Cerebellar White Matter Research Articles

A Rare Symptomatic Case of Heterozygous Cerebro-Tendinous Xanthomatosis (CTX) Treated with Urso-Deoxycholic Acid (UDCA): With Mini Review

Cerebrotendinous Xanthamatosis (CTX) is a rare autosomal recessive disorder caused by a mutation in the CYP27A1 gene leading to impaired metabolism of cholesterol and accumulation of cholestenol and the cholesterol in various tissues such as the brain, eyes, lungs and bones and reduced formation of cheno-deoxycholic acid (CDCA). The clinical presentation is diverse, starting in the early neonatal period and progressing till adulthood unless treated early. A common neurological manifestation is a spino-cerebellar ataxia followed by spastic paraparesis. Tendon xanthoma is a classical finding that usually helps in clinching the diagnosis but may not be present in all cases. Brain MRI also reveals characteristic abnormalities with cerebellar atrophy and hyper-intensities in the dentate nucleus and surrounding cerebellar white matter on T1weighted images. It is a rare cause of treatable ataxia in young individuals. Treatment is by replacement by CDCA or Urso-deoxycholic acid (UDCA). Supplemented with statins these individuals also have premature atherosclerosis causing death due to athero-sclerotic coronary artery disease. Here a rare case of symptomatic heterologous CYP27A1 mutation is reported with syndrome of spino-cerebellar ataxia treated with UDCA.

Potential Clinical Benefit of Very Long Chain Fatty Acid Supplementation in Spinocerebellar Ataxia Type 34.

Spinocerebellar ataxia type 34 (SCA34) is a dominantly inherited disease that causes late-onset ataxia, in association with skin lesions in the form of erythrokeratodermia variabilis. It is caused by mutations in the ELOVL4 gene, which encodes for the ELOVL4 protein and has the function of lengthening very long chain (VLC) fatty acids (FA), which are important components of central myelin. The aim of this work was to review the medical literature on the biochemical abnormalities of SCA34, and based on the obtained information, to propose supplementation of deficient FAs. A review of the ad hoc medical literature was performed. Plasma levels of the ELOVL4 products C32, C34 and C36 FA have not been reported in SCA34 yet. However, pathogenic variants of ELOVL4 revealed deficient biosynthesis of C28, C30, C32, C34 and C36 FA compared to WT in cell cultures, and the levels of ceramides and phosphatidylcholines containing ≥ 34C FA were decreased compared to WT in HeLa cells expressing mutant SCA34 proteins. Besides, a pathological study of SCA34 revealed myelin destruction and loss of oligodendrocytes in cerebral and cerebellar white matter. Levels of VLC-FA should be determined, to identify specifically deficient FAs in SCA34. Cerebellar ataxia could possibly be improved by administration of the deficient FAs, as found in SCA38 with supplementation of docosahexaenoic acid. The authors suggest investigators with access to SCA34, to take into consideration this therapeutic hypothesis, and try to verify the potential efficacy of administration of VLCFA in this disease.

I saw the “shrimp sign”: Cerebellar progressive multifocal leukoencephalopathy

The shrimp sign is characterized by a well-defined lesion in the deep cerebellar white matter, with hyperintense signal on T2- and hypointense signal on T1-weighted imaging, abutting and outlining the dentate nucleus, unilaterally or bilaterally. This sign has high sensitivity and specificity for cerebellar progressive multifocal leukoencephalopathy (PML) within the correct clinical scenario. In this article, we present a case of cerebellar PML in a woman living with human immunodeficiency virus, who was not using antiretroviral therapy, and presented the shrimp sign on brain MRI.

Elucidating the association of obstructive sleep apnea with brain structure and cognitive performance

BackgroundObstructive sleep apnea (OSA) is a pervasive, chronic sleep-related respiratory condition that causes brain structural alterations and cognitive impairments. However, the causal association of OSA with brain morphology and cognitive performance has not been determined.MethodsWe conducted a two-sample bidirectional Mendelian randomization (MR) analysis to investigate the causal relationship between OSA and a range of neurocognitive characteristics, including brain cortical structure, brain subcortical structure, brain structural change across the lifespan, and cognitive performance. Summary-level GWAS data for OSA from the FinnGen consortium was used to identify genetically predicted OSA. Data regarding neurocognitive characteristics were obtained from published meta-analysis studies. Linkage disequilibrium score regression analysis was employed to reveal genetic correlations between OSA and related traits.ResultsOur MR study provided evidence that OSA was found to significantly increase the volume of the hippocampus (IVW β (95% CI) = 158.997 (76.768 to 241.227), P = 1.51e-04), with no heterogeneity and pleiotropy detected. Nominally causal effects of OSA on brain structures, such as the thickness of the temporal pole with or without global weighted, amygdala structure change, and cerebellum white matter change covering lifespan, were observed. Bidirectional causal links were also detected between brain cortical structure, brain subcortical, cognitive performance, and OSA risk. LDSC regression analysis showed no significant correlation between OSA and hippocampus volume.ConclusionsOverall, we observed a positive association between genetically predicted OSA and hippocampus volume. These findings may provide new insights into the bidirectional links between OSA and neurocognitive features, including brain morphology and cognitive performance.

Maternal immunoglobulin G affects brain development of mouse offspring

Maternal immunoglobulin (Ig)G is present in breast milk and has been shown to contribute to the development of the immune system in infants. In contrast, maternal IgG has no known effect on early childhood brain development. We found maternal IgG immunoreactivity in microglia, which are resident macrophages of the central nervous system of the pup brain, peaking at postnatal one week. Strong IgG immunoreactivity was observed in microglia in the corpus callosum and cerebellar white matter. IgG stimulation of primary cultured microglia activated the type I interferon feedback loop by Syk. Analysis of neonatal Fc receptor knockout (FcRn KO) mice that could not take up IgG from their mothers revealed abnormalities in the proliferation and/or survival of microglia, oligodendrocytes, and some types of interneurons. Moreover, FcRn KO mice also exhibited abnormalities in social behavior and lower locomotor activity in their home cages. Thus, changes in the mother-derived IgG levels affect brain development in offsprings.

Altered cerebellar volumes and intrinsic cerebellar networks in patients with transient global amnesia.

This study aimed to investigate the differences in cerebellar volumes and intrinsic cerebellar networks between patients with transient global amnesia (TGA) and healthy controls. We retrospectively enrolled patients with TGA and age- and sex-matched healthy controls. We used three-dimensional T1-weighted imaging at the time of TGA diagnosis to obtain cerebellar volumes, and the intrinsic cerebellar network was calculated by applying graph theory based on cerebellar volumes. The nodes were defined as individual cerebellar volumes, and edges as partial correlations, controlling for the effects of age and sex. The cerebellar volumes and intrinsic cerebellar networks were compared between the two groups. We enrolled 44 patients with TGA and 47 healthy controls. The volume of the left cerebellar white matter in patients with TGA was significantly lower than that in healthy controls (1.0328 vs. 1.0753%, p = 0.0094). In addition, there were significant differences in intrinsic cerebellar networks between the two groups. The small-worldness index in patients with TGA was higher than that in the healthy controls (0.951 vs. 0.880, p = 0.038). In the correlation analysis, the volumes of the right cerebellar cortex and lobules VIIIB were significantly correlated with age in patients with TGA (r = -0.323, p = 0.033; r = -0.313, p = 0.038, respectively). Patients with TGA exhibit alterations in cerebellar volumes and intrinsic cerebellar networks compared with healthy controls. These findings may contribute to a better understanding of the pathophysiology of the TGA.

Cerebellar degeneration in gluten ataxia is linked to microglial activation.

Gluten sensitivity has long been recognized exclusively for its gastrointestinal involvement; however, more recent research provides evidence for the existence of neurological manifestations that can appear in combination with or independent of the small bowel manifestations. Amongst all neurological manifestations of gluten sensitivity, gluten ataxia is the most commonly occurring one, accounting for up to 40% of cases of idiopathic sporadic ataxia. However, despite its prevalence, its neuropathological basis is still poorly defined. Here, we provide a neuropathological characterization of gluten ataxia and compare the presence of neuroinflammatory markers glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, major histocompatibility complex II and cluster of differentiation 68 in the central nervous system of four gluten ataxia cases to five ataxia controls and seven neurologically healthy controls. Our results demonstrate that severe cerebellar atrophy, cluster of differentiation 20+ and cluster of differentiation 8+ lymphocytic infiltration in the cerebellar grey and white matter and a significant upregulation of microglial immune activation in the cerebellar granular layer, molecular layer and cerebellar white matter are features of gluten ataxia, providing evidence for the involvement of both cellular and humoral immune-mediated processes in gluten ataxia pathogenesis.

Brain Volumes in Opsoclonus-Myoclonus Ataxia Syndrome: A Longitudinal Study.

Little is known about the longitudinal trajectory of brain growth in children with opsoclonus-myoclonus ataxia syndrome. We performed a longitudinal evaluation of brain volumes in pediatric opsoclonus-myoclonus ataxia syndrome patients compared with age- and sex-matched healthy children. This longitudinal case-control study included brain magnetic resonance imaging (MRI) scans from consecutive pediatric opsoclonus-myoclonus ataxia syndrome patients (2009-2020) and age- and sex-matched healthy control children. FreeSurfer analysis provided automatic volumetry of the brain. Paired t tests were performed on the curvature of growth trajectories, with Bonferroni correction. A total of 14 opsoclonus-myoclonus ataxia syndrome patients (12 female) and 474 healthy control children (406 female) were included. Curvature of the growth trajectories of the cerebral white and gray matter, cerebellar white and gray matter, and brainstem differed significantly between opsoclonus-myoclonus ataxia syndrome patients and healthy control children (cerebral white matter, P = .01; cerebral gray matter, P = .01; cerebellar white matter, P < .001; cerebellar gray matter, P = .049; brainstem, P < .01). We found abnormal brain maturation in the supratentorial brain, brainstem, and cerebellum in children with opsoclonus-myoclonus ataxia syndrome.

Structural connectivity at term equivalent age and language in preterm children at 2 years corrected.

We previously reported interhemispheric structural hyperconnectivity bypassing the corpus callosum in children born extremely preterm (<28 weeks) versus term children. This increased connectivity was positively associated with language performance at 4-6 years of age in our prior work. In the present study, we aim to investigate whether this extracallosal connectivity develops in extremely preterm infants at term equivalent age by leveraging a prospective cohort study of 350 very and extremely preterm infants followed longitudinally in the Cincinnati Infant Neurodevelopment Early Prediction Study. For this secondary analysis, we included only children born extremely preterm and without significant brain injury (n = 95). We use higher-order diffusion modelling to assess the degree to which extracallosal pathways are present in extremely preterm infants and predictive of later language scores at 22-26 months corrected age. We compare results obtained from two higher-order diffusion models: generalized q-sampling imaging and constrained spherical deconvolution. Advanced MRI was obtained at term equivalent age (39-44 weeks post-menstrual age). For structural connectometry analysis, we assessed the level of correlation between white matter connectivity at the whole-brain level at term equivalent age and language scores at 2 years corrected age, controlling for post-menstrual age, sex, brain abnormality score and social risk. For our constrained spherical deconvolution analyses, we performed connectivity-based fixel enhancement, using probabilistic tractography to inform statistical testing of the hypothesis that fibre metrics at term equivalent age relate to language scores at 2 years corrected age after adjusting for covariates. Ninety-five infants were extremely preterm with no significant brain injury. Of these, 53 had complete neurodevelopmental and imaging data sets that passed quality control. In the connectometry analyses adjusted for covariates and multiple comparisons (P < 0.05), the following tracks were inversely correlated with language: bilateral cerebellar white matter and middle cerebellar peduncles, bilateral corticospinal tracks, posterior commissure and the posterior inferior fronto-occipital fasciculus. No tracks from the constrained spherical deconvolution/connectivity-based fixel enhancement analyses remained significant after correction for multiple comparisons. Our findings provide critical information about the ontogeny of structural brain networks supporting language in extremely preterm children. Greater connectivity in more posterior tracks that include the cerebellum and connections to the regions of the temporal lobes at term equivalent age appears to be disadvantageous for language development.

Cerebellar Volumetry in Ataxias: Relation to Ataxia Severity and Duration.

Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Our results (i) confirmed SCA6 being considered as a pure cerebellar grey matter disease, (ii) emphasise the involvement of cerebellar white matter in the neuropathology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.

Partial volume correction in longitudinal tau PET studies: is it really needed?

Background[18F]flortaucipir (FTP) tau PET quantification is known to be affected by non-specific binding in off-target regions. Although partial volume correction (PVC) techniques partially account for this effect, their inclusion may also introduce noise and variability into the quantification process. While the impact of these effects has been studied in cross-sectional designs, the benefits and drawbacks of PVC on longitudinal FTP studies is still under scrutiny. The aim of this work was to study the performance of the most common PVC techniques for longitudinal FTP imaging. MethodsA cohort of 247 individuals from the Alzheimer's Disease Neuroimaging Initiative with concurrent baseline FTP-PET, amyloid-beta (Aβ) PET and structural MRI, as well as with follow-up FTP-PET and MRI were included in the study. FTP-PET scans were corrected for partial volume effects using Meltzer's, a simple and popular analytical PVC, and both the region-based voxel-wise (RBV) and the iterative Yang (iY) corrections. FTP SUVR values and their longitudinal rates of change were calculated for regions of interest (ROI) corresponding to Braak Areas I-VI, for a temporal meta-ROI and for regions typically displaying off-target FTP binding (caudate, putamen, pallidum, thalamus, choroid plexus, hemispheric white matter, cerebellar white matter, and cerebrospinal fluid). The longitudinal correlation between binding in off-target and target ROIs was analysed for the different PVCs. Additionally, group differences in longitudinal FTP SUVR rates of change between Aβ-negative (A-) and Aβ-positive (A+), and between cognitively unimpaired (CU) and cognitively impaired (CI) individuals, were studied. Finally, we compared the ability of different partial-volume-corrected baseline FTP SUVRs to predict longitudinal brain atrophy and cognitive decline. ResultsAmong off-target ROIs, hemispheric white matter showed the highest correlation with longitudinal FTP SUVR rates from cortical target ROIs (R2=0.28–0.82), with CSF coming in second (R2=0.28–0.42). Application of voxel-wise PVC techniques minimized this correlation, with RBV performing best (R2=0.00–0.07 for hemispheric white matter). PVC also increased group differences between CU and CI individuals in FTP SUVR rates of change across all target regions, with RBV again performing best (No PVC: Cohen's d = 0.26–0.66; RBV: Cohen's d = 0.43–0.74). These improvements were not observed for differentiating A- from A+ groups. Additionally, voxel-wise PVC techniques strengthened the correlation between baseline FTP SUVR and longitudinal grey matter atrophy and cognitive decline. ConclusionQuantification of longitudinal FTP SUVR rates of change is affected by signal from off-target regions, especially the hemispheric white matter and the CSF. Voxel-wise PVC techniques significantly reduce this effect. PVC provided a significant but modest benefit for tasks involving the measurement of group-level longitudinal differences. These findings are particularly relevant for the estimations of sample sizes and analysis methodologies of longitudinal group studies.

Quantitative brain morphometry identifies cerebellar, cortical, and subcortical gray and white matter atrophy in late-onset Tay-Sachs disease

Quantitative brain morphometry identifies cerebellar, cortical, and subcortical gray and white matter atrophy in late-onset Tay-Sachs disease

Temporal evolution of microstructural integrity in cerebellar peduncles in Parkinson’s disease: Stage-specific patterns and dopaminergic correlates

BackgroundPrevious research revealed differences in cerebellar white matter integrity by disease stages, indicating a compensatory role in Parkinson’s disease (PD). However, the temporal evolution of cerebellar white matter microstructure in patients with PD (PwPD) remains unclear. ObjectiveTo unravel temporal evolution of cerebellar white matter and its dopaminergic correlates in PD. MethodsWe recruited 124 PwPD from the PPMI study. The participants were divided into two subsets: Subset 1 (n = 41) had three MRI scans (baseline, 2 years, and 4 years), and Subset 2 (n = 106) had at least two MRI scans at baseline, 1 year, and/or 2 years. Free water-corrected diffusion metrics were used to measure the microstructural integrity in cerebellar peduncles (CP), the main white matter tracts connecting to and from the cerebellum. The ACAPULCO processing pipeline was used to assess cerebellar lobules volumes. Linear mixed-effect models were used to study longitudinal changes. We also examined the relationships between microstructural integrity in CP, striatal dopamine transporter specific binding ratio (SBR), and clinical symptoms. ResultsMicrostructural changes in CP showed a non-linear pattern in PwPD. Free water-corrected fractional anisotropy (FAt) increased in the first two years but declined from 2 to 4 years, while free water-corrected mean diffusivity exhibited the opposite trend. The initial increased FAt in CP correlated with cerebellar regional volume atrophy, striatal dopaminergic SBR decline, and worsening clinical symptoms, but this correlation varied across disease stages. ConclusionsOur findings suggest a non-linear evolution of microstructural integrity in CP throughout the course of PD, indicating the adaptive structural reorganization of the cerebellum simultaneously with progressive striatal dopaminergic degeneration in PD.

An Effective Therapy of Acute Necrotizing Encephalopathy of Childhood: a Case Report

Acute necrotizing encephalopathy of childhood is a rare type of encephalopathy characterized by multiple bilateral brain lesions, mainly involving the thalami but also the putamina, internal and external capsules, cerebellar white matter, and the brainstem tegmentum. It is a rare condition; the first case was described in 1995, and many cases have been reported in Asia and in many Western countries. Most cases are sporadic; however, a few cases of recurrent and/or familial episodes have been reported, secondary to mutations in the RANBP2 gene) and other gene mutations that are all responsible of normal mitochondrial functions. Clinically, it is characterized by acute encephalopathy with dramatic neurological deficits/symptoms. The condition usually has a poor prognosis with high morbidity and mortality rates. We report a 5-year-old boy who showed a typical presentation of this rare condition after obtaining the consent of his legal guardians. We demonstrate how the effective combination of immune suppressive therapy with the mitochondrial cocktail during the early course of the disease leads to clinical and radiological improvement.

Possibilities of magnetic resonance morphometry and laboratory biomarkers in studying the progression of multiple sclerosis

To show that magnetic resonance morphometry and laboratory biomarkers are promising methods for early detection of progressive forms of multiple sclerosis (MS). Eighty-one patients with MS were examined, magnetic resonance morphometry was performed in all of them, 60 patients were analyzed for neurofilament light chains (sNFL), phosphorylated neurofilament heavy chains (spNFH) and glial fibrillary protein (sGFAP) in serum by enzyme-linked immunosorbent assay. Brain volumes were negatively correlated with disease duration, EDSS score, 25-foot walk test score and 9-ring test and positively correlated with the Symbol-Numeric Test and the Montreal Cognitive Assessment. Patients with progressive types of MS (PMS) had smaller volumes of brain gray matter, cerebellar white matter, occipital lobes, caudate nucleus, hippocampus, pallidum, thalamus, and contiguous nucleus. A CSF volume greater than 15.06% could suggest progression (CI 54.79-91%) with a sensitivity of 77.78% and specificity of 70.18%. When patients were on DMT, they had larger thalamic volumes (median 1.09% [1.6; 1.16] vs 1.04% [0.95; 1.14]; p=0.02) and smaller CSF volumes (13.86±2.87% vs. 15.55±3.49%; p=0.03). The levels of sNFL and spNFH were not increased in PMS and during exacerbations, and the low obtained values of sNFL suggest poor sensitivity of the method. There were trends (p=0.374) towards higher sGFAP in patients with PRS (median 3.2 ng/mL [1.85; 4.6] compared to remitting MS (2.05 ng/mL [1.29; 4.52]). The results demonstrate the differences in brain volumes in patients with different types of MS and emphasize the importance of long-term follow-up to better assess disease progression.

MRI radiomics combined with machine learning for diagnosing mild cognitive impairment: a focus on the cerebellar gray and white matter.

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

Cerebellar white and gray matter abnormalities in temporal lobe epilepsy: a voxel-based morphometry study.

Previous structural neuroimaging studies linked cerebellar deficits to temporal lobe epilepsy (TLE). The functions of various cerebellar regions are increasingly being valued, and their changes in TLE patients warrant further in-depth investigation. In this study, we used the Spatially Unbiased Infratentorial (SUIT) toolbox with a new template to evaluate the cerebellar structural abnormalities in patients with TLE, and further explored the relationship between the changes of different cerebellar regions and cognition. Thirty-two patients with TLE were compared with 39 healthy controls (HC) matched according to age, gender, handedness, and education level. All participants underwent a high-resolution T1-weighted MRI scan on a 3.0 Tesla scanner. We used a voxel-based morphometry (VBM) approach utilizing the SUIT toolbox to provide an optimized and fine-grained exploration of cerebellar structural alterations associated with TLE. Compared with HC, TLE patients showed a significant reduction in the volume of gray matter in the Left lobule VI and white matter in the Right Crus II. In the TLE patient group, we conducted partial correlation analysis between the volumes of different cerebellar regions and cognitive rating scale scores, such as MMSE and MoCA. The volume of the Left lobule VI (GM) exhibited a positive correlation with the MMSE score, but no significant correlation was found with the MoCA score. On the other hand, there was no significant correlation observed between the volume of the Right Crus II (WM) and the two cognitive scale scores mentioned above. Furthermore, it was observed that the MMSE was more effective than the MoCA in identifying epilepsy patients with cognitive impairment. This study supported previous research indicating that temporal lobe epilepsy (TLE) is linked to structural changes in the cerebellum, specifically affecting the volume of both gray and white matter. These findings offer valuable insights into the neurobiology of TLE and hold potential to inform the development of enhanced diagnostic methods and more effective treatment approaches.

Structural volumetric and Periodic Table DTI patterns in Complex Normal Pressure Hydrocephalus-Toward the principles of a translational taxonomy.

We previously proposed a novel taxonomic framework to describe the diffusion tensor imaging (DTI) profiles of white matter tracts by their diffusivity and neural properties. We have shown the relevance of this strategy toward interpreting brain tissue signatures in Classic Normal Pressure Hydrocephalus vs. comparator cohorts of mild traumatic brain injury and Alzheimer's disease. In this iteration of the Periodic Table of DTI Elements, we examined patterns of tissue distortion in Complex NPH (CoNPH) and validated the methodology against an open-access dataset of healthy subjects, to expand its accessibility to a larger community. DTI measures for 12 patients with CoNPH with multiple comorbidities and 45 cognitively normal controls from the ADNI database were derived using the image processing pipeline on the brainlife.io open cloud computing platform. Using the Periodic Table algorithm, DTI profiles for CoNPH vs. controls were mapped according to injury patterns. Structural volumes in most structures tested were significantly lower and the lateral ventricles higher in CoNPH vs. controls. In CoNPH, significantly lower fractional anisotropy (FA) and higher mean, axial, and radial diffusivities (MD, L1, and L2 and 3, respectively) were observed in white matter related to the lateral ventricles. Most diffusivity measures across supratentorial and infratentorial structures were significantly higher in CoNPH, with the largest differences in the cerebellum cortex. In subcortical deep gray matter structures, CoNPH and controls differed most significantly in the hippocampus, with the CoNPH group having a significantly lower FA and higher MD, L1, and L2 and 3. Cerebral and cerebellar white matter demonstrated more potential reversibility of injury compared to cerebral and cerebellar cortices. The findings of widespread and significant reductions in subcortical deep gray matter structures, in comparison to healthy controls, support the hypothesis that Complex NPH cohorts retain imaging features associated with Classic NPH. The use of the algorithm of the Periodic Table allowed for greater consistency in the interpretation of DTI results by focusing on patterns of injury rather than an over-reliance on the interrogation of individual measures by statistical significance alone. Our aim is to provide a prototype that could be refined for an approach toward the concept of a "translational taxonomy."

Detecting ferroptosis and immune infiltration profiles in multiple system atrophy using postmortem brain tissue.

The importance of ferroptosis and the immune system has been mentioned in the pathogenesis of α-synucleinopathy. The α-synuclein-immunoreactive inclusions that primarily affect oligodendrocytes are the hallmark of multiple system atrophy (MSA). Limited evidence implicates that iron and immune responses are involved in the pathogenesis of MSA, which is associated with neurodegeneration and α-synuclein aggregation. The RNA sequencing data were collected from the Gene Expression Omnibus database. MSA-C-related module genes were identified through weighted gene co-expression network analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to predict the potential molecular functions. The candidate ferroptosis-related genes associated with MSA-C were obtained using a machine-learning algorithm. CIBERSORT was used to estimate the compositional patterns of the 22 types of immune cells. The tissues for sequencing were extracted from postmortem cerebellar white matter tissues of 11 MSA-C patients and 47 healthy controls. The diagnostic ability of the six MSA-C-related ferroptosis-related genes in discriminating MSA-C from the healthy controls demonstrated a favorable diagnostic value, with the AUC ranging from 0.662 to 0.791. The proportion of CD8+ T cells in MSA-C was significantly higher than in the controls (P = 0.02). The proportion of NK cells resting in MSA-C was significantly higher than in the controls (P = 0.011). Ferroptosis and T-cell infiltration may be important pathways of disease development in MSA-C, and targeting therapies for these pathways may be disease-modifying.

CGG repeat expansion in LOC642361/NUTM2B-AS1 typically presents as oculopharyngodistal myopathy

CGG repeat expansions in LOC642361/NUTM2B-AS1 have recently been identified as a cause of oculopharyngeal myopathy with leukoencephalopathy. However, since only three patients from a single family were reported, it remains unknown whether their clinicopathological features are typical for CGG repeat expansions in LOC642361/NUTM2B-AS1. Here, using repeat-primed-polymerase chain reaction (RP-PCR) and long-read sequencing, we identify 12 individuals from 3 unrelated families with CGG repeat expansions in LOC642361/NUTM2B-AS1, typically presenting with oculopharyngodistal myopathy. The CGG repeat expansions range from 161 to 669 repeat units. Most of the patients present with ptosis, restricted eye movements, dysphagia, dysarthria, and diffuse limb muscle weakness. Only one patient shows T2-weighted hyperintensity in the cerebellar white matter surrounding the deep cerebellar nuclei on brain magnetic resonance imaging. Muscle biopsies from three patients show a myopathic pattern and rimmed vacuoles. Analyses of muscle biopsies suggest that CGG repeat expansions in LOC642361/NUTM2B-AS1 may deleteriously affect aggrephagic capacity, suggesting that ribonucleic acid (RNA) toxicity and mitochondrial dysfunction may contribute to pathogenesis. Our study thus expands the phenotypic spectrum for the CGG repeat expansion of LOC642361/NUTM2B-AS1 and indicates that this genetic variant typically manifests as oculopharyngodistal myopathy with chronic myopathic changes with rimmed vacuoles and filamentous intranuclear inclusions in muscle fibers.