Video-oculographic Differences between Parkinson Disease and Multiple System Atrophy (P9-11.016)

Phosphorylated α-synuclein and phosphorylated tau-protein in sural nerves may contribute to differentiate Parkinson’s disease from multiple system atrophy and progressive supranuclear paralysis

IntroductionClinical diagnosis of Parkinsonism is still challenging, and the diagnostic biomarkers of Multiple System Atrophy (MSA) are scarce. This study aimed to investigate the diagnostic value of the combined eye movement tests in patients with Parkinson's disease (PD) and those with MSA.MethodsWe enrolled 96 PD patients, 33 MSA patients (18 with MSA‐P and 15 with MSA‐C), and 40 healthy controls who had their horizontal ocular movements measured. The multiple‐step pattern of memory‐guided saccade (MGS), the hypometria/hypermetria of the reflexive saccade, the abnormal saccade in smooth pursuit movement (SPM), gaze‐evoked nystagmus, and square‐wave jerks in gaze‐holding test were qualitatively analyzed. The reflexive saccadic parameters and gain of SPM were also quantitatively analyzed.ResultsThe MGS test showed that patients with either diagnosis had a significantly higher incidence of multiple‐step pattern compared with controls (68.6%, 65.2%, and versus. 2.5%, p < .05, in PD, MSA, versus. controls, respectively). The reflexive saccade test showed that MSA patients showing a prominent higher incidence of the abnormal saccade (63.6%, both hypometria and hypermetria) than that of PD patients and controls (33.3%, 7.5%, respectively, hypometria) (p < .05). The SPM test showed PD patients had mildly decreased gain among whom 28.1% presenting “saccade intrusions”; and that MSA patients had the significant decreased gain with 51.5% presenting “catch‐up saccades”(p < .05). Only MSA patients showed gaze‐evoked nystagmus (24.2%), square‐wave jerks (6.1%) in gaze‐holding test (p < .05).ConclusionsA panel of eye movements tests may help to differentiate PD from MSA. The combined presence of hypometria and hypermetria in saccadic eye movement, the impaired gain of smooth pursuit movement with “catch‐up saccades,” gaze‐evoked nystagmus, square‐wave jerks in gaze‐holding test, and multiple‐step pattern in MGS may provide clues to the diagnosis of MSA.

Disease-modifying therapeutics in the α-synucleinopathies multiple system atrophy (MSA) and Parkinson’s Disease (PD) are in early phases of clinical testing. Involving patients’ preferences including therapy-associated risk willingness in initial stages of therapy development has been increasingly pursued in regulatory approval processes. In our study with 49 MSA and 38 PD patients, therapy-associated risk willingness was quantified using validated standard gamble scenarios for varying severities of potential drug or surgical side effects. Demonstrating a non-gaussian distribution, risk willingness varied markedly within, and between groups. MSA patients accepted a median 1% risk [interquartile range: 0.001–25%] of sudden death for a 99% [interquartile range: 99.999–75%] chance of cure, while PD patients reported a median 0.055% risk [interquartile range: 0.001–5%]. Contrary to our hypothesis, a considerable proportion of MSA patients, despite their substantially impaired quality of life, were not willing to accept increased therapy-associated risks. Satisfaction with life situation, emotional, and nonmotor disease burden were associated with MSA patients’ risk willingness in contrast to PD patients, for whom age, and disease duration were associated factors. An individual approach towards MSA and PD patients is crucial as direct inference from disease (stage) to therapy-associated risk willingness is not feasible. Such studies may be considered by regulatory agencies in their approval processes assisting with the weighting of safety aspects in a patient-centric manner. A systematic quantitative assessment of patients’ risk willingness and associated features may assist physicians in conducting individual consultations with patients who have MSA or PD by facilitating communication of risks and benefits of a treatment option.

Objective To investigate the differences of candidate cerebrospinal fluid (CSF) biomarkers associated with multiple system atrophy (MSA) and Parkinson's disease (PD). Method Here, a systematic review and meta-analysis were conducted on studies related to CSF biomarkers associated with MSA and PD obtained from PubMed, Web of Science, Embase, and Cochrane databases. Data were pooled where appropriate and used to calculate standardized mean differences (SMDs) with 95% confidence intervals (CI). Heterogeneity was assessed using the I2 statistic while Egger's test was used to test for existing publication bias. Results MSA patients had higher CSF t-tau (SMD = 0.41, 95% CI: 0.10 to 0.72) and YKL-40 (SMD = 0.63, 95% CI 0.12 to1.15) as well as DJ-1 (SMD = 1.05, 95% CI 0.67 to 1.42) levels than PD patients, while CSF p-tau (SMD = −0.17, 95% CI, -0.31 to -0.02) and Aβ-42 (SMD = −0.33, 95% CI, -0.55 to -0.12) levels in MSA patients were lower than those in PD patients. There were no differences in CSF's GFAP and Flt3 ligand levels in both MSA and PD patients. Conclusion The study revealed the differences in CSF biomarker levels between MSA and PD cohorts that can be further explored to clinically distinguish MSA from PD.

BackgroundDetection of the pathological and disease-associated alpha-synuclein (αSynD) in the brain is required to formulate the definitive diagnosis of multiple system atrophy (MSA) and Parkinson’s disease (PD). We recently showed that αSynD can be detected in the olfactory mucosa (OM) of MSA and PD patients. For this reason, we have performed the first interlaboratory study based on α-synuclein Real-Time Quaking-Induced Conversion (αSyn_RT-QuIC) analysis of OM samples collected from PD and MSA patients with the parkinsonian (MSA-P) and cerebellar (MSA-C) phenotypes.MethodsOM samples were prospectively collected from patients with a probable diagnosis of MSA-P (n = 20, mean disease duration 4.4 years), MSA-C (n = 10, mean disease duration 4 years), PD (n = 13, mean disease duration 8 years), and healthy control subjects (HS) (n = 11). Each sample was analyzed by αSyn_RT-QuIC in two independent specialized laboratories, one located in Italy (ITA-lab) and one located in the USA (USA-lab). Both laboratories have developed and used harmonized αSyn_RT-QuIC analytical procedures. Results were correlated with demographic and clinical data.ResultsThe αSyn_RT-QuIC analysis reached a 96% interrater agreement of results (IAR) between laboratories (Kappa = 0.93, 95% CI 0.83–1.00). In particular, αSyn_RT-QuIC seeding activity was found in the OM of 9/13 patients with PD (sensitivity 69%, IAR 100%) and 18/20 patients with MSA-P (sensitivity 90%, IAR 100%). Interestingly, samples collected from patients with MSA-C did not induce αSyn_RT-QuIC seeding activity, except for one subject in USA-lab. Therefore, we found that MSA-P and MSA-C induced opposite effects. Regardless of disease diagnosis, the αSyn_RT-QuIC seeding activity correlated with some clinical parameters, including the rigidity and postural instability.ConclusionsOur study provides evidence that OM-αSynD may serve as a novel biomarker for accurate clinical diagnoses of PD, MSA-P, and MSA-C. Moreover, αSyn_RT-QuIC represents a reliable assay that can distinguish patients with MSA-P from those with MSA-C, and may lead to significant advancements in patients stratification and selection for emerging pharmacological treatments and clinical trials.

A comparison of auditory and vestibular dysfunction in Parkinson's disease and Multiple System Atrophy

Analysis of colonic alpha-synuclein pathology in multiple system atrophy

Adreno-medullary sympathetic nerves and ascending baroreceptor pathways are not affected in Parkinson's disease patients with orthostatic hypotension

Hashimoto's encephalopathy with serum anti-NH2-terminal of α-enolase (NAE) antibodies occasionally displays clinical symptoms such as cerebellar ataxia and parkinsonism. We studied the frequency of anti-NAE antibodies in patients with Parkinson-plus syndrome. We examined the positive rates of anti-NAE antibodies in 47 patients with multiple system atrophy (MSA), 29 patients with Parkinson's disease (PD), eight patients with corticobasal syndrome (CBS), and 18 patients with progressive supranuclear palsy (PSP) using conventional immunoblot analysis. Positive anti-NAE antibody rates of 31.9%, 10.3%, 50.0%, and 11.1% were reported in the MSA, PD, CBS, and PSP patients, respectively. The duration from onset to a wheelchair-bound state in seropositive MSA patients tended to be shorter than that in seronegative MSA patients. Anti-NAE antibodies are detected in some patients clinically diagnosed with MSA and CBS. Although its pathophysiological significance remains uncertain, serum anti-NAE antibodies might represent a prognostic marker in the clinical course of MSA.

Multiple system atrophy (MSA) is a fatal neurodegenerative synucleinopathy characterized by the accumulation of α-synuclein in oligodendrocytes, forming glial cytoplasmic inclusions. Although iron dysregulation and ferroptosis, an iron-dependent form of regulated cell death, have been implicated in neurodegeneration, their specific role in MSA oligodendrocytes remains unknown. We investigated ferroptosis pathways in postmortem brain tissues from patients with MSA, Parkinson's disease (PD), and healthy controls (HCs) by immunofluorescence for GPX4 co-labelled with CNPase (oligodendrocyte marker) or TH (dopaminergic neuron marker). To validate these findings, we employed PLP-hαSyn transgenic mice, an established MSA model, and the human oligodendrocytic cell line MO3.13, subjected to α-synuclein over-expression, preformed fibrils (PFF) exposure, and brain homogenates derived from MSA pons. Mechanistic insights were pursued through immunofluorescence, JC-1, FerroOrange, western blotting, and co-immunoprecipitation. Finally, we developed a novel biomarker assay using nanoscale flow cytometry to quantify FTH1-containing, CNPase-positive (oligodendrocyte-derived) EVs (ODFC-EVs) in plasma samples from 49 MSA patients, 46 PD patients, and 48 HCs. GPX4, the key ferroptosis regulator, was significantly reduced in CNPase+ oligodendrocytes of MSA brains versus PD and HCs, while, as expected, GPX4 loss in PD predominated in TH+ neurons. PLP-hαSyn mice recapitulated the unique GPX4 suppression in oligodendrocytes. In MO3.13 cells, α-synuclein enhanced erastin-induced GPX4 loss, increased labile Fe2+ accumulation and aggravated mitochondrial depolarisation. Mechanistically, α-synuclein was found to directly bind and stabilize NCOA4, impairing its ubiquitination-mediated degradation. This enhanced NCOA4 activity drove excessive ferritinophagy, leading to the lysosomal degradation of the iron-storage protein FTH1 and subsequent iron overload. Translationally, plasma levels of ODFC-EVs were significantly reduced in MSA patients compared to both PD patients (AUC 0.771; sensitivity 65.3%, specificity 84.8%) and HCs (AUC 0.857; sensitivity 67.4%, specificity 91.7%). Our study provides the first in vivo and mechanistic evidence supporting a model in which α-synuclein drives oligodendrocyte-specific ferroptosis in MSA by stabilizing NCOA4, depleting FTH1 and promoting toxic iron accumulation. This cell-type-restricted mechanism distinguishes MSA pathogenesis from that of PD. Furthermore, the parallel reduction of circulating ODFC-EVs offers a readily accessible blood-based biomarker to discriminate MSA from PD. Together, these findings position the α-synuclein-NCOA4-FTH1 axis as a central pathogenic pathway and a compelling therapeutic target for MSA.

The value of neurofilament light chain (NfL) levels as a biomarker for the diagnosis and differential diagnosis in patients with Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) remains controversial. Furthermore, few studies have directly compared NfL levels among specific APS categories. This study aimed to compare cerebrospinal fluid (CSF) and blood NfL levels among PD, APS, other PD-related disorders, and controls, as well as rank NfL levels across these groups. PubMed, Embase, Web of Science, and the Cochrane Library were searched from the inception up to November 1st, 2024, to identify eligible studies reporting CSF or blood NfL concentrations in PD, PD dementia (PDD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), corticobasal syndrome (CBS), vascular parkinsonism (VP), essential tremor (ET), idiopathic rapid eye movement sleep behavior disorder (iRBD), and controls. The Bayesian approach was utilized to estimate the standardized mean difference (SMD) and the associated 95% credible intervals (CrIs) of NfL levels. The surface under the cumulative ranking curve (SUCRA) was employed to evaluate the ranking probabilities of NfL levels. Subgroup analysis and meta-regression were conducted to explore the sources of heterogeneity. The present network meta-analysis (NMA) included 78 studies with 13,120 participants (4050 controls, 5021 PD, 191 PDD, 1173 MSA, 887 PSP, 1254 DLB, 319 CBS, 160 ET, 65 iRBD, and 0 VP). Of these, the NMA of CSF NfL included 34 studies with 6,013 participants, while the NMA of blood NfL included 49 studies with 7,787 participants. Both CSF and blood NfL levels were significantly elevated in patients with PD and APS compared to controls. Compared to PD patients, CSF NfL levels were significantly elevated in MSA (SMD 1.85; 95% CrI 1.55-2.15), CBS (1.42; 1.08-1.75), PSP (1.35; 1.06-1.64), and DLB 0.52; 0.20-0.85) patients. Similarly, blood NfL levels were significantly higher in patients with MSA (1.36; 1.02-1.71), PDD (1.19; 0.65-1.72), PSP (1.15; 0.77-1.54), CBS (0.92; 0.11-1.72), and DLB (0.63; 0.14-1.12) compared to PD. Among APS, CSF NfL levels in MSA patients were significantly higher than those in PSP, DLB, and CBS patients, while blood NfL levels in MSA patients were significantly higher only compared to DLB. In both CSF and blood NfL, MSA patients exhibited the highest probability of ranking first for NfL level elevations (CSF: SUCRA = 0.998; blood: SUCRA = 0.925). Age significantly influenced the SMD of the comparison between MSA and PD in CSF NfL (β = -0.15; p = 0.016). CSF and blood NfL levels in PD and APS are higher than those in controls, and all APS categories show higher levels than PD, suggesting that NfL levels may serve as a potential biomarker for the differential diagnosis between PD and APS. However, caution is warranted when using NfL as a diagnostic biomarker for PD. Significant differences in NfL levels are also observed between certain APS categories. Patients with MSA exhibit the highest NfL levels among PD and related disorders.

Parkinson’s disease (PD) and the parkinsonian variant of multiple system atrophy (MSAp) are neurodegenerative disorders that can be difficult to differentiate clinically. This study provides the first characterization of the patterns of task-related functional magnetic resonance imaging (fMRI) changes across the whole brain in MSAp. We used fMRI during a precision grip force task and also performed voxel-based morphometry (VBM) on T1-weighted images in MSAp patients, PD patients, and healthy controls. All groups were matched on age, and the patient groups had comparable motor symptom durations and severities. There were three main findings. First, MSAp and PD had reduced fMRI activation in motor control areas, including the basal ganglia, thalamus, insula, primary sensorimotor and prefrontal cortices, and cerebellum compared with controls. Second, there were no activation differences among the disease groups in the basal ganglia, thalamus, insula, or primary sensorimotor cortices, but PD had more extensive activation deficits throughout the cerebrum compared with MSAp and controls. Third, VBM revealed reduced volume in the basal ganglia, middle and inferior cerebellar peduncles, pons, and throughout the cerebrum in MSAp compared with controls and PD, and additionally throughout the cerebellar cortex and vermis in MSAp compared with controls. Collectively, these results provide the first evidence that fMRI activation is abnormal in the basal ganglia, cerebellum, and cerebrum in MSAp, and that a key distinguishing feature between MSAp and PD is the extensive and widespread volume loss throughout the brain in MSAp.

We sought to explore the phenomenon of disproportionate antecollis in multiple system atrophy (MSA) and Parkinson's disease (PD). The etiology is much debated and the main issue is whether it represents a primary myopathy or is secondary to the underlying motor disorder. The clinical, electrophysiological, and biopsy data of MSA or PD patients with antecollis were reviewed. We reviewed 16 patients (7 MSA and 9 PD) who developed antecollis during the course of their disease. The interval between onset of motor symptoms and of antecollis was shorter in the MSA group (4.6 +/- 1.7 years vs. 10.5 +/- 7.0 years). In 6 patients, the antecollis developed subacutely, and in 2 the abnormal neck flexion was initially an off-period phenomenon. Two additional patients also showed some dopa-responsiveness. Clinically, the antecollis was characterized by a forward flexion and anterior shift of the neck, with prominent cervical paraspinal and levator scapulae muscles, usually without weakness of residual neck extension. Electromyography of cervical paraspinal muscles showed mixed myopathic, normal, and neurogenic units, without early recruitment. Cervical paraspinal muscle biopsy in 2 patients disclosed fibrosis and nonspecific myopathic changes. We suggest that, in the context of MSA or PD, the initiating event in antecollis could be a disproportionately increased tone in anterior neck muscles that leads to secondary fibrotic and myopathic changes. However, a primary but yet unexplained neck extensor myopathy still remains the alternative possibility and longitudinal studies are necessary to settle this issue.

Systemic postganglionic adrenergic studies do not distinguish parkinson's disease from multiple system atrophy

Theory of Mind is defined as the ability to attribute mental state and emotions to other people and is relevant to social relationships. The cortical and subcortical regions involved in Theory of Mind are damaged by neurodegenerative processes of Parkinsonian syndromes, so the aim of the present study was to explore, for the first time, possible deficits of Theory of Mind and their cognitive correlates in multiple system atrophy (MSA). Twenty-six patients with MSA, 25 patients with Parkinson's disease (PD) and 25 healthy subjects were enrolled. Cognitive and affective subcomponents of Theory of Mind, executive functions, long-term memory and apathy were evaluated. The three groups did not differ on demographic variables. MSA and PD groups performed worse than healthy subjects on both cognitive (advanced test of ToM) and affective (emotion attribution task) ToM tasks, but no significant difference was found between patients' groups. However, when using another affective ToM task (Eyes Test), MSA group had poorer performance than healthy subjects and Parkinsonian patients, whereas Parkinsonian patients had similar performance to healthy subjects. Regression analysis revealed an association between poor cognitive flexibility and dysfunctional cognitive component of Theory of Mind. Deficit of cognitive and affective components of Theory of Mind occurred in MSA. Dysfunction of cognitive component was related to executive dysfunction (i.e. cognitive rigidity). These findings might suggest the usefulness of an early evaluation of social cognition in MSA to identify individuals with impaired Theory of Mind who are at risk of social withdrawal, and reduced quality of life.