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Background: Multiple system atrophy (MSA), an atypical parkinsonian syndrome, is a rapidly progressive neurodegenerative disease with currently no established fluid biomarkers available. MSA is characterized by an oligodendroglial α-synucleinopathy, progressive neuronal cell loss and concomitant astrocytosis. Here, we investigate glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) as fluid biomarkers for differential diagnosis, assessment of clinical disease severity and prediction of disease progression in MSA., Methods: GFAP and NfL levels were analyzed in plasma and CSF samples of 47 MSA patients as well as 24 Parkinson's disease (PD) and 25 healthy controls (HC) as reference cohorts. In MSA, biomarker levels were correlated to baseline and longitudinal clinical disease severity (UMSARS scores)., Results: In MSA, GFAP levels in CSF and plasma predicted baseline clinical disease severity as indicated by UMSARS scores, while NfL levels predicted clinical disease progression as indicated by longitudinal changes in UMSARS scores. Cross-sectionally, NfL levels in CSF and plasma were significantly elevated in MSA compared to both PD and HC. Receiver operating curves (ROC) indicated high diagnostic accuracy of NfL for distinguishing MSA from PD (CSF: AUC = 0.97, 95% CI 0.90-1.00; plasma: AUC = 0.90, 95% CI 0.81-1.00)., Discussion: In MSA, GFAP shows promise as novel biomarker for assessing current clinical disease severity, while NfL might serve as biomarker for prediction of disease progression and differential diagnosis of MSA against PD., (© 2024. The Author(s).)

Blood biomarkers in degenerative ataxias are still largely missing. Here, we aimed to provide piloting proof-of-concept that serum Neurofilament light (NfL) could offer a promising peripheral blood biomarker in degenerative ataxias. Specifically, as a marker of neuronal damage, NfL might (1) help to differentiate multiple system atrophy of cerebellar type (MSA-C) from sporadic adult-onset ataxia (SAOA), and (2) show increases in repeat-expansion spinocerebellar ataxias (SCAs) which might be amenable to treatment in the future. To explore these two hypotheses, we measured serum NfL levels by single-molecule array (Simoa) technique in 115 subjects, comprising patients with MSA-C (n = 25), SAOA (n = 25), the most frequent repeat-expansion SCAs (SCA 1, 2, 3 and 6) (n = 20), and age-matched controls (n = 45). Compared to controls, NfL was significantly increased in MSA-C, with levels significantly higher than in SAOA (AUC = 0.74 (0.59-0.89), mean and 95% confidence interval, p = .004). NfL was also significantly increased in SCA patients as compared to controls (AUC = 0.91 (0.81-1.00), p < .001), including NfL increases in SCA1 and SCA3. These findings provide first proof-of-concept that NfL might provide a promising peripheral biomarker in degenerative ataxias, e.g. supporting the differentiation of MSA-C from SAOA, and indicating neuronal damage in repeat-expansion SCAs.

Oxidative stress is involved in the pathogenesis of multiple system atrophy (MSA). Uric acid has an antioxidative effect. Our aim is to clarify the correlations between serum uric acid and MSA in Chinese population. A total of 234 patients with probable MSA and 240 age- and gender- matched healthy controls were included in the study. The serum uric acid levels of all the patients and controls were evaluated. The Unified MSA Rating Scale (UMSARS) was used to assess the severity and the mean rate of annualized changes of UMSARS to assess the progression of MSA. The mean age of MSA patients was 58.90 ± 9.00 years and the mean disease duration was 2.60 ± 1.75 years. The serum uric acid levels of MSA patients were significantly lower than that of controls in males (p = 0.0001). The occurrence of MSA was increased in the lowest uric acid quartiles compared with the highest uric acid quartiles (p = 0.005). In a gender-specific analysis, increased occurrence was found in the lowest quartiles and second quartiles compared with the highest quartiles in males (p = 0.001 and p = 0.0001 respectively), but not in females. No correlation was found between the mean rate of annualized changes and serum levels of uric acid, as well as other independent factors, such as age, BMI, gender, subtype (C-type or P-type) and disease duration at the initial visit in 107 followed-up patients. MSA patients have lower levels of serum uric acid than controls. High levels of serum uric acid may be associated with a lower prevalence of MSA in the Chinese population, especially in males. However, serum uric acid does not deteriorate or ameliorate the progression of MSA.

Postprandial hypotension (PPH) is a major clinical problem in patients with autonomic failure such as that observed in multiple system atrophy (MSA). The pathophysiology of PPH remains unclear, although autonomic dysfunction and gastrointestinal vasoactive peptides have been suspected to participate in its pathogenesis. We measured blood pressure and plasma levels of glucose, insulin, noradrenaline, neurotensin, glucagon-like peptide (GLP)-1 and GLP-2 before and after meal ingestion in 24 patients with MSA to reveal the roles of the autonomic nervous system and gastrointestinal vasoactive peptides in PPH. We performed a second meal-ingestion test by administering acarbose to evaluate the effects of acarbose (an α-glucosidase inhibitor) on PPH and vasoactive peptides in 14 patients with MSA and PPH. We also evaluated blood pressure responses to the head-up tilt test and heart rate variability in all the patients. Severities of PPH and orthostatic hypotension were significantly correlated. Patients with PPH had significantly worse orthostatic hypotension and lower heart rate variability than those without PPH. Postprandial GLP-1 secretion was higher in patients with PPH than in those without PPH. No significant differences were observed in the postprandial increases in plasma levels of glucose, insulin, noradrenaline, neurotensin or GLP-2. Acarbose significantly attenuated postprandial hypotension and tended to decrease GLP-2 secretion. Our results indicate that autonomic failure is involved in the pathogenesis of PPH and confirm that acarbose has a preventive effect against PPH in patients with MSA. Decreased postprandial secretion of GLP-2, which increases intestinal blood pooling, may attenuate PPH in patients with MSA.

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.

Previous studies showed the reduction of dopamine transporter immunoreactivity (DAT-IR) in peripheral blood lymphocytes (PBL) in Parkinson's disease. Here we report the reduction of DAT-IR in PBL in the extrapyramidal variant of multiple system atrophy. These results suggest the reduction of DAT-IR in PBL in a variety of neurodegenerative disorders, provided the presence of damage of the central dopaminergic systems. The reduction of DAT-IR in PBL in these disorders may represent a compensatory phenomenon aimed at reducing intracellular dopamine influx and, consequently, dopamine-mediated aggravation of oxidative stress in these cells.

alpha-Synuclein, a synaptic protein of unknown function, is a major component of Lewy bodies and may play a role in the pathophysiological process of Parkinson's disease (PD). In this study, we measured the plasma alpha-synuclein levels in 105 patients with PD, 38 patients with multiple system atrophy (MSA), and 51 age-matched controls. The alpha-synuclein level was significantly elevated in patients with PD (79.9 +/- 4.0 pg/ml, p < 0.001) and in those with MSA (78.1 +/- 3.5 pg/ml, p = 0.019) compared with the level in controls (76.1 +/- 3.9 pg/ml). The alpha-synuclein level was higher in patients with PD than in those with MSA (79.9 +/- 4.0 vs 78.1 +/- 3.5, p = 0.016). Our study demonstrated that the alpha-synuclein level in plasma is elevated in patients with PD and MSA.

We evaluated the effect of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) on the response of blood pressure and vasoactive factors during head-up tilt in patients with multiple system atrophy (MSA). After the daily oral administration of 300 mg L-threo-DOPS for 2 weeks we observed a significant reduction in the decline of systolic blood pressure during 60 degrees head-up-tilt. In concordance with this result, we detected significant increases in postural changes in plasma renin activity and angiotensin II following L-threo-DOPS treatment. The enhanced responses of these vasoactive mediators by L-threo-DOPS during head-up tilt may contribute to the improvement in orthostatic hypotension in patients with MSA.