DEEPMIR: A DEEP neural network for differential detection of cerebral Microbleeds and IRon deposits in MRI

Lobar cerebral microbleeds (CMBs) and localized non-hemorrhage iron deposits in the basal ganglia have been associated with brain aging, vascular disease and neurodegenerative disorders. Particularly, CMBs are small lesions and require multiple neuroimaging modalities for accurate detection. Quantitative susceptibility mapping (QSM) derived from in vivo magnetic resonance imaging (MRI) is necessary to differentiate between iron content and mineralization. We set out to develop a deep learning-based segmentation method suitable for segmenting both CMBs and iron deposits. We included a convenience sample of 24 participants from the MESA cohort and used T2-weighted images, susceptibility weighted imaging (SWI), and QSM to segment the two types of lesions. We developed a protocol for simultaneous manual annotation of CMBs and non-hemorrhage iron deposits in the basal ganglia. This manual annotation was then used to train a deep convolution neural network (CNN). Specifically, we adapted the U-Net model with a higher number of resolution layers to be able to detect small lesions such as CMBs from standard resolution MRI. We tested different combinations of the three modalities to determine the most informative data sources for the detection tasks. In the detection of CMBs using single class and multiclass models, we achieved an average sensitivity and precision of between 0.84-0.88 and 0.40-0.59, respectively. The same framework detected non-hemorrhage iron deposits with an average sensitivity and precision of about 0.75-0.81 and 0.62-0.75, respectively. Our results showed that deep learning could automate the detection of small vessel disease lesions and including multimodal MR data (particularly QSM) can improve the detection of CMB and non-hemorrhage iron deposits with sensitivity and precision that is compatible with use in large-scale research studies

Dissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease

Alzheimer’s disease (AD) is defined by amyloid (A) and tau (T) pathologies, with T better correlated to neurodegeneration (N). However, T and N have complex regional relationships in part related to non-AD factors that influence N. With machine learning, we assessed heterogeneity in 18F-flortaucipir vs. 18F-fluorodeoxyglucose positron emission tomography as markers of T and neuronal hypometabolism (NM) in 289 symptomatic patients from the Alzheimer’s Disease Neuroimaging Initiative. We identified six T/NM clusters with differing limbic and cortical patterns. The canonical group was defined as the T/NM pattern with lowest regression residuals. Groups resilient to T had less hypometabolism than expected relative to T and displayed better cognition than the canonical group. Groups susceptible to T had more hypometabolism than expected given T and exhibited worse cognitive decline, with imaging and clinical measures concordant with non-AD copathologies. Together, T/NM mismatch reveals distinct imaging signatures with pathobiological and prognostic implications for AD

Gene-SGAN: a method for discovering disease subtypes with imaging and genetic signatures via multi-view weakly-supervised deep clustering

Disease heterogeneity has been a critical challenge for precision diagnosis and treatment, especially in neurologic and neuropsychiatric diseases. Many diseases can display multiple distinct brain phenotypes across individuals, potentially reflecting disease subtypes that can be captured using MRI and machine learning methods. However, biological interpretability and treatment relevance are limited if the derived subtypes are not associated with genetic drivers or susceptibility factors. Herein, we describe Gene-SGAN - a multi-view, weakly-supervised deep clustering method - which dissects disease heterogeneity by jointly considering phenotypic and genetic data, thereby conferring genetic correlations to the disease subtypes and associated endophenotypic signatures. We first validate the generalizability, interpretability, and robustness of Gene-SGAN in semi-synthetic experiments. We then demonstrate its application to real multi-site datasets from 28,858 individuals, deriving subtypes of Alzheimer's disease and brain endophenotypes associated with hypertension, from MRI and SNP data. Derived brain phenotypes displayed significant differences in neuroanatomical patterns, genetic determinants, biological and clinical biomarkers, indicating potentially distinct underlying neuropathologic processes, genetic drivers, and susceptibility factors. Overall, Gene-SGAN is broadly applicable to disease subtyping and endophenotype discovery, and is herein tested on disease-related, genetically-driven neuroimaging phenotypes

Identification of Arx transcriptional targets in the developing basal forebrain

Mutations in the aristaless-related homeobox (ARX) gene are associated with multiple neurologic disorders in humans. Studies in mice indicate Arx plays a role in neuronal progenitor proliferation and development of the cerebral cortex, thalamus, hippocampus, striatum, and olfactory bulbs. Specific defects associated with Arx loss of function include abnormal interneuron migration and subtype differentiation. How disruptions in ARX result in human disease and how loss of Arx in mice results in these phenotypes remains poorly understood. To gain insight into the biological functions of Arx, we performed a genome-wide expression screen to identify transcriptional changes within the subpallium in the absence of Arx. We have identified 84 genes whose expression was dysregulated in the absence of Arx. This population was enriched in genes involved in cell migration, axonal guidance, neurogenesis, and regulation of transcription and includes genes implicated in autism, epilepsy, and mental retardation; all features recognized in patients with ARX mutations. Additionally, we found Arx directly repressed three of the identified transcription factors: Lmo1, Ebf3 and Shox2. To further understand how the identified genes are involved in neural development, we used gene set enrichment algorithms to compare the Arx gene regulatory network (GRN) to the Dlx1/2 GRN and interneuron transcriptome. These analyses identified a subset of genes in the Arx GRN that are shared with that of the Dlx1/2 GRN and that are enriched in the interneuron transcriptome. These data indicate Arx plays multiple roles in forebrain development, both dependent and independent of Dlx1/2, and thus provides further insights into the understanding of the mechanisms underlying the pathology of mental retardation and epilepsy phenotypes resulting from ARX mutations

Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-Analysis of Community-Based Cohorts

BACKGROUND AND OBJECTIVES: Previous studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults. METHODS: We included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed mendelian randomization (MR) analyses to assess causality. RESULTS: We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (β = 0.04; 95% CI 0.02-0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition. DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the United States. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community

A population-based meta-analysis of circulating GFAP for cognition and dementia risk

Funding Information: The authors thank the study participants, the study teams, and the investigators and staff of the cohort studies. Dr. Pase is supported by a Heart Foundation Future Leader Fellowship (GNT102052). Dr DeCarli is supported by the UCD ADRC P30 AG 010129. Dr Aparicio is supported by an American Academy of Neurology Career Development Award, Alzheimer's Association (AARGD‐20‐685362), and National Institutes of Health (L30 NS093634). Funding was provided by the CHARGE infrastructure grant (HL105756). Funding Information: This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC15103, 75N92021D00006, and grants R01AG15928, R01AG20098, U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG053325, K24AG065525, and R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS‐NHLBI.org. Funding Information: This work was made possible by grants from the Alzheimer's Drug Discovery Foundation (GDAPB‐202010‐2020940), National Institutes of Health (N01‐HC‐25195, HHSN268201500001I, 75N92019D00031) and the National Institute on Aging (AG059421, AG054076, AG049607, AG033090, AG066524, NS017950, P30AG066546, UF1NS125513). Funding Information: The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contract Nos. HHSN26820180003I, HHSN26820180004I, HHSN26820180005I, HHSN26820180006I, and HHSN26820180007I from the National Heart, Lung, and Blood Institute (NHLBI), the Intramural Research Program of the National Institute on Aging (NIA), and an intra‐agency agreement between NIA and NHLBI (No. AG0005) . Funding Information: The Age, Gene/Environment Susceptibility‐Reykjavik Study was supported by NIH contracts N01‐AG‐1‐2100 and HHSN27120120022C, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Funding Information: Dr. Pase is supported by a Heart Foundation Future Leader Fellowship (GNT102052). Dr DeCarli is supported by the UCD ADRC P30 AG 010129. Dr Aparicio is supported by an American Academy of Neurology Career Development Award, Alzheimer's Association (AARGD‐20‐685362), and National Institutes of Health (L30 NS093634). Funding was provided by the CHARGE infrastructure grant (HL105756). Funding Information Publisher Copyright: © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.Objective: Expression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, colocalizes with neuropathology in the brain. Blood levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population-based level are necessary to broaden generalizability to community settings. Methods: Circulating GFAP levels were assayed using a Simoa HD-1 analyzer in 4338 adults without prevalent dementia from four longitudinal community-based cohort studies. The associations between GFAP levels with general cognition, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication, body mass index, apolipoprotein E ε4 status, site, and time between GFAP blood draw and the outcome. Associations with incident all-cause and Alzheimer's disease dementia were evaluated with adjusted Cox proportional hazard models. Meta-analysis was performed on the estimates derived from each cohort using random-effects models. Results: Meta-analyses indicated that higher circulating GFAP associated with lower general cognition (ß = −0.09, [95% confidence interval [CI]: −0.15 to −0.03], p = 0.005), but not with total brain or hippocampal volume (p > 0.05). However, each standard deviation unit increase in log-transformed GFAP levels was significantly associated with a 2.5-fold higher risk of incident all-cause dementia (Hazard Ratio [HR]: 2.47 (95% CI: 1.52–4.01)) and Alzheimer's disease dementia (HR: 2.54 [95% CI: 1.42–4.53]) over up to 15-years of follow-up. Interpretation: Results support the potential role of circulating GFAP levels for aiding dementia risk prediction and improving clinical trial stratification in community settings.Peer reviewe

Cellular consequences of mutations in the mouse homologs of the human lissencephaly genes LIS1 and ARX

Migration of neurons is a fundamental process of development of the mammalian neocortex. This migration occurs along one of two pathways, the radial and non-radial pathways. We hypothesize that defects in normal neural migration caused by mutations in genes critical to neural migration result in human neurodevelopmental disorders. Defects in radial neural migration have been previously identified in gene mutations that lead to human lissencephaly, a family of neurodevelopmental disorders characterized by severe structural and functional abnormalities of the neocortex. Using Lis1+/− mice, a common model of human lissencephaly caused by mutations in the Lissencephaly1 (LIS1) gene, we show that Lis1+/− mice also exhibit a decrease in non-radial cell migration (NRCM) in vivo and in vitro that is primarily cell-autonomous. This decrease in NRCM is caused by a decrease in the rate of active migration and an increase in the time migrating neurons spend at rest. Furthermore, we find that Lis1+/− non-radially migrating neurons have an abnormal morphology consisting of a longer leading process and less frequent branching. We also present evidence that these effects on migration may be conserved in humans with LIS1 mutations, who have an apparent delay in NRCM. Mutations in Aristaless-related homeobox (ARX ) have more recently been linked to human neurodevelopmental disease, including lissencephaly and infantile spasms syndrome with mental retardation. Studies of the murine homolog, Arx, have shown that it is required for normal NRCM. In order to understand how mutations in ARX affect neural migration, we generated a model for one form of ARX mutation, a polyalanine (polyA) expansion. Expression of polyA-expanded Arx in vitro and in vivo causes the formation of ubiquitinated nuclear inclusions. The formation of these inclusions is suppressed by coexpression of the Hsp70 molecular chaperone. Furthermore, we demonstrate that expression of polyA-expanded Arx increases cell death in vitro. These data suggest that misfolding of polyA-expanded Arx results in cellular toxicity that contributes to defects in neural development