Cerebellar Brain Inhibition Is Associated With the Severity of Cervical Dystonia.

PURPOSE: Cerebellar connectivity is thought to be abnormal in cervical dystonia (CD) and other dystonia subtypes, based on evidence from imaging studies and animal work. The authors investigated whether transcranial magnetic stimulation-induced cerebellar brain inhibition (CBI), a measure of cerebellar efficiency at inhibiting motor outflow, is abnormal in patients with CD and/or is associated with clinical features of CD. Because of methodological heterogeneity in CBI reporting, the authors deployed additional controls to reduce potential sources of variability in this study. METHODS: Cerebellar brain inhibition was applied in 20 CD patients and 14 healthy control subjects. Cerebellar brain inhibition consisted of a cerebellar conditioning stimulus delivered at four different interstimulus intervals (ISIs) before a test stimulus delivered to hand muscle representation in the motor cortex. The average ratio of conditioned to unconditioned motor evoked potential was computed for each ISI. Cervical dystonia clinical severity was measured using the Toronto Western Spasmodic Torticollis Rating Scale. Control experiments involved neuronavigated transcranial magnetic stimulation, neck postural control in patients, and careful screening for noncerebellar pathway inhibition via cervicomedullary evoked potentials. RESULTS: There was no difference between CBI measured in healthy control subjects and CD patients at any of the four ISIs; however, CBI efficiency was significantly correlated with worsening CD clinical severity at the 5 ms ISI. CONCLUSIONS: Cerebellar brain inhibition is a variable measure in both healthy control subjects and CD patients; much of this variability may be attributed to experimental methodology. Yet, CD severity is significantly associated with reduced CBI at the 5 ms ISI, suggestive of cerebello-thalamo-cortical tract dysfunction in this disorder.

Case Report: Biallelic Loss of Function ATM due to Pathogenic Synonymous and Novel Deep Intronic Variant c.1803-270T > G Identified by Genome Sequencing in a Child With Ataxia-Telangiectasia.

Ataxia-telangiectasia (AT) is a complex neurodegenerative disease with an increased risk for bone marrow failure and malignancy. AT is caused by biallelic loss of function variants in ATM, which encodes a phosphatidylinositol 3-kinase that responds to DNA damage. Herein, we report a child with progressive ataxia, chorea, and genome instability, highly suggestive of AT. The clinical ataxia gene panel identified a maternal heterozygous synonymous variant (NM_000051.3: c.2250G > A), previously described to result in exon 14 skipping. Subsequently, trio genome sequencing led to the identification of a novel deep intronic variant [NG_009830.1(NM_000051.3): c.1803-270T > G] inherited from the father. Transcript analyses revealed that c.1803-270T > G results in aberrant inclusion of 56 base pairs of intron 11. In silico tests predicted a premature stop codon as a consequence, suggesting non-functional ATM; and DNA repair analyses confirmed functional loss of ATM. Our findings highlight the power of genome sequencing, considering deep intronic variants in undiagnosed rare disease patients.

Microstructural Abnormalities of the Dentatorubrothalamic Tract in Cervical Dystonia.

BACKGROUND: The dentatorubrothalamic tract (DRTT) remains understudied in idiopathic cervical dystonia (CD), despite evidence that the pathway is relevant in the pathophysiology of the disorder. OBJECTIVE: The aim of this study was to examine the DRTT in patients with CD using diffusion tensor imaging (DTI)-based tractography. METHODS: Magnetic resonance imaging scans from 67 participants were collected to calculate diffusion tractography metrics using a binary tractography-based DRTT template. Fractional anisotropy and diffusivity measures of left and right DRTT were computed and compared between 32 subjects with CD and 35 age-matched healthy volunteers. RESULTS: Fractional anisotropy of right DRTT and mean and axial diffusivity of left DRTT were significantly reduced in patients with CD. Similar abnormalities were observed in patients with focal CD and patients with CD without tremor. DTI metrics did not correlate with disease duration or severity. CONCLUSIONS: Significant reductions in DTI measures suggest microstructural abnormalities within the DRTT in CD, characterized by a tractography pattern consistent with decreased axonal integrity. © 2021 International Parkinson and Movement Disorder Society.

Myoclonus and cerebellar ataxia associated with COVID-19: a case report and systematic review.

BACKGROUND: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic in December 2019, neurological manifestations have been recognized as potential complications. Relatively rare movement disorders associated with COVID-19 are increasingly reported in case reports or case series. Here, we present a case and systematic review of myoclonus and cerebellar ataxia associated with COVID-19. METHODS: A systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline using the PubMed and Ovid MEDLINE databases, from November 1, 2019 to December 6, 2020. RESULTS: 51 cases of myoclonus or ataxia associated with COVID-19, including our case, were identified from 32 publications. The mean age was 59.6 years, ranging from 26 to 88 years, and 21.6% were female. Myoclonus was multifocal or generalized and had an acute onset, usually within 1 month of COVID-19 symptoms. Myoclonus occurred in isolation (46.7%), or with ataxia (40.0%) or cognitive changes (30.0%). Most cases improved within 2 months, and treatment included anti-epileptic medications or immunotherapy. Ataxia had an acute onset, usually within 1 month of COVID-19 symptoms, but could be an initial symptom. Concurrent neurological symptoms included cognitive changes (45.5%), myoclonus (36.4%), or a Miller Fisher syndrome variant (21.2%). Most cases improved within 2 months, either spontaneously or with immunotherapy. CONCLUSIONS: This systematic review highlights myoclonus and ataxia as rare and treatable post-infectious or para-infectious, immune-mediated phenomena associated with COVID-19. The natural history is unknown and future investigation is needed to further characterize these movement disorders and COVID-19.

Patterns of brain activity during a set-shifting task linked to mild behavioral impairment in Parkinson's disease.

Mild behavioral impairment (MBI) is a neurobehavioral syndrome characterized by later life emergence of sustained neuropsychiatric symptoms, as an at-risk state for incident cognitive decline and dementia. Prior studies have reported that neuropsychiatric symptoms are associated with cognitive abilities in Parkinson's disease (PD) patients, and we have recently found a strong correlation between MBI and cognitive performance. However, the underlying neural activity patterns of cognitive performance linked to MBI in PD are unknown. Fifty-nine non-demented PD patients and 26 healthy controls were scanned using fMRI during performance of a modified version of the Wisconsin card sorting task. MBI was evaluated using the MBI-checklist, and PD patients were divided into two groups, PD-MBI and PD-noMBI. Compared to the PD-noMBI group and healthy controls, the PD-MBI group revealed less activation in the prefrontal and posterior parietal cortices, and reduced deactivation in the medial temporal region. These results suggest that in PD, MBI reflects deficits in the frontoparietal control network and the hippocampal memory system.

Association Between BDNF Val66Met Polymorphism and Mild Behavioral Impairment in Patients With Parkinson's Disease.

Neuropsychiatric symptoms (NPS) are common in Parkinson's disease (PD) and have demonstrated an association with the p. Val66Met, a polymorphism in the BDNF gene. Mild behavioral impairment (MBI) is a validated syndrome describing emergent and persistent NPS in older adults as a marker of potential cognitive decline and dementia. This study investigated if PD patients with the Met allele were more likely to have MBI and whether they had impairments in specific domains of MBI using the Mild Behavioral Impairment Checklist (MBI-C) as the MBI ascertainment tool. One hundred forty-six PD patients were screened for neuropsychiatric and cognitive impairments with the MBI-C and the Montreal Cognitive Assessment (MoCA). All participants were genotyped for the BDNF p.Val66Met single-nucleotide polymorphism (SNP) using TaqMan Genotyping Assay. Statistical analysis was performed using multiple linear and logistic regression models. Met carriers had a 2 times higher likelihood of being MBI positive (MBI-C total score ≥8) than Val carriers. Met carriers had significantly higher MBI-C total scores and significantly greater impairments in the mood/anxiety and the psychotic domains of MBI-C compared to Val carriers. These findings indicate that the BDNF Met allele is associated with a higher neuropsychiatric burden in PD.

Mild behavioral impairment is linked to worse cognition and brain atrophy in Parkinson disease.

OBJECTIVE: To evaluate the associations of mild behavioral impairment (MBI) with cognitive deficits and patterns of gray matter changes in Parkinson disease (PD). METHODS: Sixty patients with PD without dementia and 29 healthy controls underwent a cognitive neuropsychological evaluation and structural MRI scan. MBI was evaluated with the MBI Checklist (MBI-C), a rating scale designed to elicit emergent neuropsychiatric symptoms in accordance with MBI criteria. We divided the patients with PD into 2 groups: 1 group with high MBI-C scores (PD-MBI) and the other with low MBI-C scores (PD-noMBI). RESULTS: Among 60 patients with PD, 20 were categorized as having PD-MBI (33.33%). In healthy controls, no participants met the MBI cut-point threshold. The PD-MBI group had significantly lower Montreal Cognitive Assessment and z scores in all 5 domains and the global score compared to healthy controls and those with PD-noMBI. In addition, all cognitive domains except language and global cognition negatively correlated with the MBI-C total score in all patients with PD. For cortical structures, the PD-MBI group revealed middle temporal cortex thinning and decreased volume compared with the PD-noMBI group, and decreased volume in this area negatively correlated with the MBI-C total score. CONCLUSIONS: The impaired cognitive function over all domains and atrophy in the temporal area in the PD-MBI group are in line with posterior cortical circuit deficits in PD, which have been associated with a faster rate of progression to dementia. These initial results suggest that MBI might be an early and important marker for incident cognitive decline and dementia in patients with PD.

Zfp423/ZNF423 regulates cell cycle progression, the mode of cell division and the DNA-damage response in Purkinje neuron progenitors.

The Zfp423/ZNF423 gene encodes a 30-zinc-finger transcription factor involved in key developmental pathways. Although null Zfp423 mutants develop cerebellar malformations, the underlying mechanism remains unknown. ZNF423 mutations are associated with Joubert Syndrome, a ciliopathy causing cerebellar vermis hypoplasia and ataxia. ZNF423 participates in the DNA-damage response (DDR), raising questions regarding its role as a regulator of neural progenitor cell cycle progression in cerebellar development. To characterize in vivo the function of ZFP423 in neurogenesis, we analyzed allelic murine mutants in which distinct functional domains are deleted. One deletion impairs mitotic spindle orientation, leading to premature cell cycle exit and Purkinje cell (PC) progenitor pool deletion. The other deletion impairs PC differentiation. In both mutants, cell cycle progression is remarkably delayed and DDR markers are upregulated in cerebellar ventricular zone progenitors. Our in vivo evidence sheds light on the domain-specific roles played by ZFP423 in different aspects of PC progenitor development, and at the same time strengthens the emerging notion that an impaired DDR may be a key factor in the pathogenesis of JS and other ciliopathies.

Feasibility and Relevance of Antipsychotic Safety Monitoring in Children With Tourette Syndrome: A Prospective Longitudinal Study.

PURPOSE/BACKGROUND: Antipsychotics are efficacious for tics and are increasingly prescribed to children with behavioral disorders. Antipsychotics have important adverse effects, and systematic monitoring of drug safety is infrequently performed. The objectives of this study were to determine the feasibility of antipsychotic safety monitoring in children with Tourette Syndrome using a defined protocol and to evaluate the risk of adverse effects with chronic use. METHODS/PROCEDURES: A prospective longitudinal study of children prescribed antipsychotics was performed. Children were monitored for extrapyramidal, metabolic, and hormonal adverse effects using the Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotic Medications guidelines. This included the measurement of height, weight, waist circumference, the Extrapyramidal Symptom Rating Scale, and laboratory tests of lipids, glucose, insulin, and prolactin at prespecified time points. FINDINGS/RESULTS: Fifty-seven children who started on risperidone or aripiprazole were monitored for a mean of 10 months 3 days. Significant increases in body mass index (BMI) and waist circumference percentiles occurred with time. There was a significant time by drug interaction, with children on aripiprazole having smaller changes in BMI initially, followed by a faster rate of increase than with risperidone. There was a significant difference between Extrapyramidal Symptom Rating Scale scores on versus before starting antipsychotics and significant increases in insulin and prolactin. Change from a healthy to overweight or obese BMI percentile occurred in 26%. Extrapyramidal symptoms occurred in 35%. Medication was discontinued because of metabolic effects in 19%, and extrapyramidal symptoms in 7%. IMPLICATIONS/CONCLUSIONS: Monitoring of antipsychotic safety in children is feasible and recommended to inform treatment decisions.

The promise of futility trials in neurological diseases.

Double-blinded randomized controlled trials (RCTs) have contributed much important evidence to guide treatment decisions in neurology. RCTs are relatively straightforward to conduct, provided that they investigate common diseases, have clearly defined outcome measures, and are of short duration. In neurology, however, many diseases are uncommon, have no consensus outcome measures, and develop over decades. Basic research into neurological diseases continues to identify candidate therapies faster than they can be tested for their clinical utility, leading to a 'translational gap'. Futility trials were initially developed in oncology to efficiently test candidate therapies in phase II trials. As single-arm unblinded studies, futility trials are relatively easy to conduct, and they generally require smaller sample sizes than RCTs. In this article, we discuss futility models, highlighting their advantages as well as challenges to their application in several neurological diseases, including Parkinson disease, stroke and multiple sclerosis.

Neurologic complications of metronidazole.

Metronidazole (Flagyl®) is an antimicrobial agent commonly used in clinical practice. Although it is generally well tolerated with minimal side effects, there are a host of still under-recognized neurologic complications of metronidazole treatment. The following review is aimed at summarizing current literature pertaining to metronidazole-induced neurotoxicity including clinical syndromes, neuroradiological findings, prognosis and proposed pathophysiology. Recognition of the neurotoxic effects of metronidazole is critical as prompt discontinuation is generally associated with full clinical recovery and radiological resolution. Complications neurologiques du métronidazole. Le métronidazole (Flagyl®) est un agent antimicrobien utilisé couramment en pratique clinique. Bien qu'il soit généralement bien toléré et que ses effets secondaires soient minimes, il existe une myriade de complications neurologiques du traitement par le métronidazole qui ne sont pas toujours reconnues. Le but de cette revue constitue un sommaire de la littérature actuelle concernant la neurotoxicité induite par le métronidazole dont les syndromes cliniques, les constatations neuroradiologiques, le pronostic et l'hypothèse physiopathologique expliquant cette neurotoxicité. Il est important d'identifier ces effets neurotoxiques du métronidazole étant donné que l'arret immédiat du traitement est généralement associé à une guérison clinique complète et à la disparition des signes radiologiques.

The neuroplastin adhesion molecules are accessory proteins that chaperone the monocarboxylate transporter MCT2 to the neuronal cell surface.

BACKGROUND: The neuroplastins np65 and np55 are two synapse-enriched immunoglobulin (Ig) superfamily adhesion molecules that contain 3 and 2 Ig domains respectively. Np65 is implicated in long term, activity dependent synaptic plasticity, including LTP. Np65 regulates the surface expression of GluR1 receptor subunits and the localisation of GABA(A) receptor subtypes in hippocampal neurones. The brain is dependent not only on glucose but on monocarboxylates as sources of energy. The. monocarboxylate transporters (MCTs) 1-4 are responsible for the rapid proton-linked translocation of monocarboxylates including pyruvate and lactate across the plasma membrane and require association with either embigin or basigin, proteins closely related to neuroplastin, for plasma membrane expression and activity. MCT2 plays a key role in providing lactate as an energy source to neurons. METHODOLOGY/FINDINGS: Here we use co-transfection of neuroplastins and monocarboxylate transporters into COS-7 cells to demonstrate that neuroplastins can act as ancillary proteins for MCT2. We also show that Xenopus laevis oocytes contain endogenous neuroplastin and its knockdown with antisense RNA reduces the surface expression of MCT2 and associated lactate transport. Immunocytochemical studies show that MCT2 and the neuroplastins are co-localised in rat cerebellum. Strikingly neuroplastin and MCT2 are enriched in the same parasagittal zebrin II-negative stripes. CONCLUSIONS: These data strongly suggest that neuroplastins act as key ancillary proteins for MCT2 cell surface localisation and activity in some neuronal populations, thus playing an important role in facilitating the uptake of lactate for use as a respiratory fuel.

Patterned Purkinje cell loss in the ataxic sticky mouse.

The ataxic sticky (sti/sti) mouse is a spontaneous autosomal recessive mutant resulting from a disruption in the editing domain of the alanyl-tRNA synthetase (Aars) gene. The sticky phenotype is characterized by a small body size, a characteristic unkempt coat and neurological manifestations including marked tremor and ataxia starting at 6 weeks of age. The present study was undertaken to examine the spatiotemporal features of Purkinje cell degeneration in the sticky mouse. Purkinje cell loss was found to be both progressive and patterned, with vermal lobules VI, IX and X, crus 1 of the hemisphere, and the flocculus and paraflocculus being differentially resistant to degeneration. The pattern of Purkinje cell degeneration in sticky is not random - in general, the sphingosine kinase 1a-immunonegative Purkinje cell subset is preferentially susceptible to early cell death. In addition, zebrin II/aldolase C expression in the sticky cerebellum is profoundly downregulated, whereas the heat-shock protein 25 is both ectopically expressed in some scattered Purkinje cells and downregulated in other Purkinje cells in which it is normally expressed constitutively. Compared with many mouse mutants with patterned Purkinje cell death, in which successive stripes of cell loss are very clear, Purkinje cell loss in sticky shows a less clear-cut pattern between different Purkinje cell subtypes, with the result that preferential survival is less dramatic. This may represent a secondary consequence of the downregulation of zebrin II expression.