Prediction of early-wheelchair dependence in multiple system atrophy based on machine learning algorithm: A prospective cohort study.

Objective: The predictive factors for wheelchair dependence in patients with multiple system atrophy (MSA) are unclear. We aimed to explore the predictive factors for early-wheelchair dependence in patients with MSA focusing on clinical features and blood biomarkers. Methods: This is a prospective cohort study. This study included patients diagnosed with MSA between January 2014 and December 2019. At the deadline of October 2021, patients met the diagnosis of probable MSA were included in the analysis. Random forest (RF) was used to establish a predictive model for early-wheelchair dependence. Accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were used to evaluate the performance of the model. Results: Altogether, 100 patients with MSA including 49 with wheelchair dependence and 51 without wheelchair dependence were enrolled in the RF model. Baseline plasma neurofilament light chain (NFL) levels were higher in patients with wheelchair dependence than in those without (P = 0.037). According to the Gini index, the five major predictive factors were disease duration, age of onset, Unified MSA Rating Scale (UMSARS)-II score, NFL, and UMSARS-I score, followed by C-reactive protein (CRP) levels, neutrophil-to-lymphocyte ratio (NLR), UMSARS-IV score, symptom onset, orthostatic hypotension, sex, urinary incontinence, and diagnosis subtype. The sensitivity, specificity, accuracy, and AUC of the RF model were 70.82 %, 74.55 %, 72.29 %, and 0.72, respectively. Conclusion: Besides clinical features, baseline features including NFL, CRP, and NLR were potential predictive biomarkers of early-wheelchair dependence in MSA. These findings provide new insights into the trials regarding early intervention in MSA.

The Use of Cerebellar Hypoperfusion Assessment in the Differential Diagnosis of Multiple System Atrophy with Parkinsonism and Progressive Supranuclear Palsy-Parkinsonism Predominant.

The differential diagnosis of MSA-P and PSP-P remains a difficult issue in clinical practice due to their overlapping clinical manifestation and the lack of tools enabling a definite diagnosis ante-mortem. This paper describes the usefulness of SPECT HMPAO in MSA-P and PSP-P differentiation through the analysis of cerebellar perfusion of small ROIs. Thirty-one patients were included in the study­20 with MSA-P and 11 with PSP-P; the analysis performed indicated that the most significant difference in perfusion was observed in the anterior quadrangular lobule (H IV and V) on the left side (p < 0.0026). High differences in the median perfusion between the groups were also observed in a few other regions, with p < 0.05, but higher than premised p = 0.0026 (the Bonferroni correction was used in the statistical analysis). The assessment of the perfusion may be interpreted as a promising method of additional examination of atypical parkinsonisms with overlapping clinical manifestation, as in the case of PSP-P and MSA-P. The results obtained suggest that the interpretation of the differences in perfusion of the cerebellum should be made by evaluating the subregions of the cerebellum rather than the hemispheres. Further research is required.

Cognition in Patients With Multiple System Atrophy (MSA) and Its Neuroimaging Correlation: A Prospective Case-Control Study.

Objective Cognition has been reported to be involved in patients with multiple system atrophy (MSA), although initially it was considered an exclusion in the diagnosis of MSA. We assessed cognition in these patients and compared it with age and education matched healthy controls and correlated with the gray matter volume using voxel-based morphometry (VBM). Materials and methods This was a prospective, case-control, single-center study. Thirty patients with MSA (20 MSA-C (cerebellar variant) and 10 MSA-P (Parkinsonian variant)) and 25 age- and educational level-matched healthy controls were included. All the patients and controls underwent detailed neuropsychological tests and MRI brain. A battery of neuropsychological tests like Stroop test, digit span forward and backward, digit symbol substitution time test, animal naming test, color trail test and auditory verbal learning test were used to assess the various domain of cognition, which include mainly attention, executive function, memory, new learning, mental and motor speed. The gray matter volume was determined using VBM and correlated with neuropsychological scores. Results Attention, execution, verbal and visual memory, verbal fluency, and new learning were impaired in patients with MSA. MSA-P had more impairment in motor and mental speed, working memory, executive functions, and focused attention compared to MSA-C. Patients with MSA-C had more impairment in new learning, immediate recall, verbal fluency, and sustained attention compared to MSA-P. However, it was not statistically significant. There was a significant correlation between the various cognitive domains and atrophy of frontotemporal cortical areas, insula, caudate, thalamus, and cerebellum. Conclusion Cognition is impaired in patients with MSA-C and MSA-P and is likely due to the neurodegenerative process involving the cortical and subcortical structures. Long-term follow-up studies are required to find out the progression of these cognitive changes.

Platelet-to-lymphocyte ratio and neutrophil-tolymphocyte ratio may reflect differences in PD and MSA-P neuroinflammation patterns.

AIM OF THE STUDY: To assess the usefulness of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in evaluating the inflammatory process in alpha-synucleinopathies. CLINICAL RATIONALE FOR THE STUDY: The role of neuroinflammation in PD and MSA pathogenesis is indisputable. However, there is no method available in everyday use that would enable its evaluation. We suggest that NLR and PLR, as non-specific parameters of inflammation, due to its approachability could be helpful in the assessment of inflammatory activity in alpha-synucleinopathies in everyday clinical practice. MATERIAL AND METHODS: 98 patients with a clinical diagnosis of PD, 28 with MSA-P, and 99 healthy age-matched controls, were included in the study. Blood samples were analysed in order to count neutrophil and lymphocyte rates and, subsequently, NLR and PLR. The obtained parameters were compared between the groups. Results were statistically analysed. RESULTS: Our results indicate that patients with PD have higher values of NLR and PLR compared to controls. For MSA-P, only NLR was significantly higher in relation to the control group. There were no statistically significant differences between patients with PD and MSA-P in relation to NLR and PLR values. There was a positive average correlation between NLR and disease duration for MSA-P patients. CONCLUSIONS: NLR and PLR values are significantly higher in alpha-synucleinopathies (MSA-P and PD) in relation to a control group. In PD patients, both NLR and PLR values are significantly higher in relation to a control group, whereas in patients with MSA-P, only NLR is significantly increased. The observed differences may reflect distinct neuroinflammatory patterns present in these entities. CLINICAL IMPLICATIONS: NLR and PLR are features of peripheral inflammation. Their specificity is relatively low, although increased values suggest possible inflammatory pathogenesis of clinical entities. NLR is based on the observations that in chronic and acute diseases the neutrophil rate has a tendency to rise, while the lymphocyte rate tends to decline. This aspect of inflammatory processes has been primarily evaluated in Intensive Care Units. PLR is a marker presenting changes in platelet and lymphocyte counts caused by acute inflammatory or prothrombotic states. Different values of NLR and PLR in PD and MSA-P compared to healthy controls suggest that in these two alpha-synucleinopathies, different patterns of neuroinflammation might be present. The role of inflammation in the differential diagnosis of parkinsonian syndromes remains unexplored.

Simple linear brainstem MRI measurements in the differential diagnosis of progressive supranuclear palsy from the parkinsonian variant of multiple system atrophy.

Differential diagnosis of progressive supranuclear palsy (PSP) and the parkinsonian variant of multiple system atrophy (MSA-P) from Parkinson's disease (PD) can be difficult, particularly in atypical cases or early in the disease course. The Magnetic Resonance Parkinsonism Index (MRPI) utilizes linear and surface (planimetry) measurements and has been proposed as a dual MRI biomarker, with high values indicative of PSP and low values of MSA. The aim of this study was to examine the utility of simple linear MRI brainstem measurements, without the use of MRI planimetry, in the diagnosis of patients with Parkinsonism and compare them to the MRPI. A total of 51 patients (PSP: 24, MSA-P: 9, PD: 18) and 15 healthy controls were included. Simple linear MRI distances of brainstem structures were measured. These included midbrain and pons diameters as well as superior cerebellar peduncle (SCP) and middle cerebellar peduncle (MCP) widths. All relevant indices, including ratios and products, were also calculated. The SCP by midbrain product (SCP × midbrain) provided improved sensitivity (100 vs. 91%) and identical specificity (98%) for the diagnosis of PSP, compared to the MRPI. Neither the MRPI nor any of the linear measurements were able to discriminate MSA-P from PD. The SCP by midbrain product is a novel, potent MRI biomarker for PSP.

Does the Type of Multisystem Atrophy, Parkinsonism, or Cerebellar Ataxia Impact on the Nature of Sleep Disorders?

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by a combination of autonomic failure, parkinsonism, and/or cerebellar ataxia. The cause of MSA is unknown, but neuropathologically the disease is characterized by widespread α-synuclein-positive glial cytoplasmic inclusions and striatonigral and/or olivopontocerebellar neurodegeneration. Two motor phenotypes have been clinically identified: parkinsonian (MSA-P) and cerebellar (MSA-C). In order to elucidate if in addition to the motor abnormalities there are other significant differences between these two phenotypes, we performed a review of the studies on sleep disorders in the two MSA subtypes. Substantially, any significant difference in the sleep structure, as well as in the frequency and severity of the sleep disorders, has been found between MSA-P and MSA-C patients. Recent studies clearly showed similarities between the two MSA subtypes in terms of demographic distributions, natural history of the disease, and survivals. These findings suggest that although the dominant clinical presentations differ between MSA-C and MSA-P, a common pathophysiology may underlie both subtypes of MSA.

Voxelwise meta-analysis of gray matter anomalies in Parkinson variant of multiple system atrophy and Parkinson's disease using anatomic likelihood estimation.

Numerous voxel-based morphometry (VBM) studies on gray matter (GM) in patients with the Parkinson variant of multiple system atrophy (MSA-P) and Parkinson's disease (PD) have been separately conducted. Identifying the different neuroanatomical changes in GM between MSA-P and PD through meta-analysis may aid the differential diagnosis of MSA-P and PD. A systematic review of VBM studies on patients with MSA-P and PD compared to healthy controls (HC) from the PubMed and Embase databases between January 1995 and June 2014 was conducted. Five studies comparing MSA-P with HC and twenty-three studies comparing PD with HC were included. The anatomical distribution of the coordinates of GM volume (GMV) differences was analyzed using the anatomical likelihood estimation (ALE) method. GMV reductions were present in the bilateral putamen, claustrum, insula, midbrain and left cerebellum in MSA-P. In PD, GMV decreases were present in the frontal, parietal, occipital and limbic lobes. Subtraction meta-analysis was performed to explore the differences in GM abnormalities between MSA-P and PD during the early stage of the disease. For patients with disease duration within 5 years, compared with PD, the decrease in GMV focused on the bilateral putamen and claustrum in MSA-P. In contrast, for patients with disease duration within 3 years, no significant GMV difference was found between MSA-P and PD. Our meta-analysis indicated that the atrophy of bilateral putamen or claustrum is not a neuroanatomical marker for distinguishing MSA-P from PD during the early stage by using the VBM method.

In vivo evaluation of gray and white matter volume loss in the parkinsonian variant of multiple system atrophy using SPM8 plus DARTEL for VBM.

In multiple system atrophy with predominant parkinsonism (MSA-P), several voxel-based morphometry (VBM) studies have revealed gray matter loss; however, the white matter volume changes have been rarely reported. We investigated the volume changes of white matter as well as gray matter by VBM. A retrospective MRI study was performed in 20 patients with MSA-P and 30 age-matched healthy controls. We applied VBM with statistical parametric mapping (SPM8) plus diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) to explore the regional atrophy of gray and white matter in all of the MSA-P patients, 14 patients with left-side dominant and 6 patients with right-side dominant onset as compared to controls. In all of the MSA-P patients, VBM revealed a significant volume reduction of gray matter in the bilateral putamina, cerebellums and dorsal midbrain. White matter loss was located in bilateral globus pallidi, external capsules extending to the midbrain, right subcortical to precentral area through internal capsule, the pons, bilateral middle cerebellar peduncles and left cerebellum. In left-side dominant MSA-P patients, the gray and white matter volume loss was detected predominantly on the right side and vice versa in right-side dominant MSA-P patients. A correlation with disease duration and severity was not detected. VBM using SPM8 plus DARTEL detected significant volume loss not only in the gray but also in the white matter of the area affected by MSA-P.

Oligodendroglial alpha-synucleinopathy and MSA-like cardiovascular autonomic failure: experimental evidence.

Multiple system atrophy (MSA) is a fatal, rapidly progressive neurodegenerative disease with limited symptomatic treatment options. Discrimination of MSA from other degenerative disorders crucially depends on the presence of early and severe cardiovascular autonomic failure (CAF). We have previously shown that neuropathologic lesions in the central autonomic nuclei similar to the human disease are present in transgenic MSA mice generated by targeted oligodendroglial overexpression of α-syn using the PLP promoter. We here explore whether such lesions result in abnormalities of heart rate variability (HRV) and circadian rhythmicity which are typically impaired in MSA patients. HRV analysis was performed in five month old transgenic PLP-α-syn (tg) MSA mice and age-matched wild type controls. Decreased HRV and alterations in the circadian rhythmicity were detected in the tg MSA group. The number of choline-acetyltransferase-immunoreactive neurons in the nucleus ambiguus was significantly decreased in the tg group, whereas the levels of arginine-vasopressin neurons in the suprachiasmatic and paraventricular nucleus were not affected. Our finding of impaired HRV and circadian rhythmicity in tg MSA mice associated with degeneration of the nucleus ambiguus suggests that a cardinal non-motor feature of human MSA can be reproduced in the mouse model strengthening its role as a valuable testbed for studying selective vulnerability and assessing translational therapies.