Diffuse White Matter Research Articles

Effects of psilocybin on mouse brain microstructure.

There is surging interest in the therapeutic potential of psychedelic compounds like psilocybin in the treatment of psychiatric illnesses like major depressive disorder (MDD). Recent studies point to the rapid antidepressant effect of psilocybin; however, the biological mechanisms underlying these differences remain unknown. This study determines the feasibility of using diffusion MRI to characterize and define the potential spatiotemporal microstructural differences in the brain following psilocybin treatment in C57BL/6J male mice. 11-15 week-old C57BL/6J male mice were randomized to receive psilocybin, 6F-DET (6-fluoro-N,Ndiethyltryptamine), or saline and ex vivo imaged 24h (n=18) and 72h (n=18) post treatment. A one-way ANOVA with multiple comparison testing (Bonferroni correction) assessed diffusion metric differences (tractography, DTI, NODDI) between the three groups and was performed in the following regions of interest: amygdala, striatum, hippocampus, thalamus, primary visual cortex area, frontal association cortex, and medial prefrontal cortex at 24h and 72h post drug administration. Psilocybin treated mice demonstrated structural connectivity differences at 72h in the frontal association cortex (compared to saline, mean tract length increases, p=0.03). Psilocybin also induced microstructural differences at 24h post-injection in the primary visual cortex (compared to saline, MD increases, p=0.02) and 72h post-injection in the striatum (compared to saline; MD increases, p= 0.02, NDI decreases, p=0.02) and hippocampus (compared to saline; MD increases, p=0.04, NDI decreases, p=0.02). Diffusion microstructure imaging and white matter tractography are sensitive methods to detect and characterize the neural substrates and microstructural differences accompanying psilocybin treatment. These findings suggest the potential role for diffusion microstructure imaging to quantify the bioeffects of psychedelics like psilocybin on the brain, monitor treatment response, and identify salient clinical endpoints in an emerging therapeutic option for patients with MDD. dMRI= diffusion-weighted MRI; 6F-DET= 6-fluoro-N,N-diethyltryptamine; NODDI= neurite orientation dispersion and density imaging; DTI= diffusion tensor imaging; NDI= neurite density index; ODI= orientation dispersion index; FA= fractional anisotropy; MD= mean diffusivity; MTL= mean tract length; mPFC= medial prefrontal cortex.

Clinical Relevance of 'Cap' and 'Track' Development after Recent Small Subcortical Infarct.

After a recent small subcortical infarct (RSSI), some patients develop perilesional or remote hyperintensities ('caps/tracks') to the index infarct on T2/FLAIR MRI. However, their clinical relevance remains unclear. We investigated the clinicoradiological correlates of 'caps/tracks', and their impact on long-term outcomes following RSSI. We identified participants with lacunar stroke and MRI-confirmed RSSI from 3 prospective studies. At baseline, we collected risk factors, RSSI characteristics, small vessel disease (SVD) features, and microstructural integrity on diffusion imaging. Over 1-year, we repeated MRI and recorded 'caps/tracks' blinded to other data. We evaluated predictors of 'caps/tracks', and their association with 1-year functional (modified Rankin Scale score ≥2), mobility (Timed Up-and-Go), cognitive outcomes (Montreal Cognitive Assessment [MoCA] score <26), and recurrent cerebrovascular events (stroke/transient ischemic attack/incident infarct) using multivariable regression. Among 185 participants, 93 (50.3%) developed 'caps/tracks' first detected at median 198 days after stroke. 'Caps/tracks' were independently predicted by baseline factors: larger RSSI, RSSI located in white matter, higher SVD score, and higher mean diffusivity in normal-appearing white matter (odds ratio [OR] [95% confidence interval {CI}], 1.15 [1.07-1.25], 6.01 [2.80-13.57], 1.77 [1.31-2.44], 1.42 [1.01-2.03]). At 1 year, 'cap/track' formation was associated with worse functional outcome (OR: 3.17, 95% CI: 1.28-8.22), slower gait speed (β: 0.13, 95% CI: 0.01-0.25), and recurrent cerebrovascular events (hazard ratio [HR]: 2.05, 95% CI: 1.05-4.02), but not with cognitive impairment. 'Caps/tracks' after RSSI are associated with worse clinical outcomes, and may reflect vulnerability to progressive SVD-related injury. Reducing 'caps/tracks' may offer early efficacy markers in trials aiming to improve outcome after lacunar stroke. ANN NEUROL 2025.

Lifespan cardiometabolic exposures are associated with midlife white matter microstructure: The Bogalusa Heart Study.

Compartment model analysis of diffusion MRI data provides unique information on the microstructural properties of white matter. However, studies relating compartment model microstructural measures to longitudinal cardiometabolic health data are rare. 130 cognitively healthy participants in the Bogalusa Heart Study completed diffusion MRI scans. Compartment model analysis was performed, and summary metrics were measured in organized and diffuse white matter. Multiple linear regression models were used to relate the white matter microstructure metrics to demographics and cardiometabolic risk factors. In both organized and diffuse white matter, age was associated with worse diffusion metrics, women had better diffusion metrics than men, and African American participants had worse diffusion metrics compared to White participants. Greater blood pressure in pre-adulthood was associated with worse diffusion metrics in midlife. Summary metrics from compartment model analyses of diffusion MRI data were associated cardiometabolic risk factors from youth to midlife as well as demographic factors.

Choroid plexus volume is enlarged in long COVID and associated with cognitive and brain changes.

Patients with post-COVID condition (PCC) present with diverse symptoms which persist at long-term after SARS-CoV-2 infection. Among these symptoms, cognitive impairment is one of the most prevalent and has been related to brain structural and functional changes. The underlying mechanisms of these cognitive and brain alterations remain elusive but neuroinflammation and immune mechanisms have been majorly considered. In this sense, the choroid plexus (ChP) volume has been proposed as a marker of neuroinflammation in immune-mediated conditions and the ChP epithelium has been found particularly susceptible to the effects of SARS-CoV-2. The objective was to investigate the ChP in PCC and evaluate its relationships with cognition, brain, and immunological alterations. One-hundred and twenty-nine patients with PCC after a mean of 14.79 ± 7.17 months of evolution since the infection and 36 healthy controls were recruited. Participants underwent a neuropsychological, and neuroimaging assessment and immunological markers evaluation. Results revealed ChP volume enlargement in PCC compared to healthy controls. The ChP enlargement was associated with cognitive dysfunction, grey matter volume reduction in frontal and subcortical areas, white matter integrity and diffusivity changes and functional connectivity changes. These ChP changes were also related to intermediate monocytes levels. Findings suggest that the ChP integrity may play a relevant role in the pathophysiology of cognitive deficits and the observed brain changes in PCC. The previously documented function of the ChP in maintaining brain homeostasis and regulating the entry of immune cells into the brain supports the presence of neuroinflammatory mechanisms in this disorder.

Clinical characteristics of the Ala21Val variant in the myelin proteolipid protein 1 (PLP1) gene associated with Pelizaeus-Merzbacher disease in a Brazilian male patient.

Here, we report the case of a 29-year-old male with classic Pelizaeus-Merzbacher disease (PMD) harboring the PLP1 variant NM_000533.5:c.62 C > T, leading to an NP_000524.3:p.(Ala21Val) alteration in the first transmembrane domain of the protein. He presented with developmental delays, nystagmus, spastic paraparesis, optic atrophy, dysphagia, appendicular ataxia, and progressive head tremor. Brain MRI revealed hypomyelination, diffuse white matter hyperintensity, and atrophy of the corpus callosum and cerebellum, expanding the known clinical spectrum of PMD.

TSPO-PET Reveals Higher Inflammation in White Matter Disrupted by Paramagnetic Rim Lesions in Multiple Sclerosis.

To explore whether the inflammatory activity is higher in white matter (WM) tracts disrupted by paramagnetic rim lesions (PRLs) and if inflammation in PRL-disrupted WM tracts is associated with disability in people with multiple sclerosis (MS). Forty-four MS patients and 16 healthy controls were included. 18 kDa-translocator protein positron emission tomography (TSPO-PET) with the 11 C-PK11195 radioligand was used to measure the neuroinflammatory activity. The Network Modification Tool was used to identify WM tracts disrupted by PRLs and non-PRLs that were delineated on MRI. The Expanded Disability Status Scale was used to measure disability. MS patients had higher inflammatory activity in whole brain WM compared to healthy controls (p=0.001). Compared to patients without PRLs, patients with PRLs exhibited higher levels of inflammatory activity in the WM tracts disrupted by any type of lesions (p=0.02) or PRLs (p=0.004). In patients with at least one PRL, inflammatory activity was higher in WM tracts highly disrupted by PRLs compared to WM tracts highly disrupted by non-PRLs (p=0.009). Elevated inflammatory activity in highly disrupted WM tracts was associated with increased disability in patients with PRL (p=0.03), but not in patients without PRL (p=0.2). This study suggests that patients with PRLs may exhibit more diffuse WM inflammation in addition to higher inflammation along WM tracts disrupted by PRLs compared to non-PRLs, which could contribute to larger lesion volumes and faster disability progression. Imaging PRLs may serve to identify patients with both focal and diffuse inflammation, guiding therapeutic interventions aimed at reducing inflammation and preventing progressive disability in MS.

Parkinsonism associated with prolonged unresponsive wakefulness syndrome after blunt head injury: a clinico-pathological study.

Objective: Survival after traumatic brain injury (TBI) and posttraumatic parkinsonian-like symptoms is increasing, in particular in those patients developing during disease course an unresponsive wakefulness syndrome (UWS) previously termed persistent vegetative state. Material & methods: 100 patients with disorders of consciousness after a blunt TBI ranging from deep coma to defective states / minimal cognitive state survived between 12 and 900 days. 15 patients developed parkinsonian symptoms, which were correlated with their neuropathological changes. Results: The patients, surviving either UWS recovery (n = 10) or defective minimally conscious state (MCS) (n = 5), clinically presented with severe (n = 7), moderate (n = 5), or mild (n = 3) parkinsonian symptoms mainly comprising symmetrical rigidity, amimia, hypo- / akinesia and convergence disorder, which in six patients were associated with unilateral or bilateral resting tremor. Following levodopa treatment, 11 patients showed mild to moderate improvement and four patients almost complete improvement of UWS, parkinsonism or both. Neuropathology revealed in most cases supratentorial traumatic lesions such as contusions, cerebral hemorrhages and diffuse white matter lesions. In addition to lesions in the basal ganglia and hippocampus, all cases displayed older lesions in the dorsolateral or lateral parts of the pons and in lower midbrain with various involvement of substantia nigra. The periaqueductal gray and upper midbrain tegmentum were however preserved. The pattern of brainstem lesions correlated with the sequelae of transtentorial shifting due to increased intracranial pressure. Conclusions: These and other rare observations following blunt TBI confirm the importance of the pattern of secondary brainstem lesions for the development and prognosis of UWS and rare parkinson-like symptoms.

A multisite validation of brain white matter pathways of resilience to chronic back pain.

Chronic back pain (CBP) is a global health concern with significant societal and economic burden. While various predictors of back pain chronicity have been proposed, including demographic and psychosocial factors, neuroimaging studies have pointed to brain characteristics as predictors of CBP. However, large-scale, multisite validation of these predictors is currently lacking. In two independent longitudinal studies, we examined white matter diffusion imaging data and pain characteristics in patients with subacute back pain (SBP) over 6- and 12-month periods. Diffusion data from individuals with CBP and healthy controls (HC) were analyzed for comparison. Whole-brain tract-based spatial statistics analyses revealed that a cluster in the right superior longitudinal fasciculus (SLF) tract had larger fractional anisotropy (FA) values in patients who recovered (SBPr) compared to those with persistent pain (SBPp), and predicted changes in pain severity. The SLF FA values accurately classified patients at baseline and follow-up in a third publicly available dataset (Area under the Receiver Operating Curve ~0.70). Notably, patients who recovered had FA values larger than those of HC suggesting a potential role of SLF integrity in resilience to CBP. Structural connectivity-based models also classified SBPp and SBPr patients from the three data sets (validation accuracy 67%). Our results validate the right SLF as a robust predictor of CBP development, with potential for clinical translation. Cognitive and behavioral processes dependent on the right SLF, such as proprioception and visuospatial attention, should be analyzed in subacute stages as they could prove important for back pain chronicity.

A multisite validation of brain white matter pathways of resilience to chronic back pain

Chronic back pain (CBP) is a global health concern with significant societal and economic burden. While various predictors of back pain chronicity have been proposed, including demographic and psychosocial factors, neuroimaging studies have pointed to brain characteristics as predictors of CBP. However, large-scale, multisite validation of these predictors is currently lacking. In two independent longitudinal studies, we examined white matter diffusion imaging data and pain characteristics in patients with subacute back pain (SBP) over 6- and 12-month periods. Diffusion data from individuals with CBP and healthy controls (HC) were analyzed for comparison. Whole-brain tract-based spatial statistics analyses revealed that a cluster in the right superior longitudinal fasciculus (SLF) tract had larger fractional anisotropy (FA) values in patients who recovered (SBPr) compared to those with persistent pain (SBPp), and predicted changes in pain severity. The SLF FA values accurately classified patients at baseline and follow-up in a third publicly available dataset (Area under the Receiver Operating Curve ~0.70). Notably, patients who recovered had FA values larger than those of HC suggesting a potential role of SLF integrity in resilience to CBP. Structural connectivity-based models also classified SBPp and SBPr patients from the three data sets (validation accuracy 67%). Our results validate the right SLF as a robust predictor of CBP development, with potential for clinical translation. Cognitive and behavioral processes dependent on the right SLF, such as proprioception and visuospatial attention, should be analyzed in subacute stages as they could prove important for back pain chronicity.

Frontal White Matter Changes and Craving Recovery in Inpatients With Heroin Use Disorder

Amidst an unprecedented opioid epidemic, identifying neurobiological correlates of change with medication-assisted treatment of heroin use disorder is imperative. White matter impairments in individuals with heroin use disorder (HUD) have been associated with drug craving, a reliable predictor of treatment outcomes; however, little is known about structural connectivity changes with inpatient treatment and abstinence in individuals with HUD. To assess white matter microstructure and associations with drug craving changes with inpatient treatment in individuals with HUD (effects of time and rescan compared with controls). This cohort study conducted from December 2020 to September 2022 included individuals recruited from urban inpatient treatment facilities treating HUD and surrounding communities in New York City. Participants with HUD were receiving medication-assisted treatment. Data were analyzed from October 2022 to March 2023. Between scans, inpatient individuals with HUD continued treatment and related clinical interventions. Control participants were scanned at similar time intervals. Changes in white matter diffusion metrics (fractional anisotropy and mean, axial, and radial diffusivities) assessed voxelwise with general linear models in addition to baseline and cue-induced drug craving, and other clinical outcome variables (mood, sleep, affect, perceived stress, and therapy attendance). Thirty-four individuals with HUD (mean [SD] age, 40.5 [11.0] years; 9 women [36%]; 3 Black [9%], 17 White [50%], 14 other race or ethnicity [41%]) and 25 control (mean [SD] age, 42.1 [9.0]; 7 women [21%]; 8 Black [32%], 10 White [40%], 7 other race or ethnicity [28%]) were included. Main voxelwise findings showed HUD-specific white matter microstructure changes (1 - P > .949), including increased fractional anisotropy and decreased mean and radial diffusivities, encompassing mostly frontal major callosal, projection, and association tracts. The increased fractional anisotropy (r = -0.72, P < .001, slope SE = 9.0 × 10-4) and decreased mean diffusivity (r = 0.69, P < .001, slope SE = 1.25 × 10-6) and/or radial diffusivity (r = 0.67, P < .001, slope SE = 1.16 × 10-6) in the genu and body of the corpus callosum and left anterior corona radiata in individuals with HUD correlated with a reduction in baseline craving (voxelwise 1 - P > .949). No other white matter correlations with outcome variables reached significance. This cohort study of inpatients with HUD on medication-assisted treatment found whole-brain normalization of structural connectivity in frontal white matter pathways implicated in emotional regulation and top-down executive control. Observed associations with decreases in baseline craving further support the possibility of recovery, highlighting the relevance of these white matter markers to a major symptom of addiction, with implications for clinical outcome monitoring.

Structural and Functional Projections of the Nucleus Basalis of Meynert and Their Changes After Cognitive Training in Individuals With Mild Cognitive Impairment.

The nucleus basalis of Meynert (NBM) is a major source of cholinergic innervation in the central nervous system. We aimed to investigate the characteristics of structural and functional alterations in the NBM and its projections in patients with mild cognitive impairment (MCI) and the effects of computerized cognitive training (CCT). Forty-five patients with MCI and 45 cognitively unimpaired controls (CUCs) were recruited. NBM volume, mean diffusivity (MD) of NBM white matter (WM) projections, and functional connectivity (FC) of projections of the NBM were measured with T1-weighted imaging, diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI). Thirty-six MCI patients were randomly assigned to receive CCT or control training. The effects of CCT on the neuropsychological measures and MRI properties were analyzed with a linear mixed model (LMM). We detected that compared with the CUCs, the MCI patients had a reduced volume of the NBM and a greater MD of both cholinergic pathways. Increased MD values of both pathways were related to lower scores of global cognition, processing speed and attention in all participants. After CCT intervention, significant group × timepoint effects on score of the Backward Digit Span and the FC between NBM and right putamen were observed in the CCT group compared to the control group. NBM atrophy and WM pathway disruption occurred in MCI patients and were correlated with cognitive impairment. Working memory and the FC between NBM and right putamen could be improved by cognitive training.

Large‐scale Normative Modeling of Brain Microstructure over the Human Lifespan

AbstractBackgroundNormative models (NM) of brain metrics based on large, diverse populations offer novel strategies to detect individual brain abnormalities. To create an age‐dependent statistical model of brain microstructure over the human lifespan, we built the largest multi‐site NM of white matter (WM) diffusion tensor imaging (DTI) metrics based on 54,591 subjects. We used state‐of‐the‐art tools to adjust for site‐dependent effects.MethodWe used Hierarchical Bayesian Regression (HBR) to determine the age trajectory and lifespan centile curves (ages 3‐100 years) by merging data from different sections of the lifespan. We analyzed 19 international public datasets with the ENIGMA‐DTI protocol. Mean fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AxD, RD) were extracted for 21 bilateral ROIs from the JHU‐WM atlas and the whole WM skeleton. Regressions were run with each metric per ROI as a function of age and sex, and the DTI protocol as the batch effect (37 protocols). Z‐scores were derived for 81 patients with Alzheimer’s disease (AD; mean age: 77y±8.4, 46M/35F) and 225 MCI participants (mean age: 75.1y±8.1, 127M/98F) and extreme deviations (Z&gt;|2|) were quantified for each condition. ROI‐wise areas under the ROC curve were calculated to determine the classification accuracy of the Z‐scores.ResultThe average FA for the overall WM skeleton reached its peak value at 27 years, with minima for MD, RD and AxD at 47, 42 and 54 years, respectively. We found extreme FA deviations (Z&gt;2) for MCI (AUC=0.67) and AD (AUC=0.66) in the genu of the corpus callosum, extreme RD deviations (Z&lt;2) in the tapetum (AUC=0.73) and Extreme AxD deviations (Z&gt;2) for MCI in the superior longitudinal fasciculus (AUC=0.65). See Figures 1 &amp; 2.ConclusionNM of brain microstructure with HBR yielded lifespan trajectories for widely‐used DTI metrics. By pooling large scale multi‐site dMRI to create a statistical reference, single subject deviations are detectable across the lifespan for AD and MCI. These NM will be publicly available to the research community.

Clinical and MRI Evaluation of Children with Leukodystrophies

Introduction: Leukodystrophies are a diverse group of rare, inherited neurodegenerative disorders affecting the brain’s white matter, leading to progressive neurological impairment. Magnetic Resonance Imaging (MRI) plays a crucial role in diagnosing these conditions, offering detailed insight into white matter abnormalities and aiding in distinguishing various leukodystrophies. Objective: This study aims to evaluate children with leukodystrophies using MRI, establish accurate diagnoses, assess the severity and extent of white matter lesions, and demonstrate the different patterns of abnormal myelination. Methods: This prospective observational study was conducted in the Department of Radiodiagnosis and Imaging at Sher-I-Kashmir Institute of Medical Sciences, Srinagar, from June 2022 to June 2024. All children suspected of having white matter disorders based on clinical features and biochemical tests were included. MRI was performed to identify patterns of white matter involvement, and findings were correlated with clinical data. Results: A total of 29 children (age range: 2 months to 18 years) were evaluated. MRI findings revealed that demyelinating leukodystrophies were the most common, with symmetrical white matter involvement. Hypomyelinating disorders showed diffuse white matter changes with sparing of the U-fibers. Specific patterns, such as tigroid appearance in metachromatic leukodystrophy and posterior fossa involvement in Alexander disease, were identified. MRI was instrumental in narrowing down differential diagnoses and identifying characteristic patterns for various leukodystrophies. Conclusion: MRI is an invaluable tool in the diagnosis and management of leukodystrophies in children. It allows for early identification of disease patterns, which is critical for appropriate clinical management and potential therapeutic interventions. Further research is needed to explore the genetic basis of these disorders in the Kashmiri population.

Preventive treatment effects on brain structures and functions in patients with chronic migraine: A multimodel magnetic resonance imaging study.

Patients with chronic migraine (CM) often exhibit structural and functional alterations in pain-matrix regions, but it remains unclear how preventive treatment affects these changes. Therefore, this study aimed to investigate the structural and functional changes in pain-matrix regions in CM patients after 6-month treatment. A total of 24 patients with CM and 15 healthy controls were recruited for this study. Patients were divided into responder group (N = 9) and non-responder group (N = 15). After completing the Migraine Disability Assessment (MIDAS) questionnaire, all patients underwent whole-brain high-resolution T1-weighted images, diffusion-weighted imaging, and resting-state functional magnetic resonance imaging at baseline and 6-month follow-up. Whole brain gray matter volume and white matter diffusion indices were analyzed using voxel-based analysis. Structural and functional connectivity analyses were performed to understand brain changes in patients after 6-month preventive treatment. The responder group exhibited significantly higher MIDAS scores than the non-responder group at baseline, but no significant difference between the two groups at follow-up. No significant interval change was noted in gray matter volume, white matter diffusion indices, and structural connectivity in CM patients after 6-month treatment. Nonetheless, the functional connectivity was significantly increased between occipital, temporal lobes and cerebellum, and was significantly decreased between parietal and temporal lobes after 6-month preventive treatment. We concluded that resting-state functional connectivity was suitable for investigating the preventive treatment effect on CM patients.

Diffuse white matter pathology in multiple sclerosis during treatment with dimethyl fumarate-An observational study of changes in normal-appearing white matter using proton magnetic resonance spectroscopy.

Multiple sclerosis (MS) is an inflammatory demyelinating disease with neurodegenerative features causing risk for neurologic irreversible disability over time. Examination of normal-appearing white matter (NAWM) changes in MS by proton magnetic resonance spectroscopy (1H-MRS), may detect diffuse white matter pathology that is associated with neurodegeneration. In this observational study of in total twenty-six patients with MS, starting treatment with dimethyl fumarate (DMF), we measured the absolute concentration of metabolites in periventricular NAWM using 1H-MRS at baseline and after one and three years of treatment. Metabolite concentrations were analyzed both cross-sectionally, in relation to 10 controls and longitudinally in relation to disease activity. Patients with MS had higher concentrations of myo-inositol (mIns) in NAWM at baseline compared with controls (mean 5.98 ± 1.37 (SD) and 4.32 ± 1.16 (SD), p<0.01, independent samples t-test). The disease duration was inversely correlated with concentrations of total N-acetylaspartate and N-acetylaspartylglutamate (tNA) (r = -0.62, p<0.01) in NAWM as well as positively to the ratio of mIns and tNA (r = 0.51, p = 0.03). Metabolite concentrations during one-year (n = 19) and three-years (n = 11) follow-up were generally stable. The dropouts were caused by treatment switch after one year, mainly due to new MRI activity. Cross-sectional analyses showed that there was an inverse correlation between concentrations of tNA and mIns at both baseline and at 1 and 3-years follow-up (r = -0.44 to -0.65, p = 0.04 to 0.004). Metabolite concentrations were stable during 1-year follow-up independently of disease activity. Higher concentrations of the astrogliosis marker mIns in MS compared to controls, the inverse relation between MS disease duration and the neuroaxonal integrity marker tNA, as well as the consistent inverse relation between these two metabolites during follow-up, showed that non-lesional white matter pathology is present in this cohort of MS patients in early disease stages. However, metabolite concentrations during follow-up were generally stable and did not reflect differences in disease activity among patients.

Choroid Plexus Volume in Rural Chinese Older Adults: Distribution and Association With Cardiovascular Risk Factors and Cerebral Small Vessel Disease.

The choroid plexus (CP) is involved in neurodegenerative diseases. However, the association of CP with cardiovascular risk factors and cerebral small vessel disease in older adults remains unclear. This population-based study included 1263 participants (60 years and older) from the MIND-China (Multimodal Interventions to Delay Dementia and Disability in Rural China) substudy (2018-2020), of which 111 individuals completed diffusion tensor imaging examination. CP volume was automatically segmented. White matter hyperintensities (WMHs), enlarged perivascular spaces (EPVS), cerebral microbleeds, and lacunes were assessed following the Standards for Reporting Vascular Changes on Neuroimaging 1. Peak width of skeletonized mean diffusivity and free water were derived from diffusion tensor imaging images. We used linear regression models to evaluate the association between CP volume and cardiovascular risk factors, WMH volumes, and diffusion tensor imaging metrics, and logistic regression models to examine the association between CP volume and EPVS, cerebral microbleeds, and lacunes. The CP volume increased with age (P<0.001). Men (β coefficient=0.47 [95% CI, 0.29-0.64]) and participants with diabetes (β coefficient=0.16 [95% CI, 0.01-0.31]) had larger CP volumes than women and individuals without diabetes, respectively (P<0.05). Greater CP volume was significantly associated with larger total and periventricular WMH volumes and moderate to severe EPVS in basal ganglia (P<0.05) but not with deep WMHs, EPVS in centrum semiovale, lacunes, or cerebral microbleeds. In the diffusion tensor imaging subsample, enlarged CP was significantly associated with higher peak width of skeletonized mean diffusivity and free water of periventricular and deep white matter (P<0.05). An enlarged CP is associated with larger global and periventricular WMH volume and higher likelihoods of EPVS in basal ganglia and impaired white matter integrity, suggesting that an enlarged CP may represent a precursor of cerebral small vessel disease.

A Chinese CADASIL family with a rare heterozygous mutation in exon 2 of NOTCH3: A case report.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease caused by the neurogenic locus notch homolog protein 3 (NOTCH3) gene mutation. In recent years, most of the newly reported mutations of CADASIL patients mainly occur in exon 3 to 24, while the cases related to exon 2 mutation are rare, and clinical research data are relatively insufficient. In this study, we have reported a case of a rare heterozygous mutation c.128G>A (p.Cys43Tyr) in exon 2 of NOTCH3 in a 41-year-old Chinese man in the light of relevant literatures. A 41-year-old man who suffered slurred speech for 5 days and right lower limb weakness for 4 days was admitted to our hospital. Magnetic resonance imaging of the head revealed diffuse white matter lesions involving the outer capsular area and bilateral temporal poles. The rare heterozygous mutation c.128G>A (p.Cys43Tyr) in exon 2 of NOTCH3 was identified through molecular genetic testing. The proband was diagnosed as having CADASIL. Meanwhile, the same mutation was detected in 2 other family members III5 and IV9. Atorvastatin calcium tablet (20 mg qd) and aspirin enteric-coated tablet (100 mg qd). The patient was hospitalized for 3 weeks and discharged after his symptoms improved. The heterozygous Cys43Tyr mutation in exon 2 of NOTCH3 is rare. Thus, our case report complements the rare mutation of exon 2 and offers additional clinical data for CADASIL patients.

Microangiopathy in temporal lobe epilepsy with diffusion MRI alterations and cognitive decline

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.

Early Postnatal Neuroinflammation Produces Key Features of Diffuse Brain White Matter Injury in Rats.

Perinatal infection is a major risk factor for diffuse white matter injury (dWMI), which remains the most common form of neurological disability among very preterm infants. The disease primarily targets oligodendrocytes (OL) lineage cells in the white matter but also involves injury and/or dysmaturation of neurons of the gray matter. This study aimed to investigate whether neuroinflammation preferentially affects the cellular compositions of the white matter or gray matter. Neuroinflammation was initiated by intracerebral administration of lipopolysaccharide (LPS) to rat pups at postnatal (P) day 5, and neurobiological and behavioral outcomes were assessed between P6 and P21. LPS challenge rapidly activates microglia and astrocytes, which is associated with the inhibition of OL and neuron differentiation leading to myelination deficits. Specifically, neuroinflammation reduces the immature OLs but not progenitors and causes acute axonal injury (β-amyloid precursor protein immunopositivity) and impaired dendritic maturation (reduced MAP2+ neural fiber density) in the cortical area at P7. Neuroinflammation also reduces the expression of doublecortin in the hippocampus, suggesting compromise in neurogenesis. Utilizing a battery of behavioral assessments, we found that LPS-exposed animals exhibited deficits in sensorimotor, neuromuscular, and cognitive domains. Our overall results indicate that neuroinflammation alone in the early postnatal period can produce cardinal neuropathological features of dWMI.

Differences in brain structure and cognitive performance between patients with long-COVID and those with normal recovery

BackgroundThe pathophysiology of protracted symptoms after COVID-19 is unclear. This study aimed to determine if long-COVID is associated with differences in baseline characteristics, markers of white matter diffusivity in the brain, and lower scores on objective cognitive testing. MethodsIndividuals who experienced COVID-19 symptoms for more than 60 days post-infection (long-COVID) (n = 56) were compared to individuals who recovered from COVID-19 within 60 days of infection (normal recovery) (n = 35). Information regarding physical and mental health, and COVID-19 illness was collected. The National Institute of Health Toolbox Cognition Battery was administered. Participants underwent magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI). Tract-based spatial statistics were used to perform a whole-brain voxel-wise analysis on standard DTI metrics (fractional anisotropy, axial diffusivity, mean diffusivity, radial diffusivity), controlling for age and sex. NIH Toolbox Age-Adjusted Fluid Cognition Scores were used to compare long-COVID and normal recovery groups, covarying for Age-Adjusted Crystallized Cognition Scores and years of education. False discovery rate correction was applied for multiple comparisons. ResultsThere were no significant differences in age, sex, or history of neurovascular risk factors between the groups. The long-COVID group had significantly (p < 0.05) lower mean diffusivity than the normal recovery group across multiple white matter regions, including the internal capsule, anterior and superior corona radiata, corpus callosum, superior fronto-occiptal fasciculus, and posterior thalamic radiation. However, the effect sizes of these differences were small (all β<|0.3|) and no significant differences were found for the other DTI metrics. Fluid cognition composite scores did not differ significantly between the long-COVID and normal recovery groups (p > 0.05). ConclusionsDifferences in diffusivity between long-COVID and normal recovery groups were found on only one DTI metric. This could represent subtle areas of pathology such as gliosis or edema, but the small effect sizes and non-specific nature of the diffusion indices make pathological inference difficult. Although long-COVID patients reported many neuropsychiatric symptoms, significant differences in objective cognitive performance were not found.