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.

• MeSH
• alpha-Synuclein metabolism   MeSH
• Autoantibodies MeSH
• Genome-Wide Association Study MeSH
• Humans MeSH
• Multiple System Atrophy * genetics   pathology   MeSH
• Olivopontocerebellar Atrophies * MeSH
• Autopsy MeSH
• Nerve Tissue Proteins genetics   MeSH
• Striatonigral Degeneration * MeSH
• Transcription Factors genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Neurodegenerativní onemocnění tvoří širokou a heterogenní skupinu nemocí. Jejich společnou vlastností je ukládání určitého patologického proteinu v mozkové tkáni. U synukleinopatií je tímto proteinem α-synuklein, jehož abnormálně složená depozita v centrálním i periferním nervovém systému definují na základě své lokalizace a struktury jednotlivá onemocnění. V současné době jsou mezi synukleinopatie řazeny Parkinsonova nemoc, Parkinsonova nemoc s demencí, demence s Lewyho tělísky, multisystémová atrofie, čisté autonomní selhání a idiopatická porucha chování v REM spánku. Průkaz samotného α-synukleinu u těchto nemocí má efekt v odlišení od jiných neurodegenerativních onemocnění, nicméně jeho specificita v diferenciální diagnostice jednotlivých synukleinopatií je poměrně nízká. Proto je třeba hledat další diagnostické biomarkery, které by přispěly k časné a přesné diagnóze jednotlivých onemocnění. Zároveň nejde jen o to pátrat po nových markerech, ale hledat i dostupnější biologické vzorky nebo tělesné tekutiny, v nichž lze tyto biomarkery účinně detekovat. V této práci jsou v úvodu velmi stručně shrnuta jednotlivá onemocnění a následně je uveden stručný přehled převážně diagnostických laboratorních biomarkerů. Uvádíme nejprve biomarkery mozkomíšního moku, které odrážejí přímé neuropatologické změny, dále několik biomarkerů nacházejících se v periferních tkáních.

Neurodegenerative diseases represent a large and heterogeneous group of disorders. Their common feature is the deposition of a certain pathological protein in brain tissue. The location and distribution of abnormally constituted α-synuclein deposits in central and peripheral nervous system define each respective disorder. The location and distribution of a-synuclein deposits define each respective disorder. Synucleinopathies currently include Parkinson‘s disease, Parkinson‘s disease with dementia, Lewy body dementia, multiple system atrophy, pure autonomic failure, and idiopathic REM sleep disorder. The detection of α-synuclein alone in these diseases has the effect in differentiating them from other neurodegenerative diseases; however, its specificity in the differential diagnosis of individual synucleinopathies is relatively low. Therefore, it is necessary to look for other diagnostic biomarkers that would contribute to the early and accurate diagnosis of individual diseases. At the same time, it is not just a matter of looking for new markers, but also of looking for more available biological samples or body fluids in which these biomarkers can be effectively detected. In the introduction of this review there is a brief description of each disorder and subsequently there is a brief overview of mostly diagnostic laboratory biomarkers. We first present the cerebrospinal fluid biomarkers that reflect the direct neuropathological changes, and then several biomarkers found in peripheral tissues.

• MeSH
• alpha-Synuclein analysis   MeSH
• Biomarkers MeSH
• Lewy Body Disease diagnosis   pathology   therapy   MeSH
• Humans MeSH
• Multiple System Atrophy diagnosis   pathology   MeSH
• Parkinson Disease diagnosis   pathology   MeSH
• Synucleinopathies * diagnosis   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

• MeSH
• alpha-Synuclein metabolism   MeSH
• Frontotemporal Lobar Degeneration pathology   MeSH
• Humans MeSH
• Brain pathology   MeSH
• Multiple System Atrophy pathology   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Letter MeSH
• Comment MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Amyotrophic Lateral Sclerosis diagnosis   etiology   physiopathology   MeSH
• Anal Canal innervation   pathology   MeSH
• Diagnostic Techniques, Neurological * utilization   MeSH
• Electromyography * methods   utilization   MeSH
• Friedreich Ataxia diagnosis   etiology   MeSH
• Humans MeSH
• Multiple System Atrophy diagnosis   physiopathology   pathology   MeSH
• Neurodegenerative Diseases * diagnosis   etiology   MeSH
• Motor Neuron Disease diagnosis   etiology   MeSH
• Spinocerebellar Ataxias diagnosis   etiology   MeSH
• Statistics as Topic MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH

Fractional anisotropy (FA) is the most commonly used quantitative measure of diffusion in the brain. Changes in FA have been reported in many neurological disorders, but the implementation of diffusion tensor imaging (DTI) in daily clinical practice remains challenging. We propose a novel color look-up table (LUT) based on normative data as a tool for screening FA changes. FA was calculated for 76 healthy volunteers using 12 motion-probing gradient directions (MPG), a subset of 59 subjects was additionally scanned using 30 MPG. Population means and 95% prediction intervals for FA in the corpus callosum, frontal gray matter, thalamus and basal ganglia were used to create the LUT. Unique colors were assigned to inflection points with continuous ramps between them. Clinical use was demonstrated on 17 multiple system atrophy (MSA) patients compared to 13 patients with Parkinson disease (PD) and 17 healthy subjects. Four blinded radiologists classified subjects as MSA/non-MSA. Using only the LUT, high sensitivity (80%) and specificity (84%) were achieved in differentiating MSA subjects from PD subjects and controls. The LUTs generated from 12 and 30 MPG were comparable and accentuate FA abnormalities.

• MeSH
• Algorithms MeSH
• Anisotropy * MeSH
• Color * MeSH
• Basal Ganglia physiology   MeSH
• Frontal Lobe physiology   MeSH
• Corpus Callosum physiology   MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Brain Mapping methods   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Brain physiology   MeSH
• Multiple System Atrophy diagnosis   pathology   MeSH
• Parkinson Disease diagnosis   pathology   MeSH
• Signal-To-Noise Ratio MeSH
• Reference Values MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Sensitivity and Specificity MeSH
• Software MeSH
• Thalamus physiology   MeSH
• Healthy Volunteers MeSH
• Diffusion Tensor Imaging methods   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Multiple system atrophy (MSA) is a neurodegenerative disorder typically characterised by cerebellar dysfunction, parkinsonism, pyramidal signs and dysautonomy. Cognitive impairement is usually limited to a moderate subcortical dysexecutive syndrom. We report the case of a 62-year-old woman suffering from MSA who progressively developed severe dementia. Neuropathological examination confirmed the diagnosis of definite MSA and also showed histopathological hallmarks of Alzheimer's disease. This association is extremely rare in the literature. Our observation confirmes that franc dementia in MSA should prompt a search for another associated cause and underlines the usefulness of neuropathological verifications in atypical clinical pictures.

• MeSH
• Alzheimer Disease complications   pathology   MeSH
• Plaque, Amyloid pathology   MeSH
• Fatal Outcome MeSH
• Immunohistochemistry MeSH
• Middle Aged MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Cerebellum pathology   MeSH
• Brain pathology   MeSH
• Cerebral Cortex pathology   MeSH
• Multiple System Atrophy complications   pathology   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

• MeSH
• Alzheimer Disease MeSH
• Lewy Body Disease diagnosis   MeSH
• Diagnosis, Differential MeSH
• Hepatolenticular Degeneration diagnosis   therapy   MeSH
• Humans MeSH
• Multiple System Atrophy diagnosis   pathology   MeSH
• Hydrocephalus, Normal Pressure MeSH
• Parkinson Disease, Secondary diagnosis   MeSH
• Parkinson Disease diagnosis   MeSH
• Parkinsonian Disorders diagnosis   MeSH
• Signs and Symptoms MeSH
• Shy-Drager Syndrome diagnosis   MeSH
• Check Tag
• Humans MeSH