Differential Diagnosis Of Multiple System Atrophy Research Articles

Clinical value of video oculomotor evaluation in the differential diagnosis of multiple system atrophy and Parkinson's disease.

Multiple system atrophy (MSA) is a neurodegenerative disease that progresses rapidly and has a poor prognosis. This study aimed to assess the value of video oculomotor evaluation (VOE) in the differential diagnosis of MSA and Parkinson's disease (PD). In total, 28 patients with MSA, 31 patients with PD, and 30 age- and sex-matched healthy controls (HC) were screened and included in this study. The evaluation consisted of a gaze-holding test, smooth pursuit eye movement (SPEM), random saccade, and optokinetic nystagmus (OKN). The MSA and PD groups had more abnormalities and decreased SPEM gain than the HC group (64.29%, 35.48%, 10%, p<.001). The SPEM gain in the MSA group was significantly lower than that in the PD group at specific frequencies. Patients with MSA and PD showed prolonged latencies in all saccade directions compared with those with HC. However, the two diseases had no significant differences in the saccade parameters. The OKN gain gradually decreased from the HC to the PD and the MSA groups (p<.05). Compared with the PD group, the gain in the MSA group was further decreased in the OKN test at 30°/s (Left, p=.010; Right p=.016). Receiver operating characteristic curves showed that the combination of oculomotor parameters with age and course of disease could aid in the differential diagnosis of patients with MSA and PD, with a sensitivity of 89.29% and a specificity of 70.97%. The combination of oculomotor parameters and clinical data may aid in the differential diagnosis of MSA and PD. Furthermore, VOE is vital in the identification of neurodegenerative diseases.

Monocytohigh-density lipoprotein ratio has a high predictive value for the diagnosis of multiple system atrophy and the differentiation from Parkinson's disease.

Background and purposeInflammation is closely related to the pathogenesis of multiple system atrophy (MSA). As markers of inflammation, the monocyte to high-density lipoprotein ratio (MHR), neutrophil to lymphocyte ratio (NLR), and red cell distribution width to platelet ratio (RPR) have been proven to be associated with a large variety of diseases. The aim of this study was to explore the association between inflammatory markers (MHR, NLR, and RPR) and MSA, and the difference between MSA and Parkinson’s disease (PD) was further compared by these inflammatory markers.Materials and methodsThis study was divided into three groups: 47 patients with MSA, 125 patients with PD, and 124 healthy controls. The corresponding laboratory indicators of subjects were collected and analyzed to obtain MHR, NLR, and RPR values.ResultsCompared with healthy controls, the MHR, NLR, and RPR were higher in the MSA group (P < 0.05), and the MHR was higher in the MSA group than in the PD group (P < 0.001). Multivariate logistic regression analysis showed that MHR*10 (corrected OR = 1.312, 95% CI 1.093–1.575) and RPR*100 (corrected OR = 1.262, 95% CI 1.055–1.509) were positively correlated with the risk of MSA. The receiver operating characteristic (ROC) curve indicated that the areas under the curve (AUCs) of the MHR, NLR, and RPR for predicting MSA were 0.651 (95% CI 0.562–0.74; P < 0.05), 0.6 (95% CI 0.501–0.699; P < 0.05), and 0.612 (95% CI 0.516–0.708; P < 0.05), respectively. The AUC of MSA and PD predicted by the MHR was 0.727 (P < 0.001). When the cut-off value was 0.38, the sensitivity and specificity were 60 and 77%, respectively. Spearman correlation analysis showed that the MHR was significantly and positively correlated with the course of MSA cerebellar type (MSA-C) patients.ConclusionThere may be peripheral inflammation in patients with MSA. Compared with NLR and RPR, MHR has higher predictive value for the diagnosis and differential diagnosis of MSA.

Heterogeneity of Multiple System Atrophy: An Update.

Multiple system atrophy (MSA) is a fatal, rapidly progressing neurodegenerative disease of uncertain etiology, clinically characterized by various combinations of Levodopa unresponsive parkinsonism, cerebellar, autonomic and motor dysfunctions. The morphological hallmark of this α-synucleinopathy is the deposition of aberrant α-synuclein in both glia, mainly oligodendroglia (glial cytoplasmic inclusions /GCIs/) and neurons, associated with glioneuronal degeneration of the striatonigral, olivopontocerebellar and many other neuronal systems. Typical phenotypes are MSA with predominant parkinsonism (MSA-P) and a cerebellar variant (MSA-C) with olivocerebellar atrophy. However, MSA can present with a wider range of clinical and pathological features than previously thought. In addition to rare combined or “mixed” MSA, there is a broad spectrum of atypical MSA variants, such as those with a different age at onset and disease duration, “minimal change” or prodromal forms, MSA variants with Lewy body disease or severe hippocampal pathology, rare forms with an unusual tau pathology or spinal myoclonus, an increasing number of MSA cases with cognitive impairment/dementia, rare familial forms, and questionable conjugal MSA. These variants that do not fit into the current classification of MSA are a major challenge for the diagnosis of this unique proteinopathy. Although the clinical diagnostic accuracy and differential diagnosis of MSA have improved by using combined biomarkers, its distinction from clinically similar extrapyramidal disorders with other pathologies and etiologies may be difficult. These aspects should be taken into consideration when revising the current diagnostic criteria. This appears important given that disease-modifying treatment strategies for this hitherto incurable disorder are under investigation.

Advanced brain aging in multiple system atrophy compared to Parkinson’s disease

Multiple system atrophy (MSA) and Parkinson’s disease (PD) belong to alpha-synucleinopathy, but they have very different clinical courses and prognoses. An imaging biomarker that can differentiate between the two diseases early in the disease course is desirable for appropriate treatment. Neuroimaging-based brain age paradigm provides an individualized marker to differentiate aberrant brain aging patterns in neurodegenerative diseases. In this study, patients with MSA (N = 23), PD (N = 33), and healthy controls (N = 34; HC) were recruited. A deep learning approach was used to estimate brain-predicted age difference (PAD) of gray matter (GM) and white matter (WM) based on image features extracted from T1-weighted and diffusion-weighted magnetic resonance images, respectively. Spatial normative models of image features were utilized to quantify neuroanatomical impairments in patients, which were then used to estimate the contributions of image features to brain age measures. For PAD of GM (GM-PAD), patients with MSA had significantly older brain age (9.33 years) than those with PD (0.75 years; P = 0.002) and HC (-1.47 years; P < 0.001), and no significant difference was found between PD and HC (P = 1.000). For PAD of WM (WM-PAD), it was significantly greater in MSA (9.27 years) than that in PD (1.90 years; P = 0.037) and HC (-0.74 years; P < 0.001); there was no significant difference between PD and HC (P = 0.087). The most salient image features that contributed to PAD in MSA and PD were different. For GM, they were the orbitofrontal regions and the cuneus in MSA and PD, respectively, and for WM, they were the central corpus callosum and the uncinate fasciculus in MSA and PD, respectively. Our results demonstrated that MSA revealed significantly greater PAD than PD, which might be related to markedly different neuroanatomical contributions to brain aging. The image features with distinct contributions to brain aging might be of value in the differential diagnosis of MSA and PD.

Repeat expansion scanning of the NOTCH2NLC gene in patients with multiple system atrophy.

ObjectiveTrinucleotide GGC repeat expansion in the 5’UTR of the NOTCH2NLC gene has been recognized as the pathogenesis of neuronal intranuclear inclusion disease (NIID). Previous studies have described that some NIID patients showed clinical and pathological similarities with multiple system atrophy (MSA). This study aimed to address the possibility that GGC repeat expansion in NOTCH2NLC might be associated with some cases diagnosed as MSA.MethodsA total of 189 patients with probable or possible MSA were recruited to screen for GGC repeat expansion in NOTCH2NLC by repeat‐primed PCR (RP‐PCR). In addition, long‐read sequencing (LRS) was performed for all patients with RP‐PCR‐positive expansion, five patients with RP‐PCR‐negative expansion, and five controls on the Nanopore platform. Skin biopsies were performed on two patients with GGC expansion.ResultsFive of 189 patients (2.6%) were found to have GGC expansion in NOTCH2NLC. LRS results identified that the five patients had GGC expansion between 101 and 266, but five patients with RP‐PCR‐negative expansion and five controls had GGC expansion between 8 and 29. Besides the typical symptoms and signs of MSA, patients with GGC expansion might have longer disease duration, severe urinary retention, and prominent cognitive impairment. In the skin samples from the patients with GGC expansion, typical p62‐postive but alpha‐synuclein‐negative intranuclear inclusions were found in fibroblasts, adipocyte and ductal epithelial cells of sweat glands.ConclusionTrinucleotide GGC repeat expansion in NOTCH2NLC could be observed in patients with clinically diagnosed MSA. Adult‐onset NIID should be considered as a differential diagnosis of MSA.

Diagnostic utility of fluid biomarkers in multiple system atrophy: a systematic review and meta-analysis.

Multiple system atrophy (MSA) is an adult onset, fatal neurodegenerative disease. However, no reliable biomarker is currently available to guide clinical diagnosis and help to determine the prognosis. Thus, a comprehensive meta-analysis is warranted to determine effective biomarkers for MSA and provide useful guidance for clinical diagnosis. A comprehensive literature search was made of the PubMed, Embase, Cochrane and Web of Science databases for relevant clinical trial articles for 1984-2019. Two review authors examined the full-text records, respectively, and determined which studies met the inclusion criteria. We estimated the mean difference, standard deviation and 95% confidence intervals. A total of 28 studies and 11 biomarkers were included in our analysis. Several biomarkers were found to be useful to distinguish MSA patients from healthy controls, including the reduction of phosphorylated tau, α-synuclein (α-syn), 42-amino-acid form of Aβ and total tau (t-tau), the elevation of neurofilament light-chain protein (NFL) in cerebrospinal fluid, the elevation of uric acid and reduction of homocysteine and coenzyme Q10 in plasma. Importantly, α-syn, NFL and t-tau could be used to distinguish MSA from Parkinson's disease (PD), indicating that these three biomarkers could be useful biomarkers in MSA diagnosis. The findings of our meta-analysis demonstrated diagnostic biomarkers for MSA. Moreover, three biomarkers could be used in differential diagnosis of MSA and PD. The results could be helpful for the early diagnosis of MSA and the accuracy of MSA diagnosis.

Multiple system atrophy - a clinicopathological update.

Multiple system atrophy (MSA) is a fatal, adult-onset neurodegenerative disorder of uncertain etiology, clinically characterized by various combinations of Levo-dopa-unresponsive parkinsonism, and cerebellar, motor, and autonomic dysfunctions. MSA is an α-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, autonomic and peripheral nervous systems. The pathologic hallmark of this unique proteinopathy is the deposition of aberrant α-synuclein (αSyn) in both glia (mainly oligodendroglia) and neurons forming pathological inclusions that cause cell dysfunction and demise. The major variants are striatonigral degeneration (MSA with predominant parkinsonism / MSA-P) and olivopontocerebellar atrophy (MSA with prominent cerebellar ataxia / MSA-C). However, the clinical and pathological features of MSA are broader than previously considered. Studies in various mouse models and human patients have helped to better understand the molecular mechanisms that underlie the progression of the disease. The pathogenesis of MSA is characterized by propagation of disease-specific strains of αSyn from neurons to oligodendroglia and cell-to-cell spreading in a "prion-like" manner, oxidative stress, proteasomal and mitochondrial dysfunctions, myelin dysregulation, neuroinflammation, decreased neurotrophic factors, and energy failure. The combination of these mechanisms results in neurodegeneration with widespread demyelination and a multisystem involvement that is specific for MSA. Clinical diagnostic accuracy and differential diagnosis of MSA have improved by using combined biomarkers. Cognitive impairment, which has been a non-supporting feature of MSA, is not uncommon, while severe dementia is rare. Despite several pharmacological approaches in MSA models, no effective disease-modifying therapeutic strategies are currently available, although many clinical trials targeting disease modification, including immunotherapy and combined approaches, are under way. Multidisciplinary research to elucidate the genetic and molecular background of the noxious processes as the basis for development of an effective treatment of the hitherto incurable disorder are urgently needed.

The severity of motor dysfunctions and urinary dysfunction is not correlated in multiple system atrophy

ObjectiveAlthough it is well known that patients with multiple system atrophy (MSA) cerebellar dominant type (MSA-C) show severe autonomic dysfunction, the relationship between autonomic and motor dysfunction remains uncertain. Previously we reported that severe urinary voiding dysfunction is useful in differential diagnosis of MSA and other diseases. Herein, we aimed to clarify the relationship between the severity of motor dysfunctions and urinary dysfunction. MethodThis study is a retrospective review of 46 patients with MSA-C diagnosed according to Gilman's second consensus criteria. The severity of motor dysfunctions was evaluated using International Cooperative Ataxia Rating Scale (ICARS). Urinary voiding dysfunction was evaluated by measuring post-void residual (PVR). The mean duration of motor unit potentials in external anal sphincter muscles on electromyography, which represents the severity of neurodegeneration in Onuf's nucleus, was also examined. ResultsThe mean age of patients was 63.8 ± 8.2 years and mean disease duration was 3.0 ± 1.9 years. The mean ICARS score was 40.1 ± 14.7. The mean PVR was 119.1 ± 102 ml and the mean duration of motor unit potentials (MUPs) in anal sphincter electromyography was 9.2 ± 2.2 ms. The correlation coefficient between ICARS and PVR was 0.093 (p = .539), and between ICARS and mean duration of MUPs was 0.105 (p = .811). A significant positive correlation (r = 0.296, p = .005) was noted between PVR and the mean duration of MUP. ConclusionMotor and urinary dysfunctions were not correlated in MSA-C.

Multiple system atrophy and CAG repeat length: A genetic screening of polyglutamine disease genes in Italian patients

Multiple system atrophy (MSA) is an adult onset, progressive, neurodegenerative disorder of unknown etiology characterized by autonomic dysfunction, parkinsonism (MSA-P) and cerebellar ataxia (MSA-C). The phenotypic spectrum may present overlapping features with other neurodegenerative diseases, particularly the autosomal dominant inherited polyglutamine disorders.To investigate the possible contribution of CAG expansions in the MSA phenotype, we analyzed the triplet repeat length in the autosomal dominant causative genes for spinocerebellar ataxia (SCA) type 1, 2, 3, 6, 7, 17, dentatorubral-pallidoluysian atrophy (DRPLA) and Huntington disease (HD) in a cohort of 246 Italian MSA patients. As comparison, 223 controls were also analyzed. The alleles were classified on the basis of CAG repeat length as “normal”, “intermediate” or “expanded” according to literature.The MSA patients (101 men/145 women) had a mean age at onset of 58 years and a mean age at genetic testing of 63 years. MSA-C patients had significantly younger age at onset and at examination in comparison to MSA-P (p < 0.0001). We identified a SCA1 intermediate allele in a MSA-C subject (36 CAG), a SCA2 intermediate allele in a MSA-P patient (31 CAG), and a pathologically expanded SCA2 allele (36 CAG) in a patient initially misdiagnosed as MSA-C.No intermediate or expanded SCA alleles were detected in controls. The distribution of CAG repeat length was similar among groups except for SCA1 gene that showed a higher percentage of longer normal alleles in MSA-C as compared to MSA-P and controls (p < 0.0001).This study supports the utility of polyQ genetic testing in the differential diagnosis of MSA, and may suggest a possible role of SCA1 repeat length as risk factor for MSA-C. SCA1 and SCA2 genetic screening is recommended in MSA Italian patients.

Using 'swallow-tail' sign and putaminal hypointensity as biomarkers to distinguish multiple system atrophy from idiopathic Parkinson's disease: A susceptibility-weighted imaging study.

To investigate the value of 'swallow-tail' sign and putaminal hypointensity on 3T susceptibility-weighted imaging (SWI) for distinguishing multiple system atrophy (MSA) from idiopathic Parkinson's disease (IPD). Three groups - 39 MSA patients, 18 IPD patients,and 31 healthy controls (HCs) - were administered a 3T SWI sequence to evaluate 'swallow-tail' sign and putaminal hypointensity using visual scales from 0 to 2 and 0 to 3 scores, respectively. The diagnostic accuracy of the two signs separately and combined was calculated using a receiver operating characteristic curve, with clinical diagnosis as the gold standard. The scores of 'swallow-tail' sign were lower in IPD than in MSA or in HCs, as well as for putaminal hypointensity in IPD or HCs than in MSA (p < 0.05). The sensitivity and specificity of 'swallow-tail' sign and putaminal hypointensity were 87.9% and 83.3%, and 35.9% and 100%, respectively, in the respective patient groups. The area under the curve of combined signs was increased from 0.85 ('swallow tail') or 0.68 (putaminal hypointensity) to 0.93. The combination of 'swallow-tail' sign and putaminal hypointensity can increase the accuracy of discriminating between MSA and IPD. • Differential diagnosis of MSA and IPD is still challenging in clinical practice. • Absence of 'swallow-tail' sign is a valuable biomarker for IPD on SWI. • Putaminal hypointensity is a valuable biomarker for MSA on SWI. • Combined 'swallow- tail' sign and putaminal hypointensity increase diagnostic accuracy.

Diagnosis and differential diagnosis of MSA: boundary issues.

Because the progression of multiple system atrophy (MSA) is usually rapid and there still is no effective cause-related therapy, early and accurate diagnosis is important for the proper management of patients as well as the development of neuroprotective agents. However, despite the progression in the field of MSA research in the past few years, the diagnosis of MSA in clinical practice still relies largely on clinical features and there are limitations in terms of sensitivity and specificity, especially in the early course of the disease. Furthermore, recent pathological, clinical, and neuroimaging studies have shown that (1) MSA can present with a wider range of clinical and pathological features than previously thought, including features considered atypical for MSA; thus, MSA can be misdiagnosed as other diseases, and conversely, disorders with other etiologies and pathologies can be clinically misdiagnosed as MSA; and (2) several investigations may help to improve the diagnosis of MSA in clinical practice. These aspects should be taken into consideration when revising the current diagnostic criteria. This is especially true given that disease-modifying treatments for MSA are under investigation.

The comparison of clonidine, arginine and both combined: a growth hormone stimulation test to differentiate multiple system atrophy from idiopathic Parkinson’s disease

This study was aimed at comparing the diagnostic accuracy of the growth hormone (GH) response to clonidine, arginine and both combined in order to establish a more reliable test to differentiate parkinsonism type multiple system atrophy (MSA-p) from Parkinson's disease (PD). Twenty-four patients with MSA-p and 26 cases with PD entered the study. They were submitted to treatments of clonidine, arginine and a combination of the two in a random manner on three different nonconsecutive days. The GH peak in serum at different times was evaluated and used as a primary variable for analysis of the stimulation test. By ROC analysis, we compared the sensitivity and specificity of tests of clonidine, arginine and both combined. After clonidine administration, the maximal average was significantly lower in patients with MSA-p than in those with PD (3.62 +/- 0.81 vs. 6.91 +/- 1.13; P < 0.05) with a sensitivity and specificity of 82.61 and 76.92%. After arginine administration, the maximal average GH concentration in serum at 30 min was also significantly lower in patients with MSA-p than in those with PD (4.07 +/- 0.80 vs. 7.89 +/- 1.29; P < 0.05) with a sensitivity and specificity of 78.26 and 73.08%. The sensitivity and specificity in differentiating MSA-p from PD was higher in the clonidine GH stimulation test than in the arginine GH stimulation test. However, when the clonidine and arginine were applied combined, the contrast of the maximal average GH concentration in serum in two groups was markedly increased (5.02 +/- 1.12 vs. 10.75 +/- 1.11; P < 0.05) with a sensitivity and specificity of 73.91 and 92.31%, and the specificity was notably increased in the combined GH stimulation test. Compared to the arginine GH stimulation test, the clonidine GH stimulation displayed a higher sensitivity and specificity; combined GH stimulation test of clonidine plus arginine could significantly enhance the specificity in differential diagnosis of MSA-p from PD.

Proposed neuroimaging criteria for the diagnosis of multiple system atrophy

In this article, we review the state of the art knowledge concerning structural and functional imaging in multiple system atrophy (MSA). The relative value of imaging modalities in the differential diagnosis of MSA from other parkinsonian syndromes is debated. It is concluded that, although neuroimaging biomarkers provide valuable supportive data alongside clinical assessments, it is not possible to use them as surrogate markers.