Common Variants Near ZIC1 and ZIC4 in Autopsy‐Confirmed Multiple System Atrophy

Background: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Objective: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. Methods: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). Results: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). Interpretation: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. Keywords: ZIC1; ZIC4; autopsy-confirmed; genome-wide association study; multiple system atroph

Mobility Deficits Assessed With Mobile Technology: What Can We Learn From Brain Iron-Altered Animal Models?

Background: Recent developments in mobile technology have enabled the investigation of human movements and mobility under natural conditions, i.e., in the home environment. Iron accumulation in the basal ganglia is deleterious in Parkinson's disease (i.e., iron accumulation with lower striatal level of dopamine). The effect of iron chelation (i.e., re-deployment of iron) in Parkinson's disease patients is currently tested in a large investigator-initiated multicenter study. Conversely, restless legs syndrome (RLS) is associated with iron depletion and higher striatal level of dopamine. To determine from animal models which movement and mobility parameters might be associated with iron content modulation and the potential effect of therapeutic chelation inhuman. Methods: We recapitulated pathophysiological aspects of the association between iron, dopamine, and neuronal dysfunction and deterioration in the basal ganglia, and systematically searched PubMed to identify original articles reporting about quantitatively assessed mobility deficits in animal models of brain iron dyshomeostasis. Results: We found six original studies using murine and fly models fulfilling the inclusion criteria. Especially postural and trunk stability were altered in animal models with iron overload. Animal models with lowered basal ganglia iron suffered from alterations in physical activity, mobility, and sleep fragmentation. Conclusion: From preclinical investigations in the animal model, we can deduce that possibly also in humans with iron accumulation in the basal ganglia undergoing therapeutic chelation may primarily show changes in physical activity (such as daily "motor activity"), postural and trunk stability and sleep fragmentation. These changes can readily be monitored with currently available mobile technology

Serum neuronal exosomes predict and differentiate Parkinson's disease from atypical parkinsonism

ObjectiveParkinson's disease is characterised neuropathologically by α-synuclein aggregation. Currently, there is no blood test to predict the underlying pathology or distinguish Parkinson's from atypical parkinsonian syndromes. We assessed the clinical utility of serum neuronal exosomes as biomarkers across the spectrum of Parkinson's disease, multiple system atrophy and other proteinopathies.MethodsWe performed a cross-sectional study of 664 serum samples from the Oxford, Kiel and Brescia cohorts consisting of individuals with rapid eye movement sleep behavioural disorder, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome and controls. Longitudinal samples were analysed from Parkinson's and control individuals. We developed poly(carboxybetaine-methacrylate) coated beads to isolate L1 cell adhesion molecule (L1CAM)-positive extracellular vesicles with characteristics of exosomes and used mass spectrometry or multiplexed electrochemiluminescence to measure exosomal proteins.ResultsMean neuron-derived exosomal α-synuclein was increased by twofold in prodromal and clinical Parkinson's disease when compared with multiple system atrophy, controls or other neurodegenerative diseases. With 314 subjects in the training group and 105 in the validation group, exosomal α-synuclein exhibited a consistent performance (AUC=0.86) in separating clinical Parkinson's disease from controls across populations. Exosomal clusterin was elevated in subjects with non-α-synuclein proteinopathies. Combined neuron-derived exosomal α-synuclein and clusterin measurement predicted Parkinson's disease from other proteinopathies with AUC=0.98 and from multiple system atrophy with AUC=0.94. Longitudinal sample analysis showed that exosomal α-synuclein remains stably elevated with Parkinson's disease progression.ConclusionsIncreased α-synuclein egress in serum neuronal exosomes precedes the diagnosis of Parkinson's disease, persists with disease progression and in combination with clusterin predicts and differentiates Parkinson's disease from atypical parkinsonism

Structural mechanism of extranucleosomal DNA readout by the INO80 complex

The nucleosomal landscape of chromatin depends on the concerted action of chromatin remodelers. The INO80 remodeler specifically places nucleosomes at the boundary of gene regulatory elements, which is proposed to be the result of an ATP-dependent nucleosome sliding activity that is regulated by extranucleosomal DNA features. Here, we use cryo–electron microscopy and functional assays to reveal how INO80 binds and is regulated by extranucleosomal DNA. Structures of the regulatory A-module bound to DNA clarify the mechanism of linker DNA binding. The A-module is connected to the motor unit via an HSA/post-HSA lever element to chemomechanically couple the motor and linker DNA sensing. Two notable sites of curved DNA recognition by coordinated action of the four actin/actin-related proteins and the motor suggest how sliding by INO80 can be regulated by extranucleosomal DNA features. Last, the structures clarify the recruitment of YY1/Ies4 subunits and reveal deep architectural similarities between the regulatory modules of INO80 and SWI/SNF complexes

Novel SCARB2 mutation in action myoclonus-renal failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features

Background: Action myoclonus-renal failure syndrome is a hereditary form of progressive myoclonus epilepsy associated with renal failure. It is considered to be an autosomal-recessive disease related to loss-of-function mutations in SCARB2. We studied a German AMRF family, additionally showing signs of demyelinating polyneuropathy and dilated cardiomyopathy. To test the hypothesis whether isolated appearance of individual AMRF syndrome features could be related to heterozygote SCARB2 mutations, we screened for SCARB2 mutations in unrelated patients showing isolated AMRF features. Methods: In the AMRF family all exons of SCARB2 were analyzed by Sanger sequencing. The mutation screening of unrelated patients with isolated AMRF features affected by either epilepsy (n = 103, progressive myoclonus epilepsy or generalized epilepsy), demyelinating polyneuropathy (n = 103), renal failure (n = 192) or dilated cardiomyopathy (n = 85) was performed as high resolution melting curve analysis of the SCARB2 exons. Results: A novel homozygous 1 bp deletion (c.111delC) in SCARB2 was found by sequencing three affected homozygous siblings of the affected family. A heterozygous sister showed generalized seizures and reduction of nerve conduction velocity in her legs. No mutations were found in the epilepsy, renal failure or dilated cardiomyopathy samples. In the polyneuropathy sample two individuals with demyelinating disease were found to be carriers of a SCARB2 frameshift mutation (c.666delCCTTA). Conclusions: Our findings indicate that demyelinating polyneuropathy and dilated cardiomyopathy are part of the action myoclonus-renal failure syndrome. Moreover, they raise the possibility that in rare cases heterozygous SCARB2 mutations may be associated with PNP features

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Managing Essential Tremor

Essential tremor is one of the most common tremor syndromes. According to the recent tremor classification, tremor as a symptom is defined as an involuntary, rhythmic, oscillatory movement of a body part and is classified along two axes: axis 1-defining syndromes based on the clinical features such as historical features, tremor characteristics, associated signs, and laboratory tests; and axis 2-classifying the etiology (Bhatia et al., Mov Disord 33:75-87, 2018). The management of this condition has two major approaches. The first is to exclude treatable etiologies, as particularly during the onset of this condition the presentation of a variety of etiologies can be with monosymptomatic tremor. Once the few etiologies with causal treatments are excluded, all further treatment is symptomatic. Shared decision-making with enabling the patient to knowledgeably choose treatment options is needed to customize the management. Mild to moderate tremor severity can sometimes be controlled with occupational treatment, speech therapy of psychotherapy, or adaptation of coping strategy. First-line pharmacological treatments include symptomatic treatment with propranolol, primidone, and topiramate. Botulinum toxin is for selected cases. Invasive treatments for essential tremor should be considered for severe tremors. They are generally accepted as the most powerful interventions and provide not only improvement of tremor but also a significant improvement of life quality. The current standard is deep brain stimulation (DBS) of the thalamic and subthalamic region. Focused ultrasound thalamotomy is a new therapy attracting increasing interest. Radiofrequency lesioning is only rarely done if DBS or focused ultrasound is not possible. Radiosurgery is not well established. We present our treatment algorithm

Biomarkers of Parkinson's disease: 20years later

Despite intensive effort, biomarker research for the detection of prodromal stage, diagnosis and progression of Parkinson's disease (PD) falls short of expectations. This article reviews the attempts in the last 20years to find a biomarker, addresses challenges along the biomarker search and suggests the steps that should be taken to overcome these challenges. Although several biomarkers are currently available, none of them is specific enough for diagnosis, prediction of future PD or disease progression. The main reason for the failure finding a strong biomarker seems to be drastic heterogeneity of PD, which exhibits itself in all domains; from the clinic to pathophysiology or genetics. The diversity in patient selection, assessment methods or outcomes in biomarker studies also limit the interpretation and generalizability of the data. In search of a reliable biomarker, consideration of novel approaches encompassing individual demographic, clinical, genetic, epigenetic and environmental differences, employment of strategies enabling marker combinations, designing multicenter studies with compatible assessment methods, integration of data from preclinical domains and utilization of novel technology-based assessments are necessary

Validation of the QUEST for German-speaking countries

Objective: To explore the clinimetric attributes of the German version of the quality of life in essential tremor (ET) questionnaire (QUEST) as a tremor-specific measure of quality of life. Methods: This was an observational, cross-sectional study. The QUEST German version was obtained by translation-back translation procedure. ET cases were diagnosed according to the tremor investigation group criteria. Assessments included Archimedes spirals rating, EQ-5D, Beck Depression Inventory (BDI-II) and QUEST German version. Missing data were imputed for those cases in which the loss of data for one domain of the QUEST was \u3c30%. Results: Ninety three patients out of 138 (67.4%) with definite or probable ET had complete QUEST data after 43 item imputations and they constituted the sample for this study. The QUEST summary index (QSI) displayed no floor or ceiling effects. QUEST internal consistency (Cronbach\u27s alpha) ranged between 0.50 and 0.89. Item-total domain correlations ranged from 0.26 to 0.82 and the item homogeneity indexes were satisfactory (range: 0.28-0.60). The QSI correlated weakly with the EQ-5D (rS=0.20) and moderately with the BDI-II (rS = 0.31) and the QUEST self-evaluation of tremor severity (rS = 0.44). Conclusions: The QUEST German version has, despite recognized data quality problems, satisfactory acceptability and internal consistency as a whole. The correlation analysis showed that tremor in the head, voice and right hand was moderately associated with quality of life