-
Journal of Neurology Nov 2023We aimed to relate clinical measures of disability in chronic cerebellar degeneration to structural whole-brain changes using voxel-based and surface-based morphometry...
OBJECTIVE
We aimed to relate clinical measures of disability in chronic cerebellar degeneration to structural whole-brain changes using voxel-based and surface-based morphometry (vbm and sbm). We were particularly interested in remote effects of cerebellar degeneration in the cerebral cortex.
METHODS
We recruited 30 patients with cerebellar degeneration of different aetiologies (downbeat nystagmus syndrome, DBN n = 14, spinocerebellar ataxia, SCA n = 9, sporadic adult late-onset ataxia, SAOA n = 7). All patients were thoroughly characterised in the motor, cognitive, vestibular and ocular-motor domains. Vbm and sbm were used to evaluate structural differences between cerebellar degeneration patients and a group of healthy age- and gender-matched volunteers. Linear regression models were used to correlate functional measures of disease progression and postural stability with whole brain volumetry.
RESULTS
Patients with SCA and SAOA showed widespread volume loss in the cerebellar hemispheres and less prominently in the vermis. Patients with DBN showed a distinct pattern of grey matter volume (GMV) loss that was restricted to the vestibular and ocular-motor representations in lobules IX, X and V-VII. Falls were associated with brainstem white matter volume. VBM and SBM linear regression models revealed associations between severity of ataxic symptoms, cognitive performance and preferred gait velocity. This included extra-cerebellar (sub-)cortical hubs of the motor and locomotion network (putamen, caudate, thalamus, primary motor cortex, prefrontal cortex) and multisensory areas involved in spatial navigation and cognition.
CONCLUSION
Functional disability in multiple domains was associated with structural changes in the cerebral cortex.
Topics: Adult; Humans; Cerebellar Ataxia; Magnetic Resonance Imaging; Ataxia; Cerebellum; Cerebellar Diseases; Syndrome
PubMed: 37480400
DOI: 10.1007/s00415-023-11859-z -
EBioMedicine Dec 2023Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well...
BACKGROUND
Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations of SCN8A-related ataxia.
METHODS
We collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23 cells and cultured neurons.
FINDINGS
Variants associated with chronic progressive ataxia either decreased Na current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter). Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing loss-of-function by decreasing Na current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain- and loss-of function effects in ND7/23 cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms.
INTERPRETATION
We identified episodic or chronic ataxia as predominant phenotypes caused by variants in SCN8A. Genotype-phenotype correlations revealed a more pronounced loss-of-function effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions.
FUNDING
BMBF, DFG, the Italian Ministry of Health, University of Tuebingen.
Topics: Humans; Animals; Mice; Ataxia; Neurons; Codon, Nonsense; Sodium Channel Blockers; NAV1.6 Voltage-Gated Sodium Channel
PubMed: 38251463
DOI: 10.1016/j.ebiom.2023.104855 -
Nutrients Mar 2024Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by insulin resistance in various tissues. Though conventionally associated with obesity, current... (Review)
Review
Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by insulin resistance in various tissues. Though conventionally associated with obesity, current research indicates that visceral adipose tissue (VAT) is the leading determining factor, wielding more influence regardless of individual body mass. The heightened metabolic activity of VAT encourages the circulation of free fatty acid (FFA) molecules, which induce insulin resistance in surrounding tissues. Individuals most vulnerable to this preferential fat deposition are older males with ancestral ties to Asian countries because genetics and sex hormones are pivotal factors for VAT accumulation. However, interventions in one's diet and lifestyle have the potential to strategically discourage the growth of VAT. This illuminates the possibility that the expansion of VAT and, subsequently, the risk of T2D development are preventable. Therefore, by reducing the amount of VAT accumulated in an individual and preventing it from building up, one can effectively control and prevent the development of T2D.
Topics: Male; Humans; Diabetes Mellitus, Type 2; Insulin Resistance; Obesity; Asia; Fatty Acids, Nonesterified; Psychomotor Agitation
PubMed: 38613048
DOI: 10.3390/nu16071015 -
Anales de Pediatria Aug 2023
Topics: Humans; Adolescent; Tremor; Electromyography
PubMed: 37453922
DOI: 10.1016/j.anpede.2023.02.023 -
CNS Neuroscience & Therapeutics Oct 2023Levodopa (L-DOPA) is considered the most reliable drug for treating Parkinson's disease (PD) clinical symptoms. Regrettably, long-term L-DOPA therapy results in the...
BACKGROUND
Levodopa (L-DOPA) is considered the most reliable drug for treating Parkinson's disease (PD) clinical symptoms. Regrettably, long-term L-DOPA therapy results in the emergence of drug-induced abnormal involuntary movements (AIMs) in most PD patients. The mechanisms underlying motor fluctuations and dyskinesia induced by L-DOPA (LID) are still perplexing.
METHODS
Here, we first performed the analysis on the microarray data set (GSE55096) from the gene expression omnibus (GEO) repository and identified the differentially expressed genes (DEGs) using linear models for microarray analysis (Limma) R packages from the Bioconductor project. 12 genes (Nr4a2, Areg, Tinf2, Ptgs2, Pdlim1, Tes, Irf6, Tgfb1, Serpinb2, Lipg, Creb3l1, Lypd1) were found to be upregulated. Six genes were validated on quantitative polymerase chain reaction and subsequently, Amphiregulin (Areg) was selected (based on log2 fold change) for further experiments to unravel its involvement in LID. Areg LV_shRNA was used to knock down Areg to explore its therapeutic role in the LID model.
RESULTS
Western blotting and immunofluorescence results show that AREG is significantly expressed in the LID group relative to the control. Dyskinetic movements in LID mice were alleviated by Areg knockdown, and the protein expression of delta FOSB, the commonly attributable protein in LID, was decreased. Moreover, Areg knockdown reduced the protein expression of P-ERK. In order to ascertain whether the inhibition of the ERK pathway (a common pathway known to mediate levodopa-induced dyskinesia) could also impede Areg, the animals were injected with an ERK inhibitor (PD98059). Afterward, the AIMs, AREG, and ERK protein expression were measured relative to the control group. A group treated with ERK inhibitor had a significant decrease of AREG and phosphorylated ERK protein expression relative to the control group.
CONCLUSION
Taken together, our results indicate unequivocal involvement of Areg in levodopa-induced dyskinesia, thus a target for therapy development.
Topics: Mice; Animals; Levodopa; Parkinson Disease; Oxidopamine; Antiparkinson Agents; Amphiregulin; Dyskinesia, Drug-Induced; Disease Models, Animal
PubMed: 37101388
DOI: 10.1111/cns.14229 -
Neurology(R) Neuroimmunology &... Jan 2024Neurodegeneration is considered a relevant pathophysiologic feature in neurologic disorders associated with antibodies against glutamic acid decarboxylase 65 (GAD65). In...
OBJECTIVES
Neurodegeneration is considered a relevant pathophysiologic feature in neurologic disorders associated with antibodies against glutamic acid decarboxylase 65 (GAD65). In this study, we investigate surrogates of neuroaxonal damage in relation to disease duration and clinical presentation.
METHODS
In a multicentric cohort of 50 patients, we measured serum neurofilament light chain (sNfL) in relation to disease duration and disease phenotypes, applied automated MRI volumetry, and analyzed clinical characteristics.
RESULTS
In patients with neurologic disorders associated with GAD65 antibodies, we detected elevated sNfL levels early in the disease course. By contrast, this elevation of sNfL levels was less pronounced in patients with long-standing disease. Increased sNfL levels were observed in patients presenting with cerebellar ataxia and limbic encephalitis, but not in those with stiff person syndrome. Using MRI volumetry, we identified atrophy predominantly of the cerebellar cortex, cerebellar superior posterior lobe, and cerebral cortex with similar atrophy patterns throughout all clinical phenotypes.
DISCUSSION
Together, our data provide evidence for early neuroaxonal damage and support the need for timely therapeutic interventions in GAD65 antibody-associated neurologic disorders.
Topics: Humans; Atrophy; Autoantibodies; Cerebellar Ataxia; Nervous System Diseases; Stiff-Person Syndrome
PubMed: 37914416
DOI: 10.1212/NXI.0000000000200176 -
European Journal of Neurology Oct 2023Until the outbreak reported during the COVID-19 pandemic, functional tics were considered to be a relatively rare clinical phenotype, as opposed to other functional...
BACKGROUND AND PURPOSE
Until the outbreak reported during the COVID-19 pandemic, functional tics were considered to be a relatively rare clinical phenotype, as opposed to other functional movement disorders such as functional tremor and dystonia. To better characterize this phenotype, we compared the demographic and clinical characteristics of patients who developed functional tics during the pandemic and those of patients with other functional movement disorders.
METHODS
Data from 110 patients were collected at the same neuropsychiatry centre: 66 consecutive patients who developed functional tics without other functional motor symptoms or neurodevelopmental tics and 44 patients with a mix of functional dystonia, tremor, gait, and myoclonus.
RESULTS
Both groups were characterized by female sex preponderance (70%-80%) and (sub)acute onset of functional symptoms (~80%). However, patients with functional tics had a significantly earlier age at onset of functional symptoms (21 vs. 39 years). Exposure to relevant social media content was reported by almost half of the patients with functional tics, but by none of the patients with other functional movement disorders. Comorbidity profiles were similar, with relatively high rates of anxiety/affective symptoms and other functional neurological symptoms (nonepileptic attacks).
CONCLUSIONS
Patients who developed functional tics during the pandemic represent a phenotypic variant of the wider group of patients with functional movement disorders, associated with younger age at onset and influenced by pandemic-related factors, including increased exposure to specific social media content. Diagnostic protocols and treatment interventions should be tailored to address the specific features of this newly defined phenotype.
Topics: Female; Humans; Tics; Dystonia; Tremor; Pandemics; COVID-19; Tic Disorders; Dystonic Disorders; Conversion Disorder; Tourette Syndrome
PubMed: 37410535
DOI: 10.1111/ene.15967 -
Clinical and Translational Medicine Jan 2024Hereditary ataxias, especially when presenting sporadically in adulthood, present a particular diagnostic challenge owing to their great clinical and genetic... (Review)
Review
Hereditary ataxias, especially when presenting sporadically in adulthood, present a particular diagnostic challenge owing to their great clinical and genetic heterogeneity. Currently, up to 75% of such patients remain without a genetic diagnosis. In an era of emerging disease-modifying gene-stratified therapies, the identification of causative alleles has become increasingly important. Over the past few years, the implementation of advanced bioinformatics tools and long-read sequencing has allowed the identification of a number of novel repeat expansion disorders, such as the recently described spinocerebellar ataxia 27B (SCA27B) caused by a (GAA)•(TTC) repeat expansion in intron 1 of the fibroblast growth factor 14 (FGF14) gene. SCA27B is rapidly gaining recognition as one of the most common forms of adult-onset hereditary ataxia, with several studies showing that it accounts for a substantial number (9-61%) of previously undiagnosed cases from different cohorts. First natural history studies and multiple reports have already outlined the progression and core phenotype of this novel disease, which consists of a late-onset slowly progressive pan-cerebellar syndrome that is frequently associated with cerebellar oculomotor signs, such as downbeat nystagmus, and episodic symptoms. Furthermore, preliminary studies in patients with SCA27B have shown promising symptomatic benefits of 4-aminopyridine, an already marketed drug. This review describes the current knowledge of the genetic and molecular basis, epidemiology, clinical features and prospective treatment strategies in SCA27B.
Topics: Adult; Humans; Spinocerebellar Ataxias; Ataxia; Phenotype
PubMed: 38279833
DOI: 10.1002/ctm2.1504 -
European Journal of Pharmacology Sep 2023Compared with levodopa, dopamine agonists (DAs) as initial treatment are associated with lower incidences of motor complications in early Parkinson's disease (PD). There... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Compared with levodopa, dopamine agonists (DAs) as initial treatment are associated with lower incidences of motor complications in early Parkinson's disease (PD). There is no strong evidence that a given DA is more potent in lower incidences of motor complications than another.
OBJECTIVE
We performed a network meta-analysis of levodopa versus DAs as monotherapy in early PD to access the risk of motor complications.
METHODS
Databases were searched up to June 2022 for eligible RCTs. Levodopa and four DAs (pramipexole, ropinirole, bromocriptine and pergolide) were investigated. The incidences of motor complications and efficacy, tolerability and safety outcomes were analyzed.
RESULTS
Nine RCTs (2112 patients) were included in the current study. The surface under the cumulative ranking curve (SUCRA) indicated that levodopa ranked first in the incidence of dyskinesia (0.988), followed by pergolide, pramipexole, ropinirole, and bromocriptine (0.704, 0.408, 0.240, 0.160). Pramipexole was least prone to wearing-off (0.109) and on-off fluctuation (0.041). Levodopa performed best in improvements of UPDRS-II, UPDRS-III, and UPDRS-II + III (0.925, 0.952, 0.934). Bromocriptine ranked first in total withdrawals and withdrawals due to adverse events (0.736, 0.751). Four DAs showed different adverse events profiles.
CONCLUSION
In the two non-ergot DAs, ropinirole is associated with a lower risk of dyskinesia while pramipexole is associated with lower risks of wearing-off and on-off fluctuations. Our research may facilitate head-to-head research, larger sample sizes, long following-up time RCTs to confirm the findings of this network meta-analysis.
Topics: Humans; Levodopa; Dopamine Agonists; Bromocriptine; Antiparkinson Agents; Parkinson Disease; Pramipexole; Pergolide; Network Meta-Analysis; Dyskinesias
PubMed: 37385577
DOI: 10.1016/j.ejphar.2023.175884 -
Tremor and Other Hyperkinetic Movements... 2023Movement disorders, particularly chorea, are uncommon in inborn errors of metabolism, but their identification is essential for improved clinical outcomes. In this... (Review)
Review
BACKGROUND
Movement disorders, particularly chorea, are uncommon in inborn errors of metabolism, but their identification is essential for improved clinical outcomes. In this context, comprehensive descriptions of movement disorders are limited and primarily derived from single cases or small patient series, highlighting the need for increased awareness and additional research in this field.
METHODS
A systematic review was conducted using the MEDLINE database and GeneReviews. The search included studies on inborn errors of metabolism associated with chorea, athetosis, or ballismus. The review adhered to PRISMA guidelines.
RESULTS
The systematic review analyzed 76 studies out of 2350 records, encompassing the period from 1964 to 2022. Chorea was observed in 90.1% of the 173 patients, followed by athetosis in 5.7%. Various inborn errors of metabolism showed an association with chorea, with trace elements and metals being the most frequent. Cognitive and developmental abnormalities were common in the cohort. Frequent neurological features included seizures, dysarthria, and optic atrophy, whereas non-neurological features included, among others, facial dysmorphia and failure to thrive. Neuroimaging and biochemical testing played crucial roles in aiding diagnosis, revealing abnormal findings in 34.1% and 47.9% of patients, respectively. However, symptomatic treatment efficacy for movement disorders was limited.
DISCUSSION
This study emphasizes the complexities of chorea in inborn errors of metabolism. A systematic approach with red flags, biochemical testing, and neuroimaging is required for diagnosis. Collaboration between neurologists, geneticists, and metabolic specialists is crucial for improving early detection and individualized treatment. Utilizing genetic testing technologies and potential therapeutic avenues can aid in the improvement of patient outcomes.
Topics: Humans; Chorea; Athetosis; Metabolism, Inborn Errors; Movement Disorders; Dyskinesias
PubMed: 37810989
DOI: 10.5334/tohm.801