FARS-ADL across Ataxias: Construct Validity, Sensitivity to Change, and Minimal Important Change.

BACKGROUND: Patient-focused outcomes present a central need for trial-readiness across all ataxias. The Activities of Daily Living part of the Friedreich Ataxia Rating Scale (FARS-ADL) captures functional impairment and longitudinal change but is only validated in Friedreich Ataxia. OBJECTIVE: Validation of FARS-ADL regarding disease severity and patient-meaningful impairment, and its sensitivity to change across genetic ataxias. METHODS: Real-world registry data of FARS-ADL in 298 ataxia patients across genotypes were analyzed, including (1) cross-correlation with FARS-stage, Scale for the Assessment and Rating of Ataxia (SARA), Patient-Reported Outcome Measure (PROM)-ataxia, and European Quality of Life 5 Dimensions visual analogue scale (EQ5D-VAS); (2) sensitivity to change within a trial-relevant 1-year median follow-up, anchored in Patient Global Impression of Change (PGI-C); and (3) general linear modeling of factors age, sex, and depression (nine-item Patient Health Questionnaire [PHQ-9]). RESULTS: FARS-ADL correlated with overall disability (rhoFARS-stage = 0.79), clinical disease severity (rhoSARA = 0.80), and patient-reported impairment (rhoPROM-ataxia = 0.69, rhoEQ5D-VAS = -0.37), indicating comprehensive construct validity. Also at item level, and validated within genotype (SCA3, RFC1), FARS-ADL correlated with the corresponding SARA effector domains; and all items correlated to EQ5D-VAS quality of life. FARS-ADL was sensitive to change at a 1-year interval, progressing only in patients with worsening PGI-C. Minimal important change was 1.1. points based on intraindividual variability in patients with stable PGI-C. Depression was captured using FARS-ADL (+0.3 points/PHQ-9 count) and EQ5D-VAS, but not FARS-stage or SARA. CONCLUSION: FARS-ADL reflects both disease severity and patient-meaningful impairment across genetic ataxias, with sensitivity to change in trial-relevant timescales in patients perceiving change. It thus presents a promising patient-focused outcome for upcoming ataxia trials. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Perivascular PDGFRB+ cells accompany lesion formation and clinical evolution differentially in two different EAE models.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that may lead to progressive disability. Here, we explored the behavioral pattern and the role of vasculature especially PDGFRB+ pericytes/ perivascular cells, in MS pathogenesis. METHODS: We have evaluated vascular changes in two different experimental allergic encephalomyelitis (EAE) mice models (MOG and PLP-induced). PDGFRB+ cells demonstrated distinct and different behavioral patterns. In both models, fibrosis formation was detected via collagen, fibronectin, and extracellular matrix accumulation. RESULTS: The PLP-induced animal model revealed that fibrosis predominantly occurs in perivascular locations and that PDGFRB+ cells are accumulated around vessels. Also, the expression of fibrotic genes and genes coding extracellular matrix (ECM) proteins are upregulated. Moreover, the perivascular thick wall structures in affected vessels of this model presented primarily increased PDGFRB+ cells but not NG2+ cells in the transgenic NG2-DsRed transgenic animal model. On the other hand, in MOG induced model, PDGFRB+ perivascular cells were accumulated at the lesion sites. PDGFRB+ cells colocalized with ECM proteins (collagen, fibronectin, and lysyl oxidase L3). Nevertheless, both MOG and PLP-immunized mice showed increasing EAE severity, and disability parallel with enhanced perivascular cell accumulation as the disease progressed from earlier (day 15) to later (day 40). CONCLUSION: As a result, we have concluded that PDGFRB+ perivascular cells may be participating in lesion progression and as well as demonstrating different responses in different EAE models.

Hand Pronation-Supination Movement as a Proxy for Remotely Monitoring Gait and Posture Stability in Parkinson's Disease.

The Unified Parkinson's Disease Rating Scale (UPDRS) is a subjective Parkinson's Disease (PD) physician scoring/monitoring system. To date, there is no single upper limb wearable/non-contact system that can be used objectively to assess all UPDRS-III motor system subgroups (i.e., tremor (T), rigidity (R), bradykinesia (B), gait and posture (GP), and bulbar anomalies (BA)). We evaluated the use of a non-contact hand motion tracking system for potential extraction of GP information using forearm pronation-supination (P/S) motion parameters (speed, acceleration, and frequency). Twenty-four patients with idiopathic PD participated, and their UPDRS data were recorded bilaterally by physicians. Pearson's correlation, regression analyses, and Monte Carlo validation was conducted for all combinations of UPDRS subgroups versus motion parameters. In the 262,125 regression models that were trained and tested, the models within 1% of the lowest error showed that the frequency of P/S contributes to approximately one third of all models; while speed and acceleration also contribute significantly to the prediction of GP from the left-hand motion of right handed patients. In short, the P/S better indicated GP when performed with the non-dominant hand. There was also a significant negative correlation (with medium to large effect size, range: 0.3-0.58) between the P/S speed and the single BA score for both forearms and combined UPDRS score for the dominant hand. This study highlights the potential use of wearable or non-contact systems for forearm P/S to remotely monitor and predict the GP information in PD.

Genetic variants of vitamin D metabolism-related DHCR7/NADSYN1 locus and CYP2R1 gene are associated with clinical features of Parkinson's disease.

PURPOSE/AIM OF THE STUDY: Parkinson's disease (PD) is the second most common neurodegenerative disorder. Vitamin D deficiency is suggested to be related to PD. A genome-wide association study indicated that genes involved in vitamin D metabolism affect vitamin D levels. Among these genes, single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) and vitamin D binding protein (VDBP/GC) genes have also been demonstrated to be associated with PD risk. Our aim was to investigate the relevance of SNPs within the 7-dehydrocholesterol reductase/nicotinamide adenine dinucleotide synthetase 1 (DHCR7/NADSYN1) locus and vitamin D 25-hydroxylase (CYP2R1) gene, which encode important enzymes that play a role in the vitamin D synthesis pathway, with PD and its clinical features. MATERIALS AND METHODS: Genotypes of 382 PD patients and 240 cognitively healthy individuals were evaluated by a LightSNiP assay for a total of 10 SNPs within the DHCR7/NADSYN1 locus and CYP2R1 gene. RESULTS: There were no significant differences in the allele and genotype distributions of any of the SNPs between any patient groups and healthy subjects. However, our results indicated that all of the SNPs within the DHCR7/NADSYN1 locus and CYP2R1 gene, except rs1993116, were associated with clinical motor features of PD including initial predominant symptom, freezing of gait (FoG) and falls as well as disease stage and duration of the disease. CONCLUSIONS: In conclusion, genetic variants of the DHCR7/NADSYN1 locus and the CYP2R1 gene might be related to the inefficient utilization of vitamin D independent from vitamin D levels, and it might result in differences in the clinical features of PD patients.

Production and comprehension of co-speech gestures in Parkinson's disease.

This study examined how impairments in sensorimotor abilities of individuals with Parkinson's Disease (PD) can be related to the use and understanding of co-speech hand gestures involving literal and figurative actions. We tested individuals with PD (n = 18, 12 males, Mage = 56.5, SDage = 8.16, PD duration since onset: M = 5.36 years, SD = 3.51, Hoehn and Yahr Scale:MH&Y = 2.09, SDH&Y = 0.50) and age- and education-matched neurotypical controls (n = 18, 14 males, Mage = 56.61, SDage = 8.88) with two experimental tasks. In the gesture production task, participants retold the narratives presented to them in a written format. In the gesture comprehension task, participants were asked to match a gesture with a novel verb in literal and figurative sentence contexts. Results showed that patients with PD gestured significantly less than the neurotypical controls. No group differences were found for the type of gesture use. Individuals with PD performed worse than controls on matching gestures with novel verbs, particularly for figurative meanings. Individuals' severity in the disease negatively correlated with their performance for these figurative novel verb-gesture matches. The performances in the two tasks did not correlate. These findings suggest that problems in sensorimotor abilities resulting from PD can influence overall gesture production and gesture comprehension, providing further evidence on the relations between PD and the impaired use of multimodal language.

Neuropsychiatric Symptoms of COVID-19 Explained by SARS-CoV-2 Proteins' Mimicry of Human Protein Interactions.

The first clinical symptoms focused on the presentation of coronavirus disease 2019 (COVID-19) have been respiratory failure, however, accumulating evidence also points to its presentation with neuropsychiatric symptoms, the exact mechanisms of which are not well known. By using a computational methodology, we aimed to explain the molecular paths of COVID-19 associated neuropsychiatric symptoms, based on the mimicry of the human protein interactions with SARS-CoV-2 proteins. Methods: Available 11 of the 29 SARS-CoV-2 proteins' structures have been extracted from Protein Data Bank. HMI-PRED (Host-Microbe Interaction PREDiction), a recently developed web server for structural PREDiction of protein-protein interactions (PPIs) between host and any microbial species, was used to find the "interface mimicry" through which the microbial proteins hijack host binding surfaces. Classification of the found interactions was conducted using the PANTHER Classification System. Results: Predicted Human-SARS-CoV-2 protein interactions have been extensively compared with the literature. Based on the analysis of the molecular functions, cellular localizations and pathways related to human proteins, SARS-CoV-2 proteins are found to possibly interact with human proteins linked to synaptic vesicle trafficking, endocytosis, axonal transport, neurotransmission, growth factors, mitochondrial and blood-brain barrier elements, in addition to its peripheral interactions with proteins linked to thrombosis, inflammation and metabolic control. Conclusion: SARS-CoV-2-human protein interactions may lead to the development of delirium, psychosis, seizures, encephalitis, stroke, sensory impairments, peripheral nerve diseases, and autoimmune disorders. Our findings are also supported by the previous in vivo and in vitro studies from other viruses. Further in vivo and in vitro studies using the proteins that are pointed here, could pave new targets both for avoiding and reversing neuropsychiatric presentations.

The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice.

BACKGROUND: The genetic and epidemiological features of hereditary ataxias have been reported in several populations; however, Turkey is still unexplored. Due to high consanguinity, recessive ataxias are more common in Turkey than in Western European populations. OBJECTIVE: To identify the prevalence and genetic structure of hereditary ataxias in the Turkish population. METHODS: Our cohort consisted of 1296 index cases and 324 affected family members. Polymerase chain reaction followed by Sanger sequencing or fragment analysis were performed to screen for the trinucleotide repeat expansions in families with a dominant inheritance pattern, as well as in sporadic cases. The expansion in the frataxin (FXN) gene was tested in all autosomal recessive cases and in sporadic cases with a compatible phenotype. Whole-exome sequencing was applied to 251 probands, selected based on the family history, age of onset, and phenotype. RESULTS: Mutations in known ataxia genes were identified in 30% of 1296 probands. Friedreich's ataxia was found to be the most common recessive ataxia in Turkey, followed by autosomal recessive spastic ataxia of Charlevoix-Saguenay. Spinocerebellar ataxia types 2 and 1 were the most common dominant ataxias. Whole-exome sequencing was performed in 251 probands with an approximate diagnostic yield of 50%. Forty-eight novel variants were found in a plethora of genes, suggesting a high heterogeneity. Variants of unknown significance were discussed in light of clinical data. CONCLUSION: With the large sample size recruited across the country, we consider that our results provide an accurate picture of the frequency of hereditary ataxias in Turkey. © 2021 International Parkinson and Movement Disorder Society.

A novel shoulder disability staging system for scapulothoracic arthrodesis in patients with facioscapulohumeral dystrophy.

BACKGROUND: Scapulothoracic arthrodesis (STA) is a well-established surgical technique to provide scapular stabilisation in patients with facioscapulohumeral dystrophy (FSHD). There is no staging or scoring systems available to guide surgical decision. The aim of this study was to develop a staging system to evaluate the shoulder disability in patients with FSHD to guide surgical decision-making and assess its reliability among surgeons. METHODS: Fifty-seven shoulders of 29 patients (15 male, 14 female) with an average age of 34.5 years (13-73) were included. Six stages of the disease were defined to create a system consisting of shoulder elevation, deltoid function and scapular winging. Patients were assessed by two independent orthopaedic surgeons who were blind to each other. Statistical analyses included mean and standard deviation for descriptive variables, Pearson's correlation and Cohen's Kappa for inter- and intraobserver agreement. RESULTS: Measurement of elevation showed excellent correlation in both inter- and intraobserver assessment. There was substantial agreement on deltoid function and moderate agreement on scapular winging. Decisions on stage showed excellent agreement on interobserver and substantial agreement on intraobserver assessment. Surgical decision using the stage showed excellent agreement on both inter- and intraobserver assessment. CONCLUSION: This novel staging system has an excellent inter observer agreement on FSHD patients' shoulder disability. This would provide surgeons a beneficial tool to define patient groups that would have negatively or positively affected from STA.

Isolated hypoglossal nerve palsy due to a jugular foramen schwannoma.

Introduction - Although the involvement of the hypoglossal nerve together with other cranial nerves is common in several pathological conditions of the brain, particularly the brainstem, isolated hypoglossal nerve palsy is a rare condition and a diagnostic challenge. Case presentation - The presented patient arrived to the hospital with a history of slurred speech and an uncomfortable sensation on his tongue. Neurological examination showed left-sided hemiatrophy of the tongue with fasciculations and deviation towards the left side during protrusion. Based on the clinical and MRI findings, a diagnosis of hypoglossal nerve schwannoma was made. Discussion - Hypoglossal nerve palsy may arise from multiple causes such as trauma, infections, neoplasms, and endocrine, autoimmune and vascular pathologies. In our case, the isolated involvement of the hypoglossal nerve was at the skull base segment, where the damage to the hypoglossal nerve may occur mostly due to metastasis, nasopharyngeal carcinomas, nerve sheath tumors and glomus tumors. Conclusion - Because of the complexity of the region's anatomy, the patient diagnosed with hypoglossal nerve schwannoma was referred for gamma knife radiosurgery.

Crossing Y-Solitaire thrombectomy as a rescue treatment for refractory acute occlusions of the middle cerebral artery.

BACKGROUND: Mechanical thrombectomy using a stent retriever has become the standard of care for acute large-vessel occlusions in the anterior circulation. Clots that are refractory to single stent retriever thrombectomy remain a challenge for neurointerventionalists. OBJECTIVE: To assess the efficacy and safety of double stent retriever (crossing Y-Solitaire) thrombectomy as a rescue treatment for acute middle cerebral artery (MCA) occlusions that are refractory to single stent retriever thrombectomy. METHODS: We retrospectively reviewed the databases of our hospitals to identify patients who presented with an acute MCA occlusion and were treated with crossing Y-Solitaire thrombectomy. The angiographic (Thrombolysis in Cerebral Infarction (TICI) scale) and clinical outcomes (National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores) and complications were assessed. RESULTS: Ten patients were included in the study. The median initial NIHSS score and Alberta Stroke Program Early CT Score (ASPECTS) were 19.0 and 9.6, respectively. Crossing Y-Solitaire thrombectomy was performed as a rescue technique after unsuccessful single Solitaire thrombectomy passes in all cases. Successful recanalization (TICI 2b/3) was achieved in 8 (80%) patients. We observed asymptomatic reperfusion hemorrhages in 2 (20%) patients. No procedural related complications were seen other than reversible vasospasms in 5 (50%) patients. Sixty percent of the patients had a mRS score of between 2 and 0 at 90 days after the procedure. There was no mortality. CONCLUSION: Crossing Y-Solitaire thrombectomy seems to be an effective and safe alternative rescue technique to treat refractory MCA bifurcation occlusions that are refractory to standard thrombectomy procedures.

Stroke epidemiology in Karabük city Turkey: Community based study.

INTRODUCTION: Stroke has been projected to increase in developing countries like Turkey. Information about the prevalence of stroke may uncover the etiology of stroke and overcome its impact burden. However, data is limited due to a lack of studies based in Turkey and neighboring regions. We aimed to investigate the prevalence and risk factors of stroke in the Turkish city of Karabük and to pave the way for future epidemiological studies in Turkey. METHODS: The study was designed as a cross-sectional, door-to-door survey. The questionnaire was completed by a trained team in the presence of the participants according to their answers. Patients who had been diagnosed with stroke prior to the survey were re-examined by a neurologist. RESULTS: 3131 persons who were above 44 years old were screened. 129 of them were found to have had a stroke previously. The prevalence rate of stroke above 44 years was found to be 4.12% (98% confidence level and ± 2% margin of error). 72.1% of stroke patients had hypertension. Male/female ratio was 0.72. CONCLUSION: This study showed a high prevalence rate of stroke in Karabük Turkey with a low male/female ratio when compared to other studies.

Prevalence of Multiple Sclerosis in a Turkish City Bordering an Iron and Steel Factory.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination. Recent studies have shown that long-term exposure to air pollutants (including PM10 particulates) is potentially an environmental risk factor for MS. We aimed to determine the prevalence rates of MS in two cities with different levels of air pollution. METHODS: This door-to-door population-based study was conducted between April 2014 and June 2015. Two cities were screened for the prevalence rates of MS: 1) Karabük, which borders an iron-and-steel factory, and 2) Akçakoca, which is a coastal city located in the same region. A validated survey form was used for screening MS. The 2010 McDonald Criteria were used for diagnosing MS. The patients were examined twice, first by a neurology assistant in the field and then by a senior neurologist in public health centers in the cities. RESULTS: The prevalence of MS was 95.9/100,000 in Karabük and 46.1/100,000 in Akçakoca. In total, 33 patients were diagnosed with clinically definite MS. The female/male ratio was 1.5, and 21 patients were diagnosed with relapsing-remitting MS, 9 with secondary progressive MS, and 3 with primary progressive MS. CONCLUSIONS: We found that the prevalence of MS was more than two fold higher in Karabük than in Akçakoca, which supports a link between air pollution and the pathogenesis of MS. However, larger etiological and epidemiological studies are needed to confirm this hypothesis.

The Role of Pericytes in Neurovascular Unit: Emphasis on Stroke.

BACKGROUND: Among the central nervous system (CNS) disorders, diseases like ischemic and hemorrhagic stroke which are important health care problems as well as leading causes for emergency admissions, primarily affect neurovascular structure. Despite their high rate of mortality and morbidity, very few efficient treatment targets have been established until now. OBJECTIVE: Blood-brain barrier (BBB) is the mostly effected structure in stroke as detected in both clinical studies and experimental settings. BBB is composed of endothelia, astrocyte end-foot, pericytes and basal lamina. Neurovascular unit, pericytes and BBB forming endothelia play significant pathophysiological roles in both ischemic and hemorrhagic stroke. DISCUSSION: In this mini-review, the role of microcirculation and cells of blood-brain barrier in stroke pathophysiology will be discussed with a special emphasis based on pericytes. Pericytes are especially important for providing adequate microcirculatory supply according to needs of neuronal tissue and form one of the functionally important part of BBB and take role in neurovascular coupling. Understanding the role and disease producing mechanisms of neurovascular unit elements in different neurological conditions will provide novel targets for future treatments.

Rare case of glioblastoma multiforme located in posterior corpus callosum presenting with depressive symptoms and visual memory deficits.

Most of the primary brain tumours are located in the supratentorial region, and it is uncommon to see tumour growth on deep brain structures such as posterior corpus callosum (PCC). In addition, lesions in PCC are also difficult to recognise, because construction apraxia, visuospatial perception and attentional capacity impairment may be the only presenting symptoms. Here, we represent a rare case of gliobastoma multiforme located in PCC, which solely presents with depressive symptoms and visual memory deficits. Initial manifestations of primary brain tumours with psychiatric symptoms and memory disturbances, in addition to headaches and seizures, should be kept in mind.

On the Severity of Carpal Tunnel Syndrome: Diabetes or Metabolic Syndrome.

BACKGROUND AND PURPOSE: Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy. Although its etiology is unknown, certain conditions are commonly associated with CTS, such as obesity, arthritis, hypothyroidism, diabetes mellitus, trauma, mass lesions, amyloidosis, and sarcoidosis. We aimed to determine the association between metabolic syndrome and CTS, and we compared the severity of CTS between patients with diabetes (and no concomitant metabolic syndrome) and patients with metabolic syndrome. METHODS: Two hundred patients with a clinically and electrophysiological confirmed diagnosis of CTS were included in the study. Their demographic characteristics and severity of CTS were analyzed according to the presence or the absence of metabolic syndrome. Differences in the electrophysiological findings were evaluated between the following four groups: 1) metabolic syndrome alone (n=52), 2) diabetes alone (n=20), 3) combined metabolic syndrome and diabetes (n=44), and 4) no metabolic syndrome or diabetes (n=84). RESULTS: CTS was more severe in the patients with metabolic syndrome than those without this syndrome. The electrophysiological findings were worse in patients with metabolic syndrome alone than in those with diabetes alone and those without diabetes and metabolic syndrome. CONCLUSIONS: CTS appears to be more severe in patients with metabolic syndrome than patients with diabetes. Diabetes is one of the well-known risk factors for CTS, but other components of metabolic syndrome may have a greater effect on the severity of CTS.