bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing of the glymphatic system using DTI‐ALPS MRI in patients with neurodegenerative diseases
Authors: Liaskovik Alina , Fedotova Ekaterina , Konovalov Rodion , Krotenkova Marina V. , Shpilyukova Yuliya , Nevzorova Kseniya , Brsikyan Lusine 
Published: January 2025

AbstractBackgroundDysfunction of the glymphatic system (GS), a recently discovered brain by‐product elimination system, is considered to be one of the pathophysiological mechanisms for common neurodegenerative diseases such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In 2017 a new way to assess the GS was proposed – a diffusion tensor images analysis along perivascular spaces (DTI‐ALPS).In our work we evaluated the DTI‐ALPS index in groups of patients with AD, DLB, PD and in a comparison group of patients with normal pressure hydrocephalus (NPH).MethodsWe examined 32 patients diagnosed with AD [69.5±8.0 years], 15 patients with DLB [71.1±8.0 years], 31 patients with PD without dementia [64.0±6.9 years], 11 patients NPH [68.5±9.8 years] and 27 healthy controls [63.2±7.0 years]. In four patient groups cognitive impairment was rated with Montreal Cognitive Assessment scale (MоCA).The diffusion images were acquired on a SIEMENS Prisma scanner using a 2D EPI diffusion sequence. TE=82 ms, TR=5600 ms. The b‐values were 1000 and 2500 s/mm². The number of diffusion sampling directions were 64 and 64, respectively. The slice thickness was 2 mm.Post‐processing steps were performed using DSI studio software. Next, we identified ROIs corresponding to projection and associative fibers with further extraction of tensor values in the directions Dxx, Dyy, Dzz, which were entered into a table to calculate the DTI‐ALPS index using formula ALPS‐index=mean(Dxxproj+Dxxassoci)/mean(Dyyproj+Dzzassoci) for further statistical processing.ResultsPatients with AD, DLB and NPH had a significantly lower values of DTI‐ALPS index on both sides compared to healthy volunteers (p<0.001). The differences between PD and healthy controls turned out to be statistically insignificant.In addition, analysis of all the patients revealed a significant direct correlation between the MoCA score and DTI‐ALPS values on both sides (pL=0.002; pR=0.035).ConclusionThe obtained results showed that the glymphatic dysfunction assessed by DTI‐ALPS index could be considered as a possible participant in the pathogenesis of AD and DLB as well as in NPH reflecting cognitive decline. Whereas the glymphatic dysfunction in PD was not confirmed.
Improving access to dementia care community resources in the Pacific island of Guam
Authors: Twaddle Iain K. B. , Gutierrez Nikolas Jude , Saloma Maree Josephine , Maestrecampo Camille Minerva 
Published: January 2025

AbstractThe island of Guam is a U.S. territory in the Western Pacific with a population of approximately 174,000. Most persons with Alzheimer’s disease and related dementias (ADRD) in Guam live at home with their family. This is due, in part, to Guam’s indigenous Chamorro culture, which emphasizes the importance of caring for the manåmko’ (elderly), but also to the limited availability of residential care facilities for older adults. In fact, Guam currently has no nursing homes or assisted living facilities that specialize in care for persons living with ADRD. This places a heavy burden on Guam’s families. Fortunately, Guam has an impressive array of community‐based resources to support persons living with dementia and their family caregivers. However, many members of the community are not aware of these services or do not know how to access them. To improve access to Guam’s dementia care support services, a series of education outreach presentations were provided to the community through an online support group for family caregivers of persons with dementia held weekly on Wednesday evenings and Saturday mornings. The presentations were conducted by elder care specialists from local government agencies and private healthcare organizations. A wide range of services were covered including: (1) adult day care services; (2) transportation services; (3) congregate and home‐delivered meals; (4) adult protective services; (5) case management services; (6) in‐home services; (7) home health services; (8) long‐term residential care for non‐ambulatory older adults; (9) government health insurance programs for older adults including Medicaid and Guam’s Medically Indigent Program; and (10) legal services for older adults, including guardianship, powers of attorney, wills, living wills, and advance healthcare directives. Each presentation provided guidance on eligibility criteria and application procedures, as well as contact information for key personnel. Program outcomes indicate the following: (1) all sessions were well attended; (2) participant feedback was overwhelmingly positive; and (3) a significant number of participants followed through with applying for dementia care services. In sum, education outreach presentations conducted online can serve as an effective means to improve access to community resources for persons living with ADRD and their family caregivers.
BrainChart hippocampal volume age, sex and TIV adjusted centile scores in Alzheimer’s disease
Authors: Parker Thomas D , Bethlehem Richard A.I. , Seidlitz Jakob , White Simon R , Dorfschmidt Lena , Bernstock Joshua D , Bourke Niall , David Michael CB , de Taurines Anastasia Francoise L Gailly , Giovane Martina Del , Graham Neil SN , Kolanko Magdalena A. , Zimmerman Karl A , Malhotra Paresh , Patel Maneesh , Scott Gregory PT , Alexander‐Bloch Aaron , Bullmore Edward T , Sharp David J 
Published: January 2025

AbstractBackgroundThe hippocampus is a key site of atrophy in Alzheimer’s disease (AD) and MRI derived estimates of hippocampal volume have been shown to be a robust biomarker of AD‐related neurodegeneration. However, its application at the individual level is limited by the lack of reference standards from large normative datasets that can be applied across a wide range of settings. We aimed to investigate the utility of hippocampal volume centile scores adjusted for age, sex and total intracranial volume (TIV) derived from a normative data from 101,457 participants across the life course, as a biomarker of neurodegeneration in AD.MethodsBrainChart calculates age and sex adjusted centile scores for structural MRI metrics using a GAMLSS (Generalised Additive Models for Location Scale and Shape) approach and can be applied to individual datasets using an out‐of‐sample centile scoring approach that calculates study‐specific offsets (Bethlehem, Seidlitz, White et al. Nature 2022). Using this approach, we developed models for Freesurfer derived estimates of hippocampal volume additionally incorporating TIV as a co‐variate. This was then applied to 351 individuals with pathologically confirmed AD (median scan time prior to death 5.9 years) from the NACC dataset, as well as 110 amyloid‐PET positive patients from the ADNI‐3 cohort (MCI n=71, AD dementia n=39). Wilcoxon rank‐sum tests were used to assess differences between patient groups and cognitively normal controls from the relevant datasets. Spearman’s rank correlations were used to assess relationships with cognition (MMSE score).ResultsMedian centile scores were reduced in all patient groups (pathologically confirmed AD cases left = 0.13, right =0.13; amyloid‐PET positive MCI cases left=0.12, right=0.16; and amyloid‐PET positive AD dementia left=0.01, right=0.02). This was significantly different to cognitively normal controls from both the NACC dataset (n=1400, cases left=0.52, right=0.52) and ADNI‐3 dataset (n=247, cases left=0.50, right=0.50), all to a significance level of p<0.0001. Hippocampal centile scores strongly predicted MMSE score in both cohorts (Spearmans’ Rho range 0.37‐0.41, p<0.001).ConclusionBrainChart age, sex and TIV adjusted hippocampal volume centile scores, derived from an extensive normative dataset, represent a method for objectively identifying neurodegeneration in AD that is interpretable at the individual level.
Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease
Authors: Caro Ilana , Western Daniel , Okada Yukinori , Jager Philip L. De , Duperron Marie‐Gabrielle , Sargurupremraj Muralidharan , Seshadri Sudha , Tregouët David Alexandre , Cruchaga Carlos , Debette Stéphanie ,   neuroCHARGE
Published: January 2025

AbstractBackgroundCerebral small vessel disease (cSVD) is a leading cause of stroke and dementia. Its underlying mechanisms remain elusive and specific mechanism‐based drugs are lacking.MethodWe integrated more than 2,800 CSF and 4,600 plasma pQTL, derived from the largest proteomic studies so far (SOMAscan 7k and 4k; in up to 35,559 individuals), and the two most prevalent MRI‐markers of cSVD (MRI‐cSVD, white matter hyperintensities and perivascular spaces burden; in up to 48,454 individuals) in a Mendelian Randomization (MR) framework to identify causal and druggable targets for cSVD. Identified association were followed‐up using a multipronged approach: across fluids, proteomics platforms (Olink 3072, N=8,590) and lifespan (N=1,748), using both MR and individual‐level data.ResultWe found 51 proteins associated with MRI‐cSVD of which 46 in CSF and 9 in plasma. Among available significant CSF‐ and plasma‐proteins, 32% and 31% replicated in cross‐fluid and cross‐platform follow‐up, and 47% were associated with stroke and/or dementia at least at nominal significance. We found converging evidence that protein‐cSVD associations are enriched in extracellular matrix and immune response pathways. Immunity‐related proteins already showed association with MRI‐cSVD already in young adults in their twenties. Furthermore, we provide genetic support for drug repositioning opportunities for cSVD, including compounds crossing the blood brain barrier.ConclusionTogether, these findings provide a novel proteogenomic signature of cSVD and pave the way for novel therapeutic developments.
Increased blood‐brain barrier permeability following COVID‐19 and its correlation with Alzheimer’s biomarkers
Authors: Sun Zhe , Frontera Jennifer , Masurkar Arjun V. , Boutajangout Allal , Jiang Li , Thawani Sujata , Links Jon , Vedvyas Alok , Betensky Rebecca A , Debure Ludovic , Ahmed Wajiha , Wisniewski Thomas , Ge Yulin 
Published: January 2025

AbstractBackgroundPost‐COVID cognitive dysfunctions, impacting attention, memory, and learning, might be linked to inflammation‐induced blood‐brain barrier (BBB) impairment. This study explores post‐COVID BBB permeability changes using a non‐contrast water‐exchange based MRI and their associations with blood Alzheimer’s biomarkers.MethodSixty‐seven participants were classified based on COVID (COV) and cognitive (COG) statuses into three groups: COV+/COG‐ (n=34), COV+/COG+ (n=23), and COV‐ (n=10) for comparisons (COV+: Laboratory‐verified SARS‐CoV‐2 infection; COV‐: No history of SARS‐CoV‐2 infection and negative SARS‐CoV‐2 nucleocapsid antibody test.). All patients underwent neuropsychological testing and were coded as having cognitive impairment (COG+) based on neuropsychological testing (≥1 abnormal test result). Clinician interview with the patient and informant. Patients were imaged with the following 3T‐MRI sequences: 1) T1‐MPRAGE; 2) Phase contrast (PC)‐MRI for quantification of cerebral blood flow (ƒ). 3) Water‐extraction‐with‐phase‐contrast‐arterial‐spin‐tagging (WEPCAST) [1], estimating permeability‐surface‐area‐product (PS) calculated with Renkin‐Crone Model: PS = ‐ln (1‐E) ∗ƒ (Figure 1). Plasma biomarkers of Alzheimer’s disease (AD), including Aβ40, Aβ42, NFL, and pTau181, were measured on the same day as the MRI. PS was compared between groups. Correlations were computed between PS and AD biomarkers.ResultWe included 67 non‐hospitalized participants (age: 64.7, F/M: 43/24) who successfully completed their clinical and MRI exams. Illustrative WEPCAST images and the results of group comparisons indicated that BBB permeability (PS) was higher in COV+ than that in COV‐ subjects (119 vs 96 mg/100 g/min, P=0.006), as well as in any patient with cognitive dysfunction (COG+ vs COG‐, 122 vs 111 mg/100 g/min, P=0.0319). Similarly, among COV+ subjects, PS was significantly higher in COV+COG+ compared to COV+COG‐ subjects (129 vs 113 mg/100 g/min, P=0.0041; Figure 2). After adjusting age, PS was negatively correlated with plasma Aβ42 (r=‐0.28, P=0.02), and positively correlated with pTau181 (r=0.24, P=0.046) in all subjects. (Figure 3). There was no significant correlation between PS and NLF or Aβ40.ConclusionOur findings demonstrate that SARS‐CoV‐2 virus has an impact on BBB integrity. This effect correlates with several AD biomarkers, including plasma Aβ42 and pTau181, highlighting the potential contribution of increased BBB permeability in post‐COVID to AD pathology.Reference: 1. Lin Z, et al. Magn. Reson. Med. 2018;80:1507–1520.
Diagnostic and analytical performance of plasma pTau181 and 217 in a clinical laboratory
Authors: Mammel Anna , Hsiung Ging‐Yuek Robin , Encarnacion Mary , Hallett Kelsey , Biehl Donald , Mousavi Ali , Frykman Hans 
Published: January 2025

AbstractBackgroundBlood‐based biomarkers will be essential for providing clinicians an accessible and cost‐effective Alzheimer’s disease (AD) screening tool. Elevated levels of two phosphorylated tau biomarkers (pTau181 & pTau217) correlated with amyloid and tau‐PET consistent with AD diagnosis. We evaluated the analytical and clinical performance of each biomarkers using two different high‐sensitivity methodologies (CLEIA and Simoa®) in a single laboratory to compare the performance of pTau181 and 217 in a clinical (CLIA‐certified) laboratory.MethodPlasma pTau217 levels were measure using either the ALZpath pTau217 assay on the Quanterix HD‐X Simoa® platform or LUMIPULSE plasma pTau 217 on the Lumipulse G1200 platform. Plasma pTau181 levels were measured on the Simoa® platform using ADx Neurosciences antibodies.Analytical performance including sensitivity, linearity, precision, accuracy, cross‐reactivity, interference, and sample stability was determined at Neurocode’s CLIA laboratory using CLIA guidelines.Clinical testing was performed using a collection of amyloid PET confirmed samples (N = 260). And neuropathology confirmed samples collected from the University of British Columbia (UBC) at the time of initial diagnosis (N = 119).ResultpTau217 (AUC – 0.92 to 0.93) had enhanced clinical performance compared to pTau181 across platforms (AUC 0.81) and sample cohorts for diagnosing AD. pTau217 assays had a greater dynamic range (i.e. lower limit quantification) compared to pTau181, resulting in more substantial separation between lower‐limits and clinical decision points. pTau217 has a higher fold difference between PET positive and negative subjects regardless of methodology compared to pTau181. Sample stability was comparable across platforms and methodology. Between lot precision of pTau217 (≤ 13% CV) was improved compared to pTau181 (≤ 20% CV) on the Simoa platform.ConclusionIn conclusion, the superior clinical and analytical performance of pTau217 advocates for its use in clinical practice over pTau181. Plasma pTau217 is a robust screening tool that can be used by clinician for accurate and reliable Alzheimer's disease diagnosis.
The Centiloid scale: guidance on clinical context of use from the AMYPAD Consortium
Authors: Bollack Ariane , Collij Lyduine E. , Shekari Mahnaz , Bullich Santiago , Roé‐Vellvé Núria , Koglin Norman , Stephens Andrew W. , Battle Mark R , Buckley Christopher , Barkhof Frederik , Gispert Juan Domingo , Farrar Gill ,   the AMYPAD consortium
Published: January 2025

AbstractBackgroundThe Centiloid method (CL) was introduced as a tracer‐independent measure for cortical amyloid load and is now commonly used in Alzheimer’s disease (AD) clinical trials. To facilitate its implementation into clinical settings, the AMYPAD consortium set out to integrate existing literature and recent work from the consortium to provide clinical context‐of‐use recommendations of the Centiloid scale, which has been submitted to the European Medicine Agency for endorsement as a Biomarker Qualification Opinion.MethodScreening of the literature was performed on the 7/11/23 on PubMed to identify articles mentioning “Centiloid”. The 159 results were reviewed to identify all cut‐offs established based on histopathology, visual reads, fluid biomarkers and cognition. Clinical trials inclusion criteria and amyloid clearance strategies were also included.ResultCompared to histopathology (gold standard), visual reads, and cerebrospinal fluid (clinical standards), Centiloid quantification accurately reflects the amount of AD pathology. With high certainty at the individual level, a CL value below 10 excludes the presence of Aβ pathology, while a value above 30 is a conservative estimate of amyloid‐positivity (Figure 1). Values falling in between these two cut‐offs (i.e., ‘gray‐zone’) are related to an increased risk of disease progression, but future studies enriched for this population are needed. The AMYPAD consortium additionally assessed the robustness and measurement uncertainty of the Centiloid scale and demonstrated that the method is highly robust against pipeline differences, such as processing space, target region, and reference region, though use of the pons could lead to increased bias and is not recommended. Measurement uncertainty was 3 to 8.3 CL across the total scale and is amyloid burden dependent.ConclusionFour clinical context‐of‐use for CL quantification are proposed: 1) adjunct to visual inspection methodology to achieve high certainty regarding the presence or absence of Aβ pathology, 2) a CL level of >30 could be utilised as a conservative cut‐off for the presence of Aβ pathology to guide the management of patients with objective cognitive impairment who may be eligible for anti‐amyloid disease‐modifying therapies, 3) support therapy monitoring and treatment decisions, 4) identification of emerging amyloid deposition and optimize risk‐stratification. Accounting for measurement uncertainty is essential when interpreting CL units.
Cerebrovascular reactivity as a candidate biomarker in small vessel disease related VCID
Authors: Lu Hanzhang 
Published: January 2025

AbstractBackgroundThe brain’s ability to perform a cognitive task is a dynamic process and requires small blood vessels to dilate or constrict in real time to adjust blood flow in a region‐specific manner. Cerebrovascular Reactivity (CVR) measures the ability of vessels to react to vasoactive challenges. In this work, we investigated the role of CVR as a possible biomarker in small vessel disease related vascular contributions to cognitive impairment and dementia (VCID), as part of the NINDS‐funded MarkVCID study.MethodsThis work consisted of 4 studies. CVR was measured by MRI signal changes in response to inhalation of 5% carbon dioxide (CO2) (Figure 1). Study 1 was a single‐site study of 72 participants (aged 69±8 years, 28 normal cognition and 44 cognitive impairment), in which we examined the relationship between CVR and cognitive function, CSF‐measured AD pathological markers, and CDR‐sum‐of‐boxes. Study 2 conducted an instrumental validation to benchmark the test‐retest reproducibility of the CVR measure. Study 3 developed an automatic, cloud‐based tool for automatic and standardized processing of CVR MRI data. Study 4 was a multi‐site biological validation study in which CVR was measured across 3 sites and data from each site were separately analyzed to investigate the relationship between CVR and cognitive function.ResultsStudy 1 revealed that whole‐brain CVR was associated with MoCA (β=29.64, 95% CI, 9.94 to 49.34) and global composite scores (β=4.32, 95% CI, 0.05 to 8.58), and these associations were independent of CSF‐measured amyloid and tau markers. CVR was also associated with CDR‐SB score. Study 2 revealed that inter‐scanner CoV of CVR was 6.90 ± 5.08% and had an ICC of 0.8498. Study 3 showed that CVR processing can be standardized and the processing pipeline can be accessed by any researchers around the world through an installation‐free cloud platform referred to as MRICloud (https://braingps.mricloud.org/cvr.v5). Study 4 showed that CVR was significantly associated with MoCA in data analyzed separately in each of the three sites through a pre‐defined analysis (p=0.003, 0.002, 0.046 for the three sites, respectively; when pooling data together p=3.7*10^‐6) (Figure 2).ConclusionCVR measured with MRI is a promising candidate biomarker in VCID.
Interactions of VEGF 1154A and 2578C with APOE ε4 on Amyloid Load in Cognitively Unimpaired Older Adults
Authors: Malek‐Ahmadi Michael H. , Piras Ignazio , Wang Qi , Chen Kewei , Devadas Vivek , Luo Ji , Su Yi 
Published: January 2025

AbstractBackgroundPrevious studies have shown that carriage of the VEGF 1154A (rs1570360) and the VEGF 2578C (rs699947) alleles may confer a protective effect on the development of Alzheimer’s disease (AD). However, it is unknown if these associations are APOE‐dependent and whether they can be observed in asymptomatic individuals with varying levels of amyloid pathology. The aim of this study is to determine whether interactions between the APOE ε4 allele, VEGF 1154A, and VEGF 2578C are associated with amyloid load in cognitively unimpaired (CU) older adults.MethodData from 341 CU ADNI subjects (57% female) with a mean age of 74.35±6.94 years and a mean education level of 16.63±2.44 years were included in the analysis. Thirty‐two percent (n=109) were APOE ε4 carriers with the following distributions for each VEGF allele: 1154A – GG=165, AG=147, AA=29; 2578C – AA=88, AC=166, CC=87. AV‐45 mean cortical standard uptake value ratio (MCSUVR) was used to determine amyloid load. Generalized linear models were used to quantify the main effects of the VEGF alleles and their interactions with APOE ε4 on demographically‐adjusted MCSUVR values. Cohen’s d effect size was used for groupwise comparisons.ResultThe interaction between VEGF 1154A and APOE was statistically significant (β = ‐0.02, 95% CI (‐0.04, ‐0.008), p = 0.002). Further analysis among those with two A alleles of VEGF 1154 found that APOE ε4 carriers had substantially lower amyloid load relative to ε4 non‐carriers (p = 0.01, d = 1.04). Within APOE ε4 carriers, there were no significant differences among the GG, AG, and AA genotypes. The interaction for VEGF 2578C and APOE approached statistical significance for amyloid load (β = 0.01, 95% CI (‐0.001, 0.03), p = 0.06).ConclusionThe AA genotype of VEGF 1154 is associated with reduced amyloid load in APOE ε4 carriers and warrants further investigation as a potential protective factor for AD.