Cerebellar Abnormalities Research Articles

7.2 Structural Cerebellar Abnormalities in Youth With Bipolar Spectrum Disorders and Bipolar Offspring

Structural abnormalities in individuals with bipolar disorder (BD) have been reported in cortical, subcortical, and limbic brain systems. However, whether these abnormalities are present in youth with BD spectrum disorders (BPSD) or in offspring of bipolar parents and to what extent need to be explored to enable the recognition of evolving structural abnormalities in bipolar disorder. In this study, we assessed for volumetric changes in three groups of youths as follows: BPSD, bipolar offspring (BPO), and healthy control (HC).

Reduced muscle strength in ether lipid-deficient mice is accompanied by altered development and function of the neuromuscular junction.

Inherited deficiency in ether lipids, a subgroup of phospholipids whose biosynthesis needs peroxisomes, causes the fatal human disorder rhizomelic chondrodysplasia punctata. The exact roles of ether lipids in the mammalian organism and, therefore, the molecular mechanisms underlying the disease are still largely enigmatic. Here, we used glyceronephosphate O‐acyltransferase knockout (Gnpat KO) mice to study the consequences of complete inactivation of ether lipid biosynthesis and documented substantial deficits in motor performance and muscle strength of these mice. We hypothesized that, probably in addition to previously described cerebellar abnormalities and myelination defects in the peripheral nervous system, an impairment of neuromuscular transmission contributes to the compromised motor abilities. Structurally, a morphologic examination of the neuromuscular junction (NMJ) in diaphragm muscle at different developmental stages revealed aberrant axonal branching and a strongly increased area of nerve innervation in Gnpat KO mice. Post‐synaptically, acetylcholine receptor (AChR) clusters colocalized with nerve terminals within a widened endplate zone. In addition, we detected atypical AChR clustering, as indicated by decreased size and number of clusters following stimulation with agrin, in vitro. The turnover of AChRs was unaffected in ether lipid‐deficient mice. Electrophysiological evaluation of the adult diaphragm indicated that although evoked potentials were unaltered in Gnpat KO mice, ether lipid deficiency leads to fewer spontaneous synaptic vesicle fusion events but, conversely, an increased post‐synaptic response to spontaneous vesicle exocytosis. We conclude from our findings that ether lipids are essential for proper development and function of the NMJ and may, therefore, contribute to motor performance. Read the Editorial Highlight for this article on page 463.

Motor and Cerebellar Architectural Abnormalities during the Early Progression of Ataxia in a Mouse Model of SCA1 and How Early Prevention Leads to a Better Outcome Later in Life.

Exposing developing cerebellar Purkinje neurons (PNs) to mutant Ataxin1 (ATXN1) in 82Q spinocerebellar ataxia type 1 (SCA1) mice disrupts motor behavior and cerebellar climbing fiber (CF) architecture from as early as 4 weeks of age. In contrast, if mutant ATXN1 expression is silenced until after cerebellar development is complete, then its impact on motor behavior and cerebellar architecture is greatly reduced. Under these conditions even 6 month old SCA1 mice exhibit largely intact motor behavior and molecular layer (ML) and CF architecture but show a modest reduction in PN soma area as a first sign of cerebellar disruption. Our results contrast the sensitivity of the developing cerebellum and remarkable resilience of the adult cerebellum to mutant ATXN1 and imply that SCA1 in this mouse model is both a developmental and neurodegenerative disorder.

P 3 Cerebellar gray matter volume decrease is associated with epileptic seizures in multiple sclerosis

Background Prevalence rates of epileptic seizures are three times higher in patients with multiple sclerosis (MS) compared to healthy controls ( van Munster et al., 2015 ). There is some evidence of gray matter (GM) as well as white matter (WM) lesions associated with epilepsy in MS ( van Munster et al., 2015 ). Here, we compared regional GM volume decrease using voxel based morphometry (VBM) to compare MS patients with and without epilepsy. Methods MRI images of 30 MS patients (15 with, 15 without epilepsy, matched due to disease duration, disease course, EDSS and age) were analyzed using voxel based morphometry. Second level analysis was done comparing regional GM volume in MS patients without compared to with epileptic seizures. Results MS-patients with epilepsy had regional GM volume decrease in the cerebellum compared to MS patients without epilepsy, mainly in the posterior lobe. Neither cerebral or deep GM structures revealed significant regional GM volume decrease. Discussion There is some evidence of hippocampal GM pathology associated with epilepsy ( Nicholas et al., 2016 ). In contrast, our VBM analyses did not reveal any association to cortical or subcortical GM volume decrease. Against our expectations, we found significant cerebellar GM volume decrease in the patients with, compared to without epileptic seizures. Interestingly, there is some evidence of cerebellar lesions generating seizures ( Foit et al., 2016 ), cerebellar abnormalities in idiopathic generalized epilepsy ( Li et al., 2010 ) as well as a cerebellar mediated, inhibitory effect on hippocampal seizures ( Krook-Magnuson et al., 2014 ). Our data has to be confirmed in larger samples, but at least are indicating a possible role of the cerebellum in MS patients with epilepsy.

Evaluation of the fetal cerebellum by magnetic resonance imaging

Obstetric protocols dictate that the fetal cerebellum should always be assessed during sonograms during pregnancy. For various reasons, including technical limitations or inconclusive sonographic findings, suspicion of cerebellar abnormalities is one of the most common indications for prenatal magnetic resonance imaging (MRI). Although sonography is the imaging technique of choice to assess the cerebellum, MRI shows the anatomy of the posterior fossa and abnormalities in the development of the fetal cerebellum in greater detail and thus enables a more accurate prenatal diagnosis. We describe and illustrate the normal anatomy of the fetal cerebellum on MRI as well as the different diseases that can affect its development. Moreover, we review the most appropriate terminology to define developmental abnormalities, their differential diagnoses, and the role of MRI in the prenatal evaluation of the posterior fossa.

RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes

RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between -2.5 to -5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of ∼10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and invivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities invivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.

Cerebellar Gray Matter Reductions Associate With Decreased Functional Connectivity in Nicotine-Dependent Individuals.

Nicotine dependence (ND) is a chronic, relapsing mental disorder characterized by compulsive cigarette seeking and smoking. Although the cerebellum plays an increasingly implicated role in ND, the exact cerebellar alterations in ND remain unclear. Identifying the localization of these cerebellar abnormalities in ND may help to further understand the role of the cerebellum in ND. Thus, we investigated the structural and functional alterations in the cerebellum in a large sample of smokers using the spatially unbiased infratentorial template (SUIT). High-resolution structural magnetic resonance imaging (MRI) data were acquired from 85 smokers and 41 nonsmokers. We applied voxel-based morphometry (VBM) and the SUIT cerebellar atlas to compare the cerebellar gray matter (GM) volume between smokers and nonsmokers. Using resting-state functional MRI data, we also performed seed-based functional connectivity (FC) analysis to examine the functional correlates of the GM volume changes. Both VBM and lobular analyses revealed smaller GM volume in the bilateral Crus I in smokers. The GM volume of the left Crus I was inversely correlated with the severity of nicotine dependence as assessed by Fagerström Test for Nicotine Dependence (r = -.268, p = .013). We also found reduced FC between the bilateral Crus I and brain regions involved in the default mode network and motor system, as well as the frontal and temporal cortex in smokers. Our results indicate that decreased cerebellar GM volume and corticocerebellar FC are associated with ND, and these may underlie the core ND phenotypes, including automatized smoking behavior, cognitive, and emotional deficits. As smoking remains a worldwide public health problem, identifying the related neural alterations may help to understand the pathophysiology of ND. Based on previous findings in the cerebellum, we investigated the localization of the GM differences and related FC changes in ND subjects. Our findings highlight altered corticocerebellar circuits in ND, suggesting an association between the cerebellum and the phenotypes of ND.

Valoración del cerebelo fetal mediante resonancia magnética

Obstetric protocols dictate that the fetal cerebellum should always be assessed during sonograms during pregnancy. For various reasons, including technical limitations or inconclusive sonographic findings, suspicion of cerebellar abnormalities is one of the most common indications for prenatal magnetic resonance imaging (MRI). Although sonography is the imaging technique of choice to assess the cerebellum, MRI shows the anatomy of the posterior fossa and abnormalities in the development of the fetal cerebellum in greater detail and thus enables a more accurate prenatal diagnosis. We describe and illustrate the normal anatomy of the fetal cerebellum on MRI as well as the different diseases that can affect its development. Moreover, we review the most appropriate terminology to define developmental abnormalities, their differential diagnoses, and the role of MRI in the prenatal evaluation of the posterior fossa.

BRAINSTEM NEURONAL LOSS OCCURRING INDEPENDENTLY FROM NEOCORTICAL ALZHEIMER, LEWY BODY, OR FOCAL ISCHEMIC LESIONS IS COMMON AND SIGNIFICANTLY ASSOCIATED WITH BOTH MOTOR AND COGNITIVE IMPAIRMENT IN AUTOPSIED HONOLULU-ASIA AGING STUDY DECEDENTS

The neuropathologic abnormalities to which aging-related cognitive impairment is commonly attributed include neocortical neurofibrillary tangles, neuritic amyloid plaques, cortical Lewy bodies, hippocampal sclerosis, and vascular brain injury with microinfarcts and/or lacunar infarcts. Motor impairments are very common with aging and occur often but not invariably with dementia. The brain abnormalities generally recognized as common and relevant to motor impairments are infarcts, hemorrhage, and Lewy bodies in the substantia nigra, Repeated cognitive and motor function assessments were carried out over two decades on Japanese-American male Honolulu-Asia Aging Study participants. This analysis was carried out on 774 HAAS decedents who received comprehensive, highly standardized brain autopsies at death. Cognitive assessments utilized the Cognitive Assessment and Screening Instrument. Grip strength, walking speed, stride length, turn around steps, turn around time, chair stands, and standing balance were assessed on 6 occasions. Analyses utilized graphic and tabular visual representation plus linear and logistic regression statistical modeling. Decedents with cognitive impairment but little or no motor impairment were found at autopsy to have neocortical neurofibrillary tangles and amyloid plaques, microinfarcts and/or lacunar infarcts, and hippocampal sclerosis, but negligible striatal, cerebellar, or brainstem abnormalities. Those who had both cognitive and motor impairments had these same lesions plus neocortical Lewy bodies, generalized brain atrophy, and striatal and brainstem neuronal loss and gliosis. In a subset of autopsied cases without neocortical Alzheimer lesions, Lewy bodies (brainstem or neocortex), microinfarcts, or hippocampal sclerosis, neuronal loss and gliosis observed in the brainstem was nonetheless significantly associated with both cognitive and motor impairments. These findings suggest that linked cognitive and motor impairments may be associated with brainstem neuronal injury due in part to currently undefined disease processes distinct from other neuropathologic processes represented by neocortical Alzheimer lesions, Lewy bodies, vascular brain injury, and/or hippocampal sclerosis.

Disrupted implicit motor sequence learning in schizophrenia and bipolar disorder revealed with ambidextrous Serial Reaction Time Task

BackgroundImpairment of implicit motor sequence learning was shown in schizophrenia (SZ) and, most recently, in bipolar disorder (BD), and was connected to cerebellar abnormalities. The goal of this study was to compare implicit motor sequence learning in BD and SZ. MethodsWe examined 33 patients with BD, 33 patients with SZ and 31 healthy controls with a use of ambidextrous Serial Reaction Time Task (SRTT), which allows exploring asymmetries in performance depending on the hand used. ResultsBD and SZ patients presented impaired implicit motor sequence learning, although the pattern of their impairments was different. While BD patients showed no signs of implicit motor sequence learning for both hands, the SZ group presented some features of motor learning when performing with the right, but not with the left hand. ConclusionsTo our best knowledge this is the first study comparing implicit motor sequence learning in BD and SZ. We show that both diseases share impairments in this domain, however in the case of SZ this impairment differs dependently on the hand performing SRTT. We propose that implicit motor sequence learning impairments constitute an overlapping symptom in BD and SZ and suggest further neuroimaging studies to verify cerebellar underpinnings as its cause.

N-butyldeoxynojirimycin delays motor deficits, cerebellar microgliosis, and Purkinje cell loss in a mouse model of mucolipidosis type IV

Mucolipidosis type IV (MLIV) is a lysosomal storage disease exhibiting progressive intellectual disability, motor impairment, and premature death. There is currently no cure or corrective treatment. The disease results from mutations in the gene encoding mucolipin-1, a transient receptor potential channel believed to play a key role in lysosomal calcium egress. Loss of mucolipin-1 and subsequent defects lead to a host of cellular aberrations, including accumulation of glycosphingolipids (GSLs) in neurons and other cell types, microgliosis and, as reported here, cerebellar Purkinje cell loss. Several studies have demonstrated that N-butyldeoxynojirimycin (NB-DNJ, also known as miglustat), an inhibitor of the enzyme glucosylceramide synthase (GCS), successfully delays the onset of motor deficits, improves longevity, and rescues some of the cerebellar abnormalities (e.g., Purkinje cell death) seen in another lysosomal disease known as Niemann-Pick type C (NPC). Given the similarities in pathology between MLIV and NPC, we examined whether miglustat would be efficacious in ameliorating disease progression in MLIV. Using a full mucolipin-1 knockout mouse (Mcoln1−/−), we found that early miglustat treatment delays the onset and progression of motor deficits, delays cerebellar Purkinje cell loss, and reduces cerebellar microgliosis characteristic of MLIV disease. Quantitative mass spectrometry analyses provided new data on the GSL profiles of murine MLIV brain tissue and showed that miglustat partially restored the wild type profile of white matter enriched lipids. Collectively, our findings indicate that early miglustat treatment delays the progression of clinically relevant pathology in an MLIV mouse model, and therefore supports consideration of miglustat as a therapeutic agent for MLIV disease in humans.

Haploinsufficiency of BCL11A associated with cerebellar abnormalities in 2p15p16.1 deletion syndrome.

BackgroundChromosome 2p15p16.1 deletion syndrome is a rare genetic disorder characterized by intellectual disability (ID), neurodevelopmental delay, language delay, growth retardation, microcephaly, structural brain abnormalities, and dysmorphic features. More than 30 patients with 2p15p16.1 microdeletion syndrome have been reported in the literature.MethodsMolecular analysis was performed using microarray‐based comparative genomic hybridization (array CGH). Clinical characteristics and brain magnetic resonance imaging features of these patients were also reviewed.ResultsWe identified four patients with ID, neurodevelopmental delay, brain malformations, and dysmorphic features; two patients with 2p15p16.1 deletions (3.24 Mb, 5.04 Mb), one patient with 2p16.1 deletion (1.12 Mb), and one patient with 2p14p16.1 deletion (5.12 Mb). Three patients with 2p15p16.1 deletions or 2p16.1 deletions encompassing BCL11A,PAPOLG, and REL showed hypoplasia of the pons and cerebellum. The patient with 2p14p16.1 deletion, which did not include three genes showed normal size and shape of the cerebellar hemispheres and pons.ConclusionThe zinc finger transcription factor BCL11A associated with the BAF chromatin remodeling complex has been identified to be critical for neural development and BCL11A haploinsufficiency is closely related to cerebellar abnormalities.

Age exacerbates abnormal protein expression in a mouse model of Down syndrome

The Ts65Dn is a popular mouse model of Down syndrome (DS). It displays DS-relevant features of learning/memory deficits and age-related loss of functional markers in basal forebrain cholinergic neurons. Here we describe protein expression abnormalities in brain regions of 12-month-old male Ts65Dn mice. We show that the magnitudes of abnormalities of human chromosome 21 and non–human chromosome 21 orthologous proteins are greater at 12 months than at ∼6 months. Age-related exacerbations involve the number of components affected in the mechanistic target of rapamycin pathway, the levels of components of the mitogen-activated protein kinase pathway, and proteins associated with Alzheimer's disease. Among brain regions, the number of abnormalities in cerebellum decreased while the number in cortex greatly increased with age. The Ts65Dn is being used in preclinical evaluations of drugs for cognition in DS. Most commonly, drug evaluations are tested in ∼4- to 6-month-old mice. Data on age-related changes in magnitude and specificity of protein perturbations can be used to understand the molecular basis of changes in cognitive ability and to predict potential age-related specificities in drug efficacies.

The epileptology of Koolen‐de Vries syndrome: Electro‐clinico‐radiologic findings in 31 patients

This study was designed to describe the spectrum of epilepsy phenotypes in Koolen-de Vries syndrome (KdVS), a genetic syndrome involving dysmorphic features, intellectual disability, hypotonia, and congenital malformations, that occurs secondary to 17q21.31 microdeletions and heterozygous mutations in KANSL1. We were invited to attend a large gathering of individuals with KdVS and their families. While there, we recruited individuals with KdVS and seizures, and performed thorough phenotyping. Additional subjects were included who approached us after the family support group brought attention to our research via social media. Inclusion criteria were genetic testing results demonstrating 17q21.31 deletion or KANSL1 mutation, and at least one seizure. Thirty-one individuals were studied, aged 2-35 years. Median age at seizure onset was 3.5 years, and 9 of 22 had refractory seizures 2 years after onset. Focal impaired awareness seizures were the most frequent seizure type occurring in 20 of 31, usually with prominent autonomic features. Twenty-one patients had prolonged seizures and, at times, refractory status epilepticus. Electroencephalography (EEG) showed focal/multifocal epileptiform discharges in 20 of 26. MRI studies of 13 patients were reviewed, and all had structural anomalies. Corpus callosum dysgenesis, abnormal hippocampi, and dilated ventricles were the most common, although periventricular nodular heterotopia, focal cortical dysplasia, abnormal sulcation, and brainstem and cerebellum abnormalities were also observed. One patient underwent epilepsy surgery for a lesion that proved to be an angiocentric glioma. The typical epilepsy phenotype of KdVS involves childhood-onset focal seizures that are prolonged and have prominent autonomic features. Multifocal epileptiform discharges are the typical EEG pattern. Structural brain abnormalities may be universal, including signs of abnormal neuroblast migration and abnormal axonal guidance. Epilepsy surgery should be undertaken with care given the widespread neuroanatomic abnormalities; however, tumors are a rare, yet important, occurrence.

Sporadic periventricular nodular heterotopia: Classification, phenotype and correlation with Filamin A mutations

ObjectiveThe purpose of this study was to better delineate the clinical spectrum of periventricular nodular heterotopia (PNH) in a large patient population after long term follow up. Specifically, this study aimed to relate PNH subtypes to clinical or epileptic outcomes, epileptic discharges and underlying Filamin A (FLNA) mutations by analyzing anatomical features. MethodsThe study included 100 patients with radiologically confirmed nodular heterotopia. Patients’ FLNA gene sequences and medical records were analyzed. Two-sided Chi-square test and Fisher's exact t-test were used to assess associations between the distribution of PNHs and specific clinical features. ResultsBased on imaging data, patients were subdivided into three groups: (a) classical (bilateral frontal and body, n=41 patients), (b) bilateral asymmetrical or posterior (n=16) and (c) unilateral heterotopia (n=43). Most patients with classical heterotopia were females (P=0.033) and were likely to have arachnoid cysts (P=0.025) and cardiac abnormalities (P=0.041), but were mostly seizure-free. Additionally, hippocampal abnormalities (P=0.022), neurological deficits (P=0.028) and cerebellar abnormalities (P=0.005) were more common in patients with bilateral asymmetrical heterotopia. Patients with unilateral heterotopia were prone to develop refractory epilepsy (P=0.041). FLNA mutations were identified in 8 patients. ConclusionsEach group's distinctive genetic mutations, epileptic discharge patterns and overall clinical outcomes confirm that the proposed classification system is reliable. These findings could not only be an indicator of a more severe morphological and clinical phenotype, but could also have clinical implications with respect to the epilepsy management and optimization of therapeutic options.

Elucidating the aberrant brain regions in bipolar disorder using T1-weighted/T2-weighted magnetic resonance ratio images

Although diffusion tensor imaging (DTI) have revealed brain abnormalities in bipolar disorder (BD) subjects, DTI methods might not detect disease-related abnormalities in the white matter (WM) where nerve fibers are crossing. We investigated BD myelin-related abnormal brain regions in both gray matter and WM for 29 BD and 33 healthy control (HC) participants using T1-weighted (T1w)/T2-weighted (T2w) ratio images that increase myelin-related contrast irrespective of nerve fiber orientation. To check effect of the brain volume, the results were compared with those of voxel-based morphometry (VBM). We found significantly lower T1w/T2w signal intensity in broad WM regions in BD subjects, including the corpus callosum, corona radiata, internal capsule, middle cerebellar peduncle and cerebellum. Regional volume reduction was found in the WM bilateral posterior thalami and retrolenticular part of the internal capsules of BD subjects. We also performed tract-based spatial statistics (TBSS) in 25 BD and 24 HC participants and compared those for the T1w/T2w ratio images. Both methods detected the BD corpus callosum abnormality. Further, the ratio images detected the corona radiata and the cerebellar abnormality in BD. These results suggest that T1w/T2w ratio image analysis could take a complementary role with the DTI method in elucidating myelin-related abnormalities in BD.

Prenatal Diagnosis of Rhombencephalosynapsis

AbstractRhombencephalosynapsis (RS) is a rare and sporadic cerebellar malformation characterized by agenesis of cerebellar vermis, fusion of the cerebellar hemispheres, dentate nuclei, and superior cerebellar peduncles. In majority of cases, RS is associated with wide range of cerebral malformations (dysgenesis or agensis of corpus callosum (ACC) and anterior commissurae, fusion of the inferior colliculi, cerebral peduncles, or thalami and hydrocephalus). A third gravida with 32 weeks of pregnancy was evaluated for hydrocephalus. The fetus had teardrop lateral ventricles, colpocephaly, upward displacement of third ventricle with abnormal posterior fossa, and an abnormal cerebellum formed by partly fused cerebellum in a single block with no individualization of the vermian structure suggestive of complete ACC with RS. Fetal MRI showed teardrop lateral ventricles, upward displacement of the third ventricle and colpocephaly partially fused cerebellar hemispheres, and no visualization of separate and distinct vermis with suspected fused superior cerebellar peduncles corroborating the ultrasound findings of complete ACC and partial RS. The baby had a very difficult postnatal course and succumbed on postnatal day 4. Prenatal diagnosis of RS and ACC is of utmost importance for prenatal counseling, as these abnormalities are uncorrectable and in most of the cases carries poor prognosis.

P218 Cerebellar involvement in facial emotion discrimination: A TMS study

The contribution of cerebellum to affective processing has been neglected for a long time. Recently, an increasing number of studies on both healthy participants and patients with cerebellar abnormalities pointed to a possible role of the cerebellum in the emotions regulation and perception. In this study, we aimed to investigate the involvement of the cerebellum in emotion discrimination by means of transcranial magnetic stimulation (TMS). We presented participants with pairs of faces with different emotional expressions (happy or angry) and we asked them to indicate whether the two faces showed the same or a different emotion. Triple-pulse TMS (20 Hz) was delivered between the first and the second face presentation over the left cerebellum, the primary visual cortex and the vertex (control site). Analyses suggest that cerebellar TMS impaired participants’ performance in emotion discrimination, in line with previous evidence on the link between cerebellum and emotional processing.

Superior Cerebellar Peduncle Atrophy Predicts Cognitive Impairment in Relapsing Remitting Multiple Sclerosis Patients with Cerebellar Symptoms: A DTI Study

Background: Using Diffusion Tensor Imaging (DTI), we tested the hypothesis that cerebellar abnormalities in fractional anisotropy (FA) may be involved in cognitive dysfunctions in Relapsing-Remitting (RR)-Multiple Sclerosis (MS). Objective: The aim of our study was to investigate the microstructural integrity in MS of regions that connect in both feedforward and feedback pathways to cortical areas, i.e., Superior Cerebellar Peduncles (SCP), Middle Cerebellar Peduncles (MCP), Dentate nuclei (DN) and Thalamus (Th). Patients and methods: We studied 46 patients with RR-MS (21 with cerebellar signs and 25 without) and 23 normal subjects. All subjects underwent cognitive testing. Results: In patients with a cerebellar phenotype, cognitive performance in all considered domains was from moderately to strongly related (p<0.05) to abnormalities of SCP (r=0.119 to 0.735) and Thalamus (r=0.477 to 0.602). Discussion: Our study showed an important correlation between cognitive testing and FA values of SCP and thalamus in cerebellar MS patients. We found not only the involvement of thalamus but also of SCP that is an important link between cerebellar nuclei and thalamus, suggesting that a disconnection is present also out of the thalamus. These results suggest that SCP and thalamic damage is a clinically relevant biomarker of the neurodegenerative cerebellar process in MS.

Lissencephaly and nephrotic syndrome: Galloway-Mowat syndrome

The Galloway-Mowat syndrome (GMS) is a rare autosomal recessive disorder which is characterized by the presence of renal and brain abnormalities. Hiatal hernia, initially thought to be a part, is longer a consistent feature of syndrome. The neurological features include microcephaly, developmental delay, seizures, hypotonia, abnormal sulci and gyri, and abnormal cerebellum. The renal finding is that of nephrotic syndrome, but histopathologically may vary to focal segmental sclerosis or mesangial sclerosis. Nephrotic syndrome is usually diagnosed before the age of 2 years and may lead to renal failure. We describe a 29-week preterm baby of unrelated parents with intrauterine growth retardation, dysmorphic features, lissencephaly, and nephrotic syndrome. Nephrotic syndrome was diagnosed at the age of 2 months. The baby had progressive neurological deterioration and died at the age of 14 weeks.