Clinical outcomes and MRI-based neurotoxicity assessment of elderly primary CNS lymphoma.

Vibration-based therapies are understudied but promising methods for alleviating psychiatric symptoms, particularly when paired with behavioral practices. The potential neuroplastic changes associated with a novel neurostimulation method, sternal vibration, and associations with clinical change remain unknown. We examined effects of sternal vibration paired with mindfulness meditation on change in white matter microstructure and dissociation using neurite orientation dispersion and density imaging (NODDI) in trauma-exposed adults with elevated dissociative symptoms. A total of 116 trauma-exposed adults with elevated dissociation completed MRI before/after eight mindfulness meditation sessions. Approximately half (n = 60) received sternal vibration augmentation whereas n = 56 had no augmentation. Self-reported dissociation was measured at each session with the Scale of Bodily Connectedness. Significant time-by-intervention type interactions showed vibration-specific improvements in body awareness (p = 0.032; ηp2 = 0.139) and increased neurite density index (NDI) in a region within the corticospinal tract (CST), the left cerebral peduncle (CP, p < 0.01, ηp2 = 0.102). This finding replicated in tractography analyses showing increased NDI in left (p = 0.007; ηp2 = 0.066) and right CST (p = 0.004; ηp2 = 0.075). Decreased body dissociationwas associated with increased CP NDI in those who received vibration (p = 0.011, ηp2 = 0.058); no associations between clinical and white matter change were observed with non-vibration interventions. Findings indicate that brief sternal vibration in the context of mindfulness meditation enhanced body awareness and neurite density in a tract of relevance to somatosensory integration, with white matter changes corresponding with enhanced interoceptive awareness. Findings reveal the promise of sternal vibration as a low-cost, non-invasive neurostimulation method for enhancing interoception via neuroplastic alterations, with applications for various psychiatric populations.

White matter microstructural abnormalities in neurological poste-acute sequelae of coronavirus disease: Imaging signatures consistent with persistent neuroinflammation.

Hypersarcosinemia, resulting from sarcosine dehydrogenase (SARDH) gene mutation, is a rare autosomal recessive disorder with variable, often nonspecific clinical presentations, leading to diagnostic difficulty and low clinical awareness. A 6-year-old boy presented with clinical features suggestive of viral encephalitis, including headache, vomiting, intermittent fever, and lethargy. Initial MRI revealed cytotoxic edema in the subcortical white matter and splenium of the corpus callosum. Although symptoms improved transiently with steroid therapy, persistent imaging abnormalities prompted metabolic and genetic evaluations. Metabolic and genetic investigations confirmed a diagnosis of hypersarcosinemia, with markedly elevating sarcosine levels and compounding heterozygous SARDH mutations. Genetic testing identified compound heterozygous mutations in the SARDH gene (c.293G > C and c.679C > T), confirming hypersarcosinemia. Following initiation of folic acid and mecobalamin, partial radiological improvement was observed, although a causal relationship could not be established. This case highlights the diagnostic challenge of hypersarcosinemia and its potential mimicry of acquired encephalitis. To our knowledge, this is the first report describing an acute encephalitis-like presentation accompanied by persistent cytotoxic edema on MRI, thereby suggesting a possible expansion of the known clinical and neuroimaging spectrum of this disorder, although this observation requires confirmation in additional cases. However, given the rarity of hypersarcosinemia and the possibility of underreporting, the absence of prior similar reports should be interpreted with caution. In this case, genetic testing was essential for establishing the diagnosis, although the necessity of genetic testing in all cases of unexplained white matter changes cannot be determined from a single report. The temporal association of partial radiological improvement with folic acid and mecobalamin supplementation is hypothesis-generating only and requires further investigation ; no causal or therapeutic conclusion can be drawn from this single case.

Preserved white matter structure at the grey matter-white matter interface despite widespread cortical thinning in early psychosis.

Neuroplastic white matter changes in patients with major depression following lysergic acid diethylamide treatment.

Longitudinal changes in white matter (WM) microstructure from acute underweight to early weight restoration in anorexia nervosa (AN), and their underlying mechanisms, remain largely unexplored. Thus, this study aims to examine the relationship between microstructural alterations across WM regions and neurofilament light (NF-L), a marker of axonal injury; brain-derived neurotrophic factor (BDNF), a neuroprotective molecule; and leptin, a neuroplasticity-promoting hormone, during acute underweight and following short-term weight restoration. Diffusion-weighted MRI scans from 101 predominantly adolescent female participants with acute AN before and after short-term weight restoration and from 147 female healthy participants were used. Alterations in microstructural WM integrity assessed by fractional anisotropy (FA) were tested using linear mixed-effects models across groups. Additional analyses were used to investigate relationships of FA with NF-L, BDNF, and leptin. We found a mixed, mostly elevated FA signature at the acutely underweight stage, followed by incomplete normalization with weight gain. Subsequent analyses identified that change in FA was positively associated with reductions in NF-L levels above and beyond the effect of weight gain in one WM tract. Leptin increase accompanying short-term weight restoration mediated the effect of weight gain on FA decrease across four WM tracts (estimated average causal mediation effects range: −0.0050 to − 0.0026; confidence intervals within − 0.01 to 0.0). The results suggest that a decrease in FA may indicate rehabilitation of WM integrity in acute AN. In addition to nutritional rehabilitation, the increase of leptin levels during weight gain may be relevant for the normalization of specific WM tracts.

The gut-brain axis (GBA) is a complex, bidirectional communication network critical to integrating central nervous system functions with gastrointestinal (GI) health. This review examines how disruptions to the GBA during the critical early-life developmental window - a period of rapid neurogenesis and microbial colonization - contribute to long-term neurocognitive and psychiatric vulnerabilities. Evidence from animal models demonstrates that early-life stress, antibiotics, and infection induce sustained neuro-inflammation and alter microglial function, leading to long-term behavioral and cognitive impairments in adulthood. Human studies corroborate these findings, revealing that severe early GI insults, such as necrotizing enterocolitis, confer a high risk (40%) of global neurodevelopmental impairment and specific attention deficits. Chronic inflammatory conditions similarly impact the central nervous system: A high burden of early severe enteric infection is an independent risk factor for diminished intelligence quotient (IQ) and executive function, while conditions like celiac disease and inflammatory bowel disease are associated with persistent deficits in attention, processing speed, memory, and executive function. These clinical outcomes are strongly linked to systemic inflammation [elevated interleukin-6, kynurenine-to-tryptophan (Kyn:Trp) ratio], micronutrient deficiencies (iron, vitamin B12, folate), and structural white matter changes in the brain. Furthermore, chronic GI disease imposes a significant psychiatric burden, with high comorbidity of anxiety and depression often mediating poor health-related quality of life, particularly in pediatric inflammatory bowel disease. The findings underscore the necessity for a shift in clinical practice: Chronic GI disease in early life must be recognized as a red flag for neurocognitive risk. We advocate for a multidisciplinary approach encompassing early neurodevelopmental follow-up for high-risk groups and routine screening for cognitive and emotional comorbidities. Future research must focus on long-term prospective cohorts, identifying precise mechanistic biomarkers (metabolomics, microbiome signatures), and conducting interventional trials targeting the GBA to mitigate these long-term functional consequences.

Bi-allelic loss-of-function variants in TMEM63B cause syndromic surfactant dysfunction disorder.

This study compared the effectiveness of Automated Fiber Quantification (AFQ) and Tract-Based Spatial Statistics (TBSS) in detecting white matter (WM) changes in patients with moderate-to-severe obstructive sleep apnea (OSA), aiming to identify the more suitable method for investigating WM alterations of OSA patients. It also explored the potential neuropathological links between WM changes and anxiety/depression in OSA. Thirty-three untreated patients with moderate-severe OSA and 28 good sleepers without sleep disorders underwent 3.0T MRI scans. TBSS was used to construct WM skeletons and compare diffusion tensor imaging (DTI) metrics between groups. AFQ was then applied to extract 20 major fiber tracts from each subject, with each tract divided into 100 nodes to precisely localize affected areas. TBSS revealed no significant group differences after correction. In contrast, AFQ identified significant changes: decreased fractional anisotropy at nodes 77-78 of the forceps major (positively correlated with anxiety scores); increased mean diffusivity at nodes 23-24 of the right thalamic radiation; and increased axial diffusivity at nodes 54-57 of the right inferior fronto-occipital fasciculus (negatively correlated with anxiety and depression scores), and nodes 66-68 of the right superior longitudinal fasciculus. AFQ is more sensitive than TBSS in detecting focal WM changes in OSA, allowing precise localization of affected fiber nodes. These WM alterations, particularly in the corpus callosum and right inferior fronto-occipital fasciculus, are linked to anxiety and depression, offering insights into the neuropathological mechanisms of anxiety and depression in OSA.

Cerebral small vessel disease is a leading cause of cognitive decline and stroke in the elderly, with cerebral microbleeds (CMBs) serving as a key imaging biomarker. Despite their clinical significance, the pathophysiological mechanisms underlying cerebral small vessel disease remain poorly understood owing to a lack of appropriate animal models. We performed targeted deletion of Col4a1 in brain microvessels of adult mice using brain endothelium-specific adeno-associated virus (AAV)-BR1 vectors with clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9). Eight-week-old Cas9 transgenic mice received retro-orbital injections of AAV-BR1 containing single guide RNA (sgRNA) targeting Col4a1 or control Rosa26 sequences. Animals underwent longitudinal behavioural testing, including novel object recognition, Y-maze and rotarod tests, over 6 months. Brain pathology was assessed using T2*-weighted MRI, histological analysis and electron microscopy. For human studies, we analysed MRI and genomic data from 836 participants from the BICWALZS biobank, examining associations between genetic variants and CMB burden using linear regression and χ2 analyses. T2*-weighted MRI revealed numerous CMBs with distributions remarkably similar to human CMBs, appearing within 3 months post-injection. CMB burden increased progressively over 6 months in a dose-dependent manner. Behaviourally, mice exhibited progressive cognitive decline and motor incoordination. Histological examinations revealed haemosiderin deposits corresponding to MRI-detected CMBs, without macroscopic intracerebral haemorrhage or white matter changes. Ultrastructural analysis demonstrated significant basement membrane thinning in Col4a1-depleted microvessels. CMB accumulation was associated with widespread astrocytic reactivity extending beyond microbleed sites, whereas microglial activation remained localized. In human subjects, we identified significant associations between four genetic variants of TIMP2, an endogenous inhibitor of the matrix-degrading enzyme MMP2 and CMB burden, with odds ratios of 1.50-1.96 for increased microbleed susceptibility. This work provides the first animal model demonstrating that selective disruption of collagen IV in adult brain microvessels is sufficient to generate CMBs with high penetrance and dose-dependent tunability. Our findings establish that basement membrane integrity is critical for preventing microbleed formation and suggest that dysregulated collagen IV homeostasis underlies sporadic human CMB development.

Polyneuritis cranialis is characterized by the simultaneous or sequential inflammation of multiple cranial nerves, which may occur unilaterally or bilaterally. Although it is often related to infection, its exact etiology remains unclear. Due to its nonspecific clinical manifestations, diagnosis typically relies on the exclusion of other conditions. Herein, we report a case of postinfectious polyneuritis cranialis. The patient presented to our hospital with restricted mouth opening, dysphagia, coughing while drinking, dysarthria, and posterior neck pain following a finger injury. Laboratory tests showed markedly elevated inflammatory markers. Neurological examination revealed involvement of cranial nerves V, IX, X, and XII. Motor nerve conduction studies of the facial nerve suggested partial facial nerve damage. Brain magnetic resonance imaging demonstrated mild nonspecific white matter changes. After exclusion of alternative diagnoses, the patient was diagnosed with polyneuritis cranialis. The patient's condition improved following corticosteroid pulse therapy and was subsequently discharged. This case highlights that the diagnosis of polyneuritis cranialis remains one of exclusion and is often clinically challenging. When encountering patients with rapidly progressive cranial nerve palsies, polyneuritis cranialis should be included in the differential diagnosis after more common structural or systemic etiologies have been excluded.

Repetitive head impacts sustained during American football have been associated with neuropathological changes such as white matter shear injuries. However, the impact of specific factors, such as age of first exposure and cumulative head impact burden, on white matter integrity remains unclear. This study investigated in vivo white matter microstructural changes using diffusion tensor imaging and tract-based spatial statistics in 165 male former American football players (mean age 57.3 years, range 45–74) and 52 unexposed asymptomatic male controls (mean age 59.4 years, range 45–74) in the DIAGNOSE CTE Research Project. Compared to controls, former football players exhibited significantly higher fractional anisotropy (FA) in 1.97% of the white matter skeleton (1552 voxels; Cohen’s d = 0.587) and higher tissue-corrected FA (FAt) in 1.48% of the white matter skeleton (1004 voxels; Cohen’s d = 0.616). No significant differences were observed for mean diffusivity, axial diffusivity, radial diffusivity, or free water between football players and controls. Among football players, there were no significant differences in the white matter microstructure between players diagnosed with traumatic encephalopathy syndrome and those without the diagnosis. Lower FA was significantly associated with older age (P < 0.00001) and an earlier age of first exposure to tackle football (P < 0.01), while lower FAt was associated with greater cumulative head impact burden, specifically higher linear acceleration (P < 0.04) and rotational force (P < 0.02). This study highlights the influential role of exposure factors on white matter microstructure in former American football players, as well as the utility of diffusion tensor imaging to aid in characterizing the long-term effects of repetitive head impacts in contact sport athletes.

There is overlap between frontotemporal dementia (FTD) and motor neuron disease (MND) in terms of genetics, neuroimaging and clinical phenotypes. We aimed to identify in three patient cohorts, ultra-rare variants (frequency ≤ 0.00002) in genes whose mutations are associated with white matter dysfunction, and to examine impact of these variants on protein function in vitro, and neuroimaging and lipid profiles in vivo. Next generation sequencing (NGS) of N = 289 patients with clinical FTD recruited through two dementia research clinics identified ultra-rare variants in established leukodystrophy genes, including ARSA. Further, novel and ultra-rare loss-of-function and missense variants in LAMA2 increased risk of disease in three independent cohorts, including N = 598 MND and N = 14 logopenic variant primary progressive aphasia (lvPPA) patients (maximum odds ratio (OR) of 3.05, P = 0.0357 for FTD cohort, OR of 9.57, P = 0.0233 for lvPPA cohort, and 1.78, P = 0.0250 for MND cohort). An in vitro transfection assay demonstrated a loss-of-secretion phenotype in the subset of LAMA2 ultra-rare missense variants where the full-length proteins were translated but not secreted into growth media. LAMA2 ultra-rare variant carriers have a distinctive serum lipidomics profile compared with sporadic cases and cognitively normal controls. Finally, LAMA2 ultra-rare variants were associated with white matter changes in brain regions relevant to disease process. Our results broaden the phenotypes associated with LAMA2 from muscular dystrophies to include FTD, lvPPA and MND; and our data provide convergent evidence for the role of ultra-rare variants in LAMA2 as risk factors.

Vascular mechanisms have been implicated in idiopathic acute unilateral audiovestibulopathy (iAUAV, also known as labyrinthitis), especially in older patients. We investigated the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and white matter changes in patients with iAUAV/labyrinthitis to determine the potential vascular etiology in this disorder. We retrospectively analyzed complete blood count (CBC) data from patients aged over 50 years and diagnosed with iAUAV/labyrinthitis at a tertiary hospital in South Korea between March 2018 and June 2025. CBC data, Fazekas scores for white matter changes, video head-impulse tests (vHIT), and bithermal caloric test results were compared with those of patients with acute unilateral peripheral vestibulopathy (AUVP, i.e., vestibular neuritis [AUVP/VN]) and age- and sex-matched healthy controls. A total of 74 patients with iAUAV/labyrinthitis (mean age± standard deviation [SD] = 68± 9 years; 34 male), 84 with AUVP/VN (65± 9 years; 46 male), and 58 healthy controls (68± 10 years; 26 male) were included. Both NLR (p<0.001) and PLR (p=0.003) were higher in the iAUAV/labyrinthitis group than in the AUVP/VN or control groups. Patients with iAUAV/labyrinthitis had higher Fazekas scores than those with AUAV/VN (p=0.002). Compared to AUVP/VN, iAUAV/labyrinthitis was associated with a higher PLR (p=0.038), higher Fazekas score (p=0.011), increased VOR gain for the horizontal canal (p<0.001), and decreased VOR gain for the posterior canal (p=0.005). Elevated PLR and prominent white matter changes suggest a microvascular etiology of iAUAV/labyrinthitis in older adults. These serologic and imaging markers may complement standard neurotologic assessments in diagnosing iAUAV/labyrinthitis.

Standard neurocognitive and imaging assessments in research settings may not fully capture the real-world symptom burden experienced by pediatric hematologic cancer survivors. We conducted a retrospective analysis using electronic medical record data to evaluate cognitive and imaging findings as well as comorbidities in this patient population. We retrospectively reviewed data from 314 pediatric blood cancer survivors (diagnosed at age ≤21) followed at the Montefiore Survivorship Clinic between 2000 and 2024. Neurocognitive assessments, neuroimaging, and treatment exposures were extracted. The chi-square test was used for group comparison of categorical variables, and the independent t-test was used for group comparison of continuous variables. The risk of developing a neurocognitive complaint was assessed using a multivariable Cox-proportional hazards model. Neurocognitive complaints were documented in 56 of 314 patients (18%). Younger age at cancer diagnosis (adjusted hazard ratio [HR], 0.94 [0.88-0.99]; P = .03) and exposure to high-dose methotrexate (adjusted HR, 3.34 [1.67-6.67]; P < .005) were independently associated with increased risk of neurocognitive complaints. Neurocognitive testing revealed deficits across multiple domains, with most pronounced impairments in full-scale intelligence quotient (mean percentile: 27%) and verbal comprehension (mean percentile: 31%). Consistent neuroimaging abnormalities, including white matter changes and T2 hyperintensities, were observed in 25% of symptomatic patients, although most had unremarkable findings, suggesting underlying microstructural or functional disruptions undetected by standard imaging. Chemotherapy-related neurocognitive dysfunction affects nearly one in five pediatric hematologic cancer survivors, with younger age at diagnosis and methotrexate exposure as major risk factors.

Spinal Cerebellar Ataxia Type 8 (SCA8) is a rare autosomal dominant neurodegenerative disorder characterized by progressive cerebellar dysfunction. It is caused by pathogenic expansions of a CTG/CAG trinucleotide repeat sequence within the ATXN8OS/ATXN8 gene locus on chromosome 13q21. Although cerebellar atrophy is widely recognized as a cardinal neuroimaging feature of SCA8, the phenotypic spectrum remains incompletely characterized. This study identified two cases of SCA8 through genetic analysis. Pedigree information was gathered and analyzed for all available family members. A systematic literature review was conducted to identify all published SCA8 cases with available neuroimaging data. The distinctive clinical and radiological features of SCA8 were analyzed through detailed case characterization integrated with a comprehensive review of existing literature. We report two genetically confirmed SCA8 cases exhibiting a previously undescribed neuroimaging phenotype. Case 1: A 36-year-old woman presented with a one-year history of progressive gait ataxia. Brain MRI revealed confluent, symmetric white matter signal abnormalities without cerebellar atrophy. Repeat expansion analysis detected a pathogenic CTG/CAG expansion of 9/77 in the ATXN8 gene. Case 2: A 64-year-old man (father of case 1) exhibited significant gait abnormalities, cognitive impairment and dysarthria. Brain MRI showed symmetric white matter lesions similar to case 1, with a CTG/CAG repeat length of 17/73. Notably, our systematic review revealed no prior reports of SCA8 presenting with isolated, symmetric white matter abnormalities in the absence of cerebellar atrophy. These findings delineate a novel neuroimaging phenotype of SCA8, characterized by symmetric white matter alterations without cerebellar volume loss. This atypical presentation expands the radiological spectrum of SCA8 and underscores the importance of considering repeat expansion disorders in the differential diagnosis of leukoencephalopathies, even in the absence of classic neurodegenerative imaging signatures.

Chronic bilateral vestibulopathy (BVP) occurs preferably in elderly patients presenting with postural imbalance and head movement induced oscillopsia. The condition is often incomplete with residual functions in both ears. Beyond the vestibular reflexive deficits, an impairment of spatial orientation and navigation has been described associated with an atrophy of the hippocampal formation. However, this finding was inconsistent in various studies on rodents and humans. In the current MRI study on 15 BVP patients and 15 healthy controls (HC) we combined analyses of whole brain voxel-based morphometry (VBM) and the resting state fMRI (rs-fMRI) on the widely distributed multisensory vestibular network and its connections to sensorimotor, cognitive, and emotional networks at rest. Major results were gray and white matter changes in conjunction with rs-fMRI changes: the left posterior insula, angular and supramarginal gyri, and left premotor cortex; as well as bilateral anterior hippocampal formation and adjacent amygdala; visual cortex V1 and V5; thalamus; prefrontal cortex; cerebellar hemispheres and uvula; and pyramidal tract. Thus, the overlap of structural (VBM) and rs-fMRI including various correlation analyses disclosed that a bilateral reduction of peripheral vestibular input affects multiple networks from the cerebellum up to the cortical hemispheres. A possible functional interpretation is that the observed specific alterations reflect compensation and substitution by other networks - handling perception, sensorimotor balance regulation, cognition, and emotions - due to deficits in one sensory system. This is consistent with anterior hippocampal atrophy's role in spatial memory deficits, as well as the involvement of the cerebellum, amygdala, and prefrontal cortex in emotional processes. It also aligns with the top-down regulation by the prefrontal cortex via the pyramidal tract for cognitive control of balance triggered by the perception of postural instability. Further, correlation analyses support this interpretation because most morphological changes were dependent on the duration of the condition.

White matter alterations in right-onset versus left-onset Parkinson's disease in an early stage.

Integrating along-tract profiling with fixel-based analysis for tract-specific characterization of white matter.