Mark A. Mintun’s research while affiliated with Avid Radiopharmaceuticals and other places


Ad

What is this page?


This page lists works of an author who doesn't have a ResearchGate profile or hasn't added the works to their profile yet. It is automatically generated from public (personal) data to further our legitimate goal of comprehensive and accurate scientific recordkeeping. If you are this author and want this page removed, please let us know.

Publications (166)


Dynamic proportional loss of functional connectivity revealed change of left superior frontal gyrus in subjective cognitive decline: an explanatory study based on Chinese and Western cohorts
  • Article

January 2025

·

121 Reads

GeroScience

·

Wenjing Hu

·

Fan Dong

·

[...]

·

Ansgar J Furst

Brain network dynamics have been extensively explored in patients with subjective cognitive decline (SCD). However, these studies are susceptible to individual differences, scanning parameters, and other confounding factors. Therefore, how to reveal subtle SCD-related subtle changes remains unclear. Cross-sectional and longitudinal resting-state functional magnetic resonance imaging data from both Chinese and Western populations were analyzed. We proposed a framework of dynamic proportional loss of functional connectivity (DPLFC). After its stability was validated, the optimal parameters were applied for the clinical diagnosis of SCD. DPLFC yielded a relatively high intraclass correlation coefficient. In particular, the DPLFC of the left superior frontal gyrus (SFG) progressively decreased along the Alzheimer’s disease (AD) continuum. Compared with the traditional index, the DPLFC had better classification performance between cognitively normal controls and patients with SCD. Furthermore, DPLFC was related to Aβ deposition and scale scores. Patients with lower DPLFC values had a greater risk of cognitive decline. Decreased DPLFC in the left SFG may be a potential AD-related neuroimaging biomarker at an early stage.


Fig. 2 Associations between baseline NfL levels and longitudinal changes in ADAS-Cog scores, hippocampal volumes, and WMH volumes. Data show the associations between baseline plasma NfL and longitudinal changes in ADAS-Cog scores (left panel), hippocampal volumes (middle panel), and WMH volumes (right panel). Higher baseline plasma NfL levels were associated with steeper increases in ADAS-cog scores and WMH volumes, and steeper decreases in hippocampal volumes over time (all p-values < 0.001). Of outcome variables, ADAS-Cog score and WMH volume were square root transformed due to non-normal distribution. Continuous variables, including plasma NfL level and outcome variables, were standardized to z-scores. The plotted lines represent estimated z-scores of ADAS-Cog scores, hippocampal volumes, or WMH volumes over time under the condition of baseline plasma NfL at mean -1SD, mean, and mean + 1SD. P-values were calculated to identify the significance of the two-way interaction term including baseline NfL level and time. Models were adjusted for the following covariates: baseline age, sex, years of education, APOE ε4 allele count, ever smoking, alcohol abuse, SGDS, Aβ status, hypertension, DM, impaired kidney function, obesity, and baseline cognitive status (MCI or CU). Abbreviations: ADAS-Cog, Alzheimer's Disease Assessment Scale-Cognitive subscale; APOE, apolipoprotein E; CU, cognitively unimpaired; DM, diabetes mellitus; MCI, mild cognitive impairment; NfL, neurofilament light chain; SD, standard deviation; SGDS, Short form of Geriatric Depression Scale; SUVR, standard uptake value ratio; WMH, white matter hyperintensity
Impact of amyloid and cardiometabolic risk factors on prognostic capacity of plasma neurofilament light chain for neurodegeneration
  • Article
  • Full-text available

September 2024

·

184 Reads

Alzheimer's Research & Therapy

Background Plasma neurofilament light chain (NfL) is a blood biomarker of neurodegeneration, including Alzheimer’s disease. However, its usefulness may be influenced by common conditions in older adults, including amyloid-β (Aβ) deposition and cardiometabolic risk factors like hypertension, diabetes mellitus (DM), impaired kidney function, and obesity. This longitudinal observational study using the Alzheimer’s Disease Neuroimaging Initiative cohort investigated how these conditions influence the prognostic capacity of plasma NfL. Methods Non-demented participants (cognitively unimpaired or mild cognitive impairment) underwent repeated assessments including the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores, hippocampal volumes, and white matter hyperintensity (WMH) volumes at 6- or 12-month intervals. Linear mixed-effect models were employed to examine the interaction between plasma NfL and various variables of interest, such as Aβ (evaluated using Florbetapir positron emission tomography), hypertension, DM, impaired kidney function, or obesity. Results Over a mean follow-up period of 62.5 months, participants with a mean age of 72.1 years ( n = 720, 48.8% female) at baseline were observed. Higher plasma NfL levels at baseline were associated with steeper increases in ADAS-Cog scores and WMH volumes, and steeper decreases in hippocampal volumes over time (all p -values < 0.001). Notably, Aβ at baseline significantly enhanced the association between plasma NfL and longitudinal changes in ADAS-Cog scores ( p -value 0.005) and hippocampal volumes ( p -value 0.004). Regarding ADAS-Cog score and WMH volume, the impact of Aβ was more prominent in cognitively unimpaired than in mild cognitive impairment. Hypertension significantly heightened the association between plasma NfL and longitudinal changes in ADAS-Cog scores, hippocampal volumes, and WMH volumes (all p -values < 0.001). DM influenced the association between plasma NfL and changes in ADAS-Cog scores ( p -value < 0.001) without affecting hippocampal and WMH volumes. Impaired kidney function did not significantly alter the association between plasma NfL and longitudinal changes in any outcome variables. Obesity heightened the association between plasma NfL and changes in hippocampal volumes only ( p -value 0.026). Conclusion This study suggests that the prognostic capacity of plasma NfL may be amplified in individuals with Aβ or hypertension. This finding emphasizes the importance of considering these factors in the NfL-based prognostic model for neurodegeneration in non-demented older adults.

Download

MRI Signature of α-Synuclein Pathology in Asymptomatic Stages and a Memory Clinic Population

July 2024

·

157 Reads

·

3 Citations

JAMA Neurology

Importance The lack of an in vivo measure for α-synuclein (α-syn) pathology until recently has limited thorough characterization of its brain atrophy pattern, especially during early disease stages. Objective To assess the association of state-of-the-art cerebrospinal fluid (CSF) seed amplification assays (SAA) α-syn positivity (SAA α-syn+) with magnetic resonance imaging (MRI) structural measures, across the continuum from clinically unimpaired (CU) to cognitively impaired (CI) individuals, in 3 independent cohorts, and separately in CU and CI individuals, the latter reflecting a memory clinic population. Design, Setting, and Participants Cross-sectional data were used from the Swedish BioFINDER-2 study (inclusion, 2017-2023) as the discovery cohort and the Swedish BioFINDER-1 study (inclusion, 2007-2015) and Alzheimer’s Disease Neuroimaging Initiative (ADNI; inclusion 2005-2022) as replication cohorts. All cohorts are from multicenter studies, but the BioFINDER cohorts used 1 MRI scanner. CU and CI individuals fulfilling inclusion criteria and without missing data points in relevant metrics were included in the study. All analyses were performed from 2023 to 2024. Exposures Presence of α-syn pathology, estimated by baseline CSF SAA α-syn. Main Outcomes and Measures The primary outcomes were cross-sectional structural MRI measures either through voxel-based morphometry (VBM) or regions of interest (ROI) including an automated pipeline for cholinergic basal forebrain nuclei CH4/4p (nucleus basalis of Meynert [NBM]) and CH1/2/3. Secondary outcomes were domain-specific cross-sectional cognitive measures. Analyses were adjusted for CSF biomarkers of Alzheimer pathology. Results A total of 2961 participants were included in this study: 1388 (mean [SD] age, 71 [10] years; 702 female [51%]) from the BioFINDER-2 study, 752 (mean [SD] age, 72 [6] years; 406 female [54%]) from the BioFINDER-1 study, and 821 (mean [SD] age, 75 [8] years; 449 male [55%]) from ADNI. In the BioFINDER-2 study, VBM analyses in the whole cohort revealed a specific association between SAA α-syn+ and the cholinergic NBM, even when adjusting for Alzheimer copathology. ROI-based analyses in the BioFINDER-2 study focused on regions involved in the cholinergic system and confirmed that SAA α-syn+ was indeed independently associated with smaller NBM (β = −0.271; 95% CI, −0.399 to −0.142; P <.001) and CH1/2/3 volumes (β = −0.227; 95% CI, −0.377 to −0.076; P =.02). SAA α-syn+ was also independently associated with smaller NBM volumes in the separate CU (β = −0.360; 95% CI, −0.603 to −0.117; P =.03) and CI (β = −0.251; 95% CI, −0.408 to −0.095; P =.02) groups. Overall, the association between SAA α-syn+ and NBM volume was replicated in the BioFINDER-1 study and ADNI cohort. In CI individuals, NBM volumes partially mediated the association of SAA α-syn+ with attention/executive impairments in all cohorts (BioFINDER-2, β = −0.017; proportion-mediated effect, 7%; P =.04; BioFINDER-1, β = −0.096; proportion-mediated effect, 19%; P =.04; ADNI, β = −0.061; proportion-mediated effect, 20%; P =.007). Conclusions and Relevance In this cohort study, SAA α-syn+ was consistently associated with NBM atrophy already during asymptomatic stages. Further, in memory clinic CI populations, SAA α-syn+ was associated with NBM atrophy, which partially mediated α-syn–induced attention/executive impairment.


Interpretable discriminant analysis for functional data supported on random nonlinear domains with an application to Alzheimer’s disease

March 2024

·

97 Reads

Journal of the Royal Statistical Society Series B (Statistical Methodology)

We introduce a novel framework for the classification of functional data supported on nonlinear, and possibly random, manifold domains. The motivating application is the identification of subjects with Alzheimer’s disease from their cortical surface geometry and associated cortical thickness map. The proposed model is based upon a reformulation of the classification problem as a regularized multivariate functional linear regression model. This allows us to adopt a direct approach to the estimation of the most discriminant direction while controlling for its complexity with appropriate differential regularization. Our approach does not require prior estimation of the covariance structure of the functional predictors, which is computationally prohibitive in our application setting. We provide a theoretical analysis of the out-of-sample prediction error of the proposed model and explore the finite sample performance in a simulation setting. We apply the proposed method to a pooled dataset from Alzheimer’s Disease Neuroimaging Initiative and Parkinson’s Progression Markers Initiative. Through this application, we identify discriminant directions that capture both cortical geometric and thickness predictive features of Alzheimer’s disease that are consistent with the existing neuroscience literature.


Fig. 1 Comprehensive workflow of the study. a Data collection from three centers: ADNI, Xuanwu Hospital, and Tongji Hospital. b fMRI preprocessing flow. c Graph representation construction based on fMRI. d Architecture of the STGC-GCAM model. e Visualization of imaging biomarkers using BrainNet Viewer. f Correlation analysis between topological features of disease-related brain regions and clinical indicators. g Survival analysis of MCI patients using imaging markers. h Investigation of the mediating effects of brain region topology characteristics on cognitive disorders caused by Aβ, tau, and neural variants
Fig. 3 KM curves of (a) ALFF, (b) ReHo, and (c) the topological feature model. Forest plots (right of Fig. 3(d)) show HR and 95% CI for different predictors
Fig. 4 Correlation analysis between topological features (NE) and clinical indicators (MMSE score) in the important brain regions
Fig. 5 The topological characteristics of disease-related brain regions have a mediating effect on cognitive function. Please refer to the Jagust LABS PDF on LONI for calculations of global AV45-PET SUVR and FDG-PET SUVR
A novel spatiotemporal graph convolutional network framework for functional connectivity biomarkers identification of Alzheimer’s disease

March 2024

·

285 Reads

·

2 Citations

Alzheimer's Research & Therapy

Background Functional connectivity (FC) biomarkers play a crucial role in the early diagnosis and mechanistic study of Alzheimer’s disease (AD). However, the identification of effective FC biomarkers remains challenging. In this study, we introduce a novel approach, the spatiotemporal graph convolutional network (ST-GCN) combined with the gradient-based class activation mapping (Grad-CAM) model (STGC-GCAM), to effectively identify FC biomarkers for AD. Methods This multi-center cross-racial retrospective study involved 2,272 participants, including 1,105 cognitively normal (CN) subjects, 790 mild cognitive impairment (MCI) individuals, and 377 AD patients. All participants underwent functional magnetic resonance imaging (fMRI) and T1-weighted MRI scans. In this study, firstly, we optimized the STGC-GCAM model to enhance classification accuracy. Secondly, we identified novel AD-associated biomarkers using the optimized model. Thirdly, we validated the imaging biomarkers using Kaplan–Meier analysis. Lastly, we performed correlation analysis and causal mediation analysis to confirm the physiological significance of the identified biomarkers. Results The STGC-GCAM model demonstrated great classification performance (The average area under the curve (AUC) values for different categories were: CN vs MCI = 0.98, CN vs AD = 0.95, MCI vs AD = 0.96, stable MCI vs progressive MCI = 0.79). Notably, the model identified specific brain regions, including the sensorimotor network (SMN), visual network (VN), and default mode network (DMN), as key differentiators between patients and CN individuals. These brain regions exhibited significant associations with the severity of cognitive impairment ( p < 0.05). Moreover, the topological features of important brain regions demonstrated excellent predictive capability for the conversion from MCI to AD (Hazard ratio = 3.885, p < 0.001). Additionally, our findings revealed that the topological features of these brain regions mediated the impact of amyloid beta (Aβ) deposition (bootstrapped average causal mediation effect: β = -0.01 [-0.025, 0.00], p < 0.001) and brain glucose metabolism (bootstrapped average causal mediation effect: β = -0.02 [-0.04, -0.001], p < 0.001) on cognitive status. Conclusions This study presents the STGC-GCAM framework, which identifies FC biomarkers using a large multi-site fMRI dataset.


Fig. 1: The figure illustrates the original Sliding Window Association Test (SWAT) in Genome-Wide Association Studies (GWAS). SWAT begins by partitioning the entire genome into smaller, nonoverlapping fragments. For every fragment, SWAT employs a sliding window technique in conjunction with a Convolutional Neural Network (CNN) to compute a phenotype influence score (PIS) for each Single Nucleotide Polymorphism (SNP). This computation considers 'w', the number of SNPs in a fragment, and 'S k ', the position of each SNP. By distinguishing SNPs with significant PIS values, SWAT efficiently identifies phenotype-associated genetic variants.
Fig. 2: Overall structure of the c-SWAT. The phenotype influence score for the feature groups was calculated as shown in (a). Sliding windows of varying sizes overlap all feature groups except one to perform the classification prediction, thereby determining the importance of the excluded group. WGCNA was used to determine the group as shown in (b). Based on these results and the lipid classes, PIS for each metabolite was calculated and used to classify AD.
Fig. 3: An overview of how a deep learning approach was implemented in steps 1 and 3. Our model utilizes three main hidden layers, with the number of nodes in these layers optimized from 32 down to 8 using a grid search approach. The classification between AD and CN was performed with top-ranked features from each group using the CNN algorithm, and the performance was assessed by a 5-fold crossvalidation.
Fig. 4: Visualization of AD/CN classification results. (a) Bar graph on the y-axis representing the average accuracy of a 10-fold cross validation. With c-SWAT, the Random Forest model could classify AD from CN with a highest accuracy of 0.807 when using 22 features, compared to an accuracy of 0.714 when the same number of features were randomly applied without using PIS. (b) The y-axis presents the accuracy for AD/CN classification in each subset, both with and without the implementation of c-SWAT, considering subsets ranging from the top 1 to 781 features. An outer circle represents the number of metabolite features utilized. Blue dots indicate classification accuracy when incorporating the results of PIS with c-SWAT, while red dots represent cases without the application of c-SWAT.
Circular-SWAT for deep learning based diagnostic classification of Alzheimer's disease: application to metabolome data

November 2023

·

380 Reads

·

10 Citations

EBioMedicine

Background Deep learning has shown potential in various scientific domains but faces challenges when applied to complex, high-dimensional multi-omics data. Alzheimer's Disease (AD) is a neurodegenerative disorder that lacks targeted therapeutic options. This study introduces the Circular-Sliding Window Association Test (c-SWAT) to improve the classification accuracy in predicting AD using serum-based metabolomics data, specifically lipidomics. Methods The c-SWAT methodology builds upon the existing Sliding Window Association Test (SWAT) and utilizes a three-step approach: feature correlation analysis, feature selection, and classification. Data from 997 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) served as the basis for model training and validation. Feature correlations were analyzed using Weighted Gene Co-expression Network Analysis (WGCNA), and Convolutional Neural Networks (CNN) were employed for feature selection. Random Forest was used for the final classification. Findings The application of c-SWAT resulted in a classification accuracy of up to 80.8% and an AUC of 0.808 for distinguishing AD from cognitively normal older adults. This marks a 9.4% improvement in accuracy and a 0.169 increase in AUC compared to methods without c-SWAT. These results were statistically significant, with a p-value of 1.04 × 10ˆ-4. The approach also identified key lipids associated with AD, such as Cer(d16:1/22:0) and PI(37:6). Interpretation Our results indicate that c-SWAT is effective in improving classification accuracy and in identifying potential lipid biomarkers for AD. These identified lipids offer new avenues for understanding AD and warrant further investigation. Funding The specific funding of this article is provided in the acknowledgements section.


Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease

October 2023

·

251 Reads

·

33 Citations

JAMA Neurology

Importance Increased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors. Objective To estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes. Design, Setting, and Participants This cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019). Main Outcome and Measures The main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH. Results Data from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [ P = .001]; ADNI: t = 2.7 [ P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [ P = .002]; ADNI: t = −5.6 [ P < .001]; HABS: t = −2.2 [ P = .03]), greater in older individuals (DIAN: t = 6.8 [ P < .001]; ADNI: t = 9.1 [ P < .001]; HABS: t = 5.4 [ P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [ P = .40]; ADNI: t = 0.6 [ P = .50]; HABS: t = 1.8 [ P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001). Conclusions and Relevance The findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.


Deep Neural Network Classifier for Multi‐Dimensional Functional Data

May 2023

·

249 Reads

·

13 Citations

Scandinavian Journal of Statistics

We propose a new approach, called as functional deep neural network (FDNN), for classifying multidimensional functional data. Specifically, a deep neural network is trained based on the principal components of the training data which shall be used to predict the class label of a future data function. Unlike the popular functional discriminant analysis approaches which only work for one‐dimensional functional data, the proposed FDNN approach applies to general non‐Gaussian multidimensional functional data. Moreover, when the log density ratio possesses a locally connected functional modular structure, we show that FDNN achieves minimax optimality. The superiority of our approach is demonstrated through both simulated and real‐world datasets.


Demographics and baseline characteristics.
Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort

October 2022

·

175 Reads

·

11 Citations

npj Parkinson s Disease

We examined 2-year longitudinal change in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs) enrolled in the Parkinson’s Progression Markers Initiative (PPMI). We analyzed 2-year longitudinal data from 176 LRRK2 G2019S NMCs and 185 HCs. All participants were assessed annually with comprehensive motor and non-motor scales, dopamine transporter (DAT) imaging, and biofluid biomarkers. The latter included cerebrospinal fluid (CSF) Abeta, total tau and phospho-tau; serum urate and neurofilament light chain (NfL); and urine bis(monoacylglycerol) phosphate (BMP). At baseline, LRRK2 G2019S NMCs had a mean (SD) age of 62 (7.7) years and were 56% female. 13% had DAT deficit (defined as <65% of age/sex-expected lowest putamen SBR) and 11% had hyposmia (defined as ≤15th percentile for age and sex). Only 5 of 176 LRRK2 NMCs developed PD during follow-up. Although NMCs scored significantly worse on numerous clinical scales at baseline than HCs, there was no longitudinal change in any clinical measures over 2 years or in DAT binding. There were no longitudinal differences in CSF and serum biomarkers between NMCs and HCs. Urinary BMP was significantly elevated in NMCs at all time points but did not change longitudinally. Neither baseline biofluid biomarkers nor the presence of DAT deficit correlated with 2-year change in clinical outcomes. We observed no significant 2-year longitudinal change in clinical or biomarker measures in LRRK2 G2019S NMCs in this large, well-characterized cohort even in the participants with baseline DAT deficit. These findings highlight the essential need for further enrichment biomarker discovery in addition to DAT deficit and longer follow-up to enable the selection of NMCs at the highest risk for conversion to enable future prevention clinical trials.


Fig. 1 ADNI polygenic risk score distributions. Alzheimer's disease polygenic risk score distributions are shown for a ADNI participants with a CDR ≥ 1 compared to ADNI participants with a CDR ≤ 0.5 and b ADNI participants with a CDR ≥ 0.5 compared to ADNI participants with a CDR = 0.
Fig. 2 ADNI Polygenic Risk Scores using Lambert et al., 2013 GWA Summary Statistics. PRSice-2 (dark grey), and the PRSKB (light grey) scores are shown. a PRSice-2 reports polygenic risk scores that center on 0, so 1.0 was added to each PRSice-2 score to put it on the same scale as the PRSKB, which centers polygenic risk scores based on odds ratios around 1.0. The PRSice-2 median score after transformation is 1.05207 and the PRSKB median score is 1.05338. b Since a polygenic risk score is a relative score compared to the sample population, we transformed the PRSKB scores by subtracting 0.00131 to overlap the shape of the distributions when both algorithms report the same median. Since the scores are normally distributed, a Welch's two-sample t-test was used to determine the similarity between the two distributions, which were nearly identical (t = 0.004782; P = 0.9962).
The Polygenic Risk Score Knowledge Base offers a centralized online repository for calculating and contextualizing polygenic risk scores

September 2022

·

347 Reads

·

11 Citations

Communications Biology

The process of identifying suitable genome-wide association (GWA) studies and formatting the data to calculate multiple polygenic risk scores on a single genome can be laborious. Here, we present a centralized polygenic risk score calculator currently containing over 250,000 genetic variant associations from the NHGRI-EBI GWAS Catalog for users to easily calculate sample-specific polygenic risk scores with comparable results to other available tools. Polygenic risk scores are calculated either online through the Polygenic Risk Score Knowledge Base (PRSKB; https://prs.byu.edu ) or via a command-line interface. We report study-specific polygenic risk scores across the UK Biobank, 1000 Genomes, and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), contextualize computed scores, and identify potentially confounding genetic risk factors in ADNI. We introduce a streamlined analysis tool and web interface to calculate and contextualize polygenic risk scores across various studies, which we anticipate will facilitate a wider adaptation of polygenic risk scores in future disease research.


Ad

Citations (78)


... 21 A previous study showed that the impact of SAA α-syn+ was notably confined to smaller nucleus basalis of Meynert volumes, with limited influences on widespread atrophy patterns typically observed in CI memory clinic populations. 35 The association between α-syn pathology and glucose hypometabolism may offer insights into the mechanisms of neurodegeneration in AD. ...

Reference:

Influence of alpha‐synuclein on glucose metabolism in Alzheimer's disease continuum: Analyses of α‐synuclein seed amplification assay and FDG‐PET
MRI Signature of α-Synuclein Pathology in Asymptomatic Stages and a Memory Clinic Population
  • Citing Article
  • July 2024

JAMA Neurology

... 15 However, the brain activity is not static but highly dynamic, even during the resting state. 16 Characterizing dynamics in large-scale networks allows for detecting cognition-related network changes associated with neurodegenerative diseases. ...

A novel spatiotemporal graph convolutional network framework for functional connectivity biomarkers identification of Alzheimer’s disease

Alzheimer's Research & Therapy

... However, by leveraging various deep learning frameworks and combining the characteristics of global anatomical structures with white matter changes for differential diagnosis and predicting the AD continuum, the objectivity and reliability can be significantly improved Hoang et al., 2023). Meanwhile, studies based on models such as ML, DL and AI on the brain functional connectivity and metabolomics of the AD spectrum have provided scientific imaging evidence for the early diagnosis of SCD (AlSharabi et al., Kim et al., 2023;Jo et al., 2023;Duan et al., 2023). For example, studies have found that the volume of perivascular spaces (PVS) in the centrum semiovale may be a very early imaging biomarker for AD, and the impairment of perivascular clearance ability, which is part of brain metabolomics, is regarded as a risk factor for AD. ...

Circular-SWAT for deep learning based diagnostic classification of Alzheimer's disease: application to metabolome data

EBioMedicine

... 5 Moreover, increasing evidence suggests that WMHs in neurodegeneration are not solely driven by vascular pathology but may also reflect intrinsic disease processes, including amyloidosis and gray matter degeneration, as shown in Alzheimer's disease, where WMHs have been linked to cerebral amyloid angiopathy and neurodegeneration rather than traditional vascular risk factors. 6 The overwhelming majority of neuroimaging research in FTD has centered on changes in gray matter, with less attention given to the role of WMHs. Sudre et al. 7 reported increased WMH burden in FTD patients with symptomatic GRN mutations, but not in those carrying MAPT or C9orf72 mutations. ...

Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease
  • Citing Article
  • October 2023

JAMA Neurology

... The Parkinson's Progression Markers Initiative (PPMI) database is a global, multi-center clinical research project designed to collect and share data and biomarkers related to Parkinson's disease (PD), with the aim of advancing the understanding of the disease, improving early diagnosis, monitoring disease progression, and developing potential therapies 53 . Although numerous researchers have focused on identifying early clinical biomarkers for PD [54][55][56] , this area still faces signi cant challenges and gaps. In an effort to explore more objective and accessible early diagnostic methods, we utilized only MRI T1weighted imaging in this study. ...

Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort

npj Parkinson s Disease

... The development and construction of PGS/PRS have been the focus of many methodological studies, and these studies have provided effective tools for constructing reliable PGS/PRS [15,[17][18][19]. These tools allow PGS/PRS to be derived from very large data sets or meta-analyses [20][21][22], and open-source websites have been developed that provide the information needed to compute PRS for over 3200 traits and diseases [13,23]. The ubiquity of PGS/PRS methods and the availability of large data sets have motivated studies of the polygenic basis of many nondisease traits, such as height [24], as well as healthpositive traits such as health span [25], beneficial disease treatment response [26][27][28], and resilience to disease and longevity [29][30][31][32][33][34]. ...

The Polygenic Risk Score Knowledge Base offers a centralized online repository for calculating and contextualizing polygenic risk scores

Communications Biology

... Recent advances in single-cell RNA sequencing (scRNA-seq) have unveiled cell typespecific molecular alterations and significant heterogeneity within neurons, microglia, astrocytes, oligodendrocytes, and ECs in the brains of AD patients [11]. In this study, we examined the single-cell transcriptomic dataset GSE157827 [12,13], which includes prefrontal cortical samples from 12 AD patients and 9 NC subjects. Our analysis revealed that ECs are the most substantial contributors to AD among all brain cell subpopulations. ...

An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer’s disease

Nature Aging

... Notable examples include frontotemporal dementia [57,58], Parkinson's disease [59], and Alzheimer's disease [60], where patients exhibit both dopaminergic and cholinergic degeneration, accompanied by volumetric decline within the caudate. Our findings of age-related metabolic decline in the caudate align with similar declines observed in other cortical regions, such as the frontal, temporal, and parietal cortices, which are known to undergo metabolic changes with aging [9,61,62]. These cortical regions, particularly the medial prefrontal cortex and anterior cingulate, are responsible for executive functions and emotional regulation, and their metabolic reductions have been closely linked to cognitive decline and aging-related neurodegeneration [8,29]. ...

Glucose metabolism patterns: A potential index to characterize brain ageing and predict high conversion risk into cognitive impairment

GeroScience

... Epigenetic age acceleration positively correlates with Aβ and NFTs, when measured with Horvath pan-tissue (Horvath, 2013) and PhenoAge , whereas Hannum and Phenoage clocks provide correlations with cross-sectional measures of hippocampal volume in AD (Milicic et al., 2022). However, while these clocks are typically developed in peripheral tissues and may not capture the unique aging changes in the brain of AD patients, several attempts were made to develop more AD-specific clocks. ...

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

GeroScience