Genome-wide association study of autopsy-confirmed Multiple System Atrophy identifies common variants near ZIC1 and ZIC4

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. Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied common genetic variation in only autopsy-confirmed cases (N = 731) and controls (N = 2,898). The most strongly disease-associated markers were rs16859966 on chromosome 3 (P = 8.6 * 10-7, odds ratio (OR) = 1.58, [95% confidence interval (CI) = 1.32-1.89]), rs7013955 on chromosome 8 (P = 3.7 * 10-6, OR = 1.8 [1.40-2.31]), and rs116607983 on chromosome 4 (P = 4.0 * 10-6, OR = 2.93 [1.86-4.63]), all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms with P-values below 5 * 10-5. 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). 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 positive neurons were significantly reduced in patients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy.

MRI CNS Atrophy Pattern and the Etiologies of Progressive Ataxias

MRI shows in-vivo the three archetypal patterns of CNS volume loss underlying progressive ataxias, namely spinal atrophy (SA), cortical cerebellar atrophy (CCA) and olivopontocerebellar atrophy (OPCA). The MRI-based CNS atrophy pattern was reviewed in 128 progressive ataxias. A CNS atrophy pattern was identified in 91 conditions: SA in Freidreich’s ataxia, CCA in 5 acquired and 72 (24 dominant, 47 recessive,1 X-linked) inherited ataxias, OPCA in Multi-System Atrophy and 12 (9 dominant, 2 recessive,1 X-linked) inherited ataxias. The MRI-based CNS atrophy pattern may be useful for genetic assessment, identification of shared cellular targets, and repurposing therapies or enlargement of drugs indications in progressive ataxias.

A historical review of multiple system atrophy with a critical appraisal of cellular and animal models

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and dysautonomia with cerebellar ataxia or parkinsonian motor features. Isolated autonomic dysfunction with predominant genitourinary dysfunction and orthostatic hypotension and REM sleep behavior disorder are common characteristics of a prodromal phase, which may occur years prior to motor-symptom onset. MSA is a unique synucleinopathy, in which alpha-synuclein (aSyn) accumulates and forms insoluble inclusions in the cytoplasm of oligodendrocytes, termed glial cytoplasmic inclusions (GCIs). The origin of, and precise mechanism by which aSyn accumulates in MSA are unknown, and, therefore, disease-modifying therapies to halt or slow the progression of MSA are currently unavailable. For these reasons, much focus in the field is concerned with deciphering the complex neuropathological mechanisms by which MSA begins and progresses through the course of the disease. This review focuses on the history, etiopathogenesis, neuropathology, as well as cell and animal models of MSA.

Neuropathology of multiple system atrophy: Kurt Jellinger`s legacy

Multiple System Atrophy (MSA) is a rare, fatal neurodegenerative disorder. Its etiology and exact pathogenesis still remain poorly understood and currently no disease-modifying therapy is available to halt or slow down this detrimental neurodegenerative process. Hallmarks of the disease are α-synuclein rich glial cytoplasmic inclusions (GCIs). Neuropathologically, various degrees of striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA) can be observed. Since the original descriptions of this multifaceted disorder, several steps forward have been made to clarify its neuropathological hallmarks and key pathophysiological mechanisms. The Austrian neuropathologist Kurt Jellinger substantially contributed to the understanding of the underlying neuropathology of this disease, to its standardized assessment and to a broad systematical clinic-pathological correlation. On the occasion of his 90th birthday, we reviewed the current state of the art in the field of MSA neuropathology, highlighting Prof. Jellinger’s substantial contribution.

Multisystem atrophy: a case report with clinical and functional findings relevant to functional Physiotherapy

Introduction: Multiple System Atrophy (MSA) is a severe neurodegenerative disease that has parkinsonian, autonomic, cerebellar, and pyramidal features. It is prevalent at 3.4 to 4.9 cases per 100,000 population, and is most common after the age of 60. It is called Striatonigral Degeneration, with a predominance of parkinsonian symptoms; it is known as Olivopontocerebellar Atrophy, with cerebellar symptoms, and Shy-Drager syndrome with autonomic symptoms. Physiotherapy plays an important role in the rehabilitation of kinetic- functional impairments. Objective: To report the case of a volunteer with SMA in order to highlight the neurological findings for neurofunctional rehabilitation. Methods: This is an observational, cross-sectional case report study that was conducted at the Clínica Escola de Fisioterapia da Universidade de Franca (UNIFRAN), with the approval of the CEP (CAAE 83164918.2.0000.5495), of a 55-year-old male individual, referred to physiotherapy, diagnosed with SMA. Neurological evaluation was performed in the sector, of sensitivity, movement, tone, reflexes, motor coordination, balance, gait and function. Results: The individual reports that 4 years ago he started having difficulty walking and talking. He was diagnosed with Parkinson’s disease. He underwent a new evaluation, arriving at the current diagnosis. In the physical therapy evaluation dysautonomia, dysarthria, dysdiadochokinesia, dysmetria, hypertonia by rigidity, akinesia and bradykinesia, trunk flexion posture, balance deficit, tetraparesis and fetinated gait were observed. Conclusion: The impairments found impair the patient’s ability to perform several ADLs. This study emphasizes the value of neurofunctional physiotherapeutic semiology for an effective therapeutic treatment that promotes independence and quality of life possible for the individual with SMA.

Multisystem atrophy: a case report with clinical and functional findings relevant to functional Physiotherapy

Introduction: Multiple System Atrophy (MSA) is a severe neurodegenerative disease that has parkinsonian, autonomic, cerebellar, and pyramidal features. It is prevalent at 3.4 to 4.9 cases per 100,000 population, and is most common after the age of 60. It is called Striatonigral Degeneration, with a predominance of parkinsonian symptoms; it is known as Olivopontocerebellar Atrophy, with cerebellar symptoms, and Shy-Drager syndrome with autonomic symptoms. Physiotherapy plays an important role in the rehabilitation of kinetic-functional impairments. Objective: To report the case of a volunteer with SMA in order to highlight the neurological findings for neurofunctional rehabilitation. Methods: This is an observational, cross-sectional case report study that was conducted at the Clínica Escola de Fisioterapia da Universidade de Franca (UNIFRAN), with the approval of the CEP (CAAE 83164918.2.0000.5495), of a 55-year-old male individual, referred to physiotherapy, diagnosed with SMA. Neurological evaluation was performed in the sector, of sensitivity, movement, tone, reflexes, motor coordination, balance, gait and function. Results: The individual reports that 4 years ago he started having difficulty walking and talking. He was diagnosed with Parkinson’s disease. He underwent a new evaluation, arriving at the current diagnosis. In the physical therapy evaluation dysautonomia, dysarthria, dysdiadochokinesia, dysmetria, hypertonia by rigidity, akinesia and bradykinesia, trunk flexion posture, balance deficit, tetraparesis and fetinated gait were observed. Conclusion: The impairments found impair the patient’s ability to perform several ADLs. This study emphasizes the value of neurofunctional physiotherapeutic semiology for an effective therapeutic treatment that promotes independence and quality of life possible for the individual with SMA.

Neuroimaging Biomarkers in SCA2 Gene Carriers

A variety of Magnetic Resonance (MR) and nuclear medicine (NM) techniques have been used in symptomatic and presymptomatic SCA2 gene carriers to explore, in vivo, the physiopathological biomarkers of the neurological dysfunctions characterizing the associated progressive disease that presents with a cerebellar syndrome, or less frequently, with a levodopa-responsive parkinsonian syndrome. Morphometry performed on T1-weighted images and diffusion MR imaging enable structural and microstructural evaluation of the brain in presymptomatic and symptomatic SCA2 gene carriers, in whom they show the typical pattern of olivopontocerebellar atrophy observed at neuropathological examination. Proton MR spectroscopy reveals, in the pons and cerebellum of SCA2 gene carriers, a more pronounced degree of abnormal neurochemical profile compared to other spinocerebellar ataxias with decreased NAA/Cr and Cho/Cr, increased mi/Cr ratios, and decreased NAA and increased mI concentrations. These neurochemical abnormalities are detectable also in presymtomatic gene carriers. Resting state functional MRI (rsfMRI) demonstrates decreased functional connectivity within the cerebellum and of the cerebellum with fronto-parietal cortices and basal ganglia in symptomatic SCA2 subjects. 18F-fluorodeoxyglucose Positron Emission Tomography (PET) shows a symmetric decrease of the glucose uptake in the cerebellar cortex, the dentate nucleus, the brainstem and the parahippocampal cortex. Single photon emission tomography and PET using several radiotracers have revealed almost symmetric nigrostriatal dopaminergic dysfunction irrespective of clinical signs of parkinsonism which are already present in presymtomatic gene carriers. Longitudinal small size studies have proven that morphometry and diffusion MR imaging can track neurodegeneration in SCA2, and hence serve as progression biomarkers. So far, such a capability has not been reported for proton MR spectroscopy, rsfMRI and NM techniques. A search for the best surrogate marker for future clinical trials represents the current challenge for the neuroimaging community.