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Background and objectivesPatients with ALS-FTD spectrum disorders (ALS-FTSD) have mixed motor and cognitive impairments and require valid and quantitative assessment tools to support diagnosis and tracking of bulbar motor disease. This study aimed to validate a novel automated digital speech tool that analyzes vowel acoustics from natural, connected speech as a marker for impaired articulation due to bulbar motor disease in ALS-FTSD.MethodsWe used an automatic algorithm called Forced Alignment Vowel Extraction (FAVE) to detect spoken vowels and extract vowel acoustics from 1 minute audio-recorded picture descriptions. Using automated acoustic analysis scripts, we derived two articulatory-acoustic measures: vowel space area (VSA, in Bark2) which represents tongue range-of-motion (size), and average second formant slope of vowel trajectories (F2 slope) which represents tongue movement speed. We compared vowel measures between ALS with and without clinically-evident bulbar motor disease (ALS+bulbar vs. ALS-bulbar), behavioral variant frontotemporal dementia (bvFTD) without a motor syndrome, and healthy controls (HC). We correlated impaired vowel measures with bulbar disease severity, estimated by clinical bulbar scores and perceived listener effort, and with MRI cortical thickness of the orobuccal part of the primary motor cortex innervating the tongue (oralPMC). We also tested correlations with respiratory capacity and cognitive impairment.ResultsParticipants were 45 ALS+bulbar (30 males, mean age=61±11), 22 ALS-nonbulbar (11 males, age=62±10), 22 bvFTD (13 males, age=63±7), and 34 HC (14 males, age=69±8). ALS+bulbar had smaller VSA and shallower average F2 slopes than ALS-bulbar (VSA: |d|=0.86,p=0.0088; F2 slope: |d|=0.98,p=0.0054), bvFTD (VSA: |d|=0.67,p=0.043; F2 slope: |d|=1.4,pd|=0.73,p=0.024; F2 slope: |d|=1.0,pp=0.033; F2 slope: R=0.25,p=0.048), and smaller VSA was associated with greater listener effort (R=-0.43,p=0.041). Shallower F2 slopes were related to cortical thinning in oralPMC (R=0.50,p=0.03). Neither vowel measure was associated with respiratory nor cognitive test scores.ConclusionsVowel measures extracted with automatic processing from natural speech are sensitive to bulbar motor disease in ALS-FTD and are robust to cognitive impairment.

BackgroundFrontotemporal dementia is the second most common form of early onset dementia (< 65 years). Despite this there are few known disease modifying factors. The anterior cingulate is a focal point of pathology in behavioural variant frontotemporal dementia. Sulcation of the anterior cingulate is denoted by the presence of a paracingulate sulcus, a tertiary sulcus developing, where present during the third gestational trimester and remaining stable throughout life. This study aims to examine the impact of right paracingulate sulcal presence on the expression and prognosis of behavioural variant Frontotemporal Dementia.MethodsThis retrospective analysis drew it’s population from two clinical samples recruited from memory clinics at University Hospitals in The United States of America and The Netherlands. Individuals with sporadic behavioural variant Frontotemporal Dementia were enrolled between 2004 and 2022 and followed up for an average of 7.71 years. T1-MRI data were evaluated for hemispheric paracingulate sulcal presence in accordance with an established protocol by two blinded raters. Outcome measures included age at onset, survival, cortical thickness, and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating determined clinical disease progression.ResultsThe study population consisted of 186 individuals with sporadic behavioural variant Frontotemporal Dementia, (113 males and 73 females) mean age 63.28 years (SD 8.32). The mean age at onset was 2.44 years later in individuals possessing a right paracingulate sulcus (60.2 years (SD 8.54)) versus individuals who did not (57.76 (8.05)), 95% CI >0.41,P= 0.02. Education was not associated with age at onset (β = -0.05,P=0.75). Presence of a right paracingulate sulcus was associated with a 119% increased risk of death per year after age at onset (HR 2.19, CI [1.21 - 3.96],PP= 0.7). Right paracingulate sulcal presence was not associated with baseline cortical thickness.ConclusionRight paracingulate sulcal presence is associated with disease expression and survival in sporadic behavioural variant Frontotemporal Dementia. Findings provide evidence of neurodevelopmental brain reserve in behavioural variant Frontotemporal Dementia which may be important in the design of trials for future therapeutic approaches.

We propose a new perceptual super resolution (PSR) method for 3D neuroimaging and evaluate its performance in detecting brain changes due to neurodegenerative disease. The method, concurrent super resolution and segmentation (CSRS), is trained on volumetric brain data to consistently upsample both an image intensity channel and associated segmentation labels. The simultaneous nature of the method improves not only the resolution of the images but also the resolution of associated segmentations thereby making the approach directly applicable to existing labeled datasets. One challenge to real world evaluation of SR methods such as CSRS is the lack of high resolution ground truth in the target application data: clinical neuroimages. We therefore evaluate CSRS effectiveness in an adjacent, clinically relevant signal detection problem: quantifying cross-sectional and longitudinal change across a set of phenotypically heterogeneous but related disorders that exhibit known and differentiable patterns of brain atrophy. We contrast several 3D PSR loss functions in this paradigm and show that CSRS consistently increases the ability to detect regional atrophy both longitudinally and cross-sectionally in each of five related diseases.

BackgroundNeuropsychiatric symptoms are highly prevalent in frontotemporal degeneration (FTD). Prior research suggests there are disparities in the clinical presentation of dementia when comparing Black and White individuals but this has not been investigated in the context of FTD specifically. The aim of the present study is to investigate racial disparities in dementia severity, functional impairment and neuropsychiatric symptoms in individuals with a clinical diagnosis of FTD.MethodsUsing National Alzheimer’s Coordinating Center (NACC) data, we evaluated 63 Black and 2,356 White individuals living with a clinical diagnosis of FTD (behavioral variant FTD or primary progressive aphasia) and a healthy control group of 1899 Black and 9122 White individuals with normal behavior and cognition. We compared demographic characteristics, dementia severity, functional impairment and neuropsychiatric symptoms at initial NACC visit by examining differences on Clinical Dementia Rating Scale (CDR), Functional Assessment Scale (FAS) and Neuropsychiatric Inventory (NPI) using multivariable linear and logistic regression models, covarying for age at visit, disease duration, sex, and education. Models evaluating differences in neuropsychiatric symptoms additionally controlled for dementia severity.ResultsBlack individuals with FTD were considerably underrepresented, comprising only 2.5% of the clincial sample. In comparison to White individuals, Black individuals with FTD had a higher degree of dementia severity on CDR (CDR sum of boxes; p=0.03 CDR global, p=.006), greater functional impairment (FAS total; p=0.01) and more delusions (p=0.01), agitation (p=0.04) and depression (p=0.03) on the NPI. White individuals with FTD were more likely to demonstrate apathy (p=0.03). Within the normal control group, Black individuals reported less depression, anxiety, agitation, and nighttime behaviors (depression; p < 0.001; anxiety; p = 0.006; agitation; p = 0.048; nighttime behaviors; p < 0.001) compared to White normal controls.DiscussionThe present study suggests there are significant disparities in dementia severity, functional impairment and neuropsychiatric presentations at initial visit between Black and White individuals with FTD. Future work must address racial disparities in FTD and their underlying social determinants as well as the lack of representation of non-White individuals in nationally representative neurodegenerative disease registries in order identify appropriate interventions.

Racial disparities in many aging-related health outcomes are persistent and pervasive among older Americans, reflecting accelerated biological aging for Black Americans compared to White, known as weathering. Environmental determinants that contribute to weathering are poorly understood. Having a higher biological age, measured by DNA methylation (DNAm), than chronological age is robustly associated with worse age-related outcomes and higher social adversity. We hypothesize that individual socioeconomic status (SES), neighborhood social environment, and air pollution exposures contribute to racial disparities in DNAm aging according to GrimAge and Dunedin Pace of Aging methylation (DPoAm). We perform retrospective cross-sectional analyses among 2,960 non-Hispanic participants (82% White, 18% Black) in the Health and Retirement Study whose 2016 DNAm age is linked to survey responses and geographic data. DNAm aging is defined as the residual after regressing DNAm age on chronological age. We observe Black individuals have significantly accelerated DNAm aging on average compared to White individuals according to GrimAge (239%) and DPoAm (238%). We implement multivariable linear regression models and threefold decomposition to identify exposures that contribute to this disparity. Exposure measures include individual-level SES, census-tract-level socioeconomic deprivation and air pollution (fine particulate matter, nitrogen dioxide, and ozone), and perceived neighborhood social and physical disorder. Race and gender are included as covariates. Regression and decomposition results show that individual-level SES is strongly associated with and accounts for a large portion of the disparity in both GrimAge and DPoAm aging. Higher neighborhood deprivation for Black participants significantly contributes to the disparity in GrimAge aging. Black participants are more vulnerable to fine particulate matter exposure for DPoAm, perhaps due to individual- and neighborhood-level SES, which may contribute to the disparity in DPoAm aging. DNAm aging may play a role in the environment “getting under the skin”, contributing to age-related health disparities between older Black and White Americans.

ObjectivePlasma phosphorylated tau (p-tau181) is reliably elevated in Alzheimer’s disease (AD), but less explored is its specificity relative to other neurodegenerative conditions. Here we find novel evidence that plasma p-tau181 is elevated in amytrophic lateral sclerosis (ALS), a neurodegenerative condition typically lacking tau pathology. We performed a detailed clinical evaluation to unravel the potential source of this unexpected observation.MethodsPatients were clinically or pathologically diagnosed with ALS (n=130) or AD (n=82), or were healthy non-impaired controls (n=33). Receiver operating characteristic (ROC) curves were analyzed and area under the curve (AUC) was used to discriminate AD from ALS. Within ALS, Mann-Whitney-Wilcoxon tests compared analytes by presence/absence of upper motor neuron (UMN) and lower motor neuron (LMN) signs. Spearman correlations tested associations between plasma p-tau181 and postmortem neuron loss.ResultsA Wilcoxon test showed plasma p-tau181 was higher in ALS than controls (W=3297, p=0.0000020), and ROC analyses showed plasma p-tau181 poorly discriminated AD and ALS (AUC=0.60). In ALS, elevated plasma p-tau181 was associated with LMN signs in cervical (W=827, p=0.0072), thoracic (W=469, p=0.00025), and lumbosacral regions (W=851, p=0.0000029). In support of LMN findings, plasma p-tau181 was associated with neuron loss in the spinal cord (rho=0.46, p=0.017), but not in the motor cortex (p=0.41). CSF p-tau181 and plasma neurofilament light chain (NfL) were included as reference analytes, and demonstrate specificity of findings.InterpretationWe found strong evidence that plasma p-tau181 is elevated in ALS and may be a novel marker specific to LMN dysfunction.

An understudied non-amnestic variant of Alzheimer’s disease (AD), behavioral variant AD (bvAD) is associated with progressive personality, behavior, or executive dysfunction and frontal atrophy. This study characterizes the neuropsychological and neuroanatomical features associated with bvAD by comparing it to behavioral variant frontotemporal dementia (bvFTD), amnestic AD (aAD), and subjects with normal cognition. Subjects included 16 bvAD, 67 bvFTD, and 18 aAD patients, and 26 healthy controls. Compared to bvFTD, bvAD showed more significant visuospatial impairments (Rey Figure copy and recall), more irritability (Neuropsychological Inventory), and equivalent verbal memory (Philadelphia Verbal Learning Test). Compared to aAD, bvAD indicated more executive dysfunction (F-letter fluency) and better visuospatial performance. Neuroimaging analysis found that bvAD showed cortical thinning relative to bvFTD posteriorly in left temporal-occipital regions; bvFTD had cortical thinning relative to bvAD in left inferior frontal cortex. bvAD had cortical thinning relative to aAD in prefrontal and anterior temporal regions. All patient groups had lower volumes than controls in both anterior and posterior hippocampus. However, bvAD patients had higher average volume than aAD patients in posterior hippocampus and higher volume than bvFTD patients in anterior hippocampus after adjustment for age and intracranial volume. Findings demonstrated that underlying pathology mediates disease presentation in bvAD and bvFTD.

Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies (4RT), including cortico-basal degeneration and progressive supranuclear palsy (PSP). Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4RTs, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assessed whether connectivity drives 4R-tau spreading patterns by combining resting-state fMRI connectomics with both 2nd generation 18F- PI-2620 tau-PET in 46 patients with clinically diagnosed 4RTs and post-mortem cell-type- specific regional tau assessments from two independent PSP samples (n=97/96). We found that inter-regional connectivity was associated with higher inter-regional correlation of both tau- PET and post-mortem tau levels in 4RTs. In regional cell-type specific post-mortem tau assessments, this association was stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with trans-neuronal tau spread. Using tau-PET we found that patient-level tau patterns can be predicted by the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence for brain connectivity as a key mediator of trans-neuronal tau spreading in 4RTs.

Primary age-related tauopathy (PART) is a neurodegenerative tauopathy with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) deposition in plaques. The pathogenesis of PART is unknown, but evidence suggests it is associated with genes that promote tau pathology as well as others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n=647) using Braak neurofibrillary tangle stage as a quantitative trait adjusting for sex, age, genotyping platform, and principal components. We found significant associations with some candidate loci associated with AD and progressive supranuclear palsy, a primary tauopathy (SLC24A4, MS4A6A, HS3ST1, MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brain from tauopathies containing isoforms with four microtubule-binding domain repeats (4R) and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation revealed a direct and specific binding of JADE1 protein to tau containing four (4R) and no N-terminal inserts (0N4R) in post-mortem human PART brain tissue. Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a mediator of neurofibrillary degeneration.

Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged. We performed a retrospective autopsy study in a collection (n=174) of post-mortem PART brains and used logistic regression to determine the extent to which a set of clinical and neuropathological features predict cognitive impairment. We compared Braak staging, which focuses on hierarchical neuroanatomical progression of AD tau and Aβ pathology, with quantitative assessments of neurofibrillary burden using computer-derived positive pixel counts on digitized whole slide images of sections stained immunohistochemically with antibodies targeting abnormal hyperphosphorylated tau (p-tau) in the entorhinal region and hippocampus. We also assessed other factors affecting cognition, including aging-related tau astrogliopathy (ARTAG) and atrophy. We found no association between Braak stage and cognitive impairment when controlling for age (p=0.76). In contrast, p-tau burden was significantly correlated with cognitive impairment even when adjusting for age (p=0.03). The strongest correlate of cognitive impairment was cerebrovascular disease, a well-known risk factor (pp=0.03) and hippocampal atrophy (p=0.04) were also associated. In contrast, sex, APOE, psychiatric illness, education, argyrophilic grains, and incidental Lewy bodies were not. These findings support the hypothesis that comorbid pathologies contribute to cognitive impairment in subjects with PART. Quantitative approaches beyond Braak staging are critical for advancing our understanding of the extent to which age-related tauopathy changes impact cognitive function.

Frontotemporal lobar degeneration (FTLD) is a heterogeneous spectrum of age-associated neurodegenerative diseases that include two main pathologic categories of tau (FTLD-Tau) and TDP-43 (FTLD-TDP) proteinopathies. These distinct proteinopathies are often clinically indistinguishable during life, posing a major obstacle for diagnosis and emerging therapeutic trials tailored to disease-specific mechanisms. Moreover, MRI-derived measures have had limited success to date discriminating between FTLD-Tau or FTLD-TDP. T2*-weighted (T2*w) ex vivo MRI has previously been shown to be sensitive to non-heme iron in healthy intracortical lamination and myelin, and to pathological iron deposits in amyloid-beta plaques and activated microglia in Alzheimer’s disease (AD). However, an integrated, ex vivo MRI and histopathology approach is understudied in FTLD. We apply joint, whole-hemisphere ex vivo MRI at 7T and histopathology to the study autopsy-confirmed FTLD-Tau (n=3) and FTLD-TDP (n=2), relative to an AD disease-control brain with antemortem clinical symptoms of frontotemporal dementia and an age-matched healthy control. We detect distinct laminar patterns of novel iron-laden glial pathology in both FTLD-Tau and FTLD-TDP brains. We find iron-positive ameboid and hypertrophic microglia and astrocytes largely in deeper GM and adjacent WM in FTLD-Tau. In contrast, FTLD-TDP presents prominent superficial cortical layer iron reactivity in astrocytic processes enveloping small blood vessels with limited involvement of adjacent WM, as well as more diffuse distribution of punctate iron-rich dystrophic microglial processes across all GM lamina. This integrated MRI/histopathology approach reveals ex vivo MRI features that are consistent with these pathological observations distinguishing FTLD-Tau and FTLD-TDP, including prominent irregular hypointense signal in deeper cortex in FTLD-Tau whereas FTLD-TDP showed upper cortical layer hypointense bands and diffuse cortical speckling. Moreover, differences in adjacent WM degeneration and iron-rich gliosis on histology between FTLD-Tau and FTLD-TDP were also readily apparent on MRI as hyperintense signal and irregular areas of hypointensity, respectively that were more prominent in FTLD-Tau compared to FTLD-TDP. These unique histopathological and radiographic features were distinct from HC and AD brains, suggesting that iron-sensitive T2*w MRI, adapted to in vivo application at sufficient resolution, may offer an opportunity to improve antemortem diagnosis of FTLD proteinopathies using tissue-validated methods.

Behavioral variant frontotemporal degeneration (bvFTD) is clinically characterized by progressive decline in social and executive domains. Previous work suggests that early lifestyle factors such as education and occupational attainment may relate to structural integrity and moderate the rate of cognitive decline in bvFTD, but the role of other cognitively stimulating activities is understudied. We sought to investigate the effect of such activities on cortical thickness (CT) in bvFTD. bvFTD patients (n=31) completed a baseline MRI scan, and informants for the patients completed the Lifetime of Experiences Questionnaire (LEQ), which measures specific activities considered to be undertaken primarily within one particular life phase, such as education (young-life), occupation (mid-life), and social/leisure activity (late-life). At baseline, linear models assessed the effect of LEQ scores from each life phase on regional CT. A subset (n=19) of patients completed longitudinal MRI, and to evaluate the association of LEQ with longitudinal rates of CT decline, we derived individualized slopes of decline using linear mixed effects models and these were related to LEQ scores from each life phase. At baseline, a higher late-life LEQ score was associated with less atrophy in bilateral superior anterior temporal regions. Longitudinally, we observed that higher late-life LEQ scores were associated with an attenuated rate of CT loss in insular cortex. Late-life LEQ score was positively associated with both relatively preserved CT early in bvFTD and a slower rate of cortical loss in regions important for social functioning. These findings suggest that social and leisure activities may contribute to a form of resilience against pathologic effects of disease.

ImportanceAmyotrophic lateral sclerosis (ALS) is a multi-system disorder characterized primarily by motor neuron degeneration, but may be accompanied by cognitive dysfunction. Statistically appropriate criteria for establishing cognitive impairment (CI) in ALS are lacking.ObjectiveDefine thresholds for CI in ALS using quantile regression (QR) that accounts for age and education in a North American (NAmer) cohort.DesignQR of cross-sectional data from a multi-center NAmer cohort of healthy adults was used to model the 5th percentile of cognitive scores on the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). The QR approach was compared to a traditional 2 standard deviation (SD) cut-off approach using the same NAmer cohort (2SD-NAmer) and to existing UK-based normative data derived using the 2SD approach (2SD-UK) to assess the impact of cohort selection and statistical model in identifying CI ALS patients.Participants269 healthy adults from NAmer, recruited by the University of Pennsylvania (PENN; N=82), the University of Miami through the CRiALS study (CRiALS; N=40), and the Canadian ALS Neuroimaging Consortium (CALSNIC; N=147) were included to establish ECAS thresholds for defining CI. We then evaluated the frequency of CI in 182 ALS patients from PENN.Main OutcomesWe defined two new sets of normative thresholds, based on NAmer heathy adult performance, for each ECAS domain score and the composite scores using QR and 2SD statistical approaches. We then applied the 2SD-NAmer and QR-NAmer, as well as the previously established and widely-used 2SD-UK, thresholds to evaluate the frequency of CI in ALS patients.ResultsQR-NAmer models revealed that increased age and reduced educational attainment negatively impact cognitive performance on the ECAS. Based on the QR-NAmer normative cutoffs, the prevalence of CI in the 182 PENN ALS patients was 15.9% for ECAS ALS-Specific and 15.4% for ECAS Total. These estimates are more conservative than estimates ranging from 15.4%-34.6% impaired based on 2SD approaches.Conclusions and RelevanceThis report establishes normative thresholds for using ECAS to identify whether ALS patients in the NAmer population have CI. The choice of statistical method and normative cohort has a substantial impact on defining CI in ALS.Key PointsQuestionHow to define cognitive impairment (CI) in amyotrophic lateral sclerosis (ALS) using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS)?FindingsAge- and education-adjusted quantile regression (QR) yields thresholds for defining CI that differ meaningfully from those derived from parametric methods without age- and education-adjustment. Thresholds also differ between UK and North American cohorts. Applying our North American-based QR norms to an American ALS cohort at a single center identified CI based on ECAS performance in ∼16% patients, compared to 15.4%-34.6% patients using other approaches.MeaningThe choice of statistical method and normative cohort has a substantial impact on defining CI in ALS.

BackgroundBrain structure abnormalities throughout the course of Parkinson’s disease (PD) have yet to be fully elucidated. Inconsistent findings across studies may be partly due to small sample sizes and heterogeneous analysis methods. Using a multicenter approach and harmonized analysis methods, we aimed to overcome these limitations and shed light on disease stage-specific profiles of PD pathology as suggested by in vivo neuroimaging.MethodsIndividual brain MRI and clinical data from 2,367 PD patients and 1,183 healthy controls were collected from 19 sites, deriving from 20 countries. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effect linear models. Patients were grouped according to the Hoehn & Yahr (HY) disease stages and compared to age- and sex-matched controls. Within the PD sample, we investigated associations between Montreal Cognitive Assessment (MoCA) scores and brain morphology.FindingsThe main analysis showed a thinner cortex in 38 of 68 regions in PD patients compared to controls (dmax = −0·25, dmin = −0·13). The bilateral putamen (left: d = −0·16, right: d = −0·16) and left amygdala (d = −0·15) were smaller in patients, while the left thalamus was larger (d = 0·17). HY staging indicated that a thinner cortex initially presents in the occipital, parietal and temporal cortex, and extends towards caudally located brain regions with increased disease severity. From HY stage 2 and onwards the bilateral putamen and amygdala were consistently smaller with larger effects denoting each increment. Finally, we found that poorer cognitive performance was associated with widespread cortical thinning as well as lower volumes of core limbic structures.InterpretationOur findings offer robust and novel imaging signatures that are specific to the disease severity stages and in line with an ongoing neurodegenerative process, highlighting the importance of such multicenter collaborations.FundingNIH Big Data to Knowledge program, ENIGMA World Aging Center, and ENIGMA Sex Differences Initiative, and other international agencies (listed in full in the Acknowledgments).

Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients, however factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N=327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort, and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N=90) as well as post mortem motor cortical neuronal loss (N=87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS.