Cerebellar Changes Research Articles

Thalamic and Cerebellar Regional Involvement across the ALS-FTD Spectrum and the Effect of C9orf72.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of the same disease spectrum. While thalamic–cerebellar degeneration has been observed in C9orf72 expansion carriers, the exact subregions involved across the clinical phenotypes of the ALS–FTD spectrum remain unclear. Using MRIs from 58 bvFTD, 41 ALS–FTD and 52 ALS patients compared to 57 controls, we aimed to delineate thalamic and cerebellar subregional changes across the ALS–FTD spectrum and to contrast these profiles between cases with and without C9orf72 expansions. Thalamic involvement was evident across all ALS–FTD clinical phenotypes, with the laterodorsal nucleus commonly affected across all groups (values below the 2.5th control percentile). The mediodorsal nucleus was disproportionately affected in bvFTD and ALS–FTD but not in ALS. Cerebellar changes were only observed in bvFTD and ALS–FTD predominantly in the superior–posterior region. Comparison of genetic versus sporadic cases revealed significantly lower volumes exclusively in the pulvinar in C9orf72 expansion carriers compared to non-carriers, irrespective of clinical syndrome. Overall, bvFTD showed significant correlations between thalamic subregions, level of cognitive dysfunction and severity of behavioural symptoms. Notably, strong associations were evident between mediodorsal nucleus atrophy and severity of behavioural changes in C9orf72-bvFTD (r = −0.9, p < 0.0005). Our findings reveal distinct thalamic and cerebellar atrophy profiles across the ALS–FTD spectrum, with differential impacts on behaviour and cognition, and point to a unique contribution of C9orf72 expansions in the clinical profiles of these patients.

A Standardized Pipeline for Examining Human Cerebellar Grey Matter Morphometry using Structural Magnetic Resonance Imaging.

Multiple lines of research provide compelling evidence for a role of the cerebellum in a wide array of cognitive and affective functions, going far beyond its historical association with motor control. Structural and functional neuroimaging studies have further refined understanding of the functional neuroanatomy of the cerebellum beyond its anatomical divisions, highlighting the need for the examination of individual cerebellar subunits in healthy variability and neurological diseases. This paper presents a standardized pipeline for examining cerebellum grey matter morphometry that combines high-resolution, state-of-the-art approaches for optimized and automated cerebellum parcellation (Automatic Cerebellum Anatomical Parcellation using U-Net Locally Constrained Optimization; ACAPULCO) and voxel-based registration of the cerebellum (Spatially Unbiased Infra-tentorial Template; SUIT) for volumetric quantification. The pipeline has broad applicability to a range of neurological diseases and is fully automated, with manual intervention only required for quality control of the outputs. The pipeline is freely available, with substantial accompanying documentation, and can be run on Mac, Windows, and Linux operating systems. The pipeline is applied in a cohort of individuals with Friedreich ataxia (FRDA), and representative results, as well as recommendations on group-level inferential statistical analyses, are provided. This pipeline could facilitate reliability and reproducibility across the field, ultimately providing a powerful methodological approach for characterizing and tracking cerebellar structural changes in neurological diseases.

Cerebellar integrity and contributions to cognition in C9orf72-mediated frontotemporal dementia

BackgroundThe GGGGCC hexanucleotide repeat expansion in the non-coding region of the chromosome 9 open reading frame 72 gene (C9orf72) is the most common genetic cause of familial frontotemporal dementia (FTD). This study aims to clarify the patterns of cerebellar atrophy in FTD patients with and without a C9orf72 repeat expansion compared with healthy controls and determine whether associations between cerebellar atrophy and cognition differ between patient groups. MethodsThirty C9orf72 repeat expansion-positive FTD patients, 30 C9orf72 repeat expansion-negative FTD patients, and 30 age-, sex-, and education-matched healthy controls underwent brain MRI and cognitive assessments. Patient groups were matched for clinical diagnosis, disease duration, general cognition, and disease severity. ResultsCompared with controls, the C9orf72 positive group showed cerebellar changes bilaterally involving the lobules V, VI, Crus I, Crus II, VIIb, VIIIa, left VIIIb, and right lobules I–IV. All these changes were localised within the regions affected in the C9orf72 negative group. No significant differences were found between patient groups. Correlation analyses with a liberal threshold found the cerebellar integrity to be associated with attention, language, and executive function in the C9orf72 positive group. In the C9orf72 negative group, these associations included attention, working memory, language, episodic memory, and executive function. ConclusionsThis study clarifies the impact of C9orf72 repeat expansion on cerebellar integrity in FTD. The findings reveal overlapping patterns of cerebellar atrophy in C9orf72 positive and negative groups. The associations with cognitive functions suggest that the type of pathology linked with cerebellar atrophy is another relevant variable to consider in future studies.

Aging influence on pulmonary and systemic inflammation and neural metabolomics arising from pulmonary multi-walled carbon nanotube exposure in apolipoprotein E-deficient and C57BL/6 female mice

Objective Environmental exposures exacerbate age-related pathologies, such as cardiovascular and neurodegenerative diseases. Nanoparticulates, and specifically carbon nanomaterials, are a fast-growing contributor to the category of inhalable pollutants, whose risks to health are only now being unraveled. The current study assessed the exacerbating effect of age on multiwalled-carbon nanotube (MWCNT) exposure in young and old C57BL/6 and ApoE−/− mice. Materials and methods Female C57BL/6 and apolipoprotein E-deficient (ApoE−/−) mice, aged 8 weeks and 15 months, were exposed to 0 or 40 µg MWCNT via oropharyngeal aspiration. Pulmonary inflammation, inflammatory bioactivity of serum, and neurometabolic changes were assessed at 24 h post-exposure. Results Pulmonary neutrophil infiltration was induced by MWCNT in bronchoalveolar lavage fluid in both C57BL/6 and ApoE−/−. Macrophage counts decreased with MWCNT exposure in ApoE−/− mice but were unaffected by exposure in C57BL/6 mice. Older mice appeared to have greater MWCNT-induced total protein in lavage fluid. BALF cytokines and chemokines were elevated with MWCNT exposure, but CCL2, CXCL1, and CXCL10 showed reduced responses to MWCNT in older mice. However, no significant serum inflammatory bioactivity was detected. Cerebellar metabolic changes in response to MWCNT were modest, but age and strain significantly influenced metabolite profiles assessed. ApoE−/− mice and older mice exhibited less robust metabolite changes in response to exposure, suggesting a reduced health reserve. Conclusions Age influences the pulmonary and neurological responses to short-term MWCNT exposure. However, with only the model of moderate aging (15 months) in this study, the responses appeared modest compared to inhaled toxicant impacts in more advanced aging models.

A Sweet Imbalance: Reversible Middle Cerebellar Peduncle Signal Change in Hypoglycaemic Encephalopathy.

A Sweet Imbalance: Reversible Middle Cerebellar Peduncle Signal Change in Hypoglycaemic Encephalopathy.

Quantitative evaluation of the cerebellum in patients with depression and healthy adults by VolBrain method

Objectives: Besides the well-known sensorimotor control function, the cerebellum is also associated with cognitive functions and mood via the cerebral-cerebellar circuit. This study aimed to investigate possible cerebellar morphometric changes in untreated patients with depression. Methods: Brain magnetic resonance (MR) images of 40 adults (age: 18–50 years), including 20 untreated depression patients and 20 healthy controls were analysed prospectively. Intracranial cavity and total cerebellar volumes were measured by using VolBrain. The cerebellum segmentation was performed with CERES to obtain the total gray matter volumes and cortical thickness of the lobules. Results: Total cerebellar volume was 141.27±13.12 cm3 in the depressed group and 142.63±8.01 cm3 in the control group (p&gt;0.05). The difference between males and females in the depressed group was not statistically significant (p&gt;0.05). Total cerebellar volume was approximately 11% of total intracranial volume in both groups. The cortical thickness of lobule V (right-total), lobule VIIIB (right), and lobule IX (right) was smaller in the depressed group, independent of sex (p&lt;0.05). Lobule V, VIIIB and IX volume was smaller and Crus-I cortical thickness was increased in depressed females (p&lt;0.05). Conclusion: The cerebellar volume and cortical thickness of cerebellar lobules in patients with depression show significant differences compared to healthy subjects.

Delineating the Relationships Between Motor, Cognitive-Executive and Psychiatric Symptoms in Female FMR1 Premutation Carriers.

Introduction: Premutation expansions (55–200 CGG repeats) of the Fragile X Mental Retardation 1 (FMR1) gene on the X chromosome are associated with a range of clinical features. Apart from the most severe - Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) - where the most typical white matter changes affect cerebellar peduncles, more subtle changes may include impairment of executive functioning, affective disorders and/or subtle motor changes. Here we aimed to examine whether performance in selected components of executive functioning is associated with subclinical psychiatric symptoms in non-FXTAS, adult females carrying the FMR1 premutation.Methods and Sample: A total of 47 female premutation carriers (sub-symptomatic for FXTAS) of wide age range (26–77 years; M = 50.3; SD = 10.9) were assessed using standard neuropsychological tests, three motor rating scales and self-reported measures of psychiatric symptoms using the Symptom Checklist-90-Revised (SCL-90-R).Results: After adjusting for age and educational level where appropriate, both non-verbal reasoning and response inhibition as assessed on the Stroop task (i.e., the ability to resolve cognitive interference) were associated with a range of primary psychiatric symptom dimensions, and response inhibition uniquely predicted some primary symptoms and global psychiatric features. Importantly, lower scores (worse performance) in response inhibition were also strongly correlated with higher (worse) scores on standard motor rating scales for tremor-ataxia and for parkinsonism.Conclusion: These results provide evidence for the importance of response inhibition in the manifestation of psychiatric symptoms and subtle tremor-ataxia motor features, suggestive of the presence of early cerebellar changes in female premutation carriers.

The behavioral variant of frontotemporal dementia: Linking cerebellar MRI alterations to behavioral and affective symptoms

Frontotemporal dementias (FTDs) are progressive neurodegenerative disorders associated with grey matter (GM) loss in frontal and temporal brain regions (Rascovsky et al., 2011) and presenting with marked behavioral symptoms and/or language deficits. The Behavioral variant of FTD (bvFTD) is clinically characterized by insidious changes in personality, interpersonal conduct and emotion processing (Piguet, et al. 2017). Considering its role in higher-level functions (Schmahmann & Sherman, 1998) the cerebellum was recently proposed to be implicated in FTD pathophysiology (Yu Chen et al.,2019) although its specific contribution to bvFTD symptoms still needs to be clarified. Aim of the present study was to assess cerebellar GM changes in patients with bvFTD and their potential association with affective symptoms.

The Cerebellum in Drug-naive Children with Tourette Syndrome and Obsessive–Compulsive Disorder

Tourette syndrome (TS) and obsessive–compulsive disorder (OCD) are two neurodevelopmental disorders characterized by repetitive behaviors. Our recent study in drug-naive children with TS and OCD provided evidence of cerebellar involvement in both disorders. In addition, cerebellar functional connectivity (FC) was similar in TS patients without comorbidities (TSpure) and TS patients with OCD comorbidity (TS + OCD), but differed in pure OCD patients. To investigate in detail the cerebellar involvement in the pathophysiology of TS and OCD, we explored cerebellar structural and functional abnormalities in drug-naive children with TSpure, TS + OCD, and OCD and assessed possible correlations with severity scores. We examined 53 drug-naive children, classified as TSpure (n = 16), TS + OCD (n = 14), OCD (n = 11), or controls (n = 12). All subjects underwent a multimodal 3T magnetic resonance imaging examination. Cerebellar lobular volumes and quantitative diffusion tensor imaging parameters of cerebellar peduncles were used as measures of structural integrity. The dentate nucleus was selected as a region of interest to examine cerebello-cerebral functional connectivity alterations. Structural analysis revealed that both TSpure and TS + OCD patients had higher fractional anisotropy in cerebellar peduncles than controls. Conversely, OCD patients were characterized by lower fractional anisotropy than both controls and TSpure and TS + OCD patients. Lastly, cerebellar functional connectivity analysis revealed significant alterations in the cerebello-thalamo-cortical circuit in TSpure, TS + OCD, and OCD patients. Early cerebellar structural and functional changes in drug-naive pediatric TSpure, TS + OCD, and OCD patients support a primary role of the cerebellum in the pathophysiology of these disorders.

Intermittent Fasting Attenuates High-Fat Diet-Induced Cerebellar Changes in Rats: Involvement of TNF-α, Autophagy, and Oxidative Stress

Obesity has become a prevalent global health issue, and recently it has been reported to be intimately associated with neuronal health. Obesity triggers peripheral inflammatory responses concomitant with neuroinflammation, elevated oxidative stress, and compromised autophagy. Intermittent fasting (IF) positively influences lowering body weight and improving the metabolic changes accompanying obesity. IF also has a beneficial impact on neuronal function; however, no studies have discussed this effect on high-fat diet (HFD)-induced cerebellar damage. This study examines the effect of IF on the cerebellum of HFD-fed rats. Male Wister Albino rats (n = 16) were fed HFD for 16 weeks (HFD group); half of them were subjected to IF alternating with HFD for 6 weeks starting at the 11th week till the end of the experiment (fasting + HFD group). The control group of rats (n = 8) was kept on a basal diet. The animals were euthanized after 16 weeks. Their tissue was harvested and processed for morphology using H&E, cresyl violet, and luxol fast stains, and immunohistochemical staining was carried out for inflammatory marker (TNF-α), gliosis marker (GFAP), and autophagy markers (LC3 II and P62). Oxidative stress markers (SOD, MDA) were measured, and protein expression of phosphorylated-AMP-activated protein kinase (p-AMPK) and phosphorylated-rapamycin complex (p-mTOR) in cerebellar tissue was detected via western blotting. IF mitigated HFD-induced cerebellar morphological changes, reduced cerebellar TNF-α expression, decreased oxidative stress markers, and balanced p-AMPK and p-mTOR with autophagy improvement. Moreover, a decrease in body weight and ameliorated obesity-induced metabolic changes in the serum levels of glucose, insulin, cholesterol, and triglyceride were seen. These observations suggest that IF can improve both peripheral and central changes prompted by HFD through attenuating inflammation, oxidative stress, and reestablishing the autophagy balance.

Evaluating the Effects of Aloe vera Gel on Cerebellum Histomorphometrical Changes in Diabetic Male Rats

Background: Diabetes mellitus can lead to histomorphometrical changes in the brain. Recent studies have shown that Aloe vera gel has antioxidant and neuroprotective effects, which is independent of glucose-lowering effects. Objectives: The present study aimed to investigate the effects of A. vera gel on histomorphometrical changes of cerebellum following streptozotocin (STZ)-induced diabetic male rats. Methods: A total of 25 male Wistar rats were randomly allocated into five groups as follows: (1) the control group received normal saline; (2) A. vera gel group; (3) diabetic group; (4) treatment group diabetic rats, which received A. vera; and (5) diabetic rats which received insulin. A single dose of STZ [60 mg/kg; intraperitoneal (IP)] was used for the induction of diabetes in rats. All the treatments were administered daily for eight weeks. Subsequently, histomorphometrical changes were evaluated in the cerebellum of the rats. Results: The results showed that the number of granular and purkinje cells reduced in the cerebellum granulosa region, while the number of glial cells increased in the molecular region of the cerebellum in diabetic rats compared to the control group (P &lt; 0.05). These changes were improved in treated rats by insulin or A. vera. Also, the thickness of molecular, purkinje, granular, and white matter layers at the apex of lobules and depth of sulcus in the diabetic group had a significant reduction compared to other groups (P &lt; 0.001). Conclusions: Our results confirmed that improvement of the cerebellar tissue changes in diabetic rats following the use of A. vera gel is comparable to insulin. However, more investigations are required to determine the protective effects of A. vera gel against diabetes-induced cerebellum histomorphometrical changes.

Apoptosis is involved in paraoxon-induced histological changes in rat cerebellum

Acute toxicity of organophosphorus compounds is primarily caused by inhibition of acetylcholinesterase (AChE) at cholinergic synapses. The current study was designed to investigate the effects of paraoxon on histological changes as well as the role of mitochondrion-dependent apoptosis in causing this damage in the rat cerebellum. Adult male Wistar rats were intraperitoneally injected with paraoxon at 0.3, 0.7, or 1 mg/kg. Control animals were injected with corn oil as a vehicle. At 14 or 28 days after intoxication, histological changes and alterations in the expression of apoptosis-related proteins, including Bax, Bcl-2, and caspase-3, were investigated in the cerebellum using cresyl violet staining and western blotting, respectively. Findings showed the decreased thickness of both molecular and granular layers and reduction in the number of Purkinje cells in animals treated with a higher convulsive dose of paraoxon (1 mg/kg). In addition, exposure of rats to 1 mg/kg of paraoxon activated apoptosis pathway confirmed by an increase in Bax and caspase-3 and a decrease in Bcl-2 protein levels. According to our results, cerebellar histological changes and alterations in the expression of apoptosis-related proteins occur following exposure to a high convulsive dose of paraoxon and persist for a long time.

Is there a relationship between fall status, cognition and cerebellar lobule volume in patients with multiple sclerosis?

In this prospective case control study, relationship of detailed cerebellar volumetric data and cognition in patients with multiple sclerosis considering falling status using 3 D MRI and network analysis were evaluated. Participants consist of 106 adults with relapsing-remitting multiple sclerosis. Scores of Montreal cognitive assessment test, symbol digit modality Test, nine-hole peg test, berg balance scale test, timed up and go test, timed 25-foot walk test were worse in faller group than non faller group (p < 0.05 for all tests). There was no significant difference in terms of cerebellar lobule volumes between groups. But using artificial intelligence (AI) based network analysis, we brought a new perspective to interpreting the relationship between the cerebellum, cognition, gait, and balance. Overall, data from the study suggest a possible relationship between cerebellar volume changes and cognitive dysfunction through connectivity analysis in patients with multiple sclerosis. Further studies are needed to examine this issue by using connectivity analysis.

Cerebellar involvement in hallucinations may transcend clinical conditions and perceptual modalities

Our recent neuroimaging study identified structural differences in cerebellar subfields linked to cortical attentional networks in patients with eye disease or Parkinson’s disease who experience visual hallucinations and a commentary on the study by Zorzi et al. provided additional evidence of functional cerebellar changes in Dementia with Lewy bodies. Here, we review evidence for cerebellar involvement in hallucinations across multiple clinical conditions and sensory modalities as well as examine its wider clinical and mechanistic implications. The combined structural and functional evidence is consistent with two models of cerebellar contribution to hallucination which differ in their implied direction of cause, effect and temporal sequence. Additionally, we contend that the relatively neuroanatomically localised nature of the cerebellum makes it particularly suited to identifying changes affecting distributed cortical networks using imaging techniques. As such, cerebellar subfield differences may offer value as candidate prognostic and predictive biomarkers as well as targets for neuromodulatory treatment across a range of clinical conditions.

MRI findings in a young dog with gliomatosis cerebri.

A 3-year-old male entire boxer presented with a 3-week history of lethargy, hyporexia, hypersalivation, low-head carriage, pelvic limb tremors and intermittent vestibular ataxia. Neurological examination revealed kyphosis, wide-based stance, an alternating head tilt, left leaning, bilateral positional ventral strabismus and intermittent vertical nystagmus. Exacerbation of neurological signs and increased extensor tone in all limbs were noticed after dorsal extension of the neck. Neuroanatomical localisation was cerebellum and/or brainstem. Haematology, biochemistry and blood pressure were within normal limits. Serology for common infectious diseases was negative. MRI demonstrated non-enhancing mild T2W and FLAIR hyperintensity and swelling of the whole cerebellum with more marked hyperintensity on the ventrolateral left hemisphere/flocculus (Fig. 1A,B,C). Increased intracranial pressure was suspected based on rostral transtentorial and foramen magnum herniation, cervical syringomyelia and lateral ventricular dilation, and therefore cerebrospinal fluid was not collected. Thoracic and abdominal CT was unremarkable. Differential diagnoses included inflammation (meningoencephalitis of unknown origin [MUO]), protozoal cerebellitis) or neoplasia (glioma/gliomatosis cerebri, lymphoma). MUO was considered likely; immunosuppressive prednisolone and mycophenolate and prophylactic clindamycin were started. After mild improvement, signs were static for 5 months. Mycophenolate was discontinued at 3 months due to gastrointestinal signs; owner declined another chemotherapeutic and prednisolone was continued. Two months later, the dog deteriorated (intention tremors, ataxia, intermittent collapses), with cerebellar changes being static on repeat MRI (Fig. 1D,E,F). Intravenous cytarabine was tried without response. Owners elected euthanasia. Histopathology revealed a disseminated proliferation of presumed glial origin infiltrating the subpial region, molecular layer, nuclei and white matter of the cerebellum bilaterally, the cerebrum, medulla, midbrain, hippocampus and medial geniculate bodies, consistent with gliomatosis cerebri (type 1). This case demonstrates a rare pattern of gliomatosis cerebri predominantly affecting the cerebellum. There was little progression in the imaging changes over a 5-month period, with clinical stability upon treatment.

Exploring the relationship between white matter integrity, cocaine use and GAD polymorphisms using Bayesian Model Averaging.

Past investigations utilizing diffusion tensor imaging (DTI) have demonstrated that cocaine use disorder (CUD) yields white matter changes, primarily in the corpus callosum. By applying Bayesian model averaging using multiple linear regression in DTI, we demonstrate there may exist relationships between the impaired white matter and glutamic acid decarboxylase (GAD) polymorphisms. This work explored the two-way and three-way interactions between GAD1a (SNP: rs1978340) and GAD1b (SNP: rs769390) polymorphisms and years of cocaine use (YCU). GAD1a was associated with more frontal white matter changes on its own but GAD1b was associated with more midbrain and cerebellar changes as well as a greater increase in white matter changes in the context of chronic cocaine use. The three-way interaction GAD1a|GAD1b|YCU appeared to be roughly an average of the polymorphism two-way interactions GAD1a|YCU and GAD1b|YCU. The three-way interaction demonstrated multiple regions including corpus callosum which featured fewer significant voxel changes, perhaps suggesting a small protective effect of having both polymorphisms on corpus callosum and cerebellar peduncle.

White Matter Microstructural Properties of the Cerebellar Peduncles Predict Change in Symptoms of Psychopathology in Adolescent Girls.

Internalizing symptoms typically emerge in adolescence and are more prevalent in females than in males; in contrast, externalizing symptoms typically emerge in childhood and are more commonly observed in males. Previous research has implicated aspects of white matter organization, including fractional anisotropy (FA), of cerebral tracts in both internalizing and externalizing symptoms. Although the cerebellum has been posited to integrate limbic and cortical regions, its role in psychopathology is not well understood. In this longitudinal study, we investigated whether FA of the superior (SCP), middle (MCP), and inferior cerebellar peduncles (ICP) predict change in symptoms and whether sex moderates this association. One hundred eleven adolescents completed the Youth Self-Report, assessing symptoms at baseline (ages 9-13years) and again 2years later. Participants also underwent diffusion-weighted imaging at baseline. We used deterministic tractography to segment and compute mean FA of the cerebellar peduncles. Lower FA of the right SCP at baseline predicted increases in internalizing symptoms in females only. Lower FA in the right SCP and ICP also predicted increases in externalizing symptoms in females, but these associations did not survive multiple comparison correction. There was no association between FA of the cerebellar peduncles and change in symptoms in males or between MCP FA and symptom changes in males or females. Organizational properties of the SCP may be a sex-specific marker of internalizing symptom changes in adolescence. The cerebellar peduncles should be explored further in future studies to elucidate sex differences in symptoms.

Longitudinal Evaluation of Cerebellar Signs of H-ABC Tubulinopathy in a Patient and in the taiep Model.

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a central neurodegenerative disease due to mutations in the tubulin beta-4A (TUBB4A) gene, characterized by motor development delay, abnormal movements, ataxia, spasticity, dysarthria, and cognitive deficits. Diagnosis is made by integrating clinical data and radiological signs. Differences in MRIs have been reported in patients that carry the same mutation; however, a quantitative study has not been performed so far. Our study aimed to provide a longitudinal analysis of the changes in the cerebellum (Cb), corpus callosum (CC), ventricular system, and striatum in a patient suffering from H-ABC and in the taiep rat. We correlated the MRI signs of the patient with the results of immunofluorescence, gait analysis, segmentation of cerebellum, CC, and ventricular system, performed in the taiep rat. We found that cerebellar and callosal changes, suggesting a potential hypomyelination, worsened with age, in concomitance with the emergence of ataxic gait. We also observed a progressive lateral ventriculomegaly in both patient and taiep, possibly secondary to the atrophy of the white matter. These white matter changes are progressive and can be involved in the clinical deterioration. Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) gives rise to a spectrum of clinical signs whose pathophysiology still needs to be understood.

Genotype-associated cerebellar profiles in ALS: focal cerebellar pathology and cerebro-cerebellar connectivity alterations

ObjectiveCerebellar disease burden and cerebro-cerebellar connectivity alterations are poorly characterised in amyotrophic lateral sclerosis (ALS) despite the likely contribution of cerebellar pathology to the clinical heterogeneity of the condition.MethodsA prospective...

Relationships between motor scores and cognitive functioning in FMR1 female premutation X carriers indicate early involvement of cerebello-cerebral pathways

BackgroundSmaller expansions of CGG trinucleotide repeats in the FMR1 X-linked gene termed ‘premutation’ lead to a neurodegenerative disorder: Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) in nearly half of aged carrier males, and 8–16% females. Core features include intention tremor, ataxia, and cognitive decline, and white matter lesions especially in cerebellar and periventricular locations. A ‘toxic’ role of elevated and expanded FMR1 mRNA has been linked to the pathogenesis of this disorder. The emerging issue concerns the trajectory of the neurodegenerative changes: is the pathogenetic effect confined to overt clinical manifestations? Here we explore the relationships between motor and cognitive scale scores in a sample of 57 asymptomatic adult female premutation carriers of broad age range.MethodsThree motor scale scores (ICARS-for tremor/ataxia, UPDRS-for parkinsonism, and Clinical Tremor) were related to 11 cognitive tests using Spearman’s rank correlations. Robust regression, applied in relationships between all phenotypic measures, and genetic molecular and demographic data, identified age and educational levels as common correlates of these measures, which were then incorporated as confounders in correlation analysis.ResultsCognitive tests demonstrating significant correlations with motor scores were those assessing non-verbal reasoning on Matrix Reasoning (p-values from 0.006 to 0.011), and sequencing and alteration on Trails-B (p-values from 0.008 to 0.001). Those showing significant correlations with two motor scores-ICARS and Clinical Tremor- were psychomotor speed on Symbol Digit Modalities (p-values from 0.014 to 0.02) and working memory on Digit Span Backwards (p-values from 0.024 to 0.011).ConclusionsSubtle motor impairments correlating with cognitive, particularly executive, deficits may occur in female premutation carriers not meeting diagnostic criteria for FXTAS. This pattern of cognitive deficits is consistent with those seen in other cerebellar disorders. Our results provide evidence that more than one category of clinical manifestation reflecting cerebellar changes – motor and cognitive - may be simultaneously affected by premutation carriage across a broad age range in asymptomatic carriers.