness (6.3%), and diarrhea (4.4%). ACCORD comprised 178 patients in the OLP (mean CMAI = 70.9) and 108 patients in the DBP (AXS‐05, n = 53; placebo, n = 55) (mean CMAI = 43.7). AXS‐05 increased time‐to‐relapse vs placebo (hazard ratio = 0.275; P = .014). AXS‐05 was associated with lower relapse rates vs placebo (7.5% vs 25.9%; P<.05). In ACCORD, common AEs (≥3%) included dizziness (9.6%), diarrhea (4.5%), and fall (5.1%). AXS‐05 was not associated with cognitive impairment or sedation in either study.ConclusionAXS‐05 demonstrated a substantial, rapid reduction in ADA vs controls after 5 weeks of treatment, increased time‐to‐relapse vs placebo, and was well‐tolerated, supporting its development as a promising treatment option for ADA.
Longitudinal cognitive trajectories in ADAD: The relationship with glucose metabolism [18F]FDG PET
Authors: Zapater‐Fajari Mariola , Luckett Emma S. , Chiotis Konstantinos , Bucci Marco , Wall Anders , Almkvist Ove , Rodriguez‐Vieitez Elena , Graff Caroline , Nordberg Agneta K 
Published: January 2025

AbstractBackground[18F]FDG PET is essential since it allows us to differentiate between different dementia disorders/types, revealing distinct neurodegenerative patterns in those predisposed to the condition. Individuals with Autosomal Dominant Alzheimer's Disease (ADAD) have a predictable age of onset, enabling the study of cognitive and pathological changes before clinical manifestation. Our objective was to investigate temporal course and regional links between cognition and glucose metabolism as a measure of early synaptic impairment in ADAD.MethodForty‐five participants were included in the present study: 26 non‐carriers, and 19 mutation‐carriers (11 APP and 8 PSEN1) who had up to 5 measurements of [18F]FDG PET and neuropsychological testing within a time interval of 7.2±6.4 years. Expected years to symptom onset (EYO) in mutation‐carriers ranged from ‐25.8 to 10.3 years. Nine cognitive tests, emphasizing Episodic Memory (EM: learning and delayed recall of the Rey Auditory Verbal Learning and delayed recall of the Rey‐Ostetriech Complex Figure) and Executive Function/attention (EF/A: Digit Symbol, Rey Copy, Trail Making Test A and B, Digit Span Forward and Backward), were z‐scored using non‐mutation carriers as the reference group. Mixed‐effects models were used to identify the differential effect of mutation status on the longitudinal trajectories of cognition or [18F]FDG. We also assessed whether the interaction of [18F]FDG with mutation status could predict cognitive decline.ResultCompared to non‐carriers, all cognitive tests significantly declined across EYO in carriers (all p<0.01), except Digit Span Backward (p=0.19). Notably, some EF/A and all EM tests showed decline 15‐10 years before EYO in carriers (Figure 1A‐E). [18F]FDG levels started to decline in Temporal, Parietal and Posterior Cingulate regions around 10‐5 years before EYO, with significantly steeper slopes detected for carriers vs non‐carriers (all p<0.007) (Figure 1F‐H). Steeper [18F]FDG regional decline patterns were found to predict steeper decline over EYO in most cognitive tests in carriers compared to non‐carriers (Table 1).ConclusionOur results link cognitive decline to [18F]FDG hypometabolism in several brain regions. Specific tests of EF and EM may detect early synaptic impairment due to their close relationship with [18F]FDG decline. This longitudinal study shed light on early changes in cognitive domains in ADAD individuals, offering insights into AD progression.