Prominent White Matter Research Articles

Alzheimer's disease genetic risk and changes in brain atrophy and white matter hyperintensities in cognitively unimpaired adults.

Reduced brain volumes and more prominent white matter hyperintensities on MRI scans are commonly observed among older adults without cognitive impairment. However, it remains unclear whether rates of change in these measures among cognitively normal adults differ as a function of genetic risk for late-onset Alzheimer's disease, including APOE-ɛ4, APOE-ɛ2 and Alzheimer's disease polygenic risk scores (AD-PRS), and whether these relationships are influenced by other variables. This longitudinal study examined the trajectories of regional brain volumes and white matter hyperintensities in relationship to APOE genotypes (N = 1541) and AD-PRS (N = 1093) in a harmonized dataset of middle-aged and older individuals with normal cognition at baseline (mean baseline age = 66 years, SD = 9.6) and an average of 5.3 years of MRI follow-up (max = 24 years). Atrophy on volumetric MRI scans was quantified in three ways: (i) a composite score of regions vulnerable to Alzheimer's disease (SPARE-AD); (ii) hippocampal volume; and (iii) a composite score of regions indexing advanced non-Alzheimer's disease-related brain aging (SPARE-BA). Global white matter hyperintensity volumes were derived from fluid attenuated inversion recovery (FLAIR) MRI. Using linear mixed effects models, there was an APOE-ɛ4 gene-dose effect on atrophy in the SPARE-AD composite and hippocampus, with greatest atrophy among ɛ4/ɛ4 carriers, followed by ɛ4 heterozygouts, and lowest among ɛ3 homozygouts and ɛ2/ɛ2 and ɛ2/ɛ3 carriers, who did not differ from one another. The negative associations of APOE-ɛ4 with atrophy were reduced among those with higher education (P < 0.04) and younger baseline ages (P < 0.03). Higher AD-PRS were also associated with greater atrophy in SPARE-AD (P = 0.035) and the hippocampus (P = 0.014), independent of APOE-ɛ4 status. APOE-ɛ2 status (ɛ2/ɛ2 and ɛ2/ɛ3 combined) was not related to baseline levels or atrophy in SPARE-AD, SPARE-BA or the hippocampus, but was related to greater increases in white matter hyperintensities (P = 0.014). Additionally, there was an APOE-ɛ4 × AD-PRS interaction in relation to white matter hyperintensities (P = 0.038), with greater increases in white matter hyperintensities among APOE-ɛ4 carriers with higher AD-PRS. APOE and AD-PRS associations with MRI measures did not differ by sex. These results suggest that APOE-ɛ4 and AD-PRS independently and additively influence longitudinal declines in brain volumes sensitive to Alzheimer's disease and synergistically increase white matter hyperintensity accumulation among cognitively normal individuals. Conversely, APOE-ɛ2 primarily influences white matter hyperintensity accumulation, not brain atrophy. Results are consistent with the view that genetic factors for Alzheimer's disease influence atrophy in a regionally specific manner, likely reflecting preclinical neurodegeneration, and that Alzheimer's disease risk genes contribute to white matter hyperintensity formation.

A prominent vertical occipital white matter fasciculus unique to primate brains

Vision in humans and other primates enlists parallel processing streams in the dorsal and ventral visual cortex, known to support spatial and object processing, respectively. These streams are bridged, however, by a prominent white matter tract, the vertical occipital fasciculus (VOF), identified in both classical neuroanatomy and recent diffusion-weighted magnetic resonance imaging (dMRI) studies. Understanding the evolution of the VOF may shed light on its origin, function, and role in visually guided behaviors. To this end, we acquired high-resolution dMRI data from the brains of select mammalian species, including anthropoid and strepsirrhine primates, a tree shrew, rodents, and carnivores. In each species, we attempted to delineate the VOF after first locating the optic radiations in the occipital white matter. In all primate species examined, the optic radiation was flanked laterally by a prominent and coherent white matter fasciculus recognizable as the VOF. By contrast, the equivalent analysis applied to four non-primate species from the same superorder as primates (tree shrew, ground squirrel, paca, and rat) failed to reveal white matter tracts in the equivalent location. Clear evidence for a VOF was also absent in two larger carnivore species (ferret and fox). Although we cannot rule out the existence of minor or differently organized homologous fiber pathways in the non-primate species, the results suggest that the VOF has greatly expanded, or possibly emerged, in the primate lineage. This adaptation likely facilitated the evolution of unique visually guided behaviors in primates, with direct impacts on manual object manipulation, social interactions, and arboreal locomotion.

Chapter 17 - Familial cerebral amyloid disorders with prominent white matter involvement

Familial cerebral amyloid disorders are characterized by the accumulation of fibrillar protein aggregates, which deposit in the parenchyma as plaques and in the vasculature as cerebral amyloid angiopathy (CAA). Amyloid β (Aβ) is the most common of these amyloid proteins, accumulating in familial and sporadic forms of Alzheimer's disease and CAA. However, there are also a number of rare, hereditary, non-Aβ cerebral amyloidosis. The clinical manifestations of these familial cerebral amyloid disorders are diverse, including cognitive or neuropsychiatric presentations, intracerebral hemorrhage, seizures, myoclonus, headache, ataxia, and spasticity. Some mutations are associated with extensive white matter hyperintensities on imaging, which may or may not be accompanied by hemorrhagic imaging markers of CAA; others are associated with occipital calcification. We describe the clinical, imaging, and pathologic features of these disorders and discuss putative disease mechanisms. Familial disorders of cerebral amyloid accumulation offer unique insights into the contributions of vascular and parenchymal amyloid to pathogenesis and the pathways underlying white matter involvement in neurodegeneration. With Aβ immunotherapies now entering the clinical realm, gaining a deeper understanding of these processes and the relationships between genotype and phenotype has never been more relevant.

White matter abnormalities in 15 subjects with SPG76.

Hereditary spastic paraplegias (HSPs) are heterogenous genetic disorders characterized by progressive pyramidal tract involvement. SPG76 is a recently identified form of HSP, caused by biallelic calpain-1 (CAPN1) variants. The most frequently described MRI abnormality in SPG76 is mild cerebellar atrophy and non-specific white matter abnormalities were reported in only one case. Following the identification of prominent white matter abnormalities in a subject with CAPN1 variants, which delayed the diagnosis, we aimed to verify the presence of MRI patterns of white matter involvement specific to this HSP. We performed a retrospective radiological qualitative analysis of 15 subjects with SPG76 (4 previously unreported) initially screened for white matter involvement. Moreover, we performed quantitative analyses in our proband with available longitudinal studies. We observed bilateral, periventricular white matter involvement in 12 subjects (80%), associated with multifocal subcortical abnormalities in 5 of them (33.3%). Three subjects (20%) presented only multifocal subcortical involvement. Longitudinal quantitative analyses of our proband revealed increase in multifocal white matter lesion count and increased area of periventricular white matter involvement over time. SPG76 should be added to the list of HSPs with associated white matter abnormalities. We identified periventricular white matter involvement in subjects with SPG76, variably associated with multifocal subcortical white matter abnormalities. These findings, in the presence of progressive spastic paraparesis, can mislead the diagnostic process towards an acquired white matter disorder.

Teaching Neuro Images : Prominent spinal cord atrophy and white matter changes in adult polyglucosan body disease

A 48-year-old man of Ashkenazi Jewish descent developed neurogenic bladder and mild cognitive dysfunction. Neurologic examination and CSF analysis were unremarkable. Brain MRI demonstrated white matter changes in the internal capsule, optic radiations, mesencephalon, superior cerebellar peduncles, pons, and medulla (figure 1) and prominent medullary and spinal cord atrophy (figure 2). These findings are classically found in adult polyglucosan body disease (APBD).1 Glycogen branching enzyme GBE1 gene sequencing revealed that the patient was compound heterozygous (c.691+2T>C and c.986 A>C). APBD should be considered in patients with adult-onset leukodystrophy and spinal atrophy; genetic testing is crucial to prevent misdiagnosis with multiple sclerosis and other leukodystrophies.2

Altered White Matter Integrity in ADHD Revealed by Meta-analysis of Tract-based Spatial Statistics

Objective: We conducted an updated coordinate-based meta-analysis (CBMA) to determine the most prominent and robust white matter (WM) abnormalities in ADHD based on tract-based spatial statistics (TBSS) findings. Method: The seed-based d mapping (SDM) software was applied to compare regional fractional anisotropy (FA) alterations in ADHD. Subgroup meta-analyses in the pure ADHD without comorbidity subgroup, the children and adolescents subgroup, and the adults subgroup were also explored, respectively. Meta-regression analysis was subsequently used to examine potential correlations between demographics and FA changes. Results: Only one cluster in the splenium of corpus callosum (CC) exhibited age-related FA decrease in ADHD individuals in the pooled meta-analysis. The adults ADHD subgroup revealed two clusters with reduced FA lied in the splenium and body of CC. Conclusion: This updated CBMA confirmed the WM abnormalities in the splenium of CC in ADHD, and improved our understanding of the pathogenesis of this neurodevelopmental disorder.

Callosal Fiber Length Scales with Brain Size According to Functional Lateralization, Evolution, and Development.

Brain size significantly impacts the organization of white matter fibers. Fiber length scaling, the degree to which fiber length varies according to brain size, was overlooked. We investigated how fiber lengths within the corpus callosum, the most prominent white matter tract, vary according to brain size. The results showed substantial variation in length scaling among callosal fibers, replicated in two large healthy cohorts (∼2000 human subjects, including both sexes). The underscaled callosal fibers mainly connected the precentral gyrus and parietal cortices, whereas the overscaled callosal fibers mainly connected the prefrontal cortices. The variation in such length scaling was biologically meaningful: larger scaling corresponded to larger neurite density index but smaller fractional anisotropy values; cortical regions connected by the callosal fibers with larger scaling were more lateralized functionally as well as phylogenetically and ontogenetically more recent than their counterparts. These findings highlight an interaction between interhemispheric communication and organizational and adaptive principles underlying brain development and evolution.SIGNIFICANCE STATEMENT Brain size varies across evolution, development, and individuals. Relative to small brains, the neural fiber length in large brains is inevitably increased, but the degree of such increase may differ between fiber tracts. Such a difference, if it exists, is valuable for understanding adaptive neural principles in large versus small brains during evolution and development. The present study showed a substantial difference in the length increase between the callosal fibers that connect the two hemispheres, replicated in two large healthy cohorts. Together, our study demonstrates that reorganization of interhemispheric fibers length according to brain size is intrinsically related to fiber composition, functional lateralization, cortical myelin content, and evolutionary and developmental expansion.

CCsNeT: Automated Corpus Callosum segmentation using fully convolutional network based on U-Net

BackgroundCorpus Callosum (CC) is the most prominent white matter bundle in the human brain that connects the left and right cerebral hemispheres. The present paper proposes a novel method for CC segmentation from 2D T1- weighted mid-sagittal brain MRI. The robust segmentation of CC in the mid-sagittal plane plays a vital role in the quantitative study of CC structural features related to various neurological disorders such as Autism, epilepsy, Alzheimer's disease, and more. MethodologyIn this perspective, the current work proposes a Fully Convolutional Network (FCN), a deep learning architecture-based U-Net model for automated CC segmentation from 2D brain MRI images referred to as CCsNeT. The architecture consists of a 35-layers deep, fully convolutional network with two paths, namely contracting and extracting, connected in a U-shape that automatically extracts spatial information. ResultsThis attempt uses the benchmark brain MRI database comprising ABIDE and OASIS for the experimental investigation. Compared to existing CC segmentation methodologies, the proposed CCsNeT presented improved results achieving Dice Coefficient = 96.74%, and Sensitivity = 97.01% with ABIDE dataset and were further validated against the variants of U-Net model U-Net++, MultiResU-Net, and CE-Net. Further, the performance of CCsNeT has been validated on OASIS and Real-Time Images dataset. ConclusionFinally, the proposed CCsNeT extracts important CC characteristics such as CC area (CCA) and total brain area (TBA) to categorize the considered 2D MRI slices into control and autism spectrum disorder (ASD) groups, thereby minimizing the inter-observer and intra-observer variability.

Confirming Pathogenicity of the F386L PSEN1 Variant in a South Asian Family With Early-Onset Alzheimer Disease.

ObjectivesThe F386L PSEN1 variant has been reported in 1 Japanese family with limited clinical information. We aimed to prove that F386L is pathogenic by demonstrating that it segregates with early-onset Alzheimer disease (AD).MethodsEight individuals in a South Asian family provided DNA for genetic testing and underwent a neurologic examination.ResultsThe female proband was diagnosed with AD at age 45 years and died at age 49 years. She had a CSF biomarker profile consistent with AD, and her florbetaben PET scan was amyloid positive with high uptake in the striatum. Her MRI showed no prominent white matter disease. Her affected relatives had an age at onset range of 38–57 years and had imaging and biomarker profiles similar to hers.DiscussionThe results presented here, in conjunction with the prior report, confirm the pathogenicity of F386L. Furthermore, our study highlights the importance of studying families from underrepresented populations to identify or confirm the pathogenicity of rare variants that may be specific to certain genetic ancestries.

The association of motoric cognitive risk with incident dementia and neuroimaging characteristics: The Atherosclerosis Risk in Communities Study.

Motoric cognitive risk (MCR), a clinical syndrome characterized by slow gait speed and subjective cognitive complaints, has been associated with dementia risk. The neuropathological features underlying MCR remain poorly understood. The Atherosclerosis Risk in Communities (ARIC) community-based cohort study classified participants using standardized criteria as MCR+/- and mild cognitive impairment (MCI)+/- at study baseline (2011-2013). We examined the 5-year dementia risk and baseline brain structural/molecular abnormalities associated with MCR+ and MCI+ status. Of 5023 nondemented participants included, 204 were MCR+ and 1030 were MCI+. Both MCR+ and MCI+ participants demonstrated increased dementia risk. The pattern of structural brain abnormalities associated with MCR+ differed from that of MCI+. Whereas MCI+ was associated with comparatively smaller volumes in brain regions vulnerable to Alzheimer's disease pathology, MCR+ status was associated with smaller volumes in frontoparietal regions and greater white matter abnormalities. MCR may represent a predementia syndrome characterized by prominent white matter abnormalities and frontoparietal atrophy.

Another Piece of the Puzzle of Anomalous Connectivity in Joubert's Syndrome.

We report on the conventional and diffusion tensor imaging (DTI) findings of a 2-year-old child with clinical presentation of Joubert's Syndrome (JS) and brainstem structural abnormalities as depicted by neuroimaging.Conventional magnetic resonance imaging (MRI) showed a "molar tooth" configuration of the brainstem. A band-like formation coursing in an apparent axial plane anterior to the interpeduncular fossa was noted and appeared to partially cover the interpeduncular fossa.DTI maps and three-dimensional (3D) tractography demonstrated a prominent red-encoded white matter bundle anterior to the midbrain. Probable aberrant course of the bilateral corticospinal tracts (CST) was also depicted. Absence of the decussation of the superior cerebellar peduncles and elongated thickened, horizontal superior cerebellar peduncle (SCP) reflecting the molar tooth sign were also shown.Our report and the review of the published cases suggest that DTI and tractography may be very helpful to differentiate between interpeduncular heterotopias and similarly located white matter bundles corroborating the underlying etiology of axonal guidance disorders in the complex group of ciliopathies including JS. Our case represents an important additional puzzle piece to explore the variability of these ciliopathies.

Connectivity-Based Topographical Changes of the Corpus Callosum During Aging.

Background: The corpus callosum (CC) is the most prominent white matter connection for interhemispheric information transfer. It is implicated in a variety of cognitive functions, which tend to decline with age. The region-specific projections of the fiber bundles with microstructural heterogeneity of the CC are associated with cognitive functions and diseases. However, how the CC is associated with the information transfer within functional networks and the connectivity changes during aging remain unclear. Studying the CC topography helps to understand the functional specialization and age-related changes of CC subregions.Methods: Diffusion tractography was used to subdivide the CC into seven subregions from 1,086 healthy volunteers within a wide age range (21–90 years), based on the connections to the cortical parcellations of the functional networks. Quantitative diffusion indices and connection probability were calculated to study the microstructure differences and age-related changes in the CC subregions.Results: According to the population-based probabilistic topography of the CC, part of the default mode network (DMN) and limbic network (LN) projected fibers through the genu and rostrum; the frontoparietal network (FPN), ventral attention network (VA) and somatomotor networks (SM) were interconnected by the CC body; callosal fibers arising from the part of the default mode network (DMN), dorsal attention network (DA) and visual network (VIS) passed through the splenium. Anterior CC subregions interconnecting DMN, LN, FPN, VA, and SM showed lower fractional anisotropy (FA) and higher mean diffusivity (MD) and radial diffusivity (RD) than posterior CC subregions interconnecting DA and VIS. All the CC subregions showed slightly increasing FA and decreasing MD, RD, and axial diffusivity (AD) at younger ages and opposite trends at older ages. Besides, the anterior CC subregions exhibited larger microstructural and connectivity changes compared with the posterior CC subregions during aging.Conclusion: This study revealed the callosal subregions related to functional networks and uncovered an overall “anterior-to-posterior” region-specific changing trend during aging, which provides a baseline to identify the presence and timing of callosal connection states.

Complex Protein Astrogliopathy in an Octogenarian

Combination of multiple neurodegenerative proteinopathies is frequent in the elderly. We report the case of an octogenarian who attempted suicide and deceased after hospital admission. Anatomical mapping was performed in several cortical and subcortical brain regions using antibodies against phospho-tau, 4R tau, 3R tau, phospho-TDP-43, ubiquitin, α-synuclein, Aβ and p62. Unexpectedly, histopathologic examination showed prominent subpial, subependymal, grey and white matter, and perivascular aging-related tau astrogliopathy (ARTAG) affecting cortical and subcortical brain regions. This pathology was associated with intermediate Alzheimer’s disease neuropathologic change, cerebral amyloid angiopathy, Lewy-body-type and astroglial synuclein proteinopathy and a multiple system TDP-43 proteinopathy involving also the astroglia. This unusual case of extensive and widespread ARTAG with a complex multiproteinopathy may represent an independent disease entity in the elderly with tau astrogliopathy as the leading force.Learning ObjectiveRecognize astroglial protein deposits in neurodegeneration

Homozygous missense WIPI2 variants cause a congenital disorder of autophagy with neurodevelopmental impairments of variable clinical severity and disease course.

WIPI2 is a member of the human WIPI protein family (seven-bladed b-propeller proteins binding phosphatidylinositols, PROPPINs), which play a pivotal role in autophagy and has been implicated in the pathogenesis of several neurological conditions. The homozygous WIPI2 variant c.745G>A; p.(Val249Met) (NM_015610.4) has recently been associated with a neurodevelopmental disorder in a single family. Using exome sequencing and Sanger segregation analysis, here, two novel homozygous WIPI2 variants [c.551T>G; p.(Val184Gly) and c.724C>T; p.(Arg242Trp) (NM_015610.4)] were identified in four individuals of two consanguineous families. Additionally, follow-up clinical data were sought from the previously reported family. Three non-ambulant affected siblings of the first family harbouring the p.(Val184Gly) missense variant presented with microcephaly, profound global developmental delay/intellectual disability, refractory infantile/childhood-onset epilepsy, progressive tetraplegia with joint contractures and dyskinesia. In contrast, the proband of the second family carrying the p.(Arg242Trp) missense variant, similar to the initially reported WIPI2 cases, presented with a milder phenotype, encompassing moderate intellectual disability, speech and visual impairment, autistic features, and an ataxic gait. Brain MR imaging in five patients showed prominent white matter involvement with a global reduction in volume, posterior corpus callosum hypoplasia, abnormal dentate nuclei and hypoplasia of the inferior cerebellar vermis. To investigate the functional impact of these novel WIPI2 variants, we overexpressed both in WIPI2-knockout HEK293A cells. In comparison to wildtype, expression of the Val166Gly WIPI2b mutant resulted in a deficient rescue of LC3 lipidation whereas Arg224Trp mutant increased LC3 lipidation, in line with the previously reported Val231Met variant. These findings support a dysregulation of the early steps of the autophagy pathway. Collectively, our findings provide evidence that biallelic WIPI2 variants cause a neurodevelopmental disorder of variable severity and disease course. Our report expands the clinical spectrum and establishes WIPI2-related disorder as a congenital disorders of autophagy.

Superficial Siderosis and Microbleed Restricted in Cortex Might Be Correlated to Atrophy and Cognitive Decline in Sneddon's Syndrome.

Objective: Sneddon's syndrome is a rare non-inflammatory arteriopathy affecting small and medium-sized arteries, characterized by a generalized livedo reticularis and recurrent transient ischemic attack or ischemic stroke. Hemorrhagic stroke was reported in limited cases, but microbleeds and superficial siderosis were rarely issued. We aimed to investigate the hemorrhagic imaging features of Sneddon's syndrome and explore the possible mechanism and clinical relevance.Methods: Clinical data and cerebral MR imaging including T2* sequence of seven consecutive patients with Sneddon's syndrome were reviewed.Results: The most common neurological manifestations were cognitive impairment and stroke attack (71.4%), followed by seizures and movement disorder (28.6%). Cerebral microbleeds were detected in six patients on T2* sequence, all of them presented with cortical microbleeds, only one of them with microbleeds in basal ganglion. More than five microbleeds were observed in four of these six patients. The majority of the microbleeds were predominantly cortical restricted and especially located in the cortical watersheds. Multiple superficial siderosis were identified mainly involving cortical watersheds in five cases. Significant cerebral atrophy with prominent secondary white matter hyperintensities in bilateral cortical watersheds were also observed. Abnormal tortuous and multiple focal occlusion of bilateral distal MCA were shown in one patient by DSA. No stenosis of proximal segment of cerebral arteries was detected in all the patients.Conclusions: This is the first report illustrating abundant cortical microbleeds and superficial siderosis mainly involved the anterior and posterior cortical watersheds in Sneddon's syndrome. The surprisingly identical topographic distribution of hemorrhagic lesions and the obvious atrophy suggest cerebral atrophy might be secondary to the microangiopathy related hemorrhagic lesions and further contribute to the neurological deficit, especially the early cognitive decline in Sneddon syndrome.

Brain MRI Findings in Patients in the Intensive Care Unit with COVID-19 Infection.

Online supplemental material is available for this article.

Abstract WP476: Remarkable Hemorrhagic Imaging Manifestations Might Be Responsible for the Prominent Atrophy and Cognitive Decline in Sneddon Syndrome

Objective: Sneddon syndrome is a rare non-inflammatory arteriopathy affecting small and medium-sized arteries, characterized by a generalized livedo reticularis and recurrent ischemic stroke. Hemorrhagic stroke was reported in limited cases, but microbleeds and superficial siderosis were rarely issued, which might be underdiagnosed due to the limitation of technique. We aimed to investigate the hemorrhagic imaging features of Sneddon syndrome and explore the possible mechanism and clinical relevance. Methods: Clinical data and cerebral MR imaging including T2* sequence of 6 consecutive patients with Sneddon syndrome were reviewed. Results: The most common neurological manifestations were cognitive impairment and stroke attack(66.7%), followed by seizures(33.3%) and movement disorder(16.7%). Cerebral microbleeds were detected in all the patients on T2* sequence,four of whom presented more than 5 microbleeds.The majority of the microbleeds were predominantly cortical restricted and especially located in the cortical watersheds. Multiple superficial siderosis were identified and mainly involved cortical watersheds in 5 cases. Significant cerebral atrophy with prominent secondary white matter hyperintensities in bilateral cortical watersheds were also observed. Abnormal tortuous and multiple focal occlusion of bilateral distal MCA were shown in 1 patient by DSA. No stenosis of proximal segment of cerebral arteries was detected in all the patients. Conclusions: This is the first report illustrating abundant cortical microbleeds and superficial siderosis mainly involved the anterior and posterior cortical watersheds in Sneddon syndrome. The surprisingly identical topographic distribution of hemorrhagic lesions and the corresponding obvious atrophy suggest cerebral atrophy might be secondary to the microangiopathy related hemorrhagic lesions and further contribute to the neurological deficit, especially the early cognitive decline in Sneddon syndrome,although further investigation is needed to elucidate the precise underlying pathogenesis. These highlight cortical microbleeds and superficial siderosis located in cortical watershed and the secondary atrophy in youth might be highly indicative of Sneddon syndrome.

Prominent White Matter Involvement in Multiple System Atrophy of Cerebellar Type.

Sporadic degenerative ataxia patients fall into 2 major groups: multiple system atrophy with predominant cerebellar ataxia (MSA-C) and sporadic adult-onset ataxia (SAOA). Both groups have cerebellar volume loss, but little is known about the differential involvement of gray and white matter in MSA-C when compared with SAOA. The objective of this study was to identify structural differences of brain gray and white matter between both patient groups. We used magnetic resonance imaging to acquire T1-weighted images and diffusion tensor images from 12 MSA-C patients, 31 SAOA patients, and 55 healthy controls. Magnetic resonance imaging data were analyzed with voxel-based-morphometry, tract-based spatial statistics, and tractography-based regional diffusion tensor images analysis. Whole-brain and cerebellar-focused voxel-based-morphometry analysis showed gray matter volume loss in both patient groups when compared with healthy controls, specifically in the cerebellar areas subserving sensorimotor functions. When compared with controls, the SAOA and MSA-C patients showed white matter loss in the cerebellum, whereas brainstem white matter was reduced only in the MSA-C patients. The tract-based spatial statistics revealed reduced fractional anisotropy within the pons and cerebellum in the MSA-C patients both in comparison with the SAOA patients and healthy controls. In addition, tractography-based regional analysis showed reduced fractional anisotropy along the corticospinal tracts in MSA-C, but not SAOA. Although in our cohort extent and distribution of gray and white matter loss were similar between the MSA-C and SAOA patients, magnetic resonance imaging data showed prominent microstructural white matter involvement in the MSA-C patients that was not present in the SAOA patients. Our findings highlight the significance of microstructural white matter changes in the differentiation between both conditions. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Severer nodular lesion in white matter than in gray matter in simian immunodeficiency virus-infected monkey, but not closely correlated with viral infection.

Immune cell accumulation and white matter anomaly are common features of HIV (human immunodeficiency virus) -infected patients in combination antiretroviral therapy (cART) era. Neuroimaging tests on cART treated patients displayed prominent diffuse white matter lesions. Notably, immune cell nodular lesion (NL) was a conspicuous type of pathological change in HIV/SIV (simian immunodeficiency virus) infected brain before cART. Therefore, we used SIV infected brain to investigate the distribution of those NLs in gray and white matters. We found a significant higher number of NLs in white matter than that in gray matter. However, virus infection correlated with macrophage NLs but not with microglia NLs, especially in white matter. In addition, NLs interrupted white matter integrity more severely, since even tiny nodules could disconnect nerve fibers in white matter tracts. In the gray matter with dense myelinated axons, NLs obviously encroached those fibers; in the area of few myelinated axons, small nodules well co-localized with extracellular matrix between neurons.

Evaluating spatiotemporal microstructural alterations following diffuse traumatic brain injury.

BackgroundDiffuse traumatic brain injury (TBI) is known to lead to microstructural changes within both white and grey matter detected in vivo with diffusion tensor imaging (DTI). Numerous studies have shown alterations in fractional anisotropy (FA) and mean diffusivity (MD) within prominent white matter tracts, but few have linked these to changes within the grey matter with confirmation via histological assessment. This is especially important as alterations in the grey matter may be predictive of long-term functional deficits.MethodsA total of 33 male Sprague Dawley rats underwent severe closed-head TBI. Eight animals underwent tensor-based morphometry (TBM) and DTI at baseline (pre-TBI), 24 hours (24 h), 7, 14, and 30 days post-TBI. Immunohistochemical analysis for the detection of ionised calcium-binding adaptor molecule 1 (IBA1) to assess microglia number and percentage of activated cells, β-amyloid precursor protein (APP) as a marker of axonal injury, and myelin basic protein (MBP) to investigate myelination was performed at each time-point.ResultsDTI showed significant alterations in FA and RD in numerous white matter tracts including the corpus callosum, internal and external capsule, and optic tract and in the grey-matter in the cortex, thalamus, and hippocampus, with the most significant effects observed at 14 D post-TBI. TBM confirmed volumetric changes within the hippocampus and thalamus. Changes in DTI were in line with significant axonal injury noted at 24 h post-injury via immunohistochemical analysis of APP, with widespread microglial activation seen within prominent white matter tracts and the grey matter, which persisted to 30 D within the hippocampus and thalamus. Microstructural alterations in MBP+ve fibres were also noted within the hippocampus and thalamus, as well as the cortex.ConclusionThis study confirms the widespread effects of diffuse TBI on white matter tracts which could be detected via DTI and extends these findings to key grey matter regions, with a comprehensive investigation of the whole brain. In particular, the hippocampus and thalamus appear to be vulnerable to ongoing pathology post-TBI, with DTI able to detect these alterations supporting the clinical utility in evaluating these regions post-TBI.