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INTRODUCTION: The A/T/N (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimers disease (AD) diagnosis and can encompass additional changes such as inflammation (I). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population. METHODS: Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years). RESULTS: Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (p = 0.0007) and volume (p = 0.0006). Lateral temporal FDG PET (p = 0.006) and volume (p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group. DISCUSSION: Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age. HIGHLIGHTS: Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate.

Background/aim: In this study, besides the evaluation of gray and white matter changes in cognitively normal Parkinson's disease (PD-CN) patients with volumetric magnetic resonance imaging (MRI) parameters, it was tried to show that some neuropsychological tests may be impaired in PD-CN patients. Materials and methods: Twenty-six PD-CN patients and 26 healthy elderly (HC) participants were included in the current study. Global cognitive status was assessed using the mini-mental state examination (MMSE), and the Montreal cognitive assessment scale (MoCA). Attention and executive functions were evaluated using the Wechsler memory scale-revised (WMS-R) digit span test and trail making test (TMT) part A and part B, the Stroop test, semantic and phonemic fluency tests, and clock drawing test. Magnetic resonance imaging (MRI) was acquired according to the Alzheimer's disease neuroimaging initiative (ADNI) protocol. Results: There were no significant differences among groups regarding age, sex, handedness, and years of education. In the comparison of the PD-CN group and the HC group, there was a statistical decrease in the total animal scores, lexical fluency, TMT part A and TMT part B scores in the PD-CN group. Subcortical gray matter volumes (GMV) were significantly lower in PD-CN patients. The PD-CN group had a significantly reduced total volume of right putamen and left angular gyrus compared to that in the HC group. We observed that putamen and angular gyrus volumes were lower in PD-CN patients. On the other hand, TMT part B may be a useful pretest in detecting the conversion of mild cognitive impairment in PD. Conclusion: Significant MRI volumetric measurements and neuropsychological test batteries can be helpful in the clinical follow-up in PD-CN patients. [ABSTRACT FROM AUTHOR]

Background and Purpose: Myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) is a relapsing demyelinating condition. There are several cross‐sectional studies showing evidence of brain atrophy in people with MOGAD (pwMOGAD), but longitudinal brain volumetric assessment is still an unmet need. Current recommendations do not include monitoring with MRI and assume distinct attacks. Evidence of ongoing axon loss will have diagnostic and therapeutic implications. In this study, we assessed brain volume changes in pwMOGAD over a mean follow‐up period of 2 years and compared this to changes in people with multiple sclerosis (pwMS). Methods: This is a retrospective single‐center study over a 7‐year period from 2014 to 2021. MRI brain scans at the time of diagnosis and follow‐up in remission were collected from 14 Caucasian pwMOGAD, confirmed by serum myelin oligodendrocyte glycoprotein immunoglobulin G antibody presence, detected by live cell‐based assays. Total brain volume (TBV), white matter (WM), gray matter (GM), and demyelinating lesion volumes were assessed automatically using the Statistical Parametric Mapping and FMRIB automated segmentation tools. MRI brain scans at diagnosis and follow‐up on remission were collected from 32‐matched pwMS for comparison. Statistical analysis was done using analysis of variance. Results: There is evidence of TBV loss, affecting particularly GM, over an approximately 2‐year follow‐up period in pwMOGAD (p <.05), comparable to pwMS. WM and lesion volume change over the same period were not statistically significant (p >.1). Conclusion: We found evidence of loss of GM and TBV over time in pwMOGAD, similar to pwMS, although the WM and lesion volumes were unchanged. [ABSTRACT FROM AUTHOR]

Background and purpose: Newly appearing lesions in multiple sclerosis (MS) may evolve into chronically active, slowly expanding lesions (SELs), leading to sustained disability progression. The aim of this study was to evaluate the incidence of newly appearing lesions developing into SELs, and their correlation to clinical evolution and treatment. Methods: A retrospective analysis of a fingolimod trial in primary progressive MS (PPMS; INFORMS, NCT 00731692) was undertaken. Data were available from 324 patients with magnetic resonance imaging scans up to 3 years after screening. New lesions at year 1 were identified with convolutional neural networks, and SELs obtained through a deformation‐based method. Clinical disability was assessed annually by Expanded Disability Status Scale (EDSS), Nine‐Hole Peg Test, Timed 25‐Foot Walk, and Paced Auditory Serial Addition Test. Linear, logistic, and mixed‐effect models were used to assess the relationship between the Jacobian expansion in new lesions and SELs, disability scores, and treatment status. Results: One hundred seventy patients had ≥1 new lesions at year 1 and had a higher lesion count at screening compared to patients with no new lesions (median = 27 vs. 22, p = 0.007). Among the new lesions (median = 2 per patient), 37% evolved into definite or possible SELs. Higher SEL volume and count were associated with EDSS worsening and confirmed disability progression. Treated patients had lower volume and count of definite SELs (β = −0.04, 95% confidence interval [CI] = −0.07 to −0.01, p = 0.015; β = −0.36, 95% CI = −0.67 to −0.06, p = 0.019, respectively). Conclusions: Incident chronic active lesions are common in PPMS, and fingolimod treatment can reduce their number. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate whether long-term television viewing patterns, a common sedentary behavior, in early to mid-adulthood is associated with gray matter brain volume in midlife and if this is independent of physical activity. We evaluated 599 participants (51% female, 44% black, mean age 30.3 ± 3.5 at baseline and 50.2 ± 3.5 years at follow-up and MRI) from the prospective Coronary Artery Risk Development in Young Adults (CARDIA) study. We assessed television patterns with repeated interviewer-administered questionnaire spanning 20 years. Structural MRI (3T) measures of frontal cortex, entorhinal cortex, hippocampal, and total gray matter volumes were assessed at midlife. Over the 20 years, participants reported viewing an average of 2.5 ± 1.7 h of television per day (range: 0-10 h). After multivariable adjustment, greater television viewing was negatively associated with gray matter volume in the frontal (β = - 0.77; p = 0.01) and entorhinal cortex (β = - 23.83; p = 0.05) as well as total gray matter (β = - 2.09; p = 0.003) but not hippocampus. These results remained unchanged after additional adjustment for physical activity. For each one standard deviation increase in television viewing, the difference in gray matter volume z-score was approximately 0.06 less for each of the three regions (p

BackgroundAnti-NMDA receptor encephalitis is an immune-mediated disorder characterized by antibodies against the GluN1 subunit of the NMDA receptor that is increasingly recognized as a treatable cause of childhood epileptic encephalopathy. In adults, the disorder has been associated with reversible changes in brain volume over the course of treatment and recovery, but in children, little is known about its time course and associated imaging manifestations.Case presentationA previously healthy 20-month-old boy presented with first-time unprovoked seizures, dysautonomia, and dyskinesia. Paraneoplastic workup was negative, but CSF was positive for anti-NMDAR antibodies. The patient's clinical condition waxed and waned over a 14-month course of treatment with first- and second-line immunotherapies (including steroids, IVIG, rituximab, and cyclophosphamide). Serial brain MRIs scans obtained at 5 time points spanning this same period showed no abnormal signal or enhancement but were remarkable for cycles of reversible regional cortical volume loss. All scans included identical 1-mm resolution 3D T1-weighted sequences obtained on the same 3 T scanner. Using a novel longitudinal processing stream in FreeSurfer6 (Reuter M, et. al, Neuroimage 61:1402-18, 2012) we quantified the rate of change in cortical volume at each vertex (% volume change per month) between consecutive scans and correlated these changes with the time course of the patient's treatment and clinical response. We found regionally specific changes in cortical volume (up to 7% per month) that preferentially affected the frontal and occipital lobes and paralleled the patient's clinical course, with clinical decline associated with volume loss and clinical improvement associated with volume gain.ConclusionsOur results suggest that reversible cortical volume loss in anti-NMDA encephalitis has a regional specificity that mirrors many of the clinical symptoms associated with the disorder and tracks the dynamics of disease severity over time. This case illustrates how quantitative morphometric techniques can be applied to clinical imaging data to reveal patterns of brain change that may provide insight into disease pathophysiology. More widespread application of this approach might reveal regional and temporal patterns specific to different types of autoimmune encephalitis, providing a tool for diagnosis and a surrogate marker for monitoring treatment response.

Introduction: Empathy relies on fronto‐cingular and temporal networks that are selectively vulnerable in behavioral variant frontotemporal dementia (bvFTD). This study modeled when in the disease process empathy changes begin, and how they progress. Methods: Four hundred thirty‐one individuals with asymptomatic genetic FTD (n = 114), genetic and sporadic bvFTD (n = 317), and 163 asymptomatic non‐carrier controls were enrolled. In sub‐samples, we investigated empathy measured by the informant‐based Interpersonal Reactivity Index (IRI) at each disease stage and over time (n = 91), and its correspondence to underlying atrophy (n = 51). Results: Empathic concern (estimate = 4.38, 95% confidence interval [CI] = 2.79, 5.97; p < 0.001) and perspective taking (estimate = 5.64, 95% CI = 3.81, 7.48; p < 0.001) scores declined between the asymptomatic and very mild symptomatic stages regardless of pathogenic variant status. More rapid loss of empathy corresponded with subcortical atrophy. Discussion: Loss of empathy is an early and progressive symptom of bvFTD that is measurable by IRI informant ratings and can be used to monitor behavior in neuropsychiatry practice and treatment trials. [ABSTRACT FROM AUTHOR]

Cardiac arrest survivors develop a variety of neuropsychological impairments and neuroanatomical lesions. The goal of this study is to evaluate if brain voxel‐based morphometry and lesional Magnetic Resonance Imaging (MRI) analyses performed in the acute phase of an Out‐of‐Hospital Cardiac Arrest (OHCA) can be sensitive enough to predict the persistence of neuropsychological disorders beyond 3 months. Survivors underwent a prospective brain MRI during the first month after an OHCA and performed neuropsychological assessments at 1 and 3 months. According to the second neuropsychological assessment, survivors were separated into two subgroups, a deficit subgroup with persistent memory, executive functions, attention and/or praxis disorders (n = 11) and a preserved subgroup, disorders free (n = 14). Brain vascular lesion images were investigated, and volumetric changes were compared with healthy controls. Correlations were discussed between brain MRI results, OHCA data and the second neuropsychological assessment. Analyses of acute ischemic lesions did not reveal significant differences between the two subgroups (p =.35), and correlations with cognitive impairments could not be assessed. voxel‐based morphometry analyses revealed a global cerebral volume reduction for the two subgroups and a clear decrease of the right thalamic volume for the deficit subgroup. It was associated with a cognitive dysexecutive syndrome represented by four executive indexes according to the 'Groupe de Réflexion pour l'Evaluation des Fonctions EXécutives' criteria. The right thalamus atrophy seems to be more predictive than the vascular lesions and more specific than a global cerebral volume reduction of post‐OHCA neuropsychological executive disorders. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) patients ≥70 years show smaller medial temporal volumes despite less 18F‐flortaucipir‐positron emission tomography (PET) uptake than younger counterparts. We investigated whether TAR DNA‐binding protein 43 (TDP‐43) was contributing to this volume‐uptake mismatch. Methods: Seventy‐seven participants with flortaucipir‐PET and volumetric magnetic resonance imaging underwent postmortem AD and TDP‐43 pathology assessments. Bivariate‐response linear regression estimated the effect of age and TDP‐43 pathology on volume and/or flortaucipir standardized uptake volume ratios of the hippocampus, amygdala, entorhinal, inferior temporal, and midfrontal cortices. Results: Older participants had lower hippocampal volumes and overall flortaucipir uptake. TDP‐43‐immunoreactivity correlated with reduced medial temporal volumes but was unrelated to flortaucipir uptake. TDP‐43 effect size was consistent across the age spectrum. However, at older ages, the cohort mean volumes moved toward those of TDP‐43‐positives, reflecting the increasing TDP‐43 pathology frequency with age. Discussion: TDP‐43 pathology is a relevant contributor driving the volume‐uptake mismatch in older AD participants. Highlights: TDP‐43 pathology affects medial temporal volume loss but not tau radiotracer uptake.Greater TDP‐43 pathology effect is seen in old age due to its increasing frequency.TDP‐43 pathology is a relevant driver of the volume‐uptake mismatch in old AD patients. [ABSTRACT FROM AUTHOR]

The main goal of this paper is to employ longitudinal trajectories in a significant number of sub-regional brain volumetric MRI data as statistical predictors for Alzheimer's disease (AD) classification. We use logistic regression in a Bayesian framework that includes many functional predictors. The direct sampling of regression coefficients from the Bayesian logistic model is difficult due to its complicated likelihood function. In high-dimensional scenarios, the selection of predictors is paramount with the introduction of either spike-and-slab priors, non-local priors, or Horseshoe priors. We seek to avoid the complicated Metropolis-Hastings approach and to develop an easily implementable Gibbs sampler. In addition, the Bayesian estimation provides proper estimates of the model parameters, which are also useful for building inference. Another advantage of working with logistic regression is that it calculates the log of odds of relative risk for AD compared to normal control based on the selected longitudinal predictors, rather than simply classifying patients based on cross-sectional estimates. Ultimately, however, we combine approaches and use a probability threshold to classify individual patients. We employ 49 functional predictors consisting of volumetric estimates of brain sub-regions, chosen for their established clinical significance. Moreover, the use of spike-and-slab priors ensures that many redundant predictors are dropped from the model.

Background: Sporadic adult‐onset ataxias without known genetic or acquired cause are subdivided into multiple system atrophy of cerebellar type (MSA‐C) and sporadic adult‐onset ataxia of unknown etiology (SAOA). Objectives: To study the differential evolution of both conditions including plasma neurofilament light chain (NfL) levels and magnetic resonance imaging (MRI) markers. Methods: SPORTAX is a prospective registry of sporadic ataxia patients with an onset >40 years. Scale for the Assessment and Rating of Ataxia was the primary outcome measure. In subgroups, blood samples were taken and MRIs performed. Plasma NfL was measured via a single molecule assay. Regional brain volumes were automatically measured. To assess signal changes, we defined the pons and middle cerebellar peduncle abnormality score (PMAS). Using mixed‐effects models, we analyzed changes on a time scale starting with ataxia onset. Results: Of 404 patients without genetic diagnosis, 130 met criteria of probable MSA‐C at baseline and 26 during follow‐up suggesting clinical conversion to MSA‐C. The remaining 248 were classified as SAOA. At baseline, NfL, cerebellar white matter (CWM) and pons volume, and PMAS separated MSA‐C from SAOA. NfL decreased in MSA‐C and did not change in SAOA. CWM and pons volume decreased faster, whereas PMAS increased faster in MSA‐C. In MSA‐C, pons volume had highest sensitivity to change, and PMAS was a predictor of faster progression. Fulfillment of possible MSA criteria, NfL and PMAS were risk factors, CWM and pons volume protective factors for conversion to MSA‐C. Conclusions: This study provides detailed information on differential evolution and prognostic relevance of biomarkers in MSA‐C and SAOA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Magnetic resonance imaging (MRI) markers for chronic active lesions in MS include slowly expanding lesions (SELs) and paramagnetic rim lesions (PRLs). Objectives: To identify the relationship between SELs and PRLs in MS, and their association with disability. Methods: 61 people with MS (pwMS) followed retrospectively with MRI including baseline susceptibility-weighted imaging, and longitudinal T1 and T2-weighted scans. SELs were computed using deformation field maps; PRLs were visually identified. Mixed-effects models assessed differences in Expanded Disability Status Scale (EDSS) score changes between the group defined by the presence of SELs and or PRLs. Results: The median follow-up time was 3.2 years. At baseline, out of 1492 lesions, 616 were classified as SELs, and 80 as PRLs. 92% of patients had ⩾ 1 SEL, 56% had ⩾ 1 PRL, while both were found in 51%. SELs compared to non-SELs were more likely to also be PRLs (7% vs. 4%, p = 0.027). PRL counts positively correlated with SEL counts (ρ= 0.28, p = 0.03). SEL + PRL + patients had greater increases in EDSS over time (beta = 0.15/year, 95% confidence interval (0.04, 0.27), p = 0.009) than SEL+PRL-patients. Conclusion: SELs are more numerous than PRLs in pwMS. Compared with either SELs or PRLs found in isolation, their joint occurrence was associated with greater clinical progression. [ABSTRACT FROM AUTHOR]

ObjectivesTemporal lobe epilepsy (TLE) is known to affect large-scale gray and white matter networks, and these network changes likely contribute to the verbal memory impairments observed in many patients. In this study, we investigate multimodal imaging patterns of brain alterations in TLE and evaluate the sensitivity of different imaging measures to verbal memory impairment.MethodsDiffusion tensor imaging (DTI), volumetric magnetic resonance imaging (vMRI), and resting-state functional MRI (rs-fMRI) were evaluated in 46 patients with TLE and 33 healthy controls to measure patterns of microstructural, structural, and functional alterations, respectively. These measurements were obtained within the white matter directly beneath neocortex (ie, superficial white matter [SWM]) for DTI and across neocortex for vMRI and rs-fMRI. The degree to which imaging alterations within left medial temporal lobe/posterior cingulate (LMT/PC) and left lateral temporal regions were associated with verbal memory performance was evaluated.ResultsPatients with left TLE and right TLE both demonstrated pronounced microstructural alterations (ie, decreased fractional anisotropy [FA] and increased mean diffusivity [MD]) spanning the entire frontal and temporolimbic SWM, which were highly lateralized to the ipsilateral hemisphere. Conversely, reductions in cortical thickness in vMRI and alterations in the magnitude of the rs-fMRI response were less pronounced and less lateralized than the microstructural changes. Both stepwise regression and mediation analyses further revealed that FA and MD within SWM in LMT/PC regions were the most robust predictors of verbal memory, and that these associations were independent of left hippocampal volume.SignificanceThese findings suggest that microstructural loss within the SWM is pronounced in patients with TLE, and injury to the SWM within the LMT/PC region plays a critical role in verbal memory impairment.

Parkinson's disease (PD) is a multifaceted neurodegenerative disorder accompanied by mild cognitive impairment (MCI) as a crucial nonmotor manifestation. Event-related oscillations (EROs) are suggested to reflect cognitive status associated with subcortical structures in neurodegenerative conditions. In this study, 36 individuals with PD-MCI and 32 PD-CN were compared with 60 healthy control (HC) participants using visual EROs by measures of event-related spectral perturbation and inter-trial coherence, along with subcortical gray matter volumes based on the FIRST algorithm. Cross-correlations among electrophysiological, neuropsychological, and structural parameters were investigated exploratively. Both PD-MCI and PD-CN patients had diminished delta and alpha phase-locking than HC, however, electrophysiological abnormalities were more pronounced in PD-MCI over frontal, central, parietal, and temporal locations in almost all frequency bands, accompanied by bilateral thalamus, hippocampus, and right putamen atrophy. PD-CN had lower hippocampal volumes than HC, without exhibiting any subcortical differences from PD-MCI. Lastly, EROs showed low-to-high correlations with structural and neuropsychological measures. These findings may highlight the complex interplay between electrophysiological, neuropsychological, and structural parameters in detected abnormalities of PD-CN and PD-MCI. [ABSTRACT FROM AUTHOR]

IntroductionWe examined associations between magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration with mild cognitive impairment (MCI) diagnosis at baseline and conversion from normal cognition to MCI at follow-up.MethodsFramingham Offspring participants underwent brain MRI and neuropsychological assessment at baseline (n=1049) and follow-up (n=561). Participants were classified at baseline and at follow-up as cognitively normal or MCI using sensitive neuropsychological criteria. White matter hyperintensity (WMH) volume, covert brain infarcts, hippocampal volume, and total cerebral brain volume were quantified.ResultsBaseline measures of WMH and hippocampal volume were associated with MCI status cross-sectionally and also with conversion from normal cognition to MCI at 6.5-year follow-up. Annualized change rates in total cerebral brain volume and hippocampal volume were associated with conversion from normal cognition to MCI to follow-up.DiscussionBaseline WMH and hippocampal volume are markers that are both associated with conversion from normal cognition to MCI, highlighting the role of both vascular lesions and neurodegeneration in MCI.

Background: Higher energetic costs for mobility are associated with declining gait speed, and slow gait is linked to cognitive decline and Alzheimer's disease. However, the physiological underpinnings of gait and brain health have not been well explored. We examined the associations of the energetic cost of walking with brain volume in cognitively unimpaired adults from the Baltimore Longitudinal Study of Aging.Methods: We used brain magnetic resonance imaging (MRI) data from 850 participants (mean baseline age 66.3 ± 14.5 years), of whom 451 had longitudinal MRI data (2.8 ± 1.0 MRI scans over 4.0 ± 2.0 years). The energetic cost of walking was assessed as the average energy expended (V̇O2) during 2.5 minutes of customary-paced overground walking. Multivariable linear mixed-effects models examined the associations between baseline energetic cost of walking and regional brain volumes adjusting for covariates.Results: At baseline, higher energetic cost of walking was cross-sectionally associated with lower gray and white matter volumes within the frontal, parietal, and temporal lobes, as well as hippocampal, total brain, and larger ventricular volumes (all false-discovery rate [FDR] p < .05). A baseline energetic cost of walking × time interaction demonstrated that participants with higher energetic cost of walking had faster annual decline in hippocampal volume (FDR p = .02) and accelerated annual increase in ventricular volumes (FDR p = .02).Conclusions: The energetic cost of walking is associated with gray and white matter volumes and subsequent hippocampal atrophy and ventricular enlargement. Collectively, these data suggest the energetic cost of walking may be an early marker of neurodegeneration that contributes to the gait brain connection. [ABSTRACT FROM AUTHOR]

Coffee is a highly popular beverage worldwide, containing caffeine which is a central nervous system stimulant. We examined whether habitual coffee consumption is associated with differences in brain volumes or the odds of dementia or stroke. We conducted prospective analyses of habitual coffee consumption on 398,646 UK Biobank participants (age 37–73 years), including 17,702 participants with MRI information. We examined the associations with brain volume using covariate adjusted linear regression, and with odds of dementia (4,333 incident cases) and stroke (6,181 incident cases) using logistic regression. There were inverse linear associations between habitual coffee consumption and total brain (fully adjusted β per cup −1.42, 95% CI −1.89, −0.94), grey matter (β −0.91, 95% CI −1.20, −0.62), white matter (β −0.51, 95% CI −0.83, −0.19) and hippocampal volumes (β −0.01, 95% CI −0.02, −0.003), but no evidence to support an association with white matter hyperintensity (WMH) volume (β −0.01, 95% CI −0.07, 0.05). The association between coffee consumption and dementia was non-linear (Pnon-linearity = 0.0001), with evidence for higher odds for non-coffee and decaffeinated coffee drinkers and those drinking >6 cups/day, compared to light coffee drinkers. After full covariate adjustment, consumption of >6 cups/day was associated with 53% higher odds of dementia compared to consumption of 1–2 cups/day (fully adjusted OR 1.53, 95% CI 1.28, 1.83), with less evidence for an association with stroke (OR 1.17, 95% CI 1.00, 1.37, p= 0.055). High coffee consumption was associated with smaller total brain volumes and increased odds of dementia. [ABSTRACT FROM AUTHOR]

Background and purpose: Diffusion tensor imaging (DTI) can detect microstructural changes of white matter in multiple sclerosis (MS) and might clarify mechanisms responsible for disability. Thus, we aimed to compare DTI metrics in relapsing-remitting MS patients (RRMS) with healthy controls (HCs), and explore the correlations between DTI metrics, total brain white matter (TBWM) and white matter lesion (WML) with clinical parameters compared to volumetric measures. Material and methods: 37 RRMS patients and 19 age/sex-matched HCs were included. All participants had clinical assessments, structural and diffusion scans on a 3T MRI. Volumetric and white matter DTI metrics; fractional anisotropy (FA), mean, radial and axial diffusivities (MD, RD and AD) were estimated and correlated with clinical parameters. The mean group differences were calculated using t-tests, and univariate correlations with Pearson correlation coefficients. Results: Compared to HCs, statistically significant increases in MD (+3.6%), RD (+4.8%), AD (+2.7%) and a decrease in FA (−4.3%) for TBWM in RRMS was observed (p <.01). MD and RD in TBWM and AD in WML correlated moderately with disability status. Volumetric segmentation indicated a decrease in the total brain volume, GM and WM(−5%) with a reciprocal increase in CSF(+26%) in RRMS(p <.01). Importantly, DTI parameters showed a medium correlation with cognitive domains in contrast to white matter-related volumetric measurements in RRMS(Pearson correlation, p <.05). Conclusions: Our study shows a correlation of DTI metrics with clinical symptoms of MS, in particular cognition. More generally, these findings indicated that DTI is a useful and unique technique for evaluating the clinical features of white matter disease and warrants further investigation into its clinical role. [ABSTRACT FROM AUTHOR]

Abstract Background Anti-NMDA receptor encephalitis is an immune-mediated disorder characterized by antibodies against the GluN1 subunit of the NMDA receptor that is increasingly recognized as a treatable cause of childhood epileptic encephalopathy. In adults, the disorder has been associated with reversible changes in brain volume over the course of treatment and recovery, but in children, little is known about its time course and associated imaging manifestations. Case presentation A previously healthy 20-month-old boy presented with first-time unprovoked seizures, dysautonomia, and dyskinesia. Paraneoplastic workup was negative, but CSF was positive for anti-NMDAR antibodies. The patient’s clinical condition waxed and waned over a 14-month course of treatment with first- and second-line immunotherapies (including steroids, IVIG, rituximab, and cyclophosphamide). Serial brain MRIs scans obtained at 5 time points spanning this same period showed no abnormal signal or enhancement but were remarkable for cycles of reversible regional cortical volume loss. All scans included identical 1-mm resolution 3D T1-weighted sequences obtained on the same 3 T scanner. Using a novel longitudinal processing stream in FreeSurfer6 (Reuter M, et. al, Neuroimage 61:1402–18, 2012) we quantified the rate of change in cortical volume at each vertex (% volume change per month) between consecutive scans and correlated these changes with the time course of the patient’s treatment and clinical response. We found regionally specific changes in cortical volume (up to 7% per month) that preferentially affected the frontal and occipital lobes and paralleled the patient’s clinical course, with clinical decline associated with volume loss and clinical improvement associated with volume gain. Conclusions Our results suggest that reversible cortical volume loss in anti-NMDA encephalitis has a regional specificity that mirrors many of the clinical symptoms associated with the disorder and tracks the dynamics of disease severity over time. This case illustrates how quantitative morphometric techniques can be applied to clinical imaging data to reveal patterns of brain change that may provide insight into disease pathophysiology. More widespread application of this approach might reveal regional and temporal patterns specific to different types of autoimmune encephalitis, providing a tool for diagnosis and a surrogate marker for monitoring treatment response.

Background: Cerebellar involvement is not comprehensively studied from an MRI point of view in multiple sclerosis (MS). We aimed to quantify cerebellar damage and identify predictors of physical disability and cognitive dysfunction in MS patients, and to characterize patients with cerebellar disability. Methods: In this prospective study, 164 (89 relapsing–remitting and 75 progressive) MS patients and 53 healthy controls were enrolled. Subjects underwent 3T MRI with sequences for assessing lesions and atrophy in cerebellum, supratentorial brain, brainstem and cervical cord. Cerebellar peduncle diffusion-tensor metrics were also derived. Random forest models identified MRI predictors of Expanded Disability Status Scale (EDSS) score and cognition z-score. Hierarchical clustering was applied on MRI metrics in patients with cerebellar disability. Results: In MS patients, predictors of higher EDSS score (out-of-bag-R2 = 0.83) were: lower cord grey matter (GM) and global areas, brain volume, GM volume (GMV), cortical GMV, cerebellum lobules I–IV and vermis GMV; and higher cord GM and brainstem lesion volume (LV). Predictors of lower cognition z-score (out-of-bag-R2 = 0.25) were: higher supratentorial and superior cerebellar peduncle LV; and lower brain, thalamus and basal ganglia volumes, GMV, cerebellum lobule VIIIb and Crus II GMV. In patients with cerebellar disability, we found three clusters with homogenous MRI metrics: patients with high brain lesion volumes (including cerebellar peduncles), those with marked cerebellum GM atrophy and patients with severe cord damage. Conclusions: Damage to cerebellum GM and connecting structures has a relevant role in explaining cognitive dysfunction and physical disability in MS. Data-driven MRI clustering might improve our knowledge of MRI-clinical correlations. [ABSTRACT FROM AUTHOR]

Background: The association between sleep and Alzheimer's disease (AD) biomarkers are well-established, but little is known about how they interact to change the course of AD.Objective: To determine the potential interaction between sleep disturbance and Aβ, tau, and APOE4 on brain atrophy and cognitive decline.Methods: Sample included 351 participants (mean age 72.01 ± 6.67, 50.4%female) who were followed for approximately 5 years as part of the Alzheimer's Disease Neuroimaging Initiative. Informant-reported sleep disturbance (IRSD) was measured using the Neuropsychiatric Inventory (NPI). Changes in magnetic resonance imaging (MRI)-measured AD signature brain regions and cognitive performance and IRSD's interaction with cerebrospinal fluid amyloid-β (Aβ42) and p-Tau depositions and APOE4 status were examined using the linear mixed models.Results: Baseline IRSD was not significantly associated with the rate of atrophy after adjusting for covariates (age, sex, education, total NPI severity score, and sleep medications). However, there was a significant interaction between IRSD and AD biomarkers on faster atrophy rates in multiple brain regions, including the cortical and middle temporal volumes. Post-hoc analyses indicated that Aβ and p-Tau/Aβ predicted a faster decline in these regions/domains in IRSD, compared with biomarker-negative individuals with IRSD (ps≤0.001). There was a significant IRSD*APOE4 interaction for brain atrophy rate (ps≤0.02) but not for cognition.Conclusion: IRSD may increase the future risk of AD by contributing to faster brain atrophy and cognitive decline when combined with the presence of AD biomarkers and APOE4. Early intervention for sleep disturbance could help reduce the risk of developing AD. [ABSTRACT FROM AUTHOR]

Background: The differentiation of behavioral variant frontotemporal dementia (bvFTD) from early-onset Alzheimer's disease (EOAD) by clinical criteria can be inaccurate. The volumetric quantification of clinically available magnetic resonance (MR) brain scans may facilitate early diagnosis of these neurodegenerative dementias.Objective: To determine if volumetric quantification of brain MR imaging can identify persons with bvFTD from EOAD.Methods: 3D T1 MR brain scans of 20 persons with bvFTD and 45 with EOAD were compared using Neuroreader to measure subcortical, and lobar volumes, and Volbrain for hippocampal subfields. Analyses included: 1) discriminant analysis with leave one out cross-validation; 2) input of predicted probabilities from this process into a receiver operator characteristic (ROC) analysis; and 3) Automated linear regression to identify predictive regions.Results: Both groups were comparable in age and sex with no statistically significant differences in symptom duration. bvFTD had lower volume percentiles in frontal lobes, thalamus, and putamen. EOAD had lower parietal lobe volumes. ROC analyses showed 99.3% accuracy with Neuroreader percentiles and 80.2% with subfields. The parietal lobe was the most predictive percentile. Although there were differences in hippocampal (particularly left CA2-CA3) subfields, it did not add to the discriminant analysis.Conclusion: Percentiles from an MR based volumetric quantification can help differentiate between bvFTD from EOAD in routine clinical care. Use of hippocampal subfield volumes does not enhance the diagnostic separation of these two early-onset dementias. [ABSTRACT FROM AUTHOR]

Background: In multiple sclerosis (MS), cortical, subcortical and infratentorial structural damage may have a differential contribution to clinical disability according to disease phases. Purpose: To determine the relative contributions of cortical, deep (D) grey matter (GM), cerebellar and cervical cord damage to MS disability milestones. Methods: Multi-centre 3T brain and cervical cord T2- and three-dimensional (3D) T1-weighted images were acquired from 198 MS patients (139 relapsing-remitting (RR) MS, 59 progressive (P) MS) and 67 healthy controls. Brain/cord lesion burden, cortical thickness (CTh), DGM and cerebellar volumetry and cord cross-sectional area (CSA) were quantified. Random forest analyses identified predictors of expanded disability status scale (EDSS) disability milestones (EDSS = 3.0, 4.0 and 6.0). Results: MS patients had widespread atrophy in all investigated compartments versus controls (p -range: ⩽0.001–0.05). Informative determinants of EDSS = 3.0 were cord CSA, brain lesion volume, frontal CTh and thalamic and cerebellar atrophy (out-of-bag (OOB) accuracy = 0.84, p -range: ⩽0.001–0.05). EDSS = 4.0 was mainly predicted by cerebellar and cord atrophy, frontal and sensorimotor CTh and cord lesion number (OOB accuracy = 0.84, p -range: ⩽0.001–0.04). Cervical cord CSA (p = 0.001) and cord lesion number (p = 0.003) predicted EDSS = 6.0 (OOB accuracy = 0.77). Conclusion: Brain lesion burden, cortical and thalamic atrophy were the main determinants of EDSS = 3.0 and 4.0, while cord damage played a major contribution to EDSS = 6.0. [ABSTRACT FROM AUTHOR]

Here a case is presented of a 51-year-old former high school football player with multiple concussions, including one episode with loss of consciousness. The patient experienced 6 years of cognitive and mood decline, and his wife corroborated increasing memory loss, attentional difficulties, and depressed mood without suicidal ideation. He had been unable to maintain full-time employment because of progressive decline. Based on his presentation, he had been previously diagnosed with attention deficit hyperactivity disorder and bipolar disorder, type II. Neuropsychological tests indicated domain-specific cognitive impairment, and longitudinal volumetric magnetic resonance imaging (MRI) of the brain showed progressive brainstem, diencephalic, and frontal lobe atrophy. This regional volume loss correlated with the increased signal seen on tau and amyloid imaging (FDDNP-PET scan) of a separate case of suspected chronic traumatic encephalopathy (CTE). Visual assessment of the MRI also showed evidence of old petechial hemorrhages in the frontal and temporal-parietal lobe white matter. This case raises the possibility of distinct quantitative and visual brain MRI findings in suspected CTE.

Background: Slowly expanding lesions (SELs) are MRI markers of chronic active lesions in multiple sclerosis (MS). T1-hypointense black holes, and reductions in magnetization transfer ratio (MTR) are pathologically correlated with myelin and axonal loss. While all associated with progressive MS, the relationship between these lesion’s metrics and clinical outcomes in relapse-onset MS has not been widely investigated. Objectives: To explore the relationship of SELs with T1-hypointense black holes, and longitudinal T1 intensity contrast ratio and MTR, their correlation to brain volume, and their contribution to MS disability in relapse-onset patients. Methods: 135 patients with relapsing-remitting MS (RRMS) were studied with clinical assessments and brain MRI (T2/FLAIR and T1-weighted scans at 1.5/3 T) at baseline and two subsequent follow-ups; a subset of 83 patients also had MTR acquisitions. Early-onset patients were defined when the baseline disease duration was ≤ 5 years (n = 85). SELs were identified using deformation field maps from the manually segmented baseline T2 lesions and differentiated from the non-SELs. Persisting black holes (PBHs) were defined as a subset of T2 lesions with a signal below a patient-specific grey matter T1 intensity in a semi-quantitative manner. SELs, PBH counts, and brain volume were computed, and their associations were assessed through Spearman and Pearson correlation. Clusters of patients according to low (up to 2), intermediate (3 to 10), or high (more than 10) SEL counts were determined with a Gaussian generalised mixture model. Mixed-effects and logistic regression models assessed volumes, T1 and MTR within SELs, and their correlation with Expanded Disability Status Scale (EDSS) and confirmed disability progression (CDP). Results: Mean age at study onset was 35.5 years (73% female), disease duration 5.5 years and mean time to last follow-up 6.5 years (range 1 to 12.5); median baseline EDSS 1.5 (range 0 to 5.5) and a mean EDSS change of 0.31 units at final follow-up. Among 4007 T2 lesions, 27% were classified as SELs and 10% as PBHs. Most patients (n = 65) belonged to the cluster with an intermediate SEL count (3 to 10 SELs). The percentage of PBHs was higher in SELs than non-SELs (up to 61% vs 44%, p

Introduction: The "A/T/N" (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimer's disease (AD) diagnosis and can encompass additional changes such as inflammation ("I"). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population., Methods: Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population ( N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years)., Results: Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex ( p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET ( p = 0.0007) and volume ( p = 0.0006). Lateral temporal FDG PET ( p = 0.006) and volume ( p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group., Discussion: Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age., Highlights: Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate., Competing Interests: Dawn Matthews is CEO of ADM Diagnostics, Inc., Scientific Advisor to the Alzheimer's Drug Development Foundation, and Co‐Chair of the Radiological Society of North America PET Tau Profile Working Group and PET Amyloid Profile Working Group, and reports that ADM Diagnostics received grant funding (2R44AG060861‐02) from the National Institutes of Aging, University of Arizona subaward (R01 AG063826), and University of Arizona subaward (R01 AG075122‐01 during the conduct of this work. She reports support for attending meetings and/or travel hotel and registration fees from Alzheimer's Drug Discovery Foundation, and stock or stock options in ADM Diagnostics and Abiant. Jefferson Kinney reports a grant from the National Institutes of General Medical Sciences (NIGMS) COBRE grant #P20GM109025, along with grants NIH NIA R01 AG074392‐01, NIH NIA P20 AG068053‐01, and R01AG062762‐01A1. Aaron Ritter reports payment from Corium Pharmaceuticals and Lundbeck/Otsuka for speaker board and advertisement board. He also has a leadership role in Alzheimer's Association Orange County Board and Alzheimer's Family Center. Ana Lukic, Randolph Andrews, and Lauren Koenig are employees of ADM Diagnostics, Inc. Carolyn Revta has nothing to disclose. Babak Tousi received a grant from the Alzheimer's Drug Discovery Foundation during the study, and has received consulting fees from Eisai, Biogen, Lilly, GE Healthcare, Kisbee, and Otsuka. He received honoraria from Eisai and Lily, support for attending meetings or travel from Novo Nordisk, and participated in a Data Safety Monitoring Board or Advisory Board at Eisai and Lilly. James Leverenz reports the grant P30AG072959, a Scientific Advisory leadership role for the Lewy Body Dementia Association, and receipt of ligands and software for imaging from GE Healthcare. Howard Fillit founding Executive Director and Chief Science Officer of the Alzheimer's Drug Discovery Foundation, which funded the rasagiline clinical trial, and has provided consulting support to the following pharmaceutical companies: Otsuka, LifeWorx, and Alector. He reports royalties from Icahn School of Medicine at Mount Sinai, and participation in a DSMB at Alector. He reports stock or stock options at CarePredict, and other non‐financial interests with the Lilly GERAS study and Roche Genentech Claims study. Howard Feldman reports a service agreement through UCSD with the Cleveland Clinic for data management and biostatistics during the conduct of the original study; grants from Annovis (QR Pharma), Vivoryon (Probiodrug), AC Immune, Biohaven Pharmaceuticals, and LuMind Foundation, and service agreements through UCSD for consulting with LuMind Foundation, Novo Nordisk, Arrowhead Pharmaceuticals, and Axon Neurosciences Roche/Genentech Pharmaceuticals. He reports support for attending meetings and/or travel for Novo Nordisk, and Royal Society of Canada; participation in DMC and DSMB for Tau Consortium, Rooche/Genentech Pharmaceuticals, and Janssen Research and Development; and philanthropic support for Alzheimer therapeutic research. Jeffrey Cummings reports grants from the National Institutes of General Medical Sciences (NIGMS) COBRE grant #P20GM109025; NINDS grant U01NS093334; NIA grant R01AG053798; NIA grant P30AG072959; NIA grant R35AG71476; NIA R25 AG083721‐01; Alzheimer's Disease Drug Discovery Foundation (ADDF); Ted and Maria Quirk Endowment; Joy Chambers‐Grundy Endowment during the conduct of the study. He reports consulting fees from Acadia, Actinogen, Acumen, AlphaCognition, ALZpath, Aprinoia, AriBio, Artery, Biogen, Biohaven, BioVie, BioXcel, Bristol‐Myers Squib, Cassava, Cerecin, Diadem, Eisai, GAP Foundation, GemVax, Janssen, Jocasta, Karuna, Lighthouse, Lilly, Lundbeck, LSP/eqt, Mangrove Therapeutics, Merck, NervGen, New Amsterdam, Novo Nordisk, Oligomerix, ONO, Optoceutics, Otsuka, Oxford Brain Diagnostics, Prothena, ReMYND, Roche, Sage Therapeutics, Signant Health, Simcere, sinaptica, Suven, TrueBinding, Vaxxinity, and Wren pharmaceutical, assessment, and investment companies. He reports participation in Data Safety Monitoring Board or Advisory Board for Acadia, Biogen, Genentech, Grifols, Janssen, Karuna, Otsuka, reMYND, Roche, Signant Health and stock or stock options for Artery, Vaxxinity, Behrens, Alzheon, MedAvante‐Prophase, and Acumen. Finally, outside the submitted work he is Chief Scientific Advisor to CNS Innovations, LLC and owns the copyright for the Neuropsychiatric Inventory (NPI). Kate Zhong and Erin Toledano Strom have nothing to disclose. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Volumetric magnetic resonance imaging (vMRI) has been widely studied in Huntington's disease (HD) and is commonly used to assess treatment effects on brain atrophy in interventional trials. Global and regional trajectories of brain atrophy in HD, with early involvement of striatal regions, are becoming increasingly understood. However, there remains heterogeneity in the methods used and a lack of widely-accessible multisite, longitudinal, normative datasets in HD. Consensus for standardized practices for data acquisition, analysis, sharing, and reporting will strengthen the interpretation of vMRI results and facilitate their adoption as part of a pathobiological disease staging system. The Huntington's Disease Regulatory Science Consortium (HD-RSC) currently comprises 37 member organizations and is dedicated to building a regulatory science strategy to expedite the approval of HD therapeutics. Here, we propose four recommendations to address vMRI standardization in HD research: (1) a checklist of standardized practices for the use of vMRI in clinical research and for reporting results; (2) targeted research projects to evaluate advanced vMRI methodologies in HD; (3) the definition of standard MRI-based anatomical boundaries for key brain structures in HD, plus the creation of a standard reference dataset to benchmark vMRI data analysis methods; and (4) broad access to raw images and derived data from both observational studies and interventional trials, coded to protect participant identity. In concert, these recommendations will enable a better understanding of disease progression and increase confidence in the use of vMRI for drug development. [ABSTRACT FROM AUTHOR]

To determine whether brain atrophy was present in patients with anti- N -methyl- d -aspartate receptor encephalitis (anti-NMDARE) using qualitative and quantitative analyses of brain magnetic resonance imaging (MRI) and to explore clinical differences in patients with anti-NMDARE with or without brain atrophy. A retrospective observational study encompassing the serologic, cerebrospinal fluid, and brain MRI data of 23 patients with anti-NMDARE was conducted. Median patient age was 14 years (interquartile range [IQR], 12 years). The cohort included 15 children (<18 years old) and 8 adults (≥18 years old). There were 6 male and 17 female patients. Imaging analysis involved 2 expert readers' observations of MRIs and automated volumetric quantification using NeuroQuant (CorTechs Labs, Inc.) software. Of 23 pediatric and adult patients, 11 patients had 14 brain MRIs that were quantitatively analyzed. Quantitative NeuroQuant volumetric analysis showed atrophy in 9 of 14 MRIs for 7 of 11 patients compared to age-controlled normative data. In these 9 MRIs, atrophy was present in the temporal lobes (n = 9), cerebral cortex (n = 3), and cerebellum (n = 3). Qualitative analysis of 59 MRIs (23 patients) revealed volume loss in 6 patients: 5 with global cerebral and temporal lobe volume loss and 1 with temporal lobe volume loss. No patient showed cerebellar volume loss on qualitative analysis. Mean length of stay in the intensive care unit was not significantly different for patients with or without quantitative volume loss (3.5 [5.2] vs 27.4 [23.4] days; p = 0.08). In this cohort of patients with anti-NMDARE, quantitative volumetric analysis showed brain atrophy, particularly affecting the temporal lobes, in 64% (7/11) of the patients. Qualitative analysis showed brain atrophy in 26% (6/23). These findings highlight the increased sensitivity of quantitative methods for volume loss detection. Larger studies are needed. • Brain atrophy was found in patients with anti-NMDA receptor encephalitis. • Review of diagnostic MRIs showed that 65% (15/23) of patients had unremarkable MRIs. • Qualitative volume loss in 26% (6/23) and signal abnormality in 30% (7/23) • Quantitative volume loss found in 64% (7/11) of patients • Regional atrophy on MRIs was not correlated with modified Rankin Scale scores. [ABSTRACT FROM AUTHOR]

Wilson disease (WD) can manifest with hepatic or neuropsychiatric symptoms. Our understanding of the in vivo brain changes in WD, particularly in the hepatic phenotype, is limited. Thirty subjects with WD and 30 age- and gender-matched controls participated. WD group underwent neuropsychiatric assessment. Unified WD Rating Scale neurological exam scores were used to determine neurological (WDN, score > 0) and hepatic-only (WDH, score 0) subgroups. All subjects underwent 3 Tesla anatomical and resting-state functional MRI. Diffusion tensor imaging (DTI) and susceptibility-weighted imaging (SWI) were performed only in the WD group. Volumetric, DTI, and functional connectivity analyses were performed to determine between-group differences. WDN and WDH groups were matched in demographic and psychiatric profiles. The entire WD group compared to controls showed significant thinning in the bilateral superior frontal cortex. The WDN group compared to control and WDH groups showed prominent structural brain changes including significant striatal and thalamic atrophy, more subcortical hypointense lesions on SWI, and diminished white matter integrity in the bilateral anterior corona radiata and corpus callosum. However, the WDH group also showed significant white matter volume loss compared to controls. The functional connectivity between the frontostriatal nodes was significantly reduced in the WDN group, whereas that of the hippocampus was significantly increased in the WDH group compared to controls. In summary, structural and functional brain changes were present even in neurologically non-manifesting WD patients in this cross-sectional study. Longitudinal brain MRI scans may be useful as biomarkers for prognostication and optimization of treatment strategies in WD. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder that is caused by expansion of a CAG-repeat tract in the huntingtin gene and characterized by motor impairment, cognitive decline, and neuropsychiatric disturbances. Neuropathological studies show that disease progression follows a characteristic pattern of brain atrophy, beginning in the basal ganglia structures. The HD Regulatory Science Consortium (HD-RSC) brings together diverse stakeholders in the HD community—biopharmaceutical industry, academia, nonprofit, and patient advocacy organizations—to define and address regulatory needs to accelerate HD therapeutic development. Here, the Biomarker Working Group of the HD-RSC summarizes the cross-sectional evidence indicating that regional brain volumes, as measured by volumetric magnetic resonance imaging, are reduced in HD and are correlated with disease characteristics. We also evaluate the relationship between imaging measures and clinical change, their longitudinal change characteristics, and within-individual longitudinal associations of imaging with disease progression. This analysis will be valuable in assessing pharmacodynamics in clinical trials and supporting clinical outcome assessments to evaluate treatment effects on neurodegeneration. [ABSTRACT FROM AUTHOR]

Introduction: Impaired olfaction and reduced cholinergic nucleus 4 (Ch4) volume both predict greater cognitive decline in Parkinson's disease (PD). We examined the relationship between olfaction, longitudinal change in cholinergic basal forebrain nuclei and their target regions, and cognition in early PD.Methods: We analyzed a cohort of 97 PD participants from the Parkinson's Progression Markers Initiative with brain MRIs at baseline, 1 year, 2 years, and 4 years. Using probabilistic maps, regional grey matter density (GMD) was calculated for Ch4, cholinergic nuclei 1, 2, and 3 (Ch123), and their target regions.Results: Baseline University of Pennsylvania Smell Identification Test score correlated with change in GMD of all regions of interest (all p < 0.05). Rate of change of Ch4 GMD was correlated with rate of change of Ch123 (p = 0.034), cortex (p = 0.001), and amygdala GMD (p < 0.001), but not hippocampus GMD (p = 0.38). Rate of change of Ch123 GMD was correlated with rate of change of cortex (p = 0.001) and hippocampus (p < 0.001), but not amygdala GMD (p = 0.133). In a linear regression model including change in GMD of all regions of interest and age as predictors, change in cortex GMD (βˆslope= 38.2; 95 % CI: [0.47, 75.9]) and change in hippocampus GMD (βˆslope= 24.8; 95 % CI: [0.80, 48.8]) were significant predictors of Montreal Cognitive Assessment score change over time.Conclusion: Impaired olfaction is associated with degeneration of the cholinergic basal forebrain and bilateral cortex, amygdala, and hippocampus in PD. The relationship between impaired olfaction and cognitive decline may be mediated by greater atrophy of the cortex and hippocampus. [ABSTRACT FROM AUTHOR]

Volumetric magnetic resonance imaging (vMRI) has been widely studied in Huntington's disease (HD) and is commonly used to assess treatment effects on brain atrophy in interventional trials. Global and regional trajectories of brain atrophy in HD, with early involvement of striatal regions, are becoming increasingly understood. However, there remains heterogeneity in the methods used and a lack of widely-accessible multisite, longitudinal, normative datasets in HD. Consensus for standardized practices for data acquisition, analysis, sharing, and reporting will strengthen the interpretation of vMRI results and facilitate their adoption as part of a pathobiological disease staging system. The Huntington's Disease Regulatory Science Consortium (HD-RSC) currently comprises 37 member organizations and is dedicated to building a regulatory science strategy to expedite the approval of HD therapeutics. Here, we propose four recommendations to address vMRI standardization in HD research: (1) a checklist of standardized practices for the use of vMRI in clinical research and for reporting results; (2) targeted research projects to evaluate advanced vMRI methodologies in HD; (3) the definition of standard MRI-based anatomical boundaries for key brain structures in HD, plus the creation of a standard reference dataset to benchmark vMRI data analysis methods; and (4) broad access to raw images and derived data from both observational studies and interventional trials, coded to protect participant identity. In concert, these recommendations will enable a better understanding of disease progression and increase confidence in the use of vMRI for drug development.

Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder that is caused by expansion of a CAG-repeat tract in the huntingtin gene and characterized by motor impairment, cognitive decline, and neuropsychiatric disturbances. Neuropathological studies show that disease progression follows a characteristic pattern of brain atrophy, beginning in the basal ganglia structures. The HD Regulatory Science Consortium (HD-RSC) brings together diverse stakeholders in the HD community—biopharmaceutical industry, academia, nonprofit, and patient advocacy organizations—to define and address regulatory needs to accelerate HD therapeutic development. Here, the Biomarker Working Group of the HD-RSC summarizes the cross-sectional evidence indicating that regional brain volumes, as measured by volumetric magnetic resonance imaging, are reduced in HD and are correlated with disease characteristics. We also evaluate the relationship between imaging measures and clinical change, their longitudinal change characteristics, and within-individual longitudinal associations of imaging with disease progression. This analysis will be valuable in assessing pharmacodynamics in clinical trials and supporting clinical outcome assessments to evaluate treatment effects on neurodegeneration.

Neurofilament light chain (NfL) is a marker of brain atrophy and predictor of disease progression in rare diseases such as Huntington Disease, but also in more common neurological disorders such as Alzheimer's disease. The aim of this study was to measure NfL longitudinally in autosomal dominant spinocerebellar ataxias (SCAs) and establish correlation with clinical and imaging parameters. We enrolled 62 pathological expansions carriers (17 SCA1, 13 SCA2, 19 SCA3, and 13 SCA7) and 19 age-matched controls in a prospective biomarker study between 2011 and 2015 and followed for 24 months at the Paris Brain Institute. We performed neurological examination, brain 3 T MRI and plasma NfL measurements using an ultrasensitive single-molecule array at baseline and at the two-year follow-up visit. We evaluated NfL correlations with ages, CAG repeat sizes, clinical scores and volumetric brain MRIs. NfL levels were significantly higher in SCAs than controls at both time points (p

Background: The determination of brain volumes using visual ratings is associated with an inherently low accuracy for the diagnosis of Alzheimer's disease (AD). A support-vector machine (SVM) is one of the machine learning techniques, which may be utilized as a classifier for various classification problems. This study exploratorily investigated the accuracy of SVM classification models for AD subjects using brain volume and various clinical data as features.Methods: The study was designed as a retrospective chart review. A total of 201 eligible subjects were recruited from the Memory Clinic at Siriraj Hospital, Thailand. Eighteen cases were excluded due to incomplete MRI data. Subjects were randomly assigned to a training group (AD = 46, normal = 46) and testing group (AD = 45, normal = 46) for SVM modeling and validation, respectively. The results in terms of accuracy and a receiver operating characteristic curve analysis are reported.Results: The highest accuracy for brain volumetry (62.64%) was found using the hippocampus as a single feature. A combination of clinical parameters as features provided accuracy ranging between 83 and 90%. However, a combination of brain volumetry and clinical parameters as features to the SVM models did not improve the accuracy of the result.Conclusions: In our study, the use of brain volumetry as SVM features provided low classification accuracy with the highest accuracy of 62.64% using the hippocampus volume alone. In contrast, the use of clinical parameters [Thai mental state examination score, controlled oral word association tests (animals; and letters K, S, and P), learning memory, clock-drawing test, and construction-praxis] as features for SVM models provided good accuracy between 83 and 90%.

Background: The determination of brain volumes using visual ratings is associated with an inherently low accuracy for the diagnosis of Alzheimer's disease (AD). A support-vector machine (SVM) is one of the machine learning techniques, which may be utilized as a classifier for various classification problems. This study exploratorily investigated the accuracy of SVM classification models for AD subjects using brain volume and various clinical data as features. Methods: The study was designed as a retrospective chart review. A total of 201 eligible subjects were recruited from the Memory Clinic at Siriraj Hospital, Thailand. Eighteen cases were excluded due to incomplete MRI data. Subjects were randomly assigned to a training group (AD = 46, normal = 46) and testing group (AD = 45, normal = 46) for SVM modeling and validation, respectively. The results in terms of accuracy and a receiver operating characteristic curve analysis are reported. Results: The highest accuracy for brain volumetry (62.64%) was found using the hippocampus as a single feature. A combination of clinical parameters as features provided accuracy ranging between 83 and 90%. However, a combination of brain volumetry and clinical parameters as features to the SVM models did not improve the accuracy of the result. Conclusions: In our study, the use of brain volumetry as SVM features provided low classification accuracy with the highest accuracy of 62.64% using the hippocampus volume alone. In contrast, the use of clinical parameters [Thai mental state examination score, controlled oral word association tests (animals; and letters K, S, and P), learning memory, clock-drawing test, and construction-praxis] as features for SVM models provided good accuracy between 83 and 90%. [ABSTRACT FROM AUTHOR]

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease characterized by a late clinical onset of psychiatric, cognitive, and motor symptoms. Transcriptional dysregulation is an early and central disease mechanism which is accompanied by epigenetic alterations in HD. Previous studies demonstrated that targeting transcriptional changes by inhibition of histone deacetylases (HDACs), especially the class I HDACs, provides therapeutic effects. Yet, their exact mechanisms of action and the features of HD pathology, on which these inhibitors act remain to be elucidated. Here, using transcriptional profiling, we found that selective inhibition of HDAC1 and HDAC3 by RGFP109 alleviated transcriptional dysregulation of a number of genes, including the transcription factor genes Neurod2 and Nr4a2, and gene sets and programs, especially those that are associated to insulin-like growth factor pathway, in the striatum of R6/1 mice. RGFP109 treatment led to a modest improvement of the motor skill learning and coordination deficit on the RotaRod test, while it did not alter the locomotor and anxiety-like phenotypes in R6/1 animals. We also found, by volumetric MRI, a widespread brain atrophy in the R6/1 mice at the symptomatic disease stage, on which RGFP109 showed no significant effects. Collectively, our combined work suggests that specific HDAC1 and HDAC3 inhibition may offer benefits for alleviating the motor phenotypic deficits and transcriptional dysregulation in HD.

Abstract Introduction Hippocampal dentate gyrus related to pattern separation has attracted attention as an area for neurogenesis. However, the associations between the pattern separation and the volumes of hippocampal subfields in humans remain unknown. Methods 58 young adults were examined the memory task (pattern separation, pattern completion) and the hippocampal volumes. Subjects were asked to determine whether the visual image is a new stimulus, or a similar but different stimulus (pattern separation), or the same stimulus (pattern completion), compared to preceding stimuli, and response time and correct response were measured. The volumes of the whole brain, hippocampus 6 subfields and perihippocampus 5 subfields, were measured using FreeSurfer 6.0. Results Negative associations between the pattern separation task and the volumes of whole brain areas were found in bilateral cerebellar cortex, fourth ventricle, left hippocampus, left thalamus, left ventral diencephalon, and brainstem. Simple linear regression analysis revealed a significant association with the left hippocampal‐amygdaloid transition area only, while no significant associations were found in any of the subfield volumes when adjusted with covariates. Conclusions The principle “bigger is better”—an idea that the larger the volume the better the function—could not be applied to the relation between the pattern separation ability and the dentate gyrus.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by a late clinical onset of psychiatric, cognitive, and motor symptoms. Transcriptional dysregulation is an early and central disease mechanism which is accompanied by epigenetic alterations in HD. Previous studies demonstrated that targeting transcriptional changes by inhibition of histone deacetylases (HDACs), especially the class I HDACs, provides therapeutic effects. Yet, their exact mechanisms of action and the features of HD pathology, on which these inhibitors act remain to be elucidated. Here, using transcriptional profiling, we found that selective inhibition of HDAC1 and HDAC3 by RGFP109 alleviated transcriptional dysregulation of a number of genes, including the transcription factor genes Neurod2 and Nr4a2 , and gene sets and programs, especially those that are associated to insulin-like growth factor pathway, in the striatum of R6/1 mice. RGFP109 treatment led to a modest improvement of the motor skill learning and coordination deficit on the RotaRod test, while it did not alter the locomotor and anxiety-like phenotypes in R6/1 animals. We also found, by volumetric MRI, a widespread brain atrophy in the R6/1 mice at the symptomatic disease stage, on which RGFP109 showed no significant effects. Collectively, our combined work suggests that specific HDAC1 and HDAC3 inhibition may offer benefits for alleviating the motor phenotypic deficits and transcriptional dysregulation in HD. [ABSTRACT FROM AUTHOR]

Introduction: Hippocampal dentate gyrus related to pattern separation has attracted attention as an area for neurogenesis. However, the associations between the pattern separation and the volumes of hippocampal subfields in humans remain unknown. Methods: 58 young adults were examined the memory task (pattern separation, pattern completion) and the hippocampal volumes. Subjects were asked to determine whether the visual image is a new stimulus, or a similar but different stimulus (pattern separation), or the same stimulus (pattern completion), compared to preceding stimuli, and response time and correct response were measured. The volumes of the whole brain, hippocampus 6 subfields and perihippocampus 5 subfields, were measured using FreeSurfer 6.0. Results: Negative associations between the pattern separation task and the volumes of whole brain areas were found in bilateral cerebellar cortex, fourth ventricle, left hippocampus, left thalamus, left ventral diencephalon, and brainstem. Simple linear regression analysis revealed a significant association with the left hippocampal‐amygdaloid transition area only, while no significant associations were found in any of the subfield volumes when adjusted with covariates. Conclusions: The principle "bigger is better"—an idea that the larger the volume the better the function—could not be applied to the relation between the pattern separation ability and the dentate gyrus. [ABSTRACT FROM AUTHOR]

ObjectivesTo investigate the bilateral hippocampal subfield volumetric differences in four types of mild dementia, namely typical Alzheimer’s disease (tAD), dementia with Lewy bodies (DLB), semantic dementia (SD), and posterior cortical atrophy (PCA), to assist differential diagnosis.MethodsOne hundred three participants, including 22 tAD, 34 SD (17 left SD and 17 right SD), 15 DLB, 12 PCA patients, and 20 normal controls (NC), were recruited. All subjects received standard neuropsychological assessments and magnetic resonance imaging (MRI). The hippocampal subfields were automatically segmented via Freesurfer. The study compared the volumetric differences and used the receiver operating characteristic (ROC) curves to estimate the efficacy of each hippocampal subfield to distinguish between groups. Spearman correlation analysis was used to investigate the relationship between memory recall scores and hippocampal subfield volumes.ResultsThe hippocampal subfield atrophy varied in different groups: tAD, SD, and PCA patients had subregional atrophy in bilateral hippocampi compared to NC, and DLB patients showed preserved volumes; left SD patients suffered the most severe atrophy of the left hippocampus, and right SD patients were atrophied mostly in the right hippocampus. There was no significant difference in the volume of hippocampal subregions between tAD and PCA subjects, but the former tended to be atrophied more asymmetrically. ROC analysis showed that, for discrimination, the areas under the curve (AUC) of some subfields were larger than the total hippocampus, but none observed significant difference. In addition, immediate recall scores were correlated to left CA1, CA2/3, CA4/DG, subiculum, and presubiculum (p < 0.05), and delayed recall scores were strongly related to bilateral CA2/3, CA4/DG, subiculum, and presubiculum (r = 0.38–0.52, p < 0.05).ConclusionDifferential atrophy patterns in the bilateral hippocampal subfield volumes could serve the differential diagnosis in patients with different causes of mild dementia: left CA1 for tAD; left presubiculum for LSD; right CA4/DG, right presubiculum, and right subiculum for RSD; CA4/DG and right CA2/3 for DLB; right CA2/3 and right CA4/DG for PCA. Additionally, several hippocampal subfield volumes were significantly associated with memory scores, further highlighting the essential role of the hippocampus in memory decline.

Objective: To quantify neurodegenerative changes along the cervical spinal cord rostral to a spinal cord injury (SCI) by means of quantitative MRI (qMRI) and to determine its relationship with clinical impairment. Methods: Thirty chronic SCI patients (15 tetraplegics and 15 paraplegics) and 23 healthy controls underwent a high-resolution T1-weighted and myelin-sensitive magnetization transfer (MT) MRI. We assessed macro- and microstructural changes along the cervical cord from levels C1 to C4, calculating cross-sectional spinal cord area, its anterior-posterior and left-right width and myelin content (i.e. MT). Regression analysis determined associations between qMRI parameters and clinical impairment. Results: In SCI patients, cord area decreased by 2.67 mm2 (p = 0.004) and left-right width decreased by 0.35 mm (p = 0.002) per cervical cord level in the caudal direction when compared to the healthy controls. This gradient of neurodegeneration was greater in tetraplegic than paraplegics in the cross-sectional cervical cord area (by 3.28 mm2, p = 0.011), left-right width (by 0.36 mm, p = 0.03), and mean cord MT (by 0.13%, p = 0.04), but independant of lesion severity (p > 0.05). Higher lesion level was associated with greater magnitudes of neurodegeneration. Greater loss in myelin content in the dorsal columns and spinothalamic tract was associated with worse light touch (p = 0.016) and pin prick score (p = 0.024), respectively. Conclusions: A gradient of neurodegeneration is evident in the cervical cord remote from a SCI. Tract-specific associations with appropriate clinical outcomes highlight that remote neurodegenerative changes are clinically eloquent. Monitoring the neurodegenerative gradient could be used to track treatment effects of regenerative and neuroprotective agents, both in trials targeting cervical and thoracic SCI patients.

Abstract Background With upcoming therapeutic interventions for patients with primary progressive aphasia (PPA), instruments for the follow-up of patients are needed to describe disease progression and to evaluate potential therapeutic effects. So far, volumetric brain changes have been proposed as clinical endpoints in the literature, but cognitive scores are still lacking. This study followed disease progression predominantly in language-based performance within 1 year and defined a PPA sum score which can be used in therapeutic interventions. Methods We assessed 28 patients with nonfluent variant PPA, 17 with semantic variant PPA, 13 with logopenic variant PPA, and 28 healthy controls in detail for 1 year. The most informative neuropsychological assessments were combined to a sum score, and associations between brain atrophy were investigated followed by a sample size calculation for clinical trials. Results Significant absolute changes up to 20% in cognitive tests were found after 1 year. Semantic and phonemic word fluency, Boston Naming Test, Digit Span, Token Test, AAT Written language, and Cookie Test were identified as the best markers for disease progression. These tasks provide the basis of a new PPA sum score. Assuming a therapeutic effect of 50% reduction in cognitive decline for sample size calculations, a number of 56 cases is needed to find a significant treatment effect. Correlations between cognitive decline and atrophy showed a correlation up to r = 0.7 between the sum score and frontal structures, namely the superior and inferior frontal gyrus, as well as with left-sided subcortical structures. Conclusion Our findings support the high performance of the proposed sum score in the follow-up of PPA and recommend it as an outcome measure in intervention studies.

There is substantial biological heterogeneity among older adults with amnestic mild cognitive impairment (aMCI). We hypothesized that this heterogeneity can be detected solely based on volumetric MRI measures, which potentially have clinical implications and can improve our ability to predict clinical outcomes. We used latent class analysis (LCA) to identify subgroups among persons with aMCI (n = 696) enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI), based on baseline volumetric MRI measures. We used volumetric measures of 10 different brain regions. The subgroups were validated with respect to demographics, cognitive performance, and other AD biomarkers. The subgroups were compared with each other and with normal and Alzheimer's disease (AD) groups with respect to baseline cognitive function and longitudinal rate of conversion. Four aMCI subgroups emerged with distinct MRI patterns: The first subgroup (n = 404), most similar to normal controls in volumetric characteristics and cognitive function, had the lowest incidence of AD. The second subgroup (n = 230) had the most similar MRI profile to early AD, along with poor performance in memory and executive function domains. The third subgroup (n = 36) had the highest global atrophy, very small hippocampus and worst overall cognitive performance. The fourth subgroup (n = 26) had the least amount of atrophy, however still had poor cognitive function specifically in in the executive function domain. Individuals with aMCI who were clinically categorized within one group other showed substantial heterogeneity based on MRI volumetric measures. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the bilateral hippocampal subfield volumetric differences in four types of mild dementia, namely typical Alzheimer's disease (tAD), dementia with Lewy bodies (DLB), semantic dementia (SD), and posterior cortical atrophy (PCA), to assist differential diagnosis. Methods: One hundred three participants, including 22 tAD, 34 SD (17 left SD and 17 right SD), 15 DLB, 12 PCA patients, and 20 normal controls (NC), were recruited. All subjects received standard neuropsychological assessments and magnetic resonance imaging (MRI). The hippocampal subfields were automatically segmented via Freesurfer. The study compared the volumetric differences and used the receiver operating characteristic (ROC) curves to estimate the efficacy of each hippocampal subfield to distinguish between groups. Spearman correlation analysis was used to investigate the relationship between memory recall scores and hippocampal subfield volumes. Results: The hippocampal subfield atrophy varied in different groups: tAD, SD, and PCA patients had subregional atrophy in bilateral hippocampi compared to NC, and DLB patients showed preserved volumes; left SD patients suffered the most severe atrophy of the left hippocampus, and right SD patients were atrophied mostly in the right hippocampus. There was no significant difference in the volume of hippocampal subregions between tAD and PCA subjects, but the former tended to be atrophied more asymmetrically. ROC analysis showed that, for discrimination, the areas under the curve (AUC) of some subfields were larger than the total hippocampus, but none observed significant difference. In addition, immediate recall scores were correlated to left CA1, CA2/3, CA4/DG, subiculum, and presubiculum (p < 0.05), and delayed recall scores were strongly related to bilateral CA2/3, CA4/DG, subiculum, and presubiculum (r = 0.38–0.52, p < 0.05). Conclusion: Differential atrophy patterns in the bilateral hippocampal subfield volumes could serve the differential diagnosis in patients with different causes of mild dementia: left CA1 for tAD; left presubiculum for LSD; right CA4/DG, right presubiculum, and right subiculum for RSD; CA4/DG and right CA2/3 for DLB; right CA2/3 and right CA4/DG for PCA. Additionally, several hippocampal subfield volumes were significantly associated with memory scores, further highlighting the essential role of the hippocampus in memory decline. [ABSTRACT FROM AUTHOR]

Background: Volume loss in the deep gray matter (DGM) has been reported in patients with multiple sclerosis (MS) already at early stages of the disease and is thought to progress throughout the disease course. Objective: To investigate the impact and predictive value of volume loss in DGM and thalamic subnuclei on disability worsening in patients MS over a 6-year follow-up period. Methods: Hundred and seventy-nine patients with RRMS (132 women; median Expanded Disability Status Scale, EDSS: 2.5) and 50 with SPMS (27 women; median EDSS: 4.5) were included in the study. Patients underwent annual EDSS assessments and annual MRI at 1.5 T. DGM/thalamic subnuclei volumes were identified on high-resolution T1-weighted. A hierarchical linear mixed model for each anatomical DGM area and each thalamic subnucleus was performed to investigate the associations with disability scores. Cox regression was used to estimate the predictive properties of volume loss in DGM and thalamic subnuclei on disease worsening. Results: In the whole sample and in RRMS, volumes of the thalamus and the striatum were associated with the EDSS; however, only thalamic volume loss was associated with EDSS change at follow-up. Regarding thalamic subnuclei, volume loss in the anterior nucleus, the pulvinar and the ventral anterior nucleus was associated with EDSS change in the whole cohort. A trend was observed for the ventral lateral nucleus. Volume loss in the anterior and ventral anterior nuclei was associated with EDSS change over time in patients with RRMS. Moreover, MS phenotype and annual rates of volume loss in the thalamus and ventral lateral nucleus were predictive of disability worsening. Conclusion: These results highlight the relevance of volume loss in the thalamus as a key metric for predicting disability worsening as assessed by EDSS (in RRMS). Moreover, the volume loss in specific nuclei such as the ventral lateral nucleus seems to play a role in disability worsening. [ABSTRACT FROM AUTHOR]