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Background: Recently, a network model of cervical dystonia (CD) has been adopted that implicates nodes and pathways involving cerebellar, basal-ganglia and cortico-cortical connections. Although functional changes in the cerebello-thalamo-cortical network in dystonia have been reported in several studies, structural information of this network remain sparse., Objective: To characterize the structural properties of the cerebellar motor network in isolated CD patients. This includes cerebellar lobules involved in motor processing, the dentate nucleus (DN), the thalamus, and the primary motor cortex (M1)., Methods: Magnetic resonance imaging data of 18 CD patients and 18 healthy control subjects were acquired. In CD patients, the motor part of the Toronto Western Spasmodic Torticollis Rating Scale was assessed to evaluate motor symptom severity. The volume of cerebellar lobules I-VI and VIII, the DN and thalamus, and the cortical thickness (CT) of M1 were determined for a region of interest (ROI)-based quantitative analysis. Volumes/CT of these ROIs were compared between groups and associated with motor symptom severity in patients., Results: The volume of lobule VI and the CT of M1 were reduced in CD patients. The volumes of the other ROIs were not different between groups. No association was identified between the structural properties of lobule VI or M1 and the severity of CD motor symptoms., Conclusion: Atrophy within the cerebellum and M1 contributes to CD's complex motor network pathology. Further investigations are needed to ascertain the mechanisms underlying the local volume loss., Competing Interests: Declarations. Conflict of interest: No author has any conflicts of interest that are related to the manuscript. Financial disclosures of all authors (for the preceding 3 years): Kai Grimm, Gerhard Schön and Abdullah Okar have no relevant financial or non-financial interests to disclose. Fatemeh Sadeghi received funding from the Werner Otto Foundation. Mathias Gelderblom is on the advisory board of Merz Pharmaceuticals and received honoraria from Merz Pharmaceuticals, AbbVie and Ipsen. Robert Schulz received funding from the German Research Foundation, Damp Stiftung and the Else Kröner-Fresenius-Stiftung. Simone Zittel is on the advisory board of Biomarin and received honoraria from Biomarin and Merz Pharmaceuticals. She received grant funding from the German Research Foundation, the European Commission, the Damp Foundation and the Arbeitskreis Botulinumtoxin. Consent statement: All participants completed safety questionnaires for MRI and provided written informed consent in accordance with the Declaration of Helsinki. Ethics approval: The study was approved by the local ethics committee., (© 2024. The Author(s).)

Introduction: While cerebral amyloid angiopathy is likely responsible for intracerebral hemorrhage (ICH) occurring in superficial (grey matter, vermis) cerebellar locations, it is unclear whether hypertensive arteriopathy (HA), the other major cerebral small vessel disease (cSVD), is associated with cerebellar ICH (cICH) in deep (white matter, deep nuclei, cerebellar peduncle) regions. We tested the hypothesis that HA-associated neuroimaging markers are significantly associated with deep cICH compared to superficial cICH., Patients and Methods: Brain MRI scans from consecutive non-traumatic cICH patients admitted to a referral center were analyzed for cSVD markers. Clinical risk factors, left ventricular hypertrophy (LVH, a marker of hypertensive end-organ damage), and neuroimaging markers were compared between patients with deep and superficial cICH in univariate and multivariable models., Results: Hypertension and LVH were more common among 83 (64%) patients with deep cICH compared to 46 (36%) with superficial cICH. HA-related markers such as peri-basal ganglia white matter hyperintensity pattern, deep lacunes, severe basal ganglia enlarged perivascular spaces, and deep cerebral microbleeds (CMBs) were more common among those with deep vs. superficial cICH. Strictly lobar CMBs were less common among patients with deep cICH, whereas mixed-location CMBs were more common. After multivariable adjustment, LVH (aOR 4.06, 95% CI [1.22-13.50], p = 0.02), deep lacunes (aOR 6.02, 95% CI [1.46-24.89], p = 0.01), and strictly lobar CMBs (aOR 0.09, 95% CI [0.02-0.45], p < 0.01) remained significantly associated with deep cICH., Discussion and Conclusion: Because HA-associated markers are significantly associated with deep cICH, it is likely HA is the dominant underlying microangiopathy of this ICH subtype., Competing Interests: Declarations. Conflicts of interest: MEG received research grants from AVID, Pfizer and Boston Scientific Corporation. JNG received consulting fees from Pfizer, CSL Behring, Takeda, Octapharma, Astrazeneca, Ncontrol, and Cayuga—none relevant to this analysis. The other authors have no relevant financial or non-financial interests to disclose. Informed consent: Informed consent was waived given the nature of the study and minimal risk posed to patients. Ethical approval: The institutional review board of Massachusetts General Hospital approved this study. Guarantor: ASD is the guarantor for this study., (© 2025. Springer-Verlag GmbH Germany, part of Springer Nature.)

Cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER) syndrome is a recently described entity that refers to a specific pattern of cerebellar edema with restricted diffusion and crowding of the fourth ventricle among other findings. The syndrome is commonly associated with toxic opioid exposure. While most commonly seen in adults, we present a case of a 2-year-old girl who survived characteristic history and imaging findings of CHANTER syndrome., (© 2024. The Author(s).)

Background: Primary lateral sclerosis (PLS) is traditionally solely associated with progressive upper motor neuron dysfunction manifesting in limb spasticity, gait impairment, bulbar symptoms and pseudobulbar affect. Recent studies have described frontotemporal dysfunction in some patients resulting in cognitive manifestations. Cerebellar pathology is much less well characterised despite sporadic reports of cerebellar disease., Methods: A multi-timepoint, longitudinal neuroimaging study was conducted to characterise the evolution of both intra-cerebellar disease burden and cerebro-cerebellar connectivity. The volumes of deep cerebellar nuclei, cerebellar cortical volumes, cerebro-cerebellar structural and functional connectivity were assessed longitudinally in a cohort of 43 individuals with PLS., Results: Cerebello-frontal, -temporal, -parietal, -occipital and cerebello-thalamic structural disconnection was detected at baseline based on radial diffusivity (RD) and cerebello-frontal decoupling was also evident based on fractional anisotropy (FA) alterations. Functional connectivity changes were also detected in cerebello-frontal, parietal and occipital projections. Volume reductions were identified in the vermis, anterior lobe, posterior lobe, and crura. Among the deep cerebellar nuclei, the dorsal dentate was atrophic. Longitudinal follow-up did not capture statistically significant progressive changes. Significant primary motor cortex atrophy and inter-hemispheric transcallosal degeneration were also captured., Conclusions: PLS is not only associated with upper motor neuron dysfunction, but cerebellar cortical volume loss and deep cerebellar nuclear atrophy can also be readily detected. In addition to intra-cerebellar disease burden, cerebro-cerebellar connectivity alterations also take place. Our data add to the evolving evidence of widespread neurodegeneration in PLS beyond the primary motor regions. Cerebellar dysfunction in PLS is likely to exacerbate bulbar, gait and dexterity impairment and contribute to pseudobulbar affect., (© 2024. The Author(s).)

Joubert syndrome (JS) is a recessively inherited congenital ataxia characterized by hypotonia, psychomotor delay, abnormal ocular movements, intellectual disability, and a peculiar cerebellar and brainstem malformation, the "molar tooth sign." Over 40 causative genes have been reported, all encoding for proteins implicated in the structure or functioning of the primary cilium, a subcellular organelle widely present in embryonic and adult tissues. In this paper, we developed an in vitro neuronal differentiation model using patient-derived induced pluripotent stem cells (iPSCs), to evaluate possible neurodevelopmental defects in JS. To this end, iPSCs from four JS patients harboring mutations in distinct JS genes (AHI1, CPLANE1, TMEM67, and CC2D2A) were differentiated alongside healthy control cells to obtain mid-hindbrain precursors and cerebellar granule cells. Differentiation was monitored over 31 days through the detection of lineage-specific marker expression by qRT-PCR, immunofluorescence, and transcriptomics analysis. All JS patient-derived iPSCs, regardless of the mutant gene, showed a similar impairment to differentiate into mid-hindbrain and cerebellar granule cells when compared to healthy controls. In addition, analysis of primary cilium count and morphology showed notable ciliary defects in all differentiating JS patient-derived iPSCs compared to controls. These results confirm that patient-derived iPSCs are an accessible and relevant in vitro model to analyze cellular phenotypes connected to the presence of JS gene mutations in a neuronal context., (© 2024. The Author(s).)

Purpose: To confirm the hypothesis that brain white matter damage is involved in the pathogenesis and disease progression of Langerhans cell histiocytosis (LCH)-associated neurodegenerative disease (ND), we aimed to analyze pediatric patients with LCH using diffusion tensor imaging (DTI)., Methods: We enrolled 33 patients with LCH and obtained 33 DTI datasets. Using DTI-based tractography, fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), and radial diffusivity (RD) were measured in the cerebral and cerebellar white matter tracts. The participants were divided into three groups-non-ND, ND without clinical symptoms (r-ND), and ND with clinical symptoms (c-ND)-according to their clinical status during the examination with DTI. We compared the DTI parameters in white matter tracts were compared among the three groups., Results: In the order of non-ND, r-ND, and c-ND groups, the FA in superior cerebellar peduncle (SCP) and middle cerebellar peduncle (MCP) significantly decreased, the ADC, AD, and RD of MCP, and the RD of SCP were significantly elevated (FA-SCP; p < 0.001, FA-MCP; p = 0.026, ADC-MCP; p < 0.001, AD-MCP; p = 0.002, RD-MCP; p = 0.003, and RD-SCP; p = 0.018). Furthermore, in the simple linear regression analysis, the FA, ADC, AD, and RD values in the MCP and the FA value in the SCP were significantly influenced by the presence of neurological symptoms and ND findings on MRI (all p < 0.001)., Conclusion: In LCH-ND, we identified microstructural damage in the SCP and MCP. DTI parameters in these tracts may help monitor LCH-ND; therefore, future studies are required to validate these results in a large cohort., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Spinocerebellar ataxia type 2 (SCA2) is a progressive neurodegenerative disorder characterized by cerebellar atrophy. However, studies to elucidate the longitudinal progression of the neuropathology are limited. We sought to identify brain macrostructural and microstructural alterations in patients with SCA2 using fixel-based analysis (FBA) to better understand its distribution patterns and progression., Methods: We enrolled 9 patients with SCA2 and 16 age- and gender-matched controls. Longitudinal clinical and imaging data were collected at baseline, and 3.5 years later. Fiber density (FD), fiber-bundle cross-section (FC), and a combination of FD and FC (FDC) were calculated. The paired t-test was used to examine longitudinal differences. The associations between fixel-based metrics and clinical variables were explored in SCA2 patients., Results: At baseline, patients with SCA2 displayed multiple white matter tracts with significantly decreased FD, FC, and FDC in the corticospinal tract, cerebellar peduncles, brainstem, corpus callosum, thalamus, striatum, and prefrontal cortex, compared to controls. Over time, many of these macrostructural and microstructural alterations progressed, manifesting lower FD, FC, and FDC in corticospinal tract, middle cerebellar peduncle, brainstem, striatum, fornix, and cingulum. No significant brain white matter alterations were found in the healthy controls over time. There was no association between the FBA-derived metrics and clinical variables in SCA2., Conclusion: This study provides evidence of brain macrostructural and microstructural alterations and of progression over time in SCA2. The FBA-derived metrics may serve as potential biomarkers of SCA2 progression., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Cerebellum modulates the amplitude of resting tremor in Parkinson's disease (PD) via cerebello-thalamo-cortical (CTC) circuit. Tremor-related white matter alterations have been identified in PD patients by pathological studies, but in vivo evidence is limited; the influence of such cerebellar white matter alterations on tremor-related brain network, including CTC circuit, is also unclear. In this study, we investigated the cerebral and cerebellar white matter alterations in PD patients with resting tremor using diffusion tensor imaging (DTI)., Methods: In this study, 30 PD patients with resting tremor (PDWR), 26 PD patients without resting tremor (PDNR), and 30 healthy controls (HCs) from the Parkinson's Progression Markers Initiative (PPMI) cohort were included. Tract-based spatial statistics (TBSS) and region of interest-based analyses were conducted to determine white matter difference. Correlation analysis between DTI measures and clinical characteristics was also performed., Results: In the whole brain, TBSS and region of interest-based analyses identified higher fractional anisotropy (FA) value, lower mean diffusivity (MD) value, and lower radial diffusivity (RD) in multiple fibers. In the cerebellum, TBSS analysis revealed significantly higher FA value, decreased RD value as well as MD value in multiple cerebellar tracts including the inferior cerebellar peduncle (ICP) and middle cerebellar peduncle (MCP) when comparing the PDWR with HC, and higher FA value in the MCP when compared with PDNR., Conclusion: We identified better white matter integrity in the cerebrum and cerebellum in PDWR indicating a potential association between the cerebral and cerebellar white matter and resting tremor in PD., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The pathophysiology of essential tremor (ET) is not fully understood, and studies suggest pathological changes mainly occur in the cerebellum and locus coeruleus (LC)., Methods: Fifty-three ET patients, including 30 patients with head tremor (h-ET), 23 patients without head tremor (nh-ET), 71 age and education matched healthy controls (HCs) were enrolled. All participants underwent Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) and T1 scans on a 3-Tesla MR system. Next, we assessed the relationship between the contrast-to-noise ratio of LC (CNR LC ) and the score of The Essential Tremor Rating Assessment Scale (TETRAS) and cerebellum gray matter (GM) volume., Results: Significant difference of CNR LC was found between ET and HC groups. The CNR LC of ET groups is lower than the HC group (p = 0.031). Subgroup analysis showed that the CNR LC in nh-ET was significantly lower than HCs (p = 0.016). Compared to HCs, h-ETs showed marked atrophy in the cerebellum: the vermis IV-V and lobule VI (GRF corrected, p < 0.05). A significant negative correlation was found between CNR LC and the vermis lobule IV-V in h-ETs (r = - 0.651, p < 0.001). No significant correlation was found between CNR LC and TETRAS scores., Conclusion: The LC and the cerebellum might both involve in the pathophysiology of ET. LC evaluation using NM-MRI might be an effective tool for us to explore the pathophysiology of ET further., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Cerebellar involvement is not comprehensively studied from an MRI point of view in multiple sclerosis (MS). We aimed to quantify cerebellar damage and identify predictors of physical disability and cognitive dysfunction in MS patients, and to characterize patients with cerebellar disability., Methods: In this prospective study, 164 (89 relapsing-remitting and 75 progressive) MS patients and 53 healthy controls were enrolled. Subjects underwent 3T MRI with sequences for assessing lesions and atrophy in cerebellum, supratentorial brain, brainstem and cervical cord. Cerebellar peduncle diffusion-tensor metrics were also derived. Random forest models identified MRI predictors of Expanded Disability Status Scale (EDSS) score and cognition z-score. Hierarchical clustering was applied on MRI metrics in patients with cerebellar disability., Results: In MS patients, predictors of higher EDSS score (out-of-bag-R 2  = 0.83) were: lower cord grey matter (GM) and global areas, brain volume, GM volume (GMV), cortical GMV, cerebellum lobules I-IV and vermis GMV; and higher cord GM and brainstem lesion volume (LV). Predictors of lower cognition z-score (out-of-bag-R 2  = 0.25) were: higher supratentorial and superior cerebellar peduncle LV; and lower brain, thalamus and basal ganglia volumes, GMV, cerebellum lobule VIIIb and Crus II GMV. In patients with cerebellar disability, we found three clusters with homogenous MRI metrics: patients with high brain lesion volumes (including cerebellar peduncles), those with marked cerebellum GM atrophy and patients with severe cord damage., Conclusions: Damage to cerebellum GM and connecting structures has a relevant role in explaining cognitive dysfunction and physical disability in MS. Data-driven MRI clustering might improve our knowledge of MRI-clinical correlations., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Joubert syndrome (JBTS), a rare genetic disorder resulted from primary cilium defects or basal-body dysfunction, is characterized by agenesis of cerebellar vermis and abnormal brain stem. Both genotypes and phenotypes of JBTS are highly heterogeneous. The identification of pathogenic gene variation is essential for making a definite diagnosis on JBTS. Here, we found that hypoplasia of cerebellar vermis occurred in three male members in a Chinese family. Then, we performed whole exome sequencing to identify a novel missense mutation c.599T > C (p. L200P) in the OFD1 gene which is the candidate gene of X-linked JBTS (JBST10). The following analysis showed that the variant was absent in the 1000 Genomes, ExAC and the 200 female controls; the position 200 Leucine residue was highly conserved across species; the missense variant was predicted to be deleterious using PolyPhen-2, PROVEAN, SIFT and Mutation Taster. The OFD1 expression was heavily lower in the proband and an induced male fetus compared with a healthy male with a wild-type OFD1 gene. The in vitro expression analysis of transiently transfecting c.599T or c.599C plasmids into HEK-293T cells confirmed that the missense mutation caused OFD1 reduction at the protein level. And further the mutated OFD1 decreased the level of Gli1 protein, a read-out of Sonic hedgehog (SHH) signaling essential for development of central neural system. A known pathogenic variant c.515T > C (p. L172P) showed the similar results. All of these observations suggested that the missense mutation causes the loss function of OFD1, resulting in SHH signaling impairs and brain development abnormality. In addition, the three patients have Dandy-Walker malformation, macrogyria and tetralogy of Fallot, respectively, the latter two of which are firstly found in JBTS10 patients. In conclusion, our findings expand the context of genotype and phenotype in the JBTS10 patients.

Purpose: A new form of autosomal dominant hereditary spinocerebellar ataxia (SCA) has been recently described (SCA48), and here we investigate its conventional MRI findings to identify the presence of a possible imaging feature of this condition., Methods: In this retrospective observational study, we evaluated conventional MRI scans from 10 SCA48 patients (M/F = 5/5; 44.7 ± 7.8 years). For all subjects, atrophy of both supratentorial and infratentorial compartments were recorded, as well as the presence of possible T2-weighted imaging (T2WI) signal alterations., Results: In SCA48 patients, no meaningful supratentorial changes were found, both in terms of volume loss or MRI signal changes. Atrophy of the cerebellum was present in all cases, involving both the vermis and the hemispheres, but particularly affecting the postero-lateral portions of the cerebellar hemispheres. In all patients, with the exception of only one subject (90.0% of the cases), a T2WI hyperintensity of both dentate nuclei was found. The association of such signal alteration with the pattern of cerebellar atrophy resembled the appearance of a crab ("crab sign")., Conclusion: Our findings suggest that SCA48 patients are characterized by cerebellar atrophy, mainly involving the postero-lateral hemisphere areas, along with a T2WI hyperintensity of dentate nuclei. We propose that the association of such signal change, along with the atrophy of the lateral portion of the cerebellar hemispheres, resembled the appearance of a crab, and therefore, we propose the "crab sign" as a neuroradiological sign present in SCA48 patients.

Background: No data are available on the occurrence of gray matter lesions (GML) in the cerebellum of pediatric multiple sclerosis (pedMS)., Objectives: We analyzed frequency, number and topography of GML, and their correlation with cerebellar-related disability in pedMS at clinical onset., Methods: Fifteen adolescents with pedMS (12F/3M; mean age 14.9 ± 2.2, range 11-17) were studied. Neurological and cognitive evaluations were done by means of EDSS, Trail Making Test-Part B (TMT-B) and Symbol Digit Modalities Test-oral version (SDMT). Cerebellar GML were investigated with double inversion recovery (DIR) and phase-sensitive inversion recovery (PSIR) sequences obtained with a 3 T-MRI scan., Results: All patients had white matter lesions (WML) and/or GML in the cerebellum. A significantly higher GML number was observed on PSIR compared to DIR (mean 2.3 ± 2.3 vs 1.1 ± 1.6; median 2.0 (IQR 1.0-2.0) vs 1.0 (IQR 0.0-1.5); p = 0.004). GML were observed in 14/15 (93.3%) patients and were more frequent in the posterior than in the anterior lobe (mean 1.8 ± 2.2 vs 0.47 ± 0.74; median 2.0 (IQR 0.5-2.0) vs 0.0 (IQR 0.0-1.0); p = 0.044). No correlation was found between lesion number or topography and EDSS (r = 0.12, p = 0.69), TMT-B and SDMT., Conclusion: At clinical onset, cerebellar GML are common in pedMS, are very often asymptomatic, do not correlate with physical and cognitive disability, and more frequently affect the posterior lobe.

Objective: To determine whether brain volumetric and white matter microstructural changes are present and correlate with neurological impairment in subjects with alternating hemiplegia of childhood (AHC)., Methods: In this prospective single-center study, 12 AHC subjects (mean age 22.9 years) and 24 controls were studied with 3DT1-weighted MR imaging and high angular resolution diffusion imaging at 3T. Data obtained with voxel-based morphometry and tract-based spatial statistics were correlated with motor impairment using the International Cooperative Ataxia Rating Scale (ICARS) and Movement and Disability sub-scales of Burke-Fahn-Marsden Dystonia Rating Scale (BFMMS and BFMDS)., Results: Compared to healthy controls, AHC subjects showed lower total brain volume (P < 0.001) and white matter volume (P = 0.002), with reduced clusters of white matter in frontal and parietal regions (P < 0.001). No significant regional differences were found in cortical or subcortical grey matter volumes. Lower cerebellar subvolumes correlated with worse ataxic symptoms and global motor impairment in AHC group (P < 0.001). Increased mean and radial diffusivity values were found in the corpus callosum, corticospinal tracts, superior and inferior longitudinal fasciculi, subcortical frontotemporal white matter, internal and external capsules, and optic radiations (P < 0.001). These diffusion scalar changes correlated with higher ICARS and BFMDS scores (P < 0.001)., Interpretation: AHC subjects showed prevalent white matter involvement, with reduced volume in several cerebral and cerebellar regions associated with widespread microstructural changes reflecting secondary myelin injury rather than axonal loss. Conversely, no specific pattern of grey matter atrophy emerged. Lower cerebellar volumes, correlating with severity of neurological manifestations, seems related to disrupted developmental rather than neurodegenerative processes.

Background: Progressive multifocal leukoencephalopathy (PML) is a subacute onset demyelinating disease caused by JC virus and characterized by multifocal involvement of the subcortical white matter and cerebellar hemispheres or peduncles on magnetic resonance imaging (MRI). However, non-HIV PML patients with brain lesions limited to the cerebellum and brainstem have not been well characterized., Methods: We report a 68-year-old man with systemic lupus erythematosus under treatment with immunosuppressants who developed non-HIV PML with brain lesions limited to the cerebellum and brainstem and successfully treated with a combination of mefloquine and mirtazapine. We performed a literature review to characterize patients with non-HIV PML with brain lesions limited to the cerebellum and brainstem., Results: Eight cases with non-HIV brainstem/cerebellar form PML were identified including our case. All cases had compromised status related underlying diseases. Four (50%) had a good prognosis. Five cases were treated, including 3 with favourable outcomes. Between the good prognosis group (n = 4) and the poor prognosis group (n = 4), treatment status for PML and the interval between the initial manifestation and diagnosis did not differ. Among those who performed contrast-enhanced brain imaging, lesion enhancement was related to good prognosis (good prognosis group vs. poor prognosis group; 100% vs. 0%)., Conclusion: PML should be considered in the differential diagnosis of brain lesions limited to the cerebellum and brainstem in immunocompromised patients. The presence of immune response against JC virus and inflammatory reactions may indicate good prognosis in non-HIV brainstem/cerebellar form PML.

Background: Recent studies have suggested the presence of a significant atrophy affecting the cerebellar cortex in Friedreich ataxia (FRDA) patients, an area of the brain long considered to be relatively spared by neurodegenerative phenomena. Cognitive deficits, which occur in FRDA patients, have been associated with cerebellar volume loss in other conditions. The aim of this study was to investigate the correlation between cerebellar volume and cognition in FRDA., Methods: Nineteen FRDA patients and 20 healthy controls (HC) were included in this study and evaluated via a neuropsychological examination. Cerebellar global and lobular volumes were computed using the Spatially Unbiased Infratentorial Toolbox (SUIT). Furthermore, a cerebellar voxel-based morphometry (VBM) analysis was also carried out. Correlations between MRI metrics and clinical data were tested via partial correlation analysis., Results: FRDA patients showed a significant reduction of the total cerebellar volume (p = 0.004), significantly affecting the Lobule IX (p = 0.001). At the VBM analysis, we found a cluster of significant reduced GM density encompassing the entire lobule IX (p = 0.003). When correlations were probed, we found a direct correlation between Lobule IX volume and impaired visuo-spatial functions (r = 0.58, p = 0.02), with a similar correlation that was found between the same altered function and results obtained at the VBM (r = 0.52; p = 0.03)., Conclusions: With two different image analysis techniques, we confirmed the presence of cerebellar volume loss in FRDA, mainly affecting the posterior lobe. In particular, Lobule IX atrophy correlated with worse visuo-spatial abilities, further expanding our knowledge about the physiopathology of cognitive impairment in FRDA.

Developmental language disorder (DLD) and developmental speech disorder (DSD) are common, yet their etiologies are not well understood. Atypical volume of the inferior and posterior language regions and striatum have been reported in DLD; however, variability in both methodology and study findings limits interpretations. Imaging research within DSD, on the other hand, is scarce. The present study compared grey matter volume in children with DLD, DSD, and typically developing speech and language. Compared to typically developing controls, children with DLD had larger volume in the right cerebellum, possibly associated with the procedural learning deficits that have been proposed in DLD. Children with DSD showed larger volume in the left inferior occipital lobe compared to controls, which may indicate a compensatory role of the visual processing regions due to sub-optimal auditory-perceptual processes. Overall, these findings suggest that different neural systems may be involved in the specific deficits related to DLD and DSD.

Mass spectrometry imaging (MSI) is a powerful tool to perform untargeted mapping of biomolecules in situ. In the current study, we performed matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) to evaluate lipid changes during disease progression (asymptomatic to symptomatic time points) in Niemann-Pick disease, type C1 (NPC1), a cerebellar neurodegenerative, lipid storage disorder. Our data show that gangliosides GM2 and GM3 are elevated in NPC1 disease and localize in the posterior lobules of the cerebellum, which is enhanced over a time-course analysis of the disease. Further analysis of sphingolipids in negative ion mode indicated reduction of sulfatides in white matter of the cerebellum and patterned distribution and co-localization of ceramide species Cer(d36:1), HexCer(d36:1), and the ganglioside GM1(d36:1) during disease progression. Finally, a putative lipid of unknown structure demonstrated similar patterning during NPC1 cerebellar degeneration. These studies provide insight into lipid markers of neurodegeneration in NPC1 and link lipid alterations to altered pathways that lead to cell death.

The cerebellar intrinsic connectivity is of remarkable regularity with a similar build repeated many times over. However, several modifications of this basic circuitry occur that can provide important clues to evolutionary adaptations. We have observed differences in the wiring of the cerebellar output structures (the deep cerebellar nuclei, DCN) with higher dendritic length density in the phylogenetically newer DCN. In rats, we showed that an increase in wiring is associated with an increase in the presynaptic vesicular glutamate transporter 1 (vGluT1). In this study, we have extended our analysis to the rhesus monkey and can show similarities and differences between the two species. The similarities confirm a higher density in vGluT1+ boutons in the lateral (LN/dentate) and posterior interpositus nucleus compared to the phylogenetically older DCN. In general, we also observe a lower density of vGluT1 and 2+ boutons in the monkey, which however, yields a similar number of excitatory boutons per neuron in both species. The only exception is the vGlut1+ boutons in the macaque LN/dentate, which showed a significantly lower number of vGluT1+ boutons per neuron. We also detected a higher percentage of co-labelled vGluT1 and 2 boutons in the macaque than we found in the rat. In summary, these results confirm that the hyposcalled dendrites of the monkey LN/dentate also show a lower number of vGluT1+ boutons per neuron. These results provide further support of our model relating the dendritic morphology of the LN/dentate neurons to the morphology of the specially enlarged LN/dentate nucleus in primates.

Purpose: Cerebellar herniation in Chiari patients can be dynamic, following the cerebrospinal fluid pulsatility during the cardiac cycle. We present a voxel intensity distribution method (VIDM) to automatically extract the pulsatility-dependent herniation in time-resolved MRI (CINE MRI) and compare it to the simple linear measurements. The degree of herniation is furthermore compared on CINE and static sequences, and the cerebellar movement is correlated to the presence of hydrocephalus and syringomyelia., Methods: The cerebellar movement in 27 Chiari patients is analyzed with VIDM and the results were compared to linear measurements on an image viewer (visual inspection, VI) using a paired t test. Second, an ANOVA test is applied to compare the degree of herniation on static 3D MRI and CINE. Finally, the Pearson's correlation coefficient is calculated for the correlation between cerebellar movement and the presence of hydrocephalus and syringomyelia., Results: VIDM showed significant movement in 85% of our patients. Assuming that movement < 1 mm cannot be detected reliably on an image viewer, VI identified movement in 29.6% of the patients (p = 0.002). The herniation was greater on static sequences than on CINE in most cases, but this was not statistically significant. The cerebellar movement was not correlated with hydrocephalus or syringomyelia (Pearson's coefficient < 0.3)., Conclusions: VIDM is a sensitive method to detect tissue movement on CINE MRI and could be used for Chiari patients, but also for the evaluation of cyst membranes, ventriculostomies, etc. The cerebellar movement appears not to correlate with hydrocephalus and syringomyelia in Chiari patients.

Despite the common co-occurrence of cognitive impairment and brain structural deficits in alcoholism, demonstration of relations between regional gray matter volumes and cognitive and motor processes have been relatively elusive. In pursuit of identifying brain structural substrates of impairment in alcoholism, we assessed executive functions (EF), episodic memory (MEM), and static postural balance (BAL) and measured regional brain gray matter volumes of cortical, subcortical, and cerebellar structures commonly affected in individuals with alcohol dependence (ALC) compared with healthy controls (CTRL). ALC scored lower than CTRL on all composite scores (EF, MEM, and BAL) and had smaller frontal, cingulate, insular, parietal, and hippocampal volumes. Within the ALC group, poorer EF scores correlated with smaller frontal and temporal volumes; MEM scores correlated with frontal volume; and BAL scores correlated with frontal, caudate, and pontine volumes. Exploratory analyses investigating relations between subregional frontal volumes and composite scores in ALC yielded different patterns of associations, suggesting that different neural substrates underlie these functional deficits. Of note, orbitofrontal volume was a significant predictor of memory scores, accounting for almost 15% of the variance; however, this relation was evident only in ALC with a history of a non-alcohol substance diagnosis and not in ALC without a non-alcohol substance diagnosis. The brain-behavior relations observed provide evidence that the cognitive and motor deficits in alcoholism are likely a result of different neural systems and support the hypothesis that a number of identifiable neural systems rather than a common or diffuse neural pathway underlies cognitive and motor deficits observed in chronic alcoholism.

The cerebellum is increasingly recognized to be involved in limbic and cognitive-associative functioning. Cerebellar cognitive affective syndromes may result from various types of injuries. Cerebellar mutism may occur in children after resection of midline tumors in the posterior fossa, which has been thought to be related to damage to the cerebellar vermis. Here, we investigated whether bilateral lesions of the fastigial nucleus, which is located within the upper vermis, would affect social behavior in a rat model. Juvenile male Sprague-Dawley rats, aged 23 days, underwent bilateral thermocoagulation of the fastigial nucleus via stereotaxically implanted electrodes under general anesthesia. Electrodes were inserted without application of electric current in a sham-lesion group and naïve rats served as additional controls. All groups underwent standardized examination before surgery and on specific time points up to 49 days after surgery to investigate locomotor activity, motor coordination, social behavior, and ultrasound vocalizations during social interaction. Finally, lesions were verified histologically. Playing behavior and vocalizations were reduced up to 4 weeks after surgery in rats of the lesion group compared to rats with sham-lesions and controls. After surgery in rats of the lesion group, locomotor activity was disturbed for 3 days as compared to sham-lesion rats, but for 4 weeks as compared to controls. Motor coordination measured by the rotarod and balance beam test was compromised until adulthood. Bilateral lesions of the fastigial nucleus in juvenile rats cause a severe and long-lasting reduction of social interaction and motor coordination in juvenile rats, which has some similarities to cerebellar cognitive affective syndromes in the human context. This indicates a modulating role of the fastigial nucleus with regard to neural circuitries relevant for social behavior, such as the limbic system and the prefrontal cortex.

Cerebellar ataxias (CA) include a range of neurodegenerative disorders hallmarked by deterioration of the cerebellum. Cell replacement therapy (CRT) offers a potential remedy for the diseases associated with the central nervous system (CNS). This study was designed to assess the neurorestorative/protective effects of dental pulp stem cell (DPSC) implantation on a rat model of CA induced by 3-acetylpyridine (3-AP) as a neurotoxin. To begin, human DPSCs were extracted, cultured and phenotypically characterized. Then, experimental ataxia was induced in 20 male adult rats by a single injection of 3-AP and bilateral DPSC transplantation was performed 3 days after 3-AP administration, followed by stereological analysis of cerebellar layers along with assessment of motor skills and inflammatory response. The findings showed that transplantation of DPSCs in a 3-AP model of ataxia ameliorated motor coordination and muscle activity, increased cerebellar volumes of molecular and granular layers plus white matter, reduced the levels of inflammatory cytokines and thwarted the degeneration of Purkinje cells against 3-AP toxicity. Taken together, human DPSCs could be considered as a suitable candidate for CRT-based therapies with a specific focus on CA.

Objective: We examined the anatomical involvement related to cognitive impairment in patients with multiple system atrophy (MSA)., Methods: We examined 30 patients with probable MSA and 15 healthy controls. All MSA patients were assessed by the Unified MSA-Rating scale and Addenbrooke's Cognitive Examination-Revised (ACE-R). We classified 15 MSA patients with ACE-R scores > 88 as having normal cognition (MSA-NC) and 15 with scores ≤ 88 as having cognitive impairment (MSA-CI). All subjects underwent 3 T MRI scanning and were investigated using voxel-based morphometry and diffusion tensor imaging., Results: Both the MSA-NC and MSA-CI patients exhibited cerebellar but not cerebral atrophy in voxel-based morphometry compared to controls. In contrast, tract-based spatial statistics revealed widespread and significantly decreased fractional anisotropy (FA) values, as well as increased mean diffusivity, radial diffusivity, and axial diffusivity in both the cerebrum and cerebellum in MSA-CI patients compared to controls. MSA-NC patients also exhibited similar involvement of the cerebellum but less extensive involvement of the cerebrum compared with the MSA-CI patients. In particular, FA values in MSA-CI patients were significantly decreased in the anterior part of the left corpus callosum compared with those in MSA-NC patients. The mean FA values in the left anterior part of the corpus callosum were significantly correlated with total ACE-R scores and subscores (memory, fluency, and language) in MSA patients., Conclusions: Decreased FA values in the anterior corpus callosum showed a significant correlation with cognitive impairment in MSA.

Blood biomarkers in degenerative ataxias are still largely missing. Here, we aimed to provide piloting proof-of-concept that serum Neurofilament light (NfL) could offer a promising peripheral blood biomarker in degenerative ataxias. Specifically, as a marker of neuronal damage, NfL might (1) help to differentiate multiple system atrophy of cerebellar type (MSA-C) from sporadic adult-onset ataxia (SAOA), and (2) show increases in repeat-expansion spinocerebellar ataxias (SCAs) which might be amenable to treatment in the future. To explore these two hypotheses, we measured serum NfL levels by single-molecule array (Simoa) technique in 115 subjects, comprising patients with MSA-C (n = 25), SAOA (n = 25), the most frequent repeat-expansion SCAs (SCA 1, 2, 3 and 6) (n = 20), and age-matched controls (n = 45). Compared to controls, NfL was significantly increased in MSA-C, with levels significantly higher than in SAOA (AUC = 0.74 (0.59-0.89), mean and 95% confidence interval, p = .004). NfL was also significantly increased in SCA patients as compared to controls (AUC = 0.91 (0.81-1.00), p < .001), including NfL increases in SCA1 and SCA3. These findings provide first proof-of-concept that NfL might provide a promising peripheral biomarker in degenerative ataxias, e.g. supporting the differentiation of MSA-C from SAOA, and indicating neuronal damage in repeat-expansion SCAs.

Purpose: To investigate imaging features of crossed cerebellar diaschisis (CCD) in cerebral gliomas, and its underlying pathophysiological mechanisms., Methods: Thirty-three pre-surgical patients with cerebral gliomas and 33 healthy controls underwent arterial spin-labeling, diffusion tensor imaging, and high-resolution T1-weighted imaging using MRI, in order to estimate cerebral blood flow (CBF), white matter integrity, and lesion volume, respectively. Asymmetry indices of CBF in the cerebellum were used for evaluating the level of CCD in the patients. These indices were correlated with clinical variables (lesion size and position, tumor histological grade, and CBF asymmetry) and diffusion tensor imaging parameters (fractional anisotropy and number of fibers in the cortico-ponto-cerebellar pathway and across the cerebral hemispheres), respectively., Results: The patients showed decreased CBF in the cerebellar hemisphere contralateral to the supratentorial tumor, and increased CBF asymmetry in the cerebellum (both P < 0.05). CCD levels in high-grade gliomas were higher than those of low-grade gliomas (P < 0.05). CCD levels were negatively correlated with the size of the supratentorial lesions, and positively correlated with FA asymmetry in the cerebral fibers (both P < 0.05)., Conclusions: CCD in cerebral gliomas was specifically associated with tumor histological grade, lesion size, and white matter impairments in the hemisphere ipsilateral to the tumor. The findings implicated that observing CCD might have potential for assisting grading diagnosis of cerebral gliomas.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum and characterized by a typical motor syndrome. In addition, the presence of cognitive impairment is now widely acknowledged as a feature of SCA2. Given the extensive connections between the cerebellum and associative cerebral areas, it is reasonable to hypothesize that cerebellar neurodegeneration associated with SCA2 may impact on the cerebellar modulation of the cerebral cortex, thus resulting in functional impairment. The aim of the present study was to investigate and quantitatively map the pattern of cerebellar gray matter (GM) atrophy due to SCA2 neurodegeneration and to correlate that with patients' cognitive performances. Cerebellar GM maps were extracted and compared between SCA2 patients (n = 9) and controls (n = 33) by using voxel-based morphometry. Furthermore, the relationship between cerebellar GM atrophy and neuropsychological scores of the patients was assessed. Specific cerebellar GM regions were found to be affected in patients. Additionally, GM loss in cognitive posterior lobules (VI, Crus I, Crus II, VIIB, IX) correlated with visuospatial, verbal memory and executive tasks, while additional correlations with motor anterior (V) and posterior (VIIIA, VIIIB) lobules were found for the tasks engaging motor and planning components. Our results provide evidence that the SCA2 neurodegenerative process affects the cerebellar cortex and that MRI indices of atrophy in different cerebellar subregions may account for the specificity of cognitive symptomatology observed in patients, as result of a cerebello-cerebral dysregulation.

Dizziness/vertigo is the most common symptoms of posterior circulation strokes. Isolated vestibular symptoms and signs without other neurologic deficits have been found in infarctions involving the brainstem and cerebellum. In the brainstem, infarctions responsible for isolated vestibular syndrome are usually restricted to the dorsal portion that contains the vestibular nucleus and the nucleus prepositus hypoglossi. Cerebellar lesions confined to the flocculus, tonsil, and nodulus also produce isolated vertigo and imbalance. The cerebellar peduncle, as a conduit between the brainstem and cerebellum, can also produce isolated vestibular syndrome when damaged. Recognition of these isolated central vestibular syndromes aids in defining the function of each structure and in localizing the involved neural structures based upon the vestibular and ocular motor findings.

Efficient coupling of the actin cytoskeleton to the cell membrane is crucial for histogenesis and maintenance of the nervous system. At this critical interface, BAR (Bin-Amphiphysin-Rvs) proteins regulate membrane bending, shown to be instrumental for mobility and morphogenesis of individual cells. Yet, the systemic significance of these proteins remains largely unexplored. Here, we probe the role of a prominent member of this protein family, the inverse-BAR protein Mtss1, for the development and function of a paradigmatic neuronal circuit, the cerebellar cortex. Mtss1-null mice show granule cell ectopias, dysmorphic Purkinje cells, malformed axons, and a protracted neurodegeneration entailing age-dependent motor deficits. In postmitotic granule cells, which transiently express Mtss1 while they migrate and form neurites, Mtss1 impinges on directional persistence and neuritogenesis. The latter effect can be specifically attributed to its exon 12a splice variant. Targeted re-expression of Mtss1 in Mtss1-null animals indicated that these pathologies were largely due to cell type-specific and intrinsic effects. Together, our results provide a mechanistic perspective on Mtss1 function for brain development and degeneration and relate it to structural features of this protein.

Tilt suppression refers to both tilting the head away from an Earth vertical axis and a reduction of an induced horizontal nystagmus. This phenomenon of reducing an induced horizontal nystagmus involves a circuitry of neurons within the vestibular nuclei and the cerebellum (collectively referred to as velocity storage) and signals from the otolith end organs. Lesions involving this circuitry can disrupt tilt suppression of induced horizontal nystagmus. We investigated the clinical value of combining the horizontal head-shaking nystagmus test with tilt suppression in 28 patients with unilateral peripheral vestibular hypofunction and 11 patients with lesions affecting the central nervous system. Each of the subjects with peripheral vestibular lesions generated an appropriately directed horizontal nystagmus after head shaking that then suppressed the induced angular slow phase velocity on average 52 ± 17.6% following tilt down of the head. In contrast, patients with central lesions had very little ability to suppress post-head-shaking nystagmus (mean 3.4 ± 56%). We recommend tilting the head after head shaking as a useful clinical test to assist in the differential diagnosis of vertiginous patients. In the case of unilateral peripheral vestibular hypofunction, head tilt suppresses the induced nystagmus via influence of the otolith organ. In the case of central pathology, the inability to suppress the nystagmus is from lesions impairing the otolith mediation on the velocity storage circuitry.

Spinocerebellar ataxia type 6 (SCA6) is a genetic disease that causes degeneration of Purkinje cells, and recent evidence points to degeneration of Betz cells in the motor cortex. The relation between functional activity of motor cortex and symptom severity during a hand-grip motor control in vivo has not yet been investigated. This study explored both functional changes in the sensorimotor cortex and cerebellar regions and structural alterations in the cerebellum for SCA6 patients as compared to age-matched healthy controls using a multimodal imaging approach (task-based fMRI, task-based functional connectivity, and free-water diffusion MRI). Further, we tested their relation with the severity of ataxia symptoms. SCA6 patients had reduced functional activity in the sensorimotor cortex, supplementary motor area (SMA), cerebellar vermis, and cerebellar lobules I-VI (corrected P < 0.05). Reduced task-based functional connectivity between cortical motor regions (i.e., primary motor cortex and SMA) and cerebellar regions (i.e., vermis and lobules I-VI) was found in SCA6 (corrected P < 0.05). SCA6 had elevated free-water values throughout the cerebellum as compared with controls (corrected P < 0.05). Importantly, reduced functional activity in the sensorimotor cortex and SMA and increased free-water in the superior cerebellar peduncle and cerebellar lobule V were related to more severe symptoms in SCA6 (all pairs: R 2  ≥ 0.4 and corrected P < 0.05). Current results demonstrate that impaired functional activity in sensorimotor cortex and SMA and elevated free-water of lobule V and superior cerebellar peduncle are both related to symptom severity, and may provide candidate biomarkers for SCA6.

Introduction: Essential tremor (ET) is the most common movement disorder among adults. Although ET has been recognized as a mono-symptomatic benign illness, reports of non-motor symptoms and non-tremor motor symptoms have increased its clinical heterogeneity. The neural correlates of ET are not clearly understood. The aim of this study was to understand the neurobiology of ET using resting state fMRI., Methods: Resting state functional MR images of 30 patients with ET and 30 age- and gender-matched healthy controls were obtained. The functional connectivity of the two groups was compared using whole-brain seed-to-voxel-based analysis., Results: The ET group had decreased connectivity of several cortical regions especially of the primary motor cortex and the primary somatosensory cortex with several right cerebellar lobules compared to the controls. The thalamus on both hemispheres had increased connectivity with multiple posterior cerebellar lobules and vermis. Connectivity of several right cerebellar seeds with the cortical and thalamic seeds had significant correlation with an overall score of Fahn-Tolosa-Marin tremor rating scale (FTM-TRS) as well as the subscores for head tremor and limb tremor., Conclusion: Seed-to-voxel resting state connectivity analysis revealed significant alterations in the cerebello-thalamo-cortical network in patients with ET. These alterations correlated with the overall FTM scores as well as the subscores for limb tremor and head tremor in patients with ET. These results further support the previous evidence of cerebellar pathology in ET.

Classical teaching in epileptology localizes the origins of focal seizures solely in the cerebral cortex, with only inhibitory effects attributed to subcortical structures. However, electrophysiological and neuroimaging studies over the last decades now provide evidence for an initiation of epileptic seizures within subcortical structures. Intrinsic epileptogenicity of hypothalamic hamartoma has already been established in recognition of subcortical epilepsy, whereas a seizure-generating impact of dysplastic cerebellar lesions remains to be clarified. Herein, we examine the supportive evidence and clinical presentation of cerebellar seizures and review therapy options.

Friedreich ataxia (FRDA) is traditionally associated with neuropathology in the cerebellar dentate nucleus and spinal cord. Growing evidence also suggests involvement of the cerebral and cerebellar cortices, although reports of structural abnormalities remain mixed. This study assessed the structural integrity of cortical grey matter in FRDA, focussing on regions in which pathology may underlie the motor deficits characteristic of this disorder. T1-weighted anatomical magnetic resonance imaging scans were acquired from 31 individuals with FRDA and 37 healthy controls. Cortical thickness (FreeSurfer) and cortical volume (SPM-VBM) were measured in cerebral motor regions-of-interest (primary motor, dorsal and ventral premotor, and supplementary motor areas) alongside unconstrained exploratory analyses of the cerebral and cerebellar cortices. Correlations were assessed between cortical thickness/volume measures and each of disease severity, length of the causative genetic triplet-repeat expansion, and finger-tapping behavioural measures. Individuals with FRDA had significantly reduced cortical thickness, relative to controls, in the premotor and supplementary motor areas. Reduced cortical thickness and/or volume were also observed in the cuneus and precuneus, posterior aspects of the medial and lateral prefrontal cortices, insula, temporal poles, and cerebellar lobules V, VI, and VII. Measures of clinical severity, genetic abnormality, and motor dysfunction correlated with volume loss in the lateral cerebellar hemispheres. These results suggest that atrophy preferentially affects premotor relative to primary areas of the cortical motor system, and also extends to a range of non-motor brain regions. Furthermore, cortical thickness and cortical volume findings were largely divergent, suggesting that each is sensitive to different aspects of neuropathology in FRDA. Overall, this study supports a disease model involving neural aberrations within the cerebral and cerebellar cortices, beyond those traditionally associated with this disorder.

Introduction: Although the diagnostic performance of whole-brain computed tomographic perfusion (WB-CTP) in the detection of supratentorial infarctions is well established, its value in the detection of infratentorial strokes remains less well defined. We examined its diagnostic accuracy in the detection of infratentorial infarctions and compared it to nonenhanced computed tomography (NECT), aiming to identify factors influencing its detection rate., Methods: Out of a cohort of 1380 patients who underwent WB-CTP due to suspected stroke, we retrospectively included all patients with MRI-confirmed infratentorial strokes and compared it to control patients without infratentorial strokes. Two blinded readers evaluated NECT and four different CTP maps independently for the presence and location of infratentorial ischemic perfusion deficits., Results: The study was designed as a retrospective case-control study and included 280 patients (cases/controls = 1/3). WB-CTP revealed a greater diagnostic sensitivity than NECT (41.4 vs. 17.1 %, P = 0.003). The specificity, however, was comparable (93.3 vs. 95.0 %). Mean transit time (MTT) and time to drain (TTD) were the most sensitive (41.4 and 40.0 %) and cerebral blood volume (CBV) the most specific (99.5 %) perfusion maps. Infarctions detected using WB-CTP were significantly larger than those not detected (15.0 vs. 2.2 ml; P = 0.0007); infarct location, however, did not influence the detection rate., Conclusion: The detection of infratentorial infarctions can be improved by assessing WB-CTP as part of the multimodal stroke workup. However, it remains a diagnostic challenge, especially small volume infarctions in the brainstem are likely to be missed.

Windmill nystagmus is characterized by a clock-like rotation of the beating direction of a jerk nystagmus suggesting separate horizontal and vertical oscillators, usually 90° out of phase. We report oculographic characteristics in three patients with variants of windmill nystagmus in whom the common denominator was profound visual loss due to retinal diseases. Two patients showed a clock-like pattern, while in the third, the nystagmus was largely diagonal (in phase or 180° out of phase) but also periodically changed direction by 180°. We hypothesize that windmill nystagmus is a unique manifestation of "eye movements of the blind." It emerges when the central structures, including the cerebellum, that normally keep eye movements calibrated and gaze steady can no longer perform their task, because they are deprived of the retinal image motion that signals a need for adaptive recalibration.

Introduction: Brain herniations (BH) into arachnoid granulations (AG) in dural venous sinuses and calvarium have rarely been reported in the literature., Methods: MRIs of 38 patients with BH into AG (BHAG) were retrospectively analyzed. Locations of BHAG, gyrus/lobe of the herniated brain, parenchymal abnormalities of the BH, and clinical and radiological conditions with raised intracranial pressure were recorded., Results: Sixty-eight BHAG were found, by order of frequency, in the occipital squama (OS), transverse sinus (TS), lateral lacuna of the superior sagittal sinus (LLSSS), and straight sinus (SS), with cerebellar tissue being the most frequently involved in BHAG (94.5 % of OS, 55 % of TS, 100 % SS BHAG). Multiple BHAG were found in 58 % of the patients (up to five per patient). Parenchymal signal and structural changes (SSCG) were observed in 46 % of BHAG (100 % were cerebellar). Three patients had pseudotumor cerebri (PTCS); one patient had only MRI signs of PTCS. Twenty-one percent of patients had intracranial conditions susceptible of increasing cerebrospinal fluid (CSF) pressure other than PTCS., Conclusions: BHAG occurred in the OS, TS, LLSSS, and the SS. SSCG of the herniated cerebellum were frequent and possibly result from tethering/strangulation in the AG. No symptoms could be clearly attributed to BHAG, though in three cases of PTCS, TS BHAG could have contributed to sustaining the raised CSF pressure. Various factors are probably involved in the development of BHAG including normal pia-arachnoid bridges between the brain surface and the AG, hydrodynamic constrains on the brain and AG, and, in some cases, increased intracranial pressure.

Granule cell neuronopathy (GCN) is a rare JC virus infection of the cerebellar granule cell neurons in immunocompromised patients. On brain imaging, GCN is characterized by cerebellar atrophy which can be accompanied by infratentorial white matter lesions. The objective of this study is to investigate the prevalence of MRI findings suggestive of GCN in a large natalizumab-associated progressive multifocal leukoencephalopathy (PML) cohort. MRI scans from before, at the time of, and during follow-up after diagnosis of PML in 44 natalizumab-treated MS patients, and a control group of 25 natalizumab-treated non-PML MS patients were retrospectively reviewed for imaging findings suggestive of GCN. To assess and quantify the degree of cerebellar atrophy, we used a 4 grade rating scale. Three patients in the PML group showed imaging findings suggestive of GCN and none in the control group. In two of these PML patients, cerebellar atrophy progressed from grade 0 at the time of diagnosis of isolated supratentorial PML to grade 1 and 2 after 2.5 and 3 months, respectively, in the absence of infratentorial white mater lesions. The third patient had grade 1 cerebellar atrophy before diagnosis of infra- and supratentorial PML, and showed progression of cerebellar atrophy to grade 2 in the 3 months following PML diagnosis. None of the other eight patients with infratentorial PML lesions developed cerebellar atrophy suggestive of GCN. Three cases with imaging findings suggestive of GCN were detected among 44 natalizumab-associated PML patients. GCN may, therefore, be more common than previously considered in natalizumab-associated PML patients.

The purpose of this study was to describe a pedigree with NEFL N98S mutation associated with a dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) and heterogeneous early-onset phenotype. The pedigree comprised two patients, the proband and her son, aged 38 and 5 years. The proband, evaluated at age 31, showed delayed motor milestones that, as of the second decade, evolved into severe phenotype consisting of sensorimotor neuropathy, pes cavus, clawing hands, gait and kinetic cerebellar ataxia, nystagmus and dysarthria, she being wheelchair bound. By then, a working diagnosis of sporadic early onset cerebellar ataxia with peripheral neuropathy was established. Screening of mutations associated with SCA and autosomal recessive cerebellar ataxias was negative. Her son showed a mild phenotype characterized by delayed motor milestones, and lower-limb hypotonia and areflexia. Electrophysiology in both patients showed nerve conduction slowing in the intermediate range, both in proximal and distal nerve segments, but where compound muscle action potentials exhibited severe attenuation there was conduction slowing down to the demyelinating range. In the proband, cranial magnetic resonance imaging (MRI) showed cerebellar atrophy, electromyography disclosed active denervation in tibialis anterior, and MRI of lower-limb musculature demonstrated widespread and distally accentuated muscle fatty atrophy; furthermore, on water sensitive MRI sequences there was edema of calf muscles. We conclude that the NEFL N98S mutation is associated with a DI-CMT phenotype characterized by early-onset sensorimotor neuropathy delaying motor milestones, which may evolve into a severe and complex clinical picture including cerebellar ataxia.

Lipofuscin pigment accumulation is among the most prominent markers of cellular aging in postmitotic cells. The formation of lipofuscin is related to oxidative enzymatic activity and free radical-induced lipid peroxidation. In various mammals such as rat, dog, macaque as well as in cheirogaleid primates, most of the large neurons, such as cerebellar Purkinje cells and neocortical pyramidal cells, show heavy lipofuscin accumulation in adulthood. In contrast, a well-known yet poorly studied feature of the aging human brain is that although lipofuscin accumulation is most marked in large neurons of the cerebral cortex, the large neurons of the cerebellar cortex-the Purkinje cells-appear to remain free of lipofuscin accumulation. It is however, not known whether this characteristic of human Purkinje cells is shared with other primates or other mammals. This study reports results from histological observation of Purkinje cells in humans, non-human primates, and other mammals. Procedures include histochemistry, immunocytochemistry, and fluorescence microscopy. Abundant lipofuscin deposition was observed in Purkinje cells of all the species we examined except Homo sapiens (including Alzheimer's disease cases) and Pan troglodytes. In contrast, lipofuscin deposition was observed in neurons of the dentate nucleus. Our findings suggest that when compared with other primates, Purkinje cells in chimpanzees and humans might share a common aging pattern that involves mechanisms for neuroprotection. This observation is important when considering animal models of aging.

Two French-Canadian sibs with cerebellar ataxia and dysarthria were seen in our neurogenetics clinic. The older brother had global developmental delay and spastic paraplegia. Brain MRIs from these two affected individuals showed moderate to severe cerebellar atrophy. To identify the genetic basis for their disease, we conducted a whole exome sequencing (WES) investigation using genomic DNA prepared from the affected sibs and their healthy father. We identified two mutations in the SIL1 gene, which is reported to cause Marinesco-Sjögren syndrome. This study emphasizes how the diagnosis of patients with ataxic gait and cerebellar atrophy may benefit from WES to identify the genetic cause of their condition.

Neuroferritinopathy is an autosomal dominant adult-onset movement disorder which occurs due to mutations in the ferritin light chain gene (FTL). Extensive iron deposition and cavitation are observed post-mortem in the basal ganglia, but whether more widespread pathological changes occur, and whether they correlate with disease severity is unknown. 3D-T1w and quantitative T2 whole brain MRI scans were performed in 10 clinically symptomatic patients with the 460InsA FTL mutation and 10 age-matched controls. Voxel-based morphometry (VBM) and voxel-based relaxometry (VBR) were subsequently performed. Clinical assessment using the Unified Dystonia Rating Scale (UDRS) and Unified Huntington's Disease Rating Scale (UHDRS) was undertaken in all patients. VBM detected significant tissue changes within the substantia nigra, midbrain and dentate together with significant cerebellar atrophy in patients (FWE, p < 0.05). Iron deposition in the caudate head and cavitation in the lateral globus pallidus correlated with UDRS score (p < 0.001). There were no differences between groups with VBR. Our data show that progressive iron accumulation in the caudate nucleus, and cavitation of the globus pallidus correlate with disease severity in neuroferritinopathy. We also confirm sub-clinical cerebellar atrophy as a feature of the disease. We suggest that VBM is an effective technique to detect regions of iron deposition and cavitation, with potential wider utility to determine radiological markers of disease severity for all NBIA disorders.

Niemann-Pick disease type C (NPC) is a rare neurovisceral disorder resulting in impaired intracellular lipid trafficking. The only disease-modifying treatment available to date is miglustat, an iminosugar inhibiting the accumulation of lipid by-products in neurons. This study explored how changes in cerebellar grey and white matter volumes, and in subcortical volumes, related to patient treatment status and disability and ataxia ratings. Nine adult-onset NPC patients and 17 matched controls underwent T1-weighted MRI. One patient was not receiving miglustat, and pre-treatment data were available for a further patient. Semi-automated cerebellar and subcortical segmentation was undertaken, and the rates of change in putamen, hippocampal, thalamic and caudal volumes, and grey and white matter cerebellar volumes, were compared to rates of change in Iturriaga disability score, Brief Ataxia Rating Scale (BARS), and horizontal saccadic gain. Untreated NPC patients appeared to lose cerebellar grey and white matter, bilateral thalamic volume, and right caudate volume faster than treated patients. Cerebellar grey matter volume loss and volume loss in the left thalamus were significantly correlated with Iturriaga disability scale changes. Change in both cerebellar grey and white matter was correlated with decrease in horizontal saccadic gain, but not with change in BARS. This is the first study to examine longitudinal treatment effects of miglustat on cerebellar and subcortical volumes in patients with adult-onset NPC, and is evidence that miglustat may have a protective effect on cerebellar and subcortical structure and function.

Neuroimaging studies have indicated that people with alexithymia show structural and functional alterations in brain areas associated with emotional awareness, as amygdala, insula, anterior cingulate cortex, fusiform gyrus and parahippocampal gyrus, and only occasionally alterations in the cerebellar activity were reported. The main goal of the present study was to investigate the associations between gray and white matter cerebellar macro- (Voxel-Based Morphometry) and micro- (Mean Diffusivity and Fractional Anisotropy) structural measures (evaluated by means of a 3-T high-resolution structural Magnetic Resonance Imaging and a Diffusion Tensor Imaging scan protocol) and the presence of alexithymia (evaluated by means of 20-item Toronto Alexithymia Scale), in a sample of 60 healthy subjects having low, borderline or high alexithymia. As a corollary aim, the associations between volumes of amygdala, insula, anterior cingulate cortex, fusiform gyrus or parahippocampal gyrus and alexithymia scores have been investigated. Cerebellar gray matter volumes were positively associated with alexithymia scores. The subjects with high alexithymic traits had larger volumes in the bilateral Crus 1 in comparison to the remaining subjects. Volumes of right amygdala, left insula and left parahippocampal gyrus were negatively associated with the alexithymia scores. Thus, alexithymia scores were linked directly with cerebellar areas and inversely with limbic and para-limbic system, proposing a possible functional modality for the cerebellar involvement in emotional processing. The increased volumes in Crus 1 of subjects with high alexithymic traits may be related to an altered embodiment process leading to not-cognitively interpreted emotions.

Introduction: Recent diffusion tensor imaging (DTI) studies have demonstrated that leakage of hemosiderin into cerebrospinal fluid (CSF), which is caused by high-grade intraventricular hemorrhage (IVH), can affect cerebellar development in preterm born infants. However, a direct effect of low-grade IVH on cerebellar development is unknown. Thus, we evaluated the cerebellar and cerebral white matter (WM) of preterm infants with low-grade IVH., Methods: Using DTI tractography performed at term-equivalent age, we analyzed 42 infants who were born less than 30 weeks gestational age (GA) at birth (22 with low-grade IVH, 20 without). These infants were divided into two birth groups depending on GA, and we then compared the presence and absence of IVH which was diagnosed by cerebral ultrasound (CUS) within 10 days after birth or conventional magnetic resonance imaging (MRI) at term-equivalent age in each group. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) at the superior cerebellar peduncle (SCP), middle cerebellar peduncle (MCP), motor tract, and sensory tract were measured., Results: In the SCP, preterm born infants with IVH had lower FA values compared with infants without IVH. In particular, younger preterm birth with IVH had lower FA values in the SCP and motor tract and higher ADC values in the MCP., Conclusion: Low-grade IVH impaired cerebellar and cerebral WM, especially in the SCP. Moreover, younger preterm infants exhibited greater disruptions to cerebellar WM and the motor tract than infants of older preterm birth.

Introduction: Studies with diffusion tensor imaging (DTI) analysis have produced conflicting information about the involvement of the cerebellar hemispheres in Parkinson's disease (PD). We, thus, used a new approach for the analysis of DTI parameters in order to ascertain the involvement of the cerebellum in PD., Methods: We performed a fiber tract-based analysis of cerebellar peduncles and cerebellar hemispheres in 16 healthy subjects and in 16 PD patients with more than 5 years duration of disease, using a 3T MRI scanner and a constrained spherical deconvolution (CSD) approach for tractographic reconstructions. In addition, we performed statistical analysis of DTI parameters and fractional anisotropy (FA) XYZ direction samplings., Results: We found a statistically significant decrement of FA values in PD patients compared to controls (p < 0.05). In addition, extrapolating and analyzing FA XYZ direction samplings for each patient and each control, we found that this result was due to a stronger decrement of FA values along the Y axis (antero-posterior direction) (p < 0.01); FA changes along X and Z axes were not statistically significant (p > 0.05). We confirmed also no statistically significant differences of FA and apparent diffusion coefficient (ADC) for cerebellar peduncles in PD patients compared to healthy controls., Conclusions: The DTI-based cerebellar abnormalities in PD could constitute an advance in the knowledge of this disease. We demonstrated a statistically significant reduction of FA in cerebellar hemispheres of PD patients compared to healthy controls. Our work also demonstrated that the use of more sophisticated approaches in the DTI parameter analysis could potentially have a clinical relevance.