Cerebellar White Matter Research Articles

Closer correlations between florbetapir PET measurements of amyloid plaque burden using a cerebral white matter reference region and Alzheimer’s disease‐related hypometabolism

AbstractBackgroundAlzheimer’s disease (AD) is associated with amyloid‐β (Aß) plaque deposition and a characteristic pattern of cerebral glucose hypometabolism. While a cerebellar reference region is commonly used to characterize cerebral Aβ burden, we demonstrated improvements in the ability of florbetapir PET to track Aβ burden using a cerebral white matter reference region (Chen, et al., 2015). Here, we compare associations between cerebral‐to‐reference region florbetapir PET standard value uptake ratios (SUVRs) using cerebral white matter versus cerebellar reference regions to two FDG PET indices of AD‐related cerebral hypometabolism: “hypometabolic convergence index” (HCI) and “statistical region‐of‐interest” (sROI) (Chen et al, 2010; 2011).MethodWe analyzed 1722 florbetapir and FDG PET scan pairs from the AD Neuroimaging Initiative, including 267 with probable AD dementia (pAD), 592 with MCI and 379 cognitively unimpaired (CU). Florbetapir SUVRs were computed using measures from the cerebral regions‐of‐interest with the cerebral white matter or cerebellar reference regions. HCI and sROI were generated from the FDG PET images. Pearson’s correlations and the Steiger statistical test were used to characterize and compare the extent to which florbetapir SUVRs using cerebellar versus cerebral white matter reference regions were associated with HCI or sROI in the overall group, the pAD, MCI and CU sub‐groups.ResultCorrelations between florbetapir SUVRs using the white matter reference region and HCI (0.59, 0.41, 0.45, and 0.40 in the overall, pAD, MCI and CU groups) were significantly stronger than those using the cerebellar reference region (0.40, 0.23, 0.26, and 0.20, P=1.1e‐16, 3.6e‐06, 1.3e‐09, and 1.0e‐11, respectively). Similarly, inverse correlations between florbetapir SUVR measurements using the white matter reference region and sROI measurements (‐0.51, ‐0.32, ‐0.38, and ‐0.28 in the overall, pAD, MCI and CU groups) were significantly stronger than those using the cerebellar reference region (‐0.34, ‐0.09, ‐0.24, and ‐0.13, P=2.0e‐15, 3.2e‐07, 1.7e‐0, and 4.0e‐07, respectively).ConclusionFlorbetapir PET Aβ plaque measures are more closely associated with the AD‐related pattern of cerebral hypometabolism when SUVRs are generated using a white matter rather than cerebellar reference regions. Additional research is needed to examine if our results are generalizable for other Aβ PET tracers and longitudinal change measures.

Amyloid pathology, small‐vessel disease, atrophy, and cognition in normal adults with type 2 diabetes

AbstractBackgroundVarious factors contribute to cognitive decline in older adults with type 2 diabetes (T2D). We assessed the association between imaging metrics of brain pathology (including global atrophy, small vessel disease, and amyloid deposition) with cognitive functioning in older adults with T2D.MethodCommunity‐dwelling, cognitively normal, older adults with T2D from the Israel Diabetes and Cognitive Decline Study with brain MRI and/or F18‐Flutemetamol amyloid‐PET were included. Gray matter (GM) and white matter hyperintensities (WMH) volume were extracted from high‐resolution T1‐weighted and fluid‐attenuated inversion recovery (FLAIR), respectively, using Statistical Parametric Mapping (SPM8). Amyloid PET was visually read and quantified using standardized uptake value ratio (SUVR) with the cerebellar gray and white matter as reference region. Global mean and lobar SUVR were extracted. Global cognitive functioning was assessed by neuropsychological testing and summarized into four domains including executive functions, attention, memory, and language, and an average of the four domains comprised global cognition. Linear regression models were used in a stepwise manner controlling for age, sex, education, HbA1c, and duration of T2D. MRI measures were also adjusted for intracranial volume.Result236 participants, 232 with MRI and 52 with amyloid‐PET were included, mean age 75 [66‐89], 39% females, 11 (21.1%) amyloid positive (Table 1). On average, participants had good glycemic control (mean HbA1C=6.7). An increase in global SUVR was associated with lower global cognition (Estimate=‐1.23, p=0.02). Additional adjustment for GM volume did not alter the results (Table 2). These results were driven by associations of SUVR with executive functioning (‐1.32, p=0.01), though a trend toward the same direction was also seen with attention (‐0.95, p=0.09), language (‐0.86, p=0.13), and memory (‐0.85, p=0.14) (Figure 1). Amyloid in all lobes contributed significantly to the associations (Table 2). No association was found between WMH volume and any of the cognitive outcomes (p‐values>0.21).ConclusionIn our cohort of normal cognitive older adults with well controlled T2D, amyloid load but not small vessel disease nor glycemic control was associated with cognitive functioning. This association was not mediated by GM volume suggesting other neurobiological substrates underlying the effect of amyloid on cognition in this population.

Morphological analysis of the cerebellum and its efferent system in a basal actinopterygian fish, Polypterus senegalus.

Although all vertebrate cerebella contain granule cells, Purkinje cells, and efferent neurons, the cellular arrangement and neural circuitry are highly diverse. In amniotes, cerebellar efferent neurons form clusters, deep cerebellar nuclei, lie deep in the cerebellum, and receive synaptic inputs from Purkinje cells but not granule cells. However, in the cerebellum of teleosts, the efferent neurons, called eurydendroid cells, lie near the cell bodies of Purkinje cells and receive inputs both from axons of Purkinje cells and granule cell parallel fibers. It is largely unknown how the cerebellar structure evolved in ray-finned fish (actinopterygians). To address this issue, we analyzed the cerebellum of a bichir Polypterus senegalus, one of the most basal actinopterygians. We found that the cell bodies of Purkinje cells are not aligned in a layer; incoming climbing fibers terminate mainly on the basal portion of Purkinje cells, revealing that the Polypterus cerebellum has unique features among vertebrate cerebella. Retrograde labeling and marker analyses of the efferent neurons revealed that their cell bodies lie in restricted granular areas but not as deep cerebellar nuclei in the cerebellar white matter. The efferent neurons have long dendrites like eurydendroid cells, although they do not reach the molecular layer. Our findings suggest that the efferent system of the bichir cerebellum has intermediate features between teleosts and amniote vertebrates, and provides a model to understand the basis generating diversity in actinopterygian cerebella.

Brain structural abnormalities in the preclinical stage of Machado-Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3): evaluation by MRI morphometry, diffusion tensor imaging and neurite orientation dispersion and density imaging.

To investigate whether neurite orientation dispersion and density imaging (NODDI) could provide the added value for detecting brain microstructural alterations in the preclinical stage of Machado-Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3) compared with MRI morphometry and diffusion tensor imaging (DTI). Twenty preclinical MJD/SCA3 patients and 21 healthy controls were enrolled. Three b values DWI and 3D T1-weighted images were acquired at 3.0T. Tract-based spatial statistics (TBSS) approach was used to investigate the white matter (WM) alterations in the DTI metrics and NODDI metrics. Gray matter-based spatial statistics (GBSS) approach was used to investigate the grey matter (GM) alterations in the NODDI metrics. Voxel-based morphometry (VBM) approach was performed on the 3D T1-weighted images. The relationship between the cytosine-adenine-guanine (CAG) repeat length and brain microstructural alterations of preclinical MJD/SCA3 was identified. Compared with healthy controls, the preclinical MJD/SCA3 patients showed decreased FA and NDI as well as increased MD, AD, and RD in the WM of cerebellum and brainstem (corrected P < 0.05), and decreased NDI in the GM of cerebellar vermis (corrected P < 0.05). The CAG repeat length in preclinical MJD/SCA3 patients was negatively correlated with the reduced FA and NDI of the infratentorial WM and the reduced NDI of the cerebellum, and positively with the increased MD and RD of the infratentorial WM. NOODI can provide novel quantitative microstructural changes in MJD/SCA3 carriers, expanding our understanding of the gray and white matter (axons and dendrites) degeneration in this frequent ataxia syndrome.

Abstract 10137: Functional Brain Imaging Reveals Decreased Cerebellar Volume and Altered Brain Connectivity in Pulmonary Arterial Hypertension

Introduction: Psychiatric and cognitive deficiencies are increasingly appreciated in pulmonary arterial hypertension (PAH). Brain abnormalities potentially underlying these disease manifestations have been ill-defined. Hypothesis: Altered brain structure and functional connectivity correlate with neurocognitive changes in PAH patients. Methods: PAH patients at UPMC were enrolled from 2017 to 2018. Participants underwent T1/T2 structural and resting functional brain MRI (fMRI) in addition to cognitive testing. Case data were compared in a 1:4 ratio to that of age-, gender-, and education-matched non-PAH controls. Linear regression analysis with clustered sandwich estimator and adjustment for multiple hypothesis testing was used for comparisons. Most recent hemodynamic data for PAH patients were reviewed including pulmonary vascular resistance (PVR). Pearson correlations were computed between PVR and brain volumes. Results: 12 PAH patients (median age, 45 years [range 26-61]; 9 women) were enrolled. T1/T2 MRI analysis identified 18 regions with volumetric differences (q&lt;0.05), with notable involvement of limbic (6/18, 33%) and basal ganglia (4/18, 22%) structures. PAH patients showed decreased left cerebellar cortical (45178 ± 1417 vs 53295 ± 583 mm 3 ; q=0.01) and right cerebellar white matter volumes (16458 ± 727 vs 39675 ± 5846 mm 3 ; q=0.018). Structural changes concorded with results from fMRI analysis: PAH patients had decreased functional connectivity in the left cerebellum (q=0.003). Corresponding with modulation of executive functions by the cerebellum, a trend was seen toward decreased inhibitory control and attention (83 ± 3 vs 95 ± 1; q=0.07) and pattern comparison processing speed (93 ± 5 vs 106 ± 4; q=0.07) in PAH patients. A trend toward negative correlation of PVR with left cerebellar white matter volume (r = -0.82, q = 0.06) was also observed. Conclusion: Limbic, basal ganglia, and cerebellar regions were smaller and less functionally connected in PAH cases than in matched controls. Decreased cerebellar volume may correlate with more severe hemodynamic disease. Any links among brain changes, cognitive dysfunction, and PAH pathophysiology deserve further study and may lead to neurologic modalities to diagnose and treat disease.

Cerebellar White Matter Abnormalities in Charcot-Marie-Tooth Disease: A Combined Volumetry and Diffusion Tensor Imaging Analysis.

Charcot–Marie–Tooth disease (CMT) is a genetically heterogeneous hereditary peripheral neuropathy. Brain volumetry and diffusion tensor imaging (DTI) were performed in 47 controls and 47 CMT patients with PMP22 duplication (n = 10), MFN2 (n = 15), GJB1 (n = 11), or NEFL mutations (n = 11) to investigate for structural changes in the cerebellum. Volume of cerebellar white matter (WM) was significantly reduced in CMT patients with NEFL mutations. Abnormal DTI findings were observed in the superior, middle, and inferior cerebellar peduncles, predominantly in NEFL mutations and partly in GJB1 mutations. Cerebellar ataxia was more prevalent in the NEFL mutation group (72.7%) than the GJB1 mutation group (9.1%) but was not observed in other genotypic subtypes, which indicates that structural cerebellar abnormalities were associated with the presence of cerebellar ataxia. However, NEFL and GJB1 mutations did not affect cerebellar gray matter (GM), and neither cerebellar GM nor WM abnormalities were observed in the PMP22 duplication or MFN2 mutation groups. We found structural evidence of cerebellar WM abnormalities in CMT patients with NEFL and GJB1 mutations and an association between cerebellar WM involvement and cerebellar ataxia in these genetic subtypes, especially in the NEFL subgroup. Therefore, we suggest that neuroimaging, such as MRI volumetry or DTI, for CMT patients could play an important role in detecting abnormalities of cerebellar WM.

Erdheim\u2013Chester disease: with neurological manifestation and multisystem involvement: case report and radiological review

BackgroundErdheim–Chester disease (ECD) is a rarely encountered idiopathic systemic form of non-Langerhans cell histiocytosis. The clinical manifestations of ECD are highly heterogeneous, ranging from unifocal forms to life-threatening multisystem involvement. Patients with CNS involvement often do not show clinical remission.Case presentationWe present a case of a 60-year-old male patient with worsening complaints of loss of balance, involuntary jerky movements, emotional lability and scanning speech developing over a period of 5 years. Magnetic resonance imaging of the brain at present institute revealed signal abnormalities in the midbrain, pons, cerebellar peduncles and cerebellar white matter with mineral deposition and volume loss in the bilateral basal ganglia and midbrain. Positron emission tomography–computed tomography of chest and abdomen revealed 18-fluorodeoxyglucose avid soft tissues lesion in the retroperitoneum involving bilateral perinephric spaces with intra-renal sinus extension, in pre- and paraaortic regions with enlargement of both adrenal glands. The radiographs of the long bones revealed multiple areas of sclerosis. The suspected diagnosis of ECD was confirmed on histopathology. ECD is a rare disease and has a predilection towards middle-aged males and is usually diagnosed late after the onset of initial symptoms.ConclusionsOur case was an atypical presentation of an extremely rare disease, presenting with ataxia and choreoathetoid movements linked to ferromagnetic deposition on brain scans. Multiple other imaging feature characteristics of the disease like the hairy kidney sign, coated aorta sign, skeletal, extra-skeletal and central nervous system manifestations were noted in this single patient.

The neuropathological findings of developmental and epileptic encephalopathy-43 (DEE43) and delineation of a the molecular spectrum of novel case

Developmental and epileptic encephalopathies (DEE) constitute an expanding group of severely disabling and, most frequently, drug-resistant disorders starting in the first year of life. Among them, there is DEE43, caused by dominant mutations in the GABRB3 gene. We present first neuropathological findings in a novel, molecularly confirmed case with the fatal course. The neuropathological analysis revealed co-existing developmental anomalies and retardation of myelination resulting from disturbed early brain growth as well as lesions caused by epileptic hypoxic-ischemic episodes. Developmental anomalies included misplaced neurons in the cerebellar white matter, heterotopic neurons in the cortical molecular layer and in the molecular layer of the hippocampal dentate gyrus, dysmorphic cerebellar dentate nuclei and inferior olivary nuclei in the medulla oblongata. The migrational and maturational disorders leading to the neuronal network dysfunction could be the cause of both the lack of development and the ineffectiveness of antiepileptic treatment in children affected by DEE. Giving the presented neuropathological description and based on the literature, we discuss the pathomechanism of the disease, to improve current understanding of both the lack of development and the ineffectiveness of treatment of affected children.

Glia Imaging Differentiates Multiple System Atrophy from Parkinson's Disease: A Positron Emission Tomography Study with [11 C]PBR28 and Machine Learning Analysis.

The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA. In this multicenter PET study, we assess the performance of TSPO imaging as a diagnostic marker for MSA. We analyzed [11 C]PBR28 binding to TSPO using imaging data of 66 patients with MSA and 24 patients with PD. Group comparisons were based on regional analysis of parametric images. The diagnostic readout included visual reading of PET images against clinical diagnosis and machine learning analyses. Sensitivity, specificity, and receiver operating curves were used to discriminate MSA from PD and cerebellar from parkinsonian variant MSA. We observed a conspicuous pattern of elevated regional [11 C]PBR28 binding to TSPO in MSA as compared with PD, with "hotspots" in the lentiform nucleus and cerebellar white matter. Visual reading discriminated MSA from PD with 100% specificity and 83% sensitivity. The machine learning approach improved sensitivity to 96%. We identified MSA subtype-specific TSPO binding patterns. We found a pattern of significantly increased regional glial TSPO binding in patients with MSA. Intriguingly, our data are in line with severe neuroinflammation in MSA. Glia imaging may have potential to support clinical MSA diagnosis and patient stratification in clinical trials on novel drug therapies for an α-synucleinopathy that remains strikingly incurable. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Siponimod (BAF312) penetrates, distributes, and acts in the central nervous system: Preclinical insights.

BackgroundSiponimod (BAF312), a selective S1P1/S1P5 agonist, reduces disability progression in secondary progressive MS. Recent observations suggest it could act via S1P1/S1P5-dependent anti-inflammatory and pro-myelination effects on CNS-resident cells.ObjectiveGenerate preclinical evidence confirming siponimod's CNS penetration and activity.MethodsSiponimod's CNS penetration and distribution was explored in rodents and non-human primates (NHPs) using: Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS), quantitative whole-body autoradiography (QWBA) using 14C-radiolabeled siponimod or non-invasive single-photon emission CT (SPECT) with a validated 123I-radiolabeled siponimod analog. Functional CNS activity was investigated by S1P1 receptor quantification in brain homogenates.ResultsIn mice/rats, siponimod treatments achieved dose-dependent efficacy and dose-proportional increase in drug blood levels, with mean brain/blood drug-exposure ratio (Brain/BloodDER) of 6–7. Efficacy in rat brain tissues was revealed by a dose-dependent reduction in brain S1P1 levels. QWBA distribution analysis in rats indicated that [14C]siponimod related radioactivity could readily penetrate CNS, with particularly high uptakes in white matter of cerebellum, corpus callosum, and medulla oblongata versus lower exposures in other areas such as olfactory bulb. SPECT monitoring in NHPs revealed CNS distribution with a brain/bloodDER of ∼6, as in rodents.ConclusionFindings demonstrate siponimod's CNS penetration and distribution across species, with high translational potential to human.

Neurological soft signs in neurodegenerative dementias: A pilot study

Neurological Soft Signs (NSS) are sensory-motor abnormalities linked with cerebellar and microstructural subcortical white matter alterations, which are not systematically evaluated during standard neurological examination. Although historically observed in psychiatric conditions, NSS have been recently associated with migraine, mild cognitive impairment and Alzheimer's disease (AD), and correlated with age and apoE polymorphisms. However, no study to date has evaluated the burden of NSS in other types of dementia. Our research aims to confirm the increase of NSS in AD patients, and extend their assessment to fronto-temporal dementia (FTD), cortico-basal syndrome (CBS) and Lewy-body dementia (LBD), correlating them with the severity of cognitive impairment.

Circulation of Nor98 Atypical Scrapie in Portuguese Sheep Confirmed by Transmission of Isolates into Transgenic Ovine ARQ-PrP Mice.

Portugal was among the first European countries to report cases of Atypical Scrapie (ASc), the dominant form of Transmissible Spongiform Encephalopathy (TSE) in Portuguese small ruminants. Although the diagnostic phenotypes observed in Portuguese ASc cases seem identical to those described for Nor98, unequivocal identification requires TSE strain-typing using murine bioassays. In this regard, we initiated characterization of ASc isolates from sheep either homozygous for the ARQ genotype or the classical scrapie-resistant ARR genotype. Isolates from such genotypes were transmitted to TgshpXI mice expressing ovine PrPARQ. Mean incubation periods were 414 ± 58 and 483 ± 107 days in mice inoculated with AL141RQ/AF141RQ and AL141RR/AL141RR sheep isolates, respectively. Both isolates produced lesion profiles similar to French ASc Nor98 ‘discordant cases’, where vacuolation was observed in the hippocampus (G6), cerebral cortex at the thalamus (G8) level, cerebellar white matter (W1) and cerebral peduncles (W3). Immunohistochemical PrPSc deposition was observed in the hippocampus, cerebellar cortex, cerebellar white matter and cerebral peduncles in the form of aggregates and fine granules. These findings were consistent with previously reported cases of ASc Nor98 transmitted to transgenic TgshpXI mice, confirming that the ASc strain present in Portuguese sheep corresponds to ASc Nor98.

Low-grade IVH in preterm infants causes cerebellar damage, motor, and cognitive impairment.

Few studies have examined the effect of low-grade intraventricular hemorrhage (IVH) on the white matter in the cerebellum and its association with neurodevelopment. We evaluated cerebellar white matter at term-equivalent age (TEA) in preterm infants with low-grade IVH. Furthermore, we assessed neurodevelopmental outcomes at 3 years of age to examine the influence of low-grade IVH on neurodevelopment. Thirteen infants with low-grade IVH and 26 without IVH, born at <30 weeks' postmenstrual age (PMA), were enrolled in this study. Diffusion tensor imaging (DTI) parameters, including fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in the middle and superior cerebellar peduncles (SCP), were measured. Neurodevelopmental outcomes at three years of age were assessed and the correlation between DTI parameters and developmental quotient (DQ) was analyzed. Preterm infants with IVH showed lower FA values (P < 0.01) and higher ADC values (P < 0.05) in the SCP at TEA than the no-IVH group. Lower Postural-Motor and Cognitive-Adaptive DQ at 3 years of age were observed in the IVH compared to the no-IVH group. A significant correlation between the FA values in the SCP at TEA and the Posture-Motor DQ was observed at three years of age (P = 0.043, r = 0.50). These data suggest that low-grade IVH in preterm infants affects the SCP at TEA and that impaired cerebellar white matter correlates with poor motor development at three years of age.

Rat Model of Widespread Cerebral Cortical Demyelination Induced by an Intracerebral Injection of Pro-Inflammatory Cytokines.

Multiple sclerosis (MS) is the most common immune-mediated disease of the central nervous system (CNS) and progressively leads to physical disability and death, caused by white matter lesions in the spinal cord and cerebellum, as well as by demyelination in grey matter. Whilst conventional models of experimental allergic encephalomyelitis are suitable for the investigation of the cell-mediated inflammation in the spinal and cerebellar white matter, they fail to address grey matter pathologies. Here, we present the experimental protocol for a novel rat model of cortical demyelination allowing the investigation of the pathological and molecular mechanisms leading to cortical lesions. The demyelination is induced by an immunization with low-dose myelin oligodendrocyte glycoprotein (MOG) in an incomplete Freund's adjuvant followed by a catheter-mediated intracerebral delivery of pro-inflammatory cytokines. The catheter, moreover, enables multiple rounds of demyelination without causing injection-induced trauma, as well as the intracerebral delivery of potential therapeutic drugs undergoing a preclinical investigation. The method is also ethically favorable as animal pain and distress or disability are controlled and relatively minimal. The expected timeframe for the implementation of the entire protocol is around 8 - 10 weeks.

Rat Model of Widespread Cerebral Cortical Demyelination Induced by an Intracerebral Injection of Pro-Inflammatory Cytokines

Multiple sclerosis (MS) is the most common immune-mediated disease of the central nervous system (CNS) and progressively leads to physical disability and death, caused by white matter lesions in the spinal cord and cerebellum, as well as by demyelination in grey matter. Whilst conventional models of experimental allergic encephalomyelitis are suitable for the investigation of the cell-mediated inflammation in the spinal and cerebellar white matter, they fail to address grey matter pathologies. Here, we present the experimental protocol for a novel rat model of cortical demyelination allowing the investigation of the pathological and molecular mechanisms leading to cortical lesions. The demyelination is induced by an immunization with low-dose myelin oligodendrocyte glycoprotein (MOG) in an incomplete Freund's adjuvant followed by a catheter-mediated intracerebral delivery of pro-inflammatory cytokines. The catheter, moreover, enables multiple rounds of demyelination without causing injection-induced trauma, as well as the intracerebral delivery of potential therapeutic drugs undergoing a preclinical investigation. The method is also ethically favorable as animal pain and distress or disability are controlled and relatively minimal. The expected timeframe for the implementation of the entire protocol is around 8 - 10 weeks.

Neuroimaging of Pediatric Cerebellum in Inherited Neurodegenerative Diseases

In the study of cerebellar degenerative diseases, morphologic imaging (computed tomography, CT and magnetic resonance imaging, MRI) is the most common examination. From the clinical and genetic point of view, cerebellar degenerative diseases include heterogeneous conditions in which MRI may show isolated cerebellar atrophy or cerebellar atrophy associated with other cerebellar or supratentorial abnormalities. Neuroradiological progression is often observed. In congenital disorders of glycosylation (CDG), for example, MRI may be normal, may demonstrate mild cerebellar atrophy or, in the advanced stages of the disease, marked atrophy of the cerebellar hemispheres and vermis associated with the abnormal signal intensity of the cerebellar cortex and white matter and brainstem hypotrophy. In spinal cerebellar ataxias (SCAs), very rare in the pediatric population, MRI may demonstrate isolated cerebellar atrophy or cerebellar and brainstem atrophy. MRI shows characteristic findings in other diseases, strongly suggesting a distinct disorder, such as neuroaxonal dystrophy, ARSACS, ataxia-telangiectasia, or precise mitochondrial diseases. An example of neurodegenerative disorder with prenatal onset is pontocerebellar hypoplasia (PCH). PCH represents a group of neurodegenerative disorders characterized by microcephaly, early cerebellar hypoplasia, and variable atrophy of the cerebellum and ventral pons, genetically divided into several subtypes. Cerebellar hypoplasia visible on MRI is often the first sign that suggests the clinical diagnosis. In most cases, the PCH subtype may demonstrate a characteristic pattern distinguishable at MRI. Selective involvement of the cerebellum, sometimes accompanied by brainstem or supratentorial abnormalities in different combinations, may help restrict the differential diagnosis and may address the specific molecular screening.

Structural brain differences in recovering and weight-recovered adult outpatient women with anorexia nervosa

BackgroundAnorexia nervosa is a complex psychiatric illness that includes severe low body weight with cognitive distortions and altered eating behaviors. Brain structures, including cortical thicknesses in many regions, are reduced in underweight patients who are acutely ill with anorexia nervosa. However, few studies have examined adult outpatients in the process of recovering from anorexia nervosa. Evaluating neurobiological problems at different physiological stages of anorexia nervosa may facilitate our understanding of the recovery process.MethodsMagnetic resonance imaging (MRI) images from 37 partially weight-restored women with anorexia nervosa (pwAN), 32 women with a history of anorexia nervosa maintaining weight restoration (wrAN), and 41 healthy control women were analyzed using FreeSurfer. Group differences in brain structure, including cortical thickness, areas, and volumes, were compared using a series of factorial f-tests, including age as a covariate, and correcting for multiple comparisons with the False Discovery Rate method.ResultsThe pwAN and wrAN cohorts differed from each other in body mass index, eating disorder symptoms, and social problem solving orientations, but not depression or self-esteem. Relative to the HC cohort, eight cortical thicknesses were thinner for the pwAN cohort; these regions were predominately right-sided and in the cingulate and frontal lobe. One of these regions, the right pars orbitalis, was also thinner for the wrAN cohort. One region, the right parahippocampal gyrus, was thicker in the pwAN cohort. One volume, the right cerebellar white matter, was reduced in the pwAN cohort. There were no differences in global white matter, gray matter, or subcortical volumes across the cohorts.ConclusionsMany regional structural differences were observed in the pwAN cohort with minimal differences in the wrAN cohort. These data support a treatment focus on achieving and sustaining full weight restoration to mitigate possible neurobiological sequela of AN. In addition, the regions showing cortical thinning are similar to structural changes reported elsewhere for suicide attempts, anxiety disorders, and autistic spectrum disorder. Understanding how brain structure and function are related to clinical symptoms expressed during the course of recovering from AN is needed.

Disrupted functional connectivity in white matter resting-state networks in unilateral temporal lobe epilepsy.

Unilateral temporal lobe epilepsy (TLE) is the most common type of focal epilepsy characterized by foci in the unilateral temporal lobe grey matters of regions such as the hippocampus. However, it remains unclear how the functional features of white matter are altered in TLE. In the current study, resting-state functional magnetic resonance imaging (fMRI) was performed on 71 left TLE (LTLE) patients, 79 right TLE (RTLE) patients and 47 healthy controls (HC). Clustering analysis was used to identify fourteen white matter networks (WMN). The functional connectivity (FC) was calculated among WMNs and between WMNs and grey matter. Furthermore, the FC laterality of hemispheric WMNs was assessed. First, both patient groups showed decreased FCs among WMNs. Specifically, cerebellar white matter illustrated decreased FCs with the cerebral superficial WMNs, implying a dysfunctional interaction between the cerebellum and the cerebral cortex in TLE. Second, the FCs between WMNs and the ipsilateral hippocampus (grey matter foci) were also reduced in patient groups, which may suggest insufficient functional integration in unilateral TLE. Interestingly, RTLE showed more severe abnormalities of white matter FCs, including links to the bilateral hippocampi and temporal white matter, than LTLE. Taken together, these findings provide functional evidence of white matter abnormalities, extending the understanding of the pathological mechanism of white matter impairments in unilateral TLE.

Oligodendrocyte-Specific Deletion of FGFR1 Reduces Cerebellar Inflammation and Neurodegeneration in MOG35-55-Induced EAE.

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult to treat. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies such as MS. In autopsy tissue from patients with MS, increased expression of FGF1, FGF2, FGF9, and FGFR1 was found in lesion areas. Recent research using mouse models has focused on regions such as the spinal cord, and data on the expression of FGF/FGFR in the cerebellum are not available. In recent EAE studies, we detected that oligodendrocyte-specific deletion of FGFRs results in a milder disease course, less cellular infiltrates, and reduced neurodegeneration in the spinal cord. The objective of this study was to characterize the role of FGFR1 in oligodendrocytes in the cerebellum. Conditional deletion of FGFR1 in oligodendrocytes (Fgfr1ind−/−) was achieved by tamoxifen application, EAE was induced using the MOG35-55 peptide. The cerebellum was analyzed by histology, immunohistochemistry, and western blot. At day 62 p.i., Fgfr1ind−/− mice showed less myelin and axonal degeneration compared to FGFR1-competent mice. Infiltration of CD3(+) T cells, Mac3(+) cells, B220(+) B cells and IgG(+) plasma cells in cerebellar white matter lesions (WML) was less in Fgfr1ind−/−mice. There were no effects on the number of OPC or mature oligodendrocytes in white matter lesion (WML). Expression of FGF2 and FGF9 associated with less myelin and axonal degeneration, and of the pro-inflammatory cytokines IL-1β, IL-6, and CD200 was downregulated in Fgfr1ind−/− mice. The FGF/FGFR signaling protein pAkt, BDNF, and TrkB were increased in Fgfr1ind−/− mice. These data suggest that cell-specific deletion of FGFR1 in oligodendrocytes has anti-inflammatory and neuroprotective effects in the cerebellum in the EAE disease model of MS.

Case Report: Diffuse Polymicrogyria Associated With a Novel ADGRG1 Variant

Pathogenic variants of the ADGRG1 gene are associated with bilateral frontoparietal polymicrogyria, defined radiologically by polymicrogyria with an anterior-posterior gradient, pontine and cerebellar hypoplasia and patchy white matter abnormalities. We report a novel homozygous ADGRG1 variant with atypical features. The patient presented at 8 months of age with motor delay, esotropia, hypotonia with hyporeflexia and subsequently developed refractory epilepsy. At the last assessment, aged 12 years, head control, sitting and language were not acquired. Magnetic resonance imaging revealed diffuse polymicrogyria with relative sparing of the anterior temporal lobes, without an anterior-posterior gradient, diffuse hypomyelination and pontine and cerebellar hypoplasia. A panel targeting brain morphogenesis defects yielded an unreported homozygous ADGRG1 nonsense variant (dbSNP rs746634404), present in the heterozygous state in both parents. We report a novel ADGRG1 variant associated with diffuse polymicrogyria without an identifiable anterior-posterior gradient, diffuse hypomyelination and a severe motor and cognitive phenotype. Our case highlights the phenotypic diversity of ADGRG1 pathogenic variants and the clinico-anatomical overlap between recognized polymicrogyria syndromes.