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Background and objectivesAmyloid pathology, vascular disease pathology, and pathologies affecting the medial temporal lobe are associated with cognitive trajectories in older adults. However, only limited evidence exists on how these pathologies influence cognition in the oldest old. We evaluated whether amyloid burden, white matter hyperintensity (WMH) volume, and hippocampal volume (HV) are associated with cognitive level and decline in the oldest old.MethodsThis was a longitudinal, observational community-based cohort study. We included participants with 18F-florbetapir PET and MRI data from the 90+ Study. Amyloid load was measured using the standardized uptake value ratio in the precuneus/posterior cingulate with eroded white matter mask as reference. WMH volume was log-transformed. All imaging measures were standardized using sample means and SDs. HV and log-WMH volume were normalized by total intracranial volume using the residual approach. Global cognitive performance was measured by the Mini-Mental State Examination (MMSE) and modified MMSE (3MS) tests, repeated every 6 months. We used linear mixed-effects models with random intercepts; random slopes; and interaction between time, time squared, and imaging variables to estimate the associations of imaging variables with cognitive level and cognitive decline. Models were adjusted for demographics, APOE genotype, and health behaviors.ResultsThe sample included 192 participants. The mean age was 92.9 years, 125 (65.1%) were female, 71 (37.0%) achieved a degree beyond college, and the median follow-up time was 3.0 years. A higher amyloid load was associated with a lower cognitive level (βMMSE = -0.82, 95% CI -1.17 to -0.46; β3MS = -2.77, 95% CI -3.69 to -1.84). A 1-SD decrease in HV was associated with a 0.70-point decrease in the MMSE score (95% CI -1.14 to -0.27) and a 2.27-point decrease in the 3MS score (95% CI -3.40 to -1.14). Clear nonlinear cognitive trajectories were detected. A higher amyloid burden and smaller HV were associated with faster cognitive decline. WMH volume was not significantly associated with cognitive level or decline.DiscussionAmyloid burden and hippocampal atrophy are associated with both cognitive level and cognitive decline in the oldest old. Our findings shed light on how different pathologies contributed to driving cognitive function in the oldest old.

Cyclic fluctuations in hypothalamic-pituitary-gonadal axis (HPG-axis) hormones exert powerful behavioral, structural, and functional effects through actions on the mammalian central nervous system. Yet, very little is known about how these fluctuations alter the structural nodes and information highways of the human brain. In a study of 30 naturally cycling women, we employed multidimensional diffusion and T1-weighted imaging during three estimated menstrual cycle phases (menses, ovulation, and mid-luteal) to investigate whether HPG-axis hormone concentrations co-fluctuate with alterations in white matter (WM) microstructure, cortical thickness (CT), and brain volume. Across the whole brain, 17β-estradiol and luteinizing hormone (LH) concentrations were directly proportional to diffusion anisotropy (μFA; 17β-estradiol: β1 = 0.145, highest density interval (HDI) = [0.211, 0.4]; LH: β1 = 0.111, HDI = [0.157, 0.364]), while follicle-stimulating hormone (FSH) was directly proportional to CT (β1 = 0 .162, HDI = [0.115, 0.678]). Within several individual regions, FSH and progesterone demonstrated opposing relationships with mean diffusivity (Diso) and CT. These regions mainly reside within the temporal and occipital lobes, with functional implications for the limbic and visual systems. Finally, progesterone was associated with increased tissue (β1 = 0.66, HDI = [0.607, 15.845]) and decreased cerebrospinal fluid (CSF; β1 = -0.749, HDI = [-11.604, -0.903]) volumes, with total brain volume remaining unchanged. These results are the first to report simultaneous brain-wide changes in human WM microstructure and CT coinciding with menstrual cycle-driven hormone rhythms. Effects were observed in both classically known HPG-axis receptor-dense regions (medial temporal lobe, prefrontal cortex) and in other regions located across frontal, occipital, temporal, and parietal lobes. Our results suggest that HPG-axis hormone fluctuations may have significant structural impacts across the entire brain.

BACKGROUND: Pathologic perivascular spaces (PVS), the fluid-filled compartments surrounding brain vasculature, may underlie cognitive decline in Parkinsons disease (PD). However, whether this impacts specific cognitive domains has not been investigated. OBJECTIVES: This study examined the relationship of PVS volume at baseline with domain-specific and global cognitive change over 2 years in PD individuals. METHODS: A total of 39 individuals with PD underwent 3T T1w magnetic resonance imaging to determine PVS volume fraction (PVS volume normalized to total regional volume) within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, and superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of cognitive domains and global cognitive function at baseline and after 2 years. RESULTS: Higher basal ganglia PVS at baseline was associated with greater decline in attention, executive function, and global cognition scores. CONCLUSIONS: While previous reports have associated elevated PVS volume in the basal ganglia with decline in global cognition in PD, our findings show such decline may affect the attention and executive function domains.

IntroductionWhite matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-β1-42 (Aβ42)-positive status.MethodsIndividual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume.ResultsVRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p

Abstract This study compared findings from whole-brain diffusion tensor imaging (DTI) and volumetric magnetic resonance imaging (MRI) among 90 Active Duty Service Members with chronic mild traumatic brain injury (TBI; n = 52), chronic moderate-to-severe TBI (n = 17), and TBI-negative controls (n = 21). Data were collected on a Philips Ingenia 3T MRI with DTI in 32 directions. Results demonstrated that history of TBI was associated with differences in white matter microstructure, white matter volume, and cortical thickness in both mild TBI and moderate-to-severe TBI groups relative to controls. However, the presence, pattern, and distribution of these findings varied substantially depending on the injury severity. Spatially-defined forms of DTI fractional anisotropy (FA) analyses identified altered white matter organization within the chronic moderate-to-severe TBI group, but they did not provide clear evidence of abnormalities within the chronic mild TBI group. In contrast, DTI FA pothole analyses identified widely distributed areas of decreased FA throughout the white matter in both the chronic mild TBI and chronic moderate-to-severe TBI groups. Additionally, decreased white matter volume was found in several brain regions for the chronic moderate-to-severe TBI group compared with the other groups. Greater number of DTI FA potholes and reduced cortical thickness were also related to greater severity of self-reported symptoms. In sum, this study expands upon a growing body of literature using advanced imaging techniques to identify potential effects of brain injury in military Service Members. These findings may differ from work in other TBI populations due to varying mechanisms and frequency of injury, as well as a potentially higher level of functioning in the current sample related to the ability to maintain continued Active Duty status after injury. In conclusion, this study provides DTI and volumetric MRI findings across the spectrum of TBI severity. These results provide support for the use of DTI and volumetric MRI to identify differences in white matter microstructure and volume related to TBI. In particular, DTI FA pothole analysis may provide greater sensitivity for detecting subtle forms of white matter injury than conventional DTI FA analyses.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR

The short association fibers or U-fibers travel in the superficial white matter (SWM) beneath the cortical layer. While the U-fibers play a crucial role in various brain disorders, there is a lack of effective tools to reconstruct their highly curved trajectory from diffusion MRI (dMRI). In this work, we propose a novel surface-based framework for the probabilistic tracking of fibers on the triangular mesh representation of the SWM. By deriving a closed-form solution to transform the spherical harmonics (SPHARM) coefficients of 3D fiber orientation distributions (FODs) to local coordinate systems on each triangle, we develop a novel approach to project the FODs onto the tangent space of the SWM. After that, we utilize parallel transport to realize the intrinsic propagation of streamlines on SWM following probabilistically sampled fiber directions. Our intrinsic and surface-based method eliminates the need to perform the necessary but challenging sharp turns in 3D compared with conventional volume-based tractography methods. Using data from the Human Connectome Project (HCP), we performed quantitative comparisons to demonstrate the proposed algorithm can more effectively reconstruct the U-fibers connecting the precentral and postcentral gyrus than previous methods. Quantitative validations were then performed on post-mortem MRIs to show the reconstructed U-fibers from our method more faithfully follow the SWM than volume-based tractography. Finally, we applied our algorithm to study the parietal U-fiber connectivity changes in autosomal dominant Alzheimers disease (ADAD) patients and successfully detected significant associations between U-fiber connectivity and disease severity.

BACKGROUND: Microvascular dysfunction is involved in the development of various cerebral disorders. It may contribute to these disorders by disrupting white matter tracts and altering brain connectivity, but evidence is scarce. We investigated the association between multiple biomarkers of microvascular function and whole-brain white matter connectivity. METHODS AND RESULTS: Cross-sectional data from The Maastricht Study, a Dutch population-based cohort (n=4326; age, 59.4±8.6 years; 49.7% women). Measures of microvascular function included urinary albumin excretion, central retinal arteriolar and venular calibers, composite scores of flicker light-induced retinal arteriolar and venular dilation, and plasma biomarkers of endothelial dysfunction (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and von Willebrand factor). White matter connectivity was calculated from 3T diffusion magnetic resonance imaging to quantify the number (average node degree) and organization (characteristic path length, global efficiency, clustering coefficient, and local efficiency) of white matter connections. A higher plasma biomarkers of endothelial dysfunction composite score was associated with a longer characteristic path length (β per SD, 0.066 [95% CI, 0.017-0.114]) after adjustment for sociodemographic, lifestyle, and cardiovascular factors but not with any of the other white matter connectivity measures. After multiple comparison correction, this association was nonsignificant. None of the other microvascular function measures were associated with any of the connectivity measures. CONCLUSIONS: These findings suggest that microvascular dysfunction as measured by indirect markers is not associated with whole-brain white matter connectivity.

BACKGROUND: Adult patients with mild traumatic brain injury (mTBI) exhibit distinct phenotypes of emotional and cognitive functioning identified by latent profile analysis of clinical neuropsychological assessments. When discerned early after injury, these latent clinical profiles have been found to improve prediction of long-term outcomes from mTBI. The present study hypothesized that white matter (WM) microstructure is better preserved in an emotionally resilient mTBI phenotype compared with a neuropsychiatrically distressed mTBI phenotype. METHODS: The present study used diffusion magnetic resonance imaging to investigate and compare WM microstructure in major association, projection, and commissural tracts between the two phenotypes and over time. Diffusion magnetic resonance images from 172 patients with mTBI were analyzed to compute individual diffusion tensor imaging maps at 2 weeks and 6 months after injury. RESULTS: By comparing the diffusion tensor imaging parameters between the two phenotypes at global, regional, and voxel levels, emotionally resilient patients were shown to have higher axial diffusivity compared with neuropsychiatrically distressed patients early after mTBI. Longitudinal analysis revealed greater compromise of WM microstructure in neuropsychiatrically distressed patients, with greater decrease of global axial diffusivity and more widespread decrease of regional axial diffusivity during the first 6 months after injury compared with emotionally resilient patients. CONCLUSIONS: These results provide neuroimaging evidence of WM microstructural differences underpinning mTBI phenotypes identified from neuropsychological assessments and show differing longitudinal trajectories of these biological effects. These findings suggest that diffusion magnetic resonance imaging can provide short- and long-term imaging biomarkers of resilience.

Perivascular spaces (PVS), fluid-filled compartments surrounding brain vasculature, are an essential component of the glymphatic system responsible for transport of waste and nutrients. Glymphatic system impairment may underlie cognitive deficits in Parkinsons disease (PD). Studies have focused on the role of basal ganglia PVS with cognition in PD, but the role of white matter PVS is unknown. This study examined the relationship of white matter and basal ganglia PVS with domain-specific and global cognition in individuals with PD. Fifty individuals with PD underwent 3T T1w magnetic resonance imaging (MRI) to determine PVS volume fraction, defined as PVS volume normalized to total regional volume, within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of global cognitive function (Montreal Cognitive Assessment, and global cognitive composite score), and cognitive-specific domains (executive function, memory, visuospatial function, attention, and language). Higher white matter rostral middle frontal PVS was associated with lower scores in both global cognitive and visuospatial function. In the basal ganglia higher PVS was associated with lower scores for memory with a trend towards lower global cognitive composite score. While previous reports have shown that greater amount of PVS in the basal ganglia is associated with decline in global cognition in PD, our findings suggest that increased white matter PVS volume may also underlie changes in cognition.

Cross-sectional studies have linked differences in white matter tissue properties to reading skills. However, past studies have reported a range of, sometimes conflicting, results. Some studies suggest that white matter properties act as individual-level traits predictive of reading skill, whereas others suggest that reading skill and white matter develop as a function of an individual's educational experience. In the present study, we tested two hypotheses: a) that diffusion properties of the white matter reflect stable brain characteristics that relate to stable individual differences in reading ability or b) that white matter is a dynamic system, linked with learning over time. To answer these questions, we examined the relationship between white matter and reading in a five-year longitudinal dataset and a series of large-scale, single-observation, cross-sectional datasets (N = 14,249 total participants). We find that gains in reading skill correspond to longitudinal changes in the white matter. However, in the cross-sectional datasets, we find no evidence for the hypothesis that individual differences in white matter predict reading skill. These findings highlight the link between dynamic processes in the white matter and learning.

BACKGROUND: Sensory processing dysfunction (SPD) is linked to altered white matter (WM) microstructure in school-age children. Sensory over-responsivity (SOR), a form of SPD, affects at least 2.5% of all children and has substantial deleterious impact on learning and mental health. However, SOR has not been well studied using microstructural imaging such as diffusion MRI (dMRI). Since SOR involves hypersensitivity to external stimuli, we test the hypothesis that children with SOR require compensatory neuroplasticity in the form of superior WM microstructural integrity to protect against internalizing behavior, leaving those with impaired WM microstructure vulnerable to somatization and depression. METHODS: Children ages 8-12 years old with neurodevelopmental concerns were assessed for SOR using a comprehensive structured clinical evaluation, the Sensory Processing 3 Dimensions Assessment, and underwent 3 Tesla MRI with multishell multiband dMRI. Tract-based spatial statistics was used to measure diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) metrics from global WM and nineteen selected WM tracts. Correlations of DTI and NODDI measures with measures of somatization and emotional disturbance from the Behavioral Assessment System for Children, 3rd edition (BASC-3), were computed in the SOR group and in matched children with neurodevelopmental concerns but not SOR. RESULTS: Global WM fractional anisotropy (FA) is negatively correlated with somatization and with emotional disturbance in the SOR group but not the non-SOR group. Also observed in children with SOR are positive correlations of radial diffusivity (RD) and free water fraction (FISO) with somatization and, in most cases, emotional disturbance. These effects are significant in boys with SOR, whereas the study is underpowered for girls. The most affected white matter are medial lemniscus and internal capsule sensory tracts, although effects of SOR are observed in many cerebral, cerebellar, and brainstem tracts. CONCLUSION: White matter microstructure is related to affective behavior in children with SOR.

BackgroundPlasma neurofilament light chain (NfL) is a promising biomarker of neurodegeneration with potential clinical utility in monitoring the progression of neurodegenerative diseases. However, the cross-sectional associations of plasma NfL with measures of cognition and brain have been inconsistent in community-dwelling populations.MethodsWe examined these associations in a large community-dwelling sample of early old age men (N = 969, mean age = 67.57 years, range = 61-73 years), who are either cognitively unimpaired (CU) or with mild cognitive impairment (MCI). Specifically, we investigated five cognitive domains (executive function, episodic memory, verbal fluency, processing speed, visual-spatial ability), as well as neuroimaging measures of gray and white matter.ResultsAfter adjusting for age, health status, and young adult general cognitive ability, plasma NfL level was only significantly associated with processing speed and white matter hyperintensity (WMH) volume, but not with other cognitive or neuroimaging measures. The association with processing speed was driven by individuals with MCI, as it was not detected in CU individuals.ConclusionsThese results suggest that in early old age men without dementia, plasma NfL does not appear to be sensitive to cross-sectional individual differences in most domains of cognition or neuroimaging measures of gray and white matter. The revealed plasma NfL associations were limited to WMH for all participants and processing speed only within the MCI cohort. Importantly, considering cognitive status in community-based samples will better inform the interpretation of the relationships of plasma NfL with cognition and brain and may help resolve mixed findings in the literature.

Accurate and scalable quantification of amyloid-β (Aβ) pathology is crucial for deeper disease phenotyping and furthering research in Alzheimer Disease (AD). This multidisciplinary study addresses the current limitations on neuropathology by leveraging a machine learning (ML) pipeline to perform a granular quantification of Aβ deposits and assess their distribution in the temporal lobe. Utilizing 131 whole-slide-images from consecutive autopsied cases at the University of California Davis Alzheimer Disease Research Center, our objectives were threefold: (1) Validate an automatic workflow for Aβ deposit quantification in white matter (WM) and gray matter (GM); (2) define the distributions of different Aβ deposit types in GM and WM, and (3) investigate correlates of Aβ deposits with dementia status and the presence of mixed pathology. Our methodology highlights the robustness and efficacy of the ML pipeline, demonstrating proficiency akin to experts' evaluations. We provide comprehensive insights into the quantification and distribution of Aβ deposits in the temporal GM and WM revealing a progressive increase in tandem with the severity of established diagnostic criteria (NIA-AA). We also present correlations of Aβ load with clinical diagnosis as well as presence/absence of mixed pathology. This study introduces a reproducible workflow, showcasing the practical use of ML approaches in the field of neuropathology, and use of the output data for correlative analyses. Acknowledging limitations, such as potential biases in the ML model and current ML classifications, we propose avenues for future research to refine and expand the methodology. We hope to contribute to the broader landscape of neuropathology advancements, ML applications, and precision medicine, paving the way for deep phenotyping of AD brain cases and establishing a foundation for further advancements in neuropathological research.

Adults with Down syndrome have a genetic form of Alzheimer's disease (AD) and evidence of cerebrovascular disease across the AD continuum, despite few systemic vascular risk factors. The onset and progression of AD in Down syndrome is highly age-dependent, but it is unknown at what age cerebrovascular disease emerges and what factors influence its severity. In the Alzheimer's Biomarker Consortium-Down Syndrome study (ABC-DS; n = 242; age = 25-72), we estimated the age inflection point at which MRI-based white matter hyperintensities (WMH), enlarged perivascular spaces (PVS), microbleeds, and infarcts emerge in relation to demographic data, risk factors, amyloid and tau, and AD diagnosis. Enlarged PVS and infarcts appear to develop in the early 30s, while microbleeds, WMH, amyloid, and tau emerge in the mid to late 30s. Age-residualized WMH were higher in women, in individuals with dementia, and with lower body mass index. Participants with hypertension and APOE-ε4 had higher age-residualized PVS and microbleeds, respectively. Lifespan trajectories demonstrate a dramatic cerebrovascular profile in adults with Down syndrome that appears to evolve developmentally in parallel with AD pathophysiology approximately two decades prior to dementia symptoms.

IntroductionDespite evidence suggesting deleterious effects of cannabis and nicotine tobacco product (NTP) use on white matter integrity, there have been limited studies examining white matter integrity among users of both cannabis and nicotine. Further, updated white matter methodology provides opportunities to investigate use patterns on neurite orientation dispersion and density (NODDI) indices and subtle tissue changes related to the intra- and extra-neurite compartment. We aimed to investigate how cannabis and NTP use among adolescents and young adults interacts to impact the white matter integrity microstructure.Materials and methodsA total of 221 participants between the ages of 16 and 22 completed the Customary Drinking and Drug Use Record (CDDR) to measure substance use, and underwent a magnetic resonance imaging (MRI) session. Participants were divided into NTP-control and NTP groupings and cannabis-control and cannabis groupings (≥26 NTP/cannabis uses in past 6 months). Tract-Based Spatial Statistics (TBSS) and two-way between-subjects ANOVA investigated the effects of NTP use group, cannabis use group, and their interaction on fractional anisotropy (FA) and NODDI indices while controlling for age and biological sex.ResultsNTP use was associated with decreased FA values and increased orientation dispersion in the left anterior capsule. There were no significant effects of cannabis use or the interaction of NTP and cannabis use on white matter outcomes.DiscussionNTP use was associated with altered white matter integrity in an adolescent and young adult sample. Findings suggest that NTP-associated alterations may be linked to altered fiber tract geometry and dispersed neurite structures versus myelination, as well as differential effects of NTP and cannabis use on white matter structure. Future work is needed to investigate how altered white matter is related to downstream behavioral effects from NTP use.

Summary Myelin is the membrane surrounding neuronal axons in the central nervous system (CNS), produced by oligodendrocytes to provide insulation for electrical impulse conduction and trophic/metabolic support. CNS dysfunction occurs following poor development of myelin in infancy, myelin damage in neurological diseases, and impaired regeneration of myelin with disease progression in aging. The lack of approved therapies aimed at supporting myelin health highlights the critical need to identify the cellular and molecular influences on oligodendrocytes. CNS macrophages have been shown to influence the development, maintenance, damage and regeneration of myelin, revealing critical interactions with oligodendrocyte lineage cells. CNS macrophages are comprised of distinct populations, including CNS‐resident microglia and cells associated with CNS border regions (the meninges, vasculature, and choroid plexus), in addition to macrophages derived from monocytes infiltrating from the blood. Importantly, the distinct contribution of these macrophage populations to oligodendrocyte lineage responses and myelin health are only just beginning to be uncovered, with the advent of new tools to specifically identify, track, and target macrophage subsets. Here, we summarize the current state of knowledge on the roles of CNS macrophages in myelin health, and recent developments in distinguishing the roles of macrophage populations in development, homeostasis, and disease. [ABSTRACT FROM AUTHOR]

Chronic pain is common in young people and can have a major life impact. Despite the burden of chronic pain, mechanisms underlying chronic pain development and persistence are still poorly understood. Specifically, white matter (WM) connectivity has remained largely unexplored in pediatric chronic pain. Using diffusion-weighted imaging, this study examined WM microstructure in adolescents (age M 5 15.8 years, SD 5 2.8 years) with chronic pain (n 5 44) compared with healthy controls (n 5 24). Neurite orientation dispersion and density imaging modeling was applied, and voxel-based whole-white-matter analyses were used to obtain an overview of potential alterations in youth with chronic pain and tract-specific profile analyses to evaluate microstructural profiles of tracts of interest more closely. Our main findings are that (1) youth with chronic pain showed widespread elevated orientation dispersion compared with controls in several tracts, indicative of less coherence; (2) signs of neurite density tract-profile alterations were observed in several tracts of interest, with mainly higher density levels in patients; and (3) several WM microstructural alterations were associated with pain catastrophizing in the patient group. Implicated tracts include both those connecting cortical and limbic structures (uncinate fasciculus, cingulum, anterior thalamic radiation), which were associated with pain catastrophizing, as well as sensorimotor tracts (corticospinal tract). By identifying alterations in the biologically informative WM microstructural metrics orientation dispersion and neurite density, our findings provide important and novel mechanistic insights for understanding the pathophysiology underlying chronic pain. Taken together, the data support alterations in fiber organization as a meaningful characteristic, contributing process to the chronic pain state. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is a progressive X‐linked neuromuscular disorder caused by the absence of functional dystrophin protein. In addition to muscle, dystrophin is expressed in the brain in both neurons and glial cells. Previous studies have shown altered white matter microstructure in patients with DMD using diffusion tensor imaging (DTI). However, DTI measures the diffusion properties of water, a ubiquitous molecule, making it difficult to unravel the underlying pathology. Diffusion‐weighted spectroscopy (DWS) is a complementary technique which measures diffusion properties of cell‐specific intracellular metabolites. Here we performed both DWS and DTI measurements to disentangle intra‐ and extracellular contributions to white matter changes in patients with DMD. Scans were conducted in patients with DMD (15.5 ± 4.6 y/o) and age‐ and sex‐matched healthy controls (16.3 ± 3.3 y/o). DWS measurements were obtained in a volume of interest (VOI) positioned in the left parietal white matter. Apparent diffusion coefficients (ADCs) were calculated for total N‐acetylaspartate (tNAA), choline compounds (tCho), and total creatine (tCr). The tNAA/tCr and tCho/tCr ratios were calculated from the non‐diffusion‐weighted spectrum. Mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), and fractional anisotropy of water within the VOI were extracted from DTI measurements. DWS and DTI data from patients with DMD (respectively n = 20 and n = 18) and n = 10 healthy controls were included. No differences in metabolite ADC or in concentration ratios were found between patients with DMD and controls. In contrast, water diffusion (MD, t = −2.727, p = 0.011; RD, t = −2.720, p = 0.011; AD, t = −2.715, p = 0.012) within the VOI was significantly higher in patients compared with healthy controls. Taken together, our study illustrates the potential of combining DTI and DWS to gain a better understanding of microstructural changes and their association with disease mechanisms in a clinical setting. [ABSTRACT FROM AUTHOR]

Purpose: To fully characterize the orientation dependence of magnetization transfer (MT) and inhomogeneous MT (ihMT) measures in the whole white matter (WM), for both single‐fiber and crossing‐fiber voxels. Methods: A characterization method was developed using the fiber orientation obtained from diffusion MRI (dMRI) with diffusion tensor imaging (DTI) and constrained spherical deconvolution. This allowed for characterization of the orientation dependence of measures in all of WM, regardless of the number of fiber orientation in a voxel. Furthermore, the orientation dependence inside 31 different WM bundles was characterized to evaluate the homogeneity of the effect. Variation of the results within and between‐subject was assessed from a 12‐subject dataset. Results: Previous results for single‐fiber voxels were reproduced and a novel characterization was produced in voxels of crossing fibers, which seems to follow trends consistent with single‐fiber results. Heterogeneity of the orientation dependence across bundles was observed, but homogeneity within similar bundles was also highlighted. Differences in behavior between MT and ihMT measures, as well as the ratio and saturation versions of these, were noted. Conclusion: Orientation dependence characterization was proven possible over the entirety of WM. The vast range of effects and subtleties of the orientation dependence on MT measures showed the need for, but also the challenges of, a correction method. [ABSTRACT FROM AUTHOR]

Chemical exchange saturation transfer (CEST) imaging may provide novel contrast for the diagnosis, prognosis, and monitoring of the progression or treatment of neurological applications. However, the reproducibility of prominent CEST contrasts like amide CEST and nuclear Overhauser enhancement (NOE) CEST must be characterized in healthy brain gray matter (GM) and white matter (GM) prior to clinical implementation. The objective of this study was to characterize the reproducibility of four different CEST contrasts in the healthy human brain. Using a 3T MRI scanner, two 3D CEST scans were acquired in 12 healthy subjects (7 females, mean age (± SD) 26 ± 4 years) approximately 10 days apart. Scan-rescan reproducibility was measured for four contrasts: amine/amide concentration-independent detection (AACID), Amide*, and inverse magnetization transfer ratio (MTRRex) contrast for amide and NOE. Reproducibility was evaluated between- and within-subjects using coefficients of variation (CV) and the percent difference between measurements. AACID and NOE-MTRRex contrasts demonstrated the lowest within-subject CVs (0.8–1.2% and 1.6-2.0%, respectively), between-subject CVs (1.2–2.1% and 3.4–4.2%, respectively), and percent difference (1.2–1.4% and 2.2–2.8%, respectively) for both GM and WM. AACID and NOE-MTRRex contrasts demonstrated the highest reproducibility and represented stable measurements suitable for characterizing changes in brain tissue caused by pathological processes. [ABSTRACT FROM AUTHOR]

Objective: Mild Cognitive Impairment (MCI) is a recognized precursor to Alzheimer's Disease (AD), presenting a significant risk of progression. Early detection and intervention in MCI can potentially slow disease advancement, offering substantial clinical benefits. This study employed radiomics and machine learning methodologies to distinguish between MCI and Normal Cognition (NC) groups. Methods: The study included 172 MCI patients and 183 healthy controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, all of whom had 3D-T1 weighted MRI structural images. The cerebellar gray and white matter were segmented automatically using volBrain software, and radiomic features were extracted and screened through Pyradiomics. The screened features were then input into various machine learning models, including Random Forest (RF), Logistic Regression (LR), eXtreme Gradient Boosting (XGBoost), Support Vector Machines (SVM), K Nearest Neighbors (KNN), Extra Trees, Light Gradient Boosting Machine (LightGBM), and Multilayer Perceptron (MLP). Each model was optimized for penalty parameters through 5-fold cross-validation to construct radiomic models. The DeLong test was used to evaluate the performance of different models. Results: The LightGBM model, which utilizes a combination of cerebellar gray and white matter features (comprising eight gray matter and eight white matter features), emerges as the most effective model for radiomics feature analysis. The model demonstrates an Area Under the Curve (AUC) of 0.863 for the training set and 0.776 for the test set. Conclusion: Radiomic features based on the cerebellar gray and white matter, combined with machine learning, can objectively diagnose MCI, which provides significant clinical value for assisted diagnosis. [ABSTRACT FROM AUTHOR]

Normal aging, though lacking widespread neurodegeneration, is nevertheless characterized by cognitive impairment in learning, memory, and executive function. The aged brain is spared from neuron loss, but white matter is lost and damage to myelin sheaths accumulates. This myelin damage is strongly associated with cognitive impairment. Although the cause of the myelin damage is not known, microglia dysregulation is a likely contributor. Immunologic proteins interact with microglial receptors to modulate microglia-mediated phagocytosis, which mediates myelin damage clearance and turn-over. Two such proteins, "eat me" signal C1q and "don't eat me" signal CD47, act in opposition with microglia. Both C1q and CD47 have been implicated in Multiple Sclerosis, a demyelinating disease, but whether they play a role in age-related myelin pathology is currently unknown. The present study investigates C1q and CD47 in relation to age-related myelin degeneration using multilabel immunofluorescence, RNAscope, and confocal microscopy in the cingulum bundle of male and female rhesus monkeys across the lifespan. Our findings showed significant age-related elevation in C1q localized to myelin basic protein, and this increase is associated with more severe cognitive impairment. In contrast, CD47 localization to myelin decreased in middle age and oligodendrocyte expression of CD47 RNA decreased with age. Lastly, microglia reactivity increased with age in association with the changes in C1q and CD47. Together, these results suggest disruption in the balance of "eat me" and "don't eat me" signals during normal aging, biasing microglia toward increased reactivity and phagocytosis of myelin, resulting in cognitive deficits. [ABSTRACT FROM AUTHOR]

Background: Mesial temporal lobe epilepsy (MTLE) epileptiform discharges have been reported to arise from the hippocampus or the extrahippocampal medial temporal cortex, such as the amygdala, and then propagate to the temporal lobe cortex. The surgical ablation of which of these structures would result in a better postoperative outcome is debatable. Objective: To assess the possible factors that might have influenced the postoperative outcome of a group of drug-resistant mesial MTLE patients who underwent stereoelectroencephalography (SEEG)-guided radiofrequency thermocoagulation (RFTC). Design: Single-center, retrospective. Methods: The present study utilized a pre- and postoperative gray matter voxel-by-voxel ablation mapping comparison approach, along with a white matter mapping of longitudinal changes in the native space technique, to evaluate the association between the post-SEEG implantation signal recordings (obtained from clinically relevant electrode contacts used during RFTC) and the post-RFTC ablation volume of the different selected regions of interest (ROIs). Results: The study included 22 patients (12 men and 10 women, mean age 28.86 ± 14.04 years). Sixteen patients (72.72%) were seizure-free (SF), and six patients (27.27%) were non-SF. Five patients (22.72%) experienced mild side effects following RFTC. The post-RFTC follow-up period varied from 12 to 48 months, with an average of 24.17 ± 9.86 months. The SF group was associated with a higher number of implanted electrode contacts in the amygdala that were used during RFTC, a larger preoperative volume of the amygdala; a larger ablation volume of both the amygdala and rhinal cortex. The ablation volume of the white matter was statistically similar between both groups. Conclusion: This study provides valuable insights into the significance of the amygdala and rhinal cortex as ROIs in the preoperative evaluation of patients with MTLE. Future implantation scheme plans should consider evaluating the preoperative volume of these ROIs. Additionally, increasing the number of electrode contacts implanted within these regions might be beneficial to capture more clinically relevant signals and enhance their ablation volume. [ABSTRACT FROM AUTHOR]

AbstractObjective: Amyotrophic lateral sclerosis (ALS) exhibits several different presentations and clinical phenotypes. Of these, classic ALS (ALS-Cl), which is the most common phenotype, presents with relatively equal amounts of upper motor neuron and lower motor neuron signs. Magnetic resonance imaging (MRI) provides a noninvasive way to assess central nervous system damage in these patients. To our knowledge no study is available where exploratory whole brain grey matter (GM) and white matter (WM) network analysis is performed considering only the ALS-Cl subgroup of ALS patients. Methods: GM voxel-based morphometry analysis and WM network analysis using graph theory was performed in the MRI dataset of 14 neurologic controls and 25 ALS-Cl patients. Results and Conclusions: No significant GM differences were observed between ALS-Cl and neurologic controls. WM network revealed significant (p < 0.05) reduction and increase in degree measure in several extramotor brain regions of ALS-Cl patients. Both global and local graph metrics revealed significant abnormal values in ALS-Cl patients when compared to neurologic controls. Significant WM changes in ALS-Cl patients with no significant GM changes suggest that neurodegeneration may onset as an “axonopathy” in this ALS subtype. [ABSTRACT FROM AUTHOR]

White matter microvascular alterations in temporal lobe epilepsy (TLE) may be relevant to acquired neurodegenerative processes and cognitive impairments associated with this condition. We quantified microvascular changes, myelin, axonal, glial and extracellular-matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in vivo pre-operative MRI diffusion measurements in co-registered regions and neuropsychological measures of cognitive impairment and decline. In resections, increased arteriolosclerosis was observed in TLE compared to non-epilepsy controls (greater sclerotic index, p < 0.001), independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (quantified with collagen-4, p < 0.05–0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (quantified with platelet-derived growth factor receptorβ and smooth muscle actin, p < 0.01) which was more marked the longer the duration of epilepsy (p < 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlation with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with white matter abnormality quantified using fixel-based analysis. Increased perivascular space was associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (p < 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features correlate with white matter diffusion MRI alterations and might explain cognitive decline in TLE. [ABSTRACT FROM AUTHOR]

Background/Objectives: Although the involvement of progressive brain alterations in epilepsy was recently suggested, individual patients' trajectories of white matter (WM) disruption are not known. Methods: We investigated the disease progression patterns of WM damage and its associations with clinical metrics. We examined the cross-sectional diffusion tensor imaging (DTI) data of 155 patients with unilateral temporal lobe epilepsy (TLE) and 270 age/gender-matched healthy controls, and we then calculated the average fractional anisotropy (FA) values within 20 WM tracts of the whole brain. We used the Subtype and Stage Inference (SuStaIn) program to detect the progression trajectory of FA changes and investigated its association with clinical parameters including onset age, disease duration, drug-responsiveness, and the number of anti-seizure medications (ASMs). Results: The SuStaIn algorithm identified a single subtype model in which the initial damage occurs in the ipsilateral uncinate fasciculus (UF), followed by damage in the forceps, superior longitudinal fasciculus (SLF), and anterior thalamic radiation (ATR). This pattern was replicated when analyzing TLE with hippocampal sclerosis (n = 50) and TLE with no lesions (n = 105) separately. Further-progressed stages were associated with longer disease duration (p < 0.001) and a greater number of ASMs (p = 0.001). Conclusions: the disease progression model based on WM tracts may be useful as a novel individual-level biomarker. [ABSTRACT FROM AUTHOR]

Aim: Brain MRI findings in sinus vein thrombosis (SVT) have been well described in many studies. However, to our knowledge, there is no diffusion tensor imaging (DTI) study in these cases in the literature. The main purpose of this article is to examine white matter integrity in SVT and to better understand the possible underlying white matter damage. Materials and Methods: Our retrospective study is a neuroimaging study including 1.5 T MRI and brain DTI to evaluate the white matter integrity of patients with SVT and healthy controls. White matter DTI abnormalities were evaluated according to ROI. DTI findings of cases and healthy controls were compared. Results: In cases with SVT, higher apparent diffusion coefficiency (ADC) values were detected in middle cerebellar peduncle, optic radiatio compared to healthy controls. Decreased fractional anisotrophy (FA) values were detected in cingulum, corona radiata, corpus callosum splenium, anterior limb of internal capsule, posterior limb of internal capsule, optic radiatio and corticospinal tract. High radial diffusivity (RD) values were detected in cingulum, corona radiata, superior longitudinal fasciculus, anterior limb of internal capsule, posterior limb of internal capsule, middle cerebellar peduncle, optic radiation and corticospinal tract. Low axial diffusivity (AD) values were detected in cingulum, posterior limb of internal capsule and corticospinal tract. Conclusion: Our findings may suggest intercellular edema and axon and myelin damage in white matter tracts in sinus thrombosis. DTI findings may be useful in quantitatively monitoring the response to treatment. [ABSTRACT FROM AUTHOR]

Aims: Spinal muscular atrophy (SMA) is a life‐limiting paediatric motor neuron disease characterised by lower motor neuron loss, skeletal muscle atrophy and respiratory failure, if untreated. Revolutionary treatments now extend patient survival. However, a limited understanding of the foundational neuropathology challenges the evaluation of therapeutic success. As opportunities to study treatment‐naïve tissue decrease, we have characterised spinal cord pathology in severe infantile SMA using gold‐standard techniques, providing a baseline to measure treatment success and therapeutic limitations. Methods: Detailed histological analysis, stereology and transmission electron microscopy were applied to post‐mortem spinal cord from severe infantile SMA patients to estimate neuron number at the end of life; characterise the morphology of ventral horn, lateral horn and Clarke's column neuron populations; assess cross‐sectional spinal cord area; and observe myelinated white matter tracts in the clinically relevant thoracic spinal cord. Results: Ventral horn neuron loss was substantial in all patients, even the youngest cases. The remaining ventral horn neurons were small with abnormal, occasionally chromatolytic morphology, indicating cellular damage. In addition to ventral horn pathology, Clarke's column sensory–associated neurons displayed morphological features of cellular injury, in contrast to the preserved sympathetic lateral horn neurons. Cellular changes were associated with aberrant development of grey and white matter structures that affected the overall dimensions of the spinal cord. Conclusions: We provide robust quantification of the neuronal deficit found at the end of life in SMA spinal cord. We question long‐accepted dogmas of SMA pathogenesis and shed new light on SMA neuropathology out with the ventral horn, which must be considered in future therapeutic design. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Stress is a common response by people to stressors or potential threats, resulting in physical, affective, and cognitive changes. Emotions are associated with interpretations of physiological changes, and the processing of emotions is largely dependent on the somatosensory cortex which includes the postcentral gyrus. The objective of this study was to examine the correlation between stress and alterations in the microstructure of white matter in the somatosensory cortex among healthy non-clincal population. MATERIALS AND METHODS: A total of 30 participants were recruited. The participants were administered the Depression, Anxiety, and Stress Scale 21 (DASS-21) questionnaire. All subjects underwent Magnetic Resonance Imaging (MRI) brain scanning, with diffusion tensor imaging (DTI) used to assess white matter integrity. The association between stress scores in DASS-21 and DTI parameters was analyzed. RESULTS: A significant negative relationship was observed between stress scores and fractional anisotropy (FA) values in the left postcentral gyrus (r=-0.393, p=0.032), suggesting that stress has an early detrimental effect in this region, while no significant correlation was found in the right postcentral gyrus (r=-0.300, p=0.107). CONCLUSION: The findings of our study indicate that stress may lead to early impairments in the microstructural somatosensory cortex, particularly in the left postcentral gyrus. These alterations were observed using DTI technique. Hence, the alterations in the microstructure of white matter in the brain prior to the onset of the disorder may play a vital role and could serve as a new and promising biomarker for the early identification and treatment of the disease in the non-clinical population. [ABSTRACT FROM AUTHOR]

Objective: This study aims to assess the microstructural abnormalities in white matter (WM) among Behcet's disease (BD) patients, both with and without neurological involvement, utilising tract-based spatial statistics (TBSS) to elucidate the underlying causes of WM microstructural changes. Methods: This prospective study comprised 43 BD patients without neurological involvement, 15 neuro-Behcet's disease (NBD) patients with normal conventional MRI, and 54 healthy controls matched for age and sex. TBSS was applied in this diffusion tensor imaging study to conduct a whole-brain voxel-wise analysis of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of WM. Results: Compared to the control group, BD patients exhibited decreased FA and increased MD and RD in nearly all WM tracts, along with increased AD in the left corticospinal tract (CST), left inferior longitudinal fasciculus (ILF), and left superior longitudinal fasciculus (SLF). NBD patients also showed a widespread decrease in FA and increased MD and RD, similar to BD patients without neurological involvement. Additionally, NBD patients had increased AD in the left CST, left ILF, left SLF, left inferior fronto-occipital fasciculus (IFOF), and right CST. Compared to BD patients without neurological involvement, NBD patients exhibited a greater reduction in FA and an increase in MD and RD in WM tracts, with no significant differences in AD. Conclusion: These results suggest that the main mechanism of microstructural changes in the WM of BD patients may be related to impaired fibre integrity, demyelination, and decreased myelin sheath integrity. Advances in knowledge: This study demonstrated BD patients without neurological involvement and NBD patients a decrease in FA and an increase in MD and RD were observed in larger areas of major WM tracts, while an increase in AD values was observed in fewer tracts. Our findings may be useful in understanding the pathophysiology underlying subclinical parenchymal involvement and neurological dysfunction in BD patients and the management of BD patients. [ABSTRACT FROM AUTHOR]

Objective: To explore the white matter structural characteristics in patients with bipolar disorder (BD) using diffusion tensor imaging (DTI) and investigate their relationship with cognitive function. Methods: A total of 15 patients with BD type I and 26 patients with BD type II who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria and 37 normal controls were included. Cognitive function was assessed with the Trail Making Test (TMT) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The tract-based spatial statistics (TBSS) method was used to explore the differences in fractional anisotropy (FA) and mean diffusivity (MD) among the three groups and perform correlation analyses with cognitive function. Results: Patients with BD I and BD II had lower scores in attention (P<0.001), delayed memory (P<0.01), and total scores (P<0.001) on the RBANS compared to the normal control group. They also exhibited lower FA values in the corpus callosum and right superior corona radiata compared to the normal control group (P < 0.05) In the BD I group, there was a positive correlation between FA values in the genu of corpus callosum and visuospatial/constructional scores (r = 0.74, P < 0.05), while in the BD II group, a positive correlation was found between FA values in the same region and language function scores (r = 0.55 P < 0.05). Conclusion: It suggests that patients with bipolar disorder may have impaired white matter integrity in the corpus callosum and right superior corona radiata, which may be associated with cognitive impairment. [ABSTRACT FROM AUTHOR]

Subtle motor signs are a common feature in children with attention‐deficit/hyperactivity disorder (ADHD). It has long been suggested that white matter abnormalities may be involved in their presentation, though no study has directly probed this question. The aim of this study was to investigate the relationship between white matter organization and the severity of subtle motor signs in children with and without ADHD. Participants were 92 children with ADHD aged between 8 and 12 years, and 185 typically developing controls. Subtle motor signs were examined using the Physical and Neurological Examination for Soft Signs (PANESS). Children completed diffusion MRI, and fixel‐based analysis was performed after preprocessing. Tracts of interest were delineated using TractSeg including the corpus callosum (CC), the bilateral corticospinal tracts (CST), superior longitudinal fasciculus, and fronto‐pontine tracts (FPT). Fiber cross‐section (FC) was calculated for each tract. Across all participants, lower FC in the CST was associated with higher PANESS Total score (greater motor deficits). Within the PANESS, similar effects were observed for Timed Left and Right maneuvers of the hands and feet, with lower FC of the CST, CC, and FPT associated with poorer performance. No significant group differences were observed in FC in white matter regions associated with PANESS performance. Our data are consistent with theoretical accounts implicating white matter organization in the expression of motor signs in childhood. However, rather than contributing uniquely to the increased severity of soft motor signs in those with ADHD, white matter appears to contribute to these symptoms in childhood in general. [ABSTRACT FROM AUTHOR]

Epileptic seizures recorded with stereo-EEG can take a fraction of a second or several seconds to propagate from one region to another. What explains such propagation patterns? We combine tractography and stereo-EEG to determine the relationship between seizure propagation and the white matter architecture and to describe seizure propagation mechanisms. Patient-specific spatiotemporal seizure propagation maps were combined with tractography from diffusion imaging of matched subjects from the Human Connectome Project. The onset of seizure activity was marked on a channel-by-channel basis by two board-certified neurologists for all channels involved in the seizure. We measured the tract connectivity (number of tracts) between regions-of-interest pairs among the seizure onset zone, regions of seizure spread and non-involved regions. We also investigated how tract-connected the seizure onset zone is to regions of early seizure spread compared with regions of late spread. Comparisons were made after correcting for differences in distance. Sixty-nine seizures were marked across 26 patients with drug-resistant epilepsy; 11 were seizure free after surgery (Engel IA) and 15 were not (Engel IB–Engel IV). The seizure onset zone was more tract-connected to regions of seizure spread than to non-involved regions (P < 0.0001); however, regions of seizure spread were not differentially tract-connected to other regions of seizure spread compared with non-involved regions. In seizure-free patients only, regions of seizure spread were more tract-connected to the seizure onset zone than to other regions of spread (P < 0.0001). Over the temporal evolution of a seizure, the seizure onset zone was significantly more tract-connected to regions of early spread compared with regions of late spread in seizure-free patients only (P < 0.0001). By integrating information on structure, we demonstrate that seizure propagation is likely to be mediated by white matter tracts. The pattern of connectivity between seizure onset zone, regions of spread and non-involved regions demonstrates that the onset zone might be largely responsible for seizures propagating throughout the brain, rather than seizures propagating to intermediate points, from which further propagation takes place. Our findings also suggest that seizure propagation over seconds might be the result of a continuous bombardment of action potentials from the seizure onset zone to regions of spread. In non-seizure-free patients, the paucity of tracts from the presumed seizure onset zone to regions of spread suggests that the onset zone was missed. Fully understanding the structure–propagation relationship might eventually provide insight into selecting the correct targets for epilepsy surgery. [ABSTRACT FROM AUTHOR]

Between 2.5% and 28% of people infected with SARS-CoV-2 suffer long COVID or persistence of symptoms for months after acute illness. Many symptoms are neurological, but the brain changes underlying the neuropsychological impairments remain unclear. This study aimed to provide a detailed description of the cognitive profile, the pattern of brain alterations in long COVID and the potential association between them. To address these objectives, 83 patients with persistent neurological symptoms after COVID-19 were recruited, and 22 now healthy control subjects chosen because they had suffered COVID-19 but did not experience persistent neurological symptoms. Patients and controls were matched for age, sex and educational level. All participants were assessed by clinical interview, comprehensive standardized neuropsychological tests and structural MRI. The mean global cognitive function of patients with long COVID assessed by Addenbrooke's Cognitive Examination-III screening test [overall cognitive level (OCLz) = −0.39 ± 0.12] was significantly below the infection recovered-controls (OCLz = +0.32 ± 0.16, P < 0.01). We observed that 48% of patients with long COVID had episodic memory deficit, with 27% also with impaired overall cognitive function, especially attention, working memory, processing speed and verbal fluency. The MRI examination included grey matter morphometry and whole brain structural connectivity analysis. Compared to infection recovered controls, patients had thinner cortex in a specific cluster centred on the left posterior superior temporal gyrus. In addition, lower fractional anisotropy and higher radial diffusivity were observed in widespread areas of the patients' cerebral white matter relative to these controls. Correlations between cognitive status and brain abnormalities revealed a relationship between altered connectivity of white matter regions and impairments of episodic memory, overall cognitive function, attention and verbal fluency. This study shows that patients with neurological long COVID suffer brain changes, especially in several white matter areas, and these are associated with impairments of specific cognitive functions. [ABSTRACT FROM AUTHOR]

Leukodystrophies are rare genetic white matter disorders that have been regarded as mainly occurring in childhood. This perception has been altered in recent years, as a growing number of leukodystrophies have been described as having an onset in adulthood. Still, many adult patients presenting with white matter changes remain without a specific molecular diagnosis. We describe a novel adult onset leukodystrophy in 16 patients from eight families carrying one of four different stop-gain or frameshift dominant variants in the CST3 gene. Clinical and radiological features differ markedly from the previously described Icelandic cerebral amyloid angiopathy found in patients carrying p.Leu68Asn substitution in CST3. The clinical phenotype consists of recurrent episodes of hemiplegic migraine associated with transient unilateral focal deficits and slowly progressing motor symptoms and cognitive decline in mid to older adult ages. In addition, in some cases acute onset clinical deterioration led to a prolonged episode with reduced consciousness and even early death. Radiologically, pathognomonic changes are found at typical predilection sites involving the deep cerebral white matter sparing a periventricular and directly subcortical rim, the middle blade of corpus callosum, posterior limb of the internal capsule, middle cerebellar peduncles, cerebral peduncles and specifically the globus pallidus. Histopathologic characterization in two autopsy cases did not reveal angiopathy, but instead micro- to macrocystic degeneration of the white matter. Astrocytes were activated at early stages and later displayed severe degeneration and loss. In addition, despite the loss of myelin, elevated numbers of partly apoptotic oligodendrocytes were observed. A structural comparison of the variants in CST3 suggests that specific truncations of cystatin C result in an abnormal function, possibly by rendering the protein more prone to aggregation. Future studies are required to confirm the assumed effect on the protein and to determine pathophysiologic downstream events at the cellular level. [ABSTRACT FROM AUTHOR]

Purpose: Pineal gland (PG) is a structure located in the midline of the brain, and is considered as a main part of the epithalamus. There are reports on the role of this area for brain function by hormone secretion, as well as few reports on its role in brain cognition. However, little knowledge is available on the PG, and in particular on the structural connectivity of this region with the other brain structures. Methods: Using diffusion-weighted images collected by a 3T MRI scanner, and using a sample of 61 (29 F) mentally and physically healthy young individuals in the age range of 20–30 years old, we tried to extract the white matter bundles connected to the PG. Based on prior knowledge, seven target bundles were suggested to be between the PG body and the PG roots, Pons, Periventricular region, thalamus, caudate, lentiform, suprachiasmatic nuclei, and the supercervical ganglia. Results: Nearly all the target bundles were successfully extracted, with the exception of the lentiform. Rate of identification of the tracts was different, with the bundle between the PG body and roots having the highest identification rate (97%); then it was with the Pons (70%), Periventricular region (57%), SCN (55%), left thalamus (52%), right thalamus (47%), left caudate (27%) and right caudate (22%). Conclusion: This study is an attempt to expand our knowledge on the neuroanatomy of the PG, which might help for identifying further roles for it in brain functionality, and also be a help for the treatment of some disorders in the future. [ABSTRACT FROM AUTHOR]

In the field of autism spectrum disorder (ASD), research on functional connectivity between gray matter and white matter remains under-researched. To address this gap, this study innovatively introduced a nested cross-validation method that integrates gray-white matter functional connectivity with an F-Score algorithm. This method calculates the correlation based on signals extracted from functional magnetic resonance imaging data using gray matter and white matter brain region templates. After applying the method to a New York University Langone Medical Center dataset consisting of 55 individuals with high-functioning ASD and 52 healthy subjects, we achieved a classification accuracy of 72.94%. This study found abnormal functional connectivity, primarily involving the left anterior prefrontal cortex and right superior corona radiata, left retrosplenial cortex and left superior corona radiata, as well as the left ventral anterior cingulate cortex and body of corpus callosum. Besides, we discovered that these abnormal connections are closely related to social impairment and restrictive and repetitive behaviors in ASD. In conclusion, this study provides a gray-white matter functional connectivity perspective for the diagnosis and understanding of ASD. • Using functional connectivity between the white matter and gray matter of the brain as features. • Using F-Score and nested cross-validation method for feature extraction. • A total of 38 Gy-white matter FC features were extracted, with some of these features showing correlation with the severity of social impairments and restricted and repetitive behaviors in ASD. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Typical Alzheimer's disease (AD) and limbic‐predominant age‐related TAR DNA‐binding protein 43 (TDP‐43) encephalopathy (LATE) are two neurodegenerative diseases that present with a similar initial amnestic clinical phenotype but are associated with distinct proteinopathies. METHODS: We investigated white matter (WM) fiber bundle alterations, using fixel‐based analysis, a state‐of‐the‐art diffusion magnetic resonance imaging model, in early AD, presumed LATE, and controls. We also investigated regional cortical atrophy. RESULTS: Both amnestic AD and presumed LATE patients exhibited WM alterations in tracts of the temporal and limbic lobes and in callosal fibers connecting superior frontal gyri. In addition, presumed LATE patients showed alterations in callosal fibers connecting the middle frontal gyri and in the cerebello–thalamo–cortical tract. Cortical thickness was reduced in regions connected by the most altered tracts. DISCUSSION: These findings, the first to describe WM fiber bundle alterations in presumed LATE, are consistent with results on cortical atrophy and with the staging system of tau or TDP‐43 accumulation. Highlights: Fixel‐based analysis revealed white matter (WM) fiber bundle alterations in presumed limbic‐predominant age‐related TAR DNA‐binding protein 43 encephalopathy (LATE) patients identified by isolated episodic/limbic amnesia, the absence of positive Alzheimer's disease (AD) biomarkers, and no other neurological diagnosis after 2 years of follow‐up.Presumed LATE and amnestic AD shared similar patterns of WM alterations in fiber bundles of the limbic and temporal lobes, in congruence with their similar limbic cognitive phenotype.Presumed LATE differed from AD by the alteration of the callosal fibers connecting the middle frontal gyri and of the cerebello–thalamo–cortical tract.WM fiber bundle alterations were consistent with results on regional cortical atrophy.The different anatomical patterns of WM degeneration could provide information on the propagation pathways of distinct proteinopathies. [ABSTRACT FROM AUTHOR]

Background: Preschooling is a critical time for intervention in children with autism spectrum disorder (ASD); thus, we analyzed brain tissue component volumes (BTCVs) and clinical indicators in preschool children with ASD to identify new biomarkers for early screening. Methods: Eighty preschool children (3–6 years) with ASD were retrospectively included. The whole-brain myelin content (MyC), white matter (WM), gray matter (GM), cerebrospinal fluid (CSF), and non-WM/GM/MyC/CSF brain component volumes were obtained using synthetic magnetic resonance imaging (SyMRI). Clinical data, such as intelligence scores, autism diagnostic observation schedule-calibrated severity scores, age at first production of single words (AFSW), age at first production of phrases (AFP), and age at walking onset (AWO), were also collected. The correlation between the BTCV and clinical data was evaluated, and the effect of BTCVs on clinical data was assessed by a regression model. Results: WM and GM volumes were positively correlated with intelligence scores (both P < 0.001), but WM and GM did not affect intelligence scores (P = 0.116, P = 0.290). AWO was positively correlated with AFSW and AFP (both P < 0.001). The multivariate linear regression analysis revealed that MyC, AFSW, AFP, and AWO were significantly different (P = 0.005, P < 0.001, P < 0.001). Conclusions: This study revealed positive correlations between WM and GM volumes and intelligence scores. Whole-brain MyC affected AFSW, AFP, and AWO in preschool children with ASD. Noninvasive quantification of BTCVs via SyMRI revealed a new visualizable and quantifiable biomarker (abnormal MyC) for early ASD screening in preschool children. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a movement-related neurological condition caused by the death of brain nerve cells that produce dopamine. T1 MR images were obtained from the Parkinson's Progression Markers Initiative (PPMI) database. Data was collected at baseline, and at 48 months duration. SPM12 software was used to segment gray matter (GM) and white matter (WM) from the MR images. For the classification of PD, CNN and machine learning (ML) classifiers were used to train on the segmented GM and WM. The findings demonstrated that utilizing the segmented GM and WM obtained from MR images at 48 months had a better predictive ability than the data obtainment at the baseline. CNNs did not perform as well as the conventional ML algorithms, especially for the baseline data. This result is most likely due to the smaller dataset available for training the CNNs, as CNNs normally require more data for best performance. Overall, machine learning algorithms were able to distinguish between people with Parkinson's disease and healthy controls by analyzing GM and WM in brain scans. The classifiers trained at different stages demonstrated varying degrees of accuracy, with the predictive accuracy for the 48-month dataset surpassing that of the baseline data by a significant margin. The accuracy rate for GM was 65.78% at baseline and improved significantly to 92.59% at 48 months. Similarly, the accuracy rate for WM was 60.52% at baseline and improved to 88.89% at 48 months. [ABSTRACT FROM AUTHOR]

Although white matter (WM) accounts for nearly half of adult brain, its wiring diagram is largely unknown. Here, an approach is developed to construct WM networks by estimating interregional morphological similarity based on structural magnetic resonance imaging. It is found that morphological WM networks showed nontrivial topology, presented good‐to‐excellent test‐retest reliability, accounted for phenotypic interindividual differences in cognition, and are under genetic control. Through integration with multimodal and multiscale data, it is further showed that morphological WM networks are able to predict the patterns of hamodynamic coherence, metabolic synchronization, gene co‐expression, and chemoarchitectonic covariance, and associated with structural connectivity. Moreover, the prediction followed WM functional connectomic hierarchy for the hamodynamic coherence, is related to genes enriched in the forebrain neuron development and differentiation for the gene co‐expression, and is associated with serotonergic system‐related receptors and transporters for the chemoarchitectonic covariance. Finally, applying this approach to multiple sclerosis and neuromyelitis optica spectrum disorders, it is found that both diseases exhibited morphological dysconnectivity, which are correlated with clinical variables of patients and are able to diagnose and differentiate the diseases. Altogether, these findings indicate that morphological WM networks provide a reliable and biologically meaningful means to explore WM architecture in health and disease. [ABSTRACT FROM AUTHOR]

Aging is the greatest known risk factor for most neurodegenerative diseases. Myelin degeneration is an early pathological indicator of these diseases and a normal part of aging; albeit, to a lesser extent. Despite this, little is known about the contribution of age-related myelin degeneration on neurodegenerative disease. Microglia participate in modulating white matter events from demyelination to remyelination, including regulation of (de)myelination by the microglial innate immune receptor triggering receptor expressed on myeloid cells 2 (TREM2). Here, we demonstrate Trem2-deficiency aggravates and accelerates age-related myelin degeneration in the striatum. We show TREM2 is necessary for remyelination by recruiting reparative glia and mediating signaling that promotes OPC differentiation/maturation. In response to demyelination, TREM2 is required for phagocytosis of large volumes of myelin debris. In addition to lysosomal regulation, we show TREM2 can modify the ER stress response, even prior to overt myelin debris, that prevents lipid accumulation and microglial dysfunction. These data support a role for Trem2-dependent interactions in age-related myelin degeneration and suggest a basis for how early dysfunctional microglia could contribute to disease pathology through insufficent repair, defective phagocytosis, and the ER stress response. [ABSTRACT FROM AUTHOR]

• Higher free-water index in bipolar group suggests neuroinflammation links. • ALPS index and disease duration are inversely related suggesting glymphatic issues. • FW-corrected measures linked with DRS indicate severe bipolar impacts myelin. The glymphatic system, an expansive cerebral waste-disposal network, harbors myriad enigmatic facets necessitating elucidation of their nexus with diverse pathologies. Murine investigations have revealed a relationship between the glymphatic system and affective disorders. This study aimed to illuminate the interplay between bipolar disorder and the glymphatic system. Fifty-eight individuals afflicted with bipolar disorder were identified through meticulous psychiatric assessment. These individuals were juxtaposed with a cohort of 66 comparably aged and sex-matched, mentally stable subjects. Subsequent analysis entailed the application of covariance analysis to evaluate along with the perivascular space (ALPS) index, a novel magnetic resonance imaging method for assessing brain interstitial fluid dynamics via diffusion tensor imaging within the bipolar and control cohorts. We also evaluated the correlation between the ALPS index and clinical parameters, which included the Hamilton Depression scale scores, disease duration, and other clinical assessments. Moreover, partial correlation analyses, incorporating age and sex as covariates, were performed to investigate the relationships between the ALPS index and clinical measures within the two cohorts. A noteworthy adverse correlation was observed between the ALPS index and illness duration. A free-water imaging analysis revealed a substantial elevation in the free-water index within the white-matter tracts, prominently centered on the corpus callosum, within the bipolar cohort relative to that in the control group. In analogous cerebral regions, a conspicuous affirmative correlation was observed between the free-water–corrected radial diffusivity and depression rating scales. Our results showed that the protracted course of bipolar disorder concomitantly exacerbated glymphatic system dysregulation. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a leading cause of non-traumatic disability in young adults. The highly dynamic nature of MS lesions has made them difficult to study using traditional histopathology due to the specificity of current stains. This requires numerous stains to track and study demyelinating activity in MS. Thus, we utilized Fourier transform infrared (FTIR) spectroscopy to generate holistic biomolecular profiles of demyelinating activities in MS brain tissue. Multivariate analysis can differentiate MS tissue from controls. Analysis of the absorbance spectra shows profound reductions of lipids, proteins, and phosphate in white matter lesions. Changes in unsaturated lipids and lipid chain length indicate oxidative damage in MS brain tissue. Altered lipid and protein structures suggest changes in MS membrane structure and organization. Unique carbohydrate signatures are seen in MS tissue compared to controls, indicating altered metabolic activities. Cortical lesions had increased olefinic lipid content and abnormal membrane structure in normal appearing MS cortex compared to controls. Our results suggest that FTIR spectroscopy can further our understanding of lesion evolution and disease mechanisms in MS paving the way towards improved diagnosis, prognosis, and development of novel therapeutics. [ABSTRACT FROM AUTHOR]

Metabolic/neurodegenerative encephalopathies encompass a wide list of conditions that share similar clinical and magnetic resonance imaging (MRI) characteristics, challenging the diagnostic process and resulting in numerous tests performed in order to reach a definitive diagnosis. The aims of this multicentric, retrospective and descriptive study are: (I) to describe the MRI features of dogs and cats with metabolic/neurodegenerative encephalopathies; (II) to attempt an MRI recognition pattern classifying these conditions according to the involvement of grey matter, white matter or both; and (III) to correlate the MRI findings with previous literature. A total of 100 cases were recruited, comprising 81 dogs and 19 cats. These included hepatic encephalopathy (20 dogs and three cats), myelinolysis (five dogs), intoxications (seven dogs and one cat), thiamine deficiency (two dogs and seven cats), hypertensive encephalopathy (three dogs and two cats), neuronal ceroid lipofuscinosis (11 dogs and one cat), gangliosidosis (three dogs and two cats), fucosidosis (one dog), L-2-hydroxyglutaric aciduria (13 dogs and one cat), Lafora disease (11 dogs), spongiform leukoencephalomyelopathy (one dog) and cerebellar cortical degeneration (four dogs and two cats). None of the hepatic encephalopathies showed the previously described T1-weighted hyperintensity of the lentiform nuclei. Instead, there was involvement of the cerebellar nuclei (8/23), which is a feature not previously described. Dogs with myelinolysis showed novel involvement of a specific white matter structure, the superior longitudinal fasciculus (5/5). Thiamine deficiency affected numerous deep grey nuclei with novel involvement of the oculomotor nuclei (3/9), thalamic nuclei, subthalamus and cerebellar nuclei (1/9). Cats with hypertensive encephalopathy had a more extensive distribution of the white matter changes when compared to dogs, extending from the parietal and occipital lobes into the frontal lobes with associated mass effect and increased brain volume. Lysosomal storage disease showed white matter involvement only, with neuronal ceroid lipofuscinosis characterised by severe brain atrophy when compared to gangliosidosis and fucosidosis. All patients with L-2-hydroxyglutaric aciduria had a characteristic T2-weighted hyperintense swelling of the cerebral and cerebellar cortical grey matter, resulting in increased brain volume. Lafora disease cases showed either normal brain morphology (5/11) or mild brain atrophy (6/11). Dogs with cerebellar cortical degeneration had more marked cerebellar atrophy when compared to cats. This study shows the important role of MRI in distinguishing different metabolic/neurodegenerative encephalopathies according to specific imaging characteristics. [ABSTRACT FROM AUTHOR]

Introduction: In past work we demonstrated different patterns of white matter (WM) plasticity in females versus males associated with learning a lab-based unilateral motor skill. However, this work was completed in neurologically intact older adults. The current manuscript sought to replicate and expand upon these WM findings in two ways: (1) we investigated biological sex differences in neurologically intact young adults, and (2) participants learned a dynamic full-body balance task. Methods: 24 participants (14 female, 10 male) participated in the balance training intervention, and 28 were matched controls (16 female, 12 male). Correlational tractography was used to analyze changes in WM from pre- to post-training. Results: Both females and males demonstrated skill acquisition, yet there were significant differences in measures of WM between females and males. These data support a growing body of evidence suggesting that females exhibit increased WM neuroplasticity changes relative to males despite comparable changes in motor behavior (e.g., balance). Discussion: The biological sex differences reported here may represent an important factor to consider in both basic research (e.g., collapsing across females and males) as well as future clinical studies of neuroplasticity associated with motor function (e.g., tailored rehabilitation approaches). [ABSTRACT FROM AUTHOR]

Background: Alcohol-related brain degeneration (ARBD) is associated with cognitive–motor impairments that can progress to disability and dementia. White matter (WM) is prominently targeted in ARBD due to chronic neurotoxic and degenerative effects on oligodendrocytes and myelin. Early detection and monitoring of WM pathology in ARBD could lead to therapeutic interventions. Objective: This study examines the potential utility of a non-invasive strategy for detecting WM ARBD using exosomes isolated from serum. Comparative analyses were made with paired tissue (Tx) and membrane vesicles (MVs) from the temporal lobe (TL). Methods: Long Evans rats were fed for 8 weeks with isocaloric liquid diets containing 37% or 0% caloric ethanol (n = 8/group). TL-Tx, TL-MVs, and serum exosomes (S-EVs) were used to examine ethanol's effects on oligodendrocyte glycoprotein, astrocyte, and oxidative stress markers. Results: Ethanol significantly decreased the TL-Tx expression of platelet-derived growth factor receptor alpha (PDGFRA), 2′,3′-cyclic nucleotide 3′ phosphodiesterase (CNPase), proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG), glial fibrillary acidic protein (GFAP), and 8-OHdG, whereas in the TL-MVs, ethanol increased CNPase, PDGFRA, and 8-OHdG, but decreased MOG and GFAP concordantly with TL-Tx. Ethanol modulated the S-EV expression by reducing PLP, nestin, GFAP, and 4-hydroxynonenal (HNE). Conclusion: Chronic ethanol exposures differentially alter the expression of oligodendrocyte/myelin, astrocyte, and oxidative stress markers in the brain, brain MVs, and S-EVs. However, directionally concordant effects across all three compartments were limited. Future studies should advance these efforts by characterizing the relationship between ABRD and molecular pathological changes in brain WM-specific exosomes in serum. [ABSTRACT FROM AUTHOR]

Background. Incidentally discovered low-grade gliomas (iLGGs) are very rare and little is still known about their associated functional imaging activation patterns, white-matter status, and plasticity potential. Recent studies shed light on several clinical factors responsible for the good clinical status observed in these patients versus those with their symptomatic counterpart (sLGGs), including small volume. Comparisons were typically carried out by comparing iLGGs with the wider and more heterogeneous sLGG group. In this study, we investigated whether iLGGs affect the brain differently from comparably small sLGGs. Method. Starting from a sample of 13 patients with iLGG, in the current comparative cross-sectional study, we identified a group of patients with sLGGs, primarily matched by lesion volume. We looked for potential differences between the two groups in language-related functional and structural parameters (the fMRI network associated with naming and white-matter fascicles). Results. The t-test did not show significant differences in the fMRI network, but these emerged when performing masking. No significant differences were observed at the white-matter level. Conclusions. Given that small volumes characterized both groups and that demographic variables were comparable, too, we hypothesized that differences between the two groups could be attributed to alternative lesion-related parameters. We discussed these findings from clinical and neurosurgical perspectives. [ABSTRACT FROM AUTHOR]

Chronic active lesions (CAL) are an important manifestation of chronic inflammation in multiple sclerosis and have implications for non-relapsing biological progression. In recent years, the discovery of innovative MRI and PET-derived biomarkers has made it possible to detect CAL, and to some extent quantify them, in the brain of persons with multiple sclerosis, in vivo. Paramagnetic rim lesions on susceptibility-sensitive MRI sequences, MRI-defined slowly expanding lesions on T1-weighted and T2-weighted scans, and 18-kDa translocator protein-positive lesions on PET are promising candidate biomarkers of CAL. While partially overlapping, these biomarkers do not have equivalent sensitivity and specificity to histopathological CAL. Standardization in the use of available imaging measures for CAL identification, quantification and monitoring is lacking. To fast-forward clinical translation of CAL, the North American Imaging in Multiple Sclerosis Cooperative developed a consensus statement, which provides guidance for the radiological definition and measurement of CAL. The proposed manuscript presents this consensus statement, summarizes the multistep process leading to it, and identifies the remaining major gaps in knowledge. [ABSTRACT FROM AUTHOR]