Young-onset multiple system atrophy: Clinical and pathological features.

The aim of this study was to evaluate differences in the clinical presentation and polysomnographic characteristics of rapid eye movement sleep behavior disorder (RBD) between patients with Parkinson's disease (PD) and those with multiple system atrophy (MSA). We conducted clinical interviews examining RBD symptoms, including violent and non-violent behaviors, in 49 patients with PD and 16 patients with MSA (as well as their bed partners) and performed polysomnography on all subject patients. Twenty-seven patients with PD (55.1%) and 11 patients with MSA (68.8%) had rapid eye movement sleep without atonia (RWA) on polysomnogram. The relative amounts of RWA were quite similar between the two groups. For most of the RWA-positive patients in both groups, RBD symptoms remained non-violent or silent. RBD symptoms in PD patients seemed to increase with the course of PD, while most of the RBD symptoms in the MSA patients occurred just prior to or at the onset of MSA and then disappeared within a short period. Although PD and MSA frequently accompany RWA, RBD symptoms often remain non-violent or silent. Differences in the course of RBD symptoms in patients with PD and MSA may reflect the difference in the degeneration process of the two disorders.

Dysphagia is a major clinical concern in multiple system atrophy (MSA). A detailed evaluation of its major endoscopic features compared with Parkinson's disease (PD) is lacking. This study systematically assessed dysphagia in MSA compared with PD and correlated subjective dysphagia to objective endoscopic findings. Fifty-seven patients with MSA (median, 64 [interquartile range (IQR): 59-71] years; 35 women) underwent flexible endoscopic evaluation of swallowing using a specific MSA-flexible endoscopic evaluation of swallowing task protocol. Findings were compared with an age-matched cohort of 57 patients with PD (median, 67 [interquartile range: 60-73] years; 28 women). In a subcohort, subjective dysphagia was assessed using the Swallowing Disturbance Questionnaire and correlated to endoscopy findings. Patients with MSA predominantly showed symptoms suggestive of oral-phase disturbance (premature spillage, 75.4%, piecemeal deglutition, 75.4%). Pharyngeal-phase symptoms occurred less often (pharyngeal residues, 50.9%; penetration/aspiration, 28.1%). In contrast, pharyngeal symptoms were the most common finding in PD (pharyngeal residues, 47.4%). Oral symptoms occurred less frequently in PD (premature spillage, 15.8%, P< 0.001; piecemeal deglutition, 1.8%, P< 0.01). Patients with MSA had a greater risk for oral-phase disturbances with increased disease severity (P < 0.05; odds ratio,3.15). Patients with MSA showed a significantly higher intraindividual interswallow variability compared with PD. When correlating Swallowing Disturbance Questionnaire scores with endoscopy results, its cutoff, validated for PD, was not sensitive enough to identify patients with MSA with dysphagia. We developed a subscore for identifying dysphagia in MSA and calculated a new cutoff (sensitivity 85%, specificity 100%). In contrast with patients with PD, patients with dysphagic MSA more frequently present with oral-phase symptoms and a significantly higher intraindividual interswallow variability. A novel Swallowing Disturbance Questionnaire MSA subscore may be a valuable tool to identify patients with MSA with early oropharyngeal dysphagia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The clinical features and natural history of 100 patients diagnosed as probable multiple system atrophy (MSA) are described. In all 14 (of 41 deceased) cases who underwent post-mortem examination of the brain, the diagnosis was confirmed pathologically, providing some validation of the clinical diagnostic criteria used. There were 67 men and 33 women. Median age at onset (at time of first reported symptom) was 53 (range 33-76) years. Autonomic symptoms were the initial feature in 41% of the patients, but had subsequently developed in 97% at latest follow-up. The most frequent autonomic symptom in men was impotence, and in women was urinary incontinence. Symptomatic orthostatic hypotension, although present in 68%, was severe in only 15% of patients. Parkinsonism was the initial feature in 46%, but had subsequently developed in 91% of subjects at latest follow-up. It was the predominant motor disorder [striatonigral degeneration (SND) type] in 82% of the patients, and was usually asymmetric (74%). Although akinesia and rigidity predominated, tremor was present at rest in 29% of patients, but in only 9% had a classical pill-rolling parkinsonian rest tremor been recorded. Twenty-nine percent of MSA patients had a good or excellent levodopa response at some stage. However, only 13% maintained this response. Prominent orofacial dyskinesias and dystonias occurred in a quarter of treated patients with MSA. Early onset (before age 49 years) MSA patients tended to have a good levodopa response. Cerebellar symptoms or signs were the only initial feature in 5%. Although subsequently developing in a further 47% of cases, in only 18% was a cerebellar syndrome the only (9%) or predominant (9%) motor disorder [olivopontocerebellar (OPCA) type]. Pyramidal involvement at latest follow-up was noted in 61% of all cases. In a further seven patients the initial features involved more than one system, and one other had presented as a parasomnia. Multiple system atrophy of the OPCA type most commonly presented with gait ataxia. Tremor, pyramidal signs and myoclonus were less common than in MSA of the SND type. Cerebellar signs were present in 42% of patients with MSA of the SND type and parkinsonian signs in 50% of patients with MSA of the OPCA type. Disease progression was faster than in idiopathic Parkinson's disease, so that > 40% of patients were markedly disabled or wheelchair bound within 5 years of onset of motor disturbance. Median survival of the whole group as calculated by Kaplan-Meier analysis was 9.5 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Whether polymorphisms rs11856808 and rs9652490 of the Leucine-rich repeat and Ig domain containing, Nogo receptor-interacting protein-1 (LINGO1) gene, as well as rs10968280, rs13362909 and rs7033345 of the LINGO2 gene, increase the risk for Parkinson's disease (PD) is controversial. Considering the overlap of the clinical and pathological characteristics among PD and multiple system atrophy (MSA), we explored the associations between these five polymorphisms and PD and MSA in a Chinese population. A total of 1055 PD patients, 320 MSA patients, and 810 healthy controls (HCs) were genotyped for these five polymorphisms in LINGO1 and LINGO 2 using Sequenom iPLEX Assay technology. Moreover, after combining our results with available published data, a meta-analysis was conducted to investigate the associations between LINGO 1 rs11856808 and rs9652490 and the risk of PD. The frequency of the minor alleles "T" of LINGO1 rs11856808 was significantly lower in PD than that in HCs (p = 0.011, OR 0.89, 95 % CI 0.81-0.97), but not in MSA. Moreover, there were no significant differences in the minor allele frequency distributions of the other four polymorphisms between PD and HCs, and between MSA and HCs. The meta-analysis showed a lack of association of rs9652490 and PD, regardless of the genetic model or ethnic origin. However, the rs11856808 allele decreased the risk of PD in patients of Asian origin in a dominant genetic model. Our findings suggest that rs11856808 plays a protective role by decreasing the risk for PD, but not for MSA, in Asian population, the other four polymorphisms do not contribute to the risk for PD and MSA.

Synucleinopathies are neurodegenerative diseases pathologically characterized by aggregates of α-synuclein protein in selectively vulnerable neurons and/or glia.1 These include neuronal Lewy bodies (LB) and Lewy neurites in Parkinson's disease (PD), dementia with LB, and PD dementia, and predominantly oligodendroglial cytoplasmic inclusions in multiple system atrophy (MSA).1 Isolated rapid eye movement sleep behavior disorder (iRBD) and pure autonomic failure (PAF) are often underpinned by α-synuclein pathology, sometimes revealing themselves as prodromal stages of the aforementioned disorders in retrospect.2, 3 The self-propagation of misfolded proteins assembling into seeds that induce normal-like proteins to misshape and aggregate was first recognized as mechanism of neurotoxicity in prion diseases. Increasing evidence supports the prion-like behavior of other proteins in neurodegeneration, including amyloid-β, tau, and α-synuclein.4 Therefore, detecting protein aggregates in easily accessible biospecimens represents a promising diagnostic avenue,5 especially in synucleinopathies, which can be difficult to clinically differentiate in early stages and lack specific positron emission tomography radiotracers. Moreover, because the prion-like process may precede their clinical onset by years or decades, iRBD and PAF are potential targets for an early biochemical diagnosis of synucleinopathies.2, 3, 5 Real-time quaking-induced conversion (RT-QuIC) is a high-sensitive amplification assay to detect the seeding activity of protein aggregates in biospecimens at the expense of a substrate (ie, the recombinant protein) under shaking conditions, which is monitored by thioflavin T fluorescence. RT-QuIC was first validated in sporadic Creutzfeldt-Jacob disease and is now included in its diagnostic criteria.6 Recently, it has also been explored in synucleinopathies.7 Following an established protocol,8 Rossi and colleagues9 performed cerebrospinal fluid α-synuclein RT-QuIC in a large cohort of (1) neuropathologically verified cases of LB-positive and LB-negative dementia, atypical parkinsonism, and LB-negative controls and (2) clinically diagnosed cases of PD, atypical parkinsonism, dementia, iRBD, and PAF. The assay accurately detected α-synuclein seeding activity across LB-related synucleinopathies (ie, PD, dementia with LB, iRBD, and PAF), with an overall sensitivity of 95.3% (100% in definite dementia with LB and iRBD) and an overall specificity of 98% against cases lacking LB on neuropathology.9 Intriguingly, negative RT-QuIC results were found in almost all MSA cases, 1 iRBD case with subsequent phenoconversion to MSA, and 1 PAF case showing normal adrenergic cardiac innervation on iodine-123 meta-iodobenzylguanidine single photon emission computed tomography, as observed in MSA.9 Finally, quantification of α-synuclein seeding activity through fluorescence analysis did not discriminate among LB-related clinical syndromes.9 Besides supporting the prion-like nature of LB-related synucleinopathies, this study demonstrates that α-synuclein RT-QuIC provides an accurate and reliable biomarker for these disorders in the largest cohort hitherto investigated.9 It also proves that RT-QuIC detects α-synuclein seeding activity in prodromal syndromes, allowing early diagnosis of synucleinopathy and identification of candidates for disease-modifying trials.9 Interpretation of negative assay results in most MSA cases is arguable. Although it might confirm that MSA and LB-related syndromes are associated with different conformational α-synuclein strains,10 further research needs to clarify whether different RT-QuIC set-ups may detect α-synuclein seeding activity in MSA, thus differentiating synucleinopathies. In conclusion, these findings endorse the inclusion of an RT-QuIC-based biomarker in diagnostic criteria for LB-related synucleinopathies and promote studies to test the α-synuclein RT-QuIC analysis of other biospecimens and its potential as a progression/prognostic tool. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Data Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. F.M.: 1A, 2A, 2B, 3A M.T.: 2C, 3B K.P.B.: 1A, 2C, 3B We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work. The authors confirm that no patient consent was required for this work. No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. F.M. is supported by the European Academy of Neurology Research Fellowship 2020. M.T. reports no disclosures. K.P.B. has received grant support from Welcome/Medical Research Council, National Institute for Health Research, Parkinsons's UK, and EU Horizon 2020. He receives royalties from publication of the Oxford Specialist Handbook Parkinson's Disease and Other Movement Disorders (Oxford University Press, 2008), Marsden's Book of Movement Disorders (Oxford University Press, 2012), and Case Studies in Movement Disorders–Common and Uncommon Presentations (Cambridge University Press, 2017). He has received honoraria/personal compensation for participating as consultant/scientific board member from Ipsen, Allergan, and Merz and honoraria for speaking at meetings and from Allergan, Ipsen, Merz, Sun Pharma, Teva, UCB Pharmaceuticals, and the American Academy of Neurology, and the International Parkinson's Disease and Movement Disorders Society.

Few studies have compared cognitive functions in multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and Parkinson's disease (PD). To compare the results of cognitive function tests in the three diseases and examine their relation with the severity of parkinsonism. Clinic-based open prospective study. Global cognitive function tests and tests specific for frontal lobe functions were used in 25 cases of each disease. UPDRS III was used to measure the severity of parkinsonism. ANOVA was done for group comparisons, followed by t-test for independent samples with Bonferroni correction. Pearson's correlation test was done to assess the relation between severity of parkinsonism and cognitive functions. The severity of parkinsonism was worst in PD followed by PSP and least in MSA. Patients with PSP exhibited the worst performance in both sets of cognitive tests. Even though patients with MSA did better than PD in global function tests, they performed worse than PD in some frontal function tests. There was a negative correlation between severity of parkinsonism and scores in cognitive tests in the MSA group but not in others. Global and frontal dysfunction was worst in PSP. The frontal dysfunction in MSA was more severe than PD, correlated with the severity of parkinsonism and was worse in clinically probable than possible cases of MSA. The severity of cognitive dysfunction in these diseases may be related to the distribution and extent of pathological changes affecting the striato-frontal circuits in them.

BackgroundMost studies have analyzed the urodynamic characteristics of patients with Parkinson's disease (PD) and multiple system atrophy (MSA) using conventional urodynamic studies.ObjectivesThis study investigated the urodynamic characteristics of both diseases using video urodynamic study (VUDS).MethodsVUDS results from November 2004 to September 2020 were retrospectively analyzed at Seoul National University Hospital. The VUDS findings in patients with PD and those with MSA were compared. Movement disorder specialists diagnosed patients with PD and MSA.ResultsA total of 709 patients, comprising 364 PD (260 men, 104 women) and 345 MSA (215 men, 130 women) cases, were identified. Patients with MSA had a significantly younger age at onset, lower maximum flow rate (Qmax), larger postvoid residual volume, higher rate of poor bladder compliance, higher prevalence of urinary incontinence, and lower detrusor pressure at Qmax than those with PD. Among the fluoroscopic findings of VUDS, patients with MSA had a higher rate of incompetent bladder neck (18.8% vs. 4.7%, P < 0.001), bladder trabeculation (33.0% vs. 17.0%, P < 0.001), and vesicoureteral reflux (2.9% vs. 0.5%, P = 0.019) than those with PD. In VUDS performed in patients without urinary incontinence in conventional urodynamic study, an incompetent bladder neck was found in 14.6% of patients with MSA and 3.3% of patients with PD (P < 0.001).ConclusionsOur results demonstrate that VUDS can provide additional information on bladder urethral dysfunction, particularly regarding the risk of upper urinary tract damage and bladder neck status in patients with PD and MSA.

Introduction Parkinsonian syndromes of different nature feature autonomic nervous system dysfunction (ANSd) which may herald or follow motor symptoms (MS) in Parkinson disease (PD), but anticipate by years and progress more rapidly in multiple system atrophy (MSA). Abnormal Heart Rate Variability (HRV) has been reported in both PD and MSA. Purpose This study aimed to evaluating if HRV analysis (HRVa) could contribute to differentiate PD from MSA and to guide early and more appropriate treatment and prognostic assessment. Methods 66 consecutive parkinsonian patients (pts) (48 males, 18 females) (mean age 63.8±10 y) were enrolled between 2010 and 2020. Initial clinical diagnosis was MSA (19), PD (20), PD with autonomic impairment (PD-AI) (10), Lewy body disease (2), supranuclear palsy (3), undefined Parkinsonism (UP) (12). The severity of MS was quantified with UPDRS and Hoehn/Yahr scales. HRV was analyzed with linear (TD and FD) and non-linear (NL) methods (Kubios Premium 3.4.1), during daily activity and NREM sleep (2-minutes intervals) and during REM sleep (1-minute Interval). 44/66 underwent also ASN functional evaluation with the Ewing protocol. Data of 52 age-matched healthy subjects (HS) were used for comparison. For statistical analysis, SPSS software (version 21) was used. Discriminant Analysis (DA) was applied to identify the more relevant parameters differentiating PD from MSA and classifying “undefined” cases. Prolonged follow-up (f-up) provided clinical diagnostic certainty, as goldstandard for validation of HRVa classification accuracy. Results UPDRS and Hoehn/Yahr scores were higher in MSA than in PD (p&amp;lt;0.0001). Along 10-years of f-up, 16/66 pts died (56,2% MSA), 5/66 had new diagnostic definition, and 15/66 were lost to f-up. Most of HRV parameters of 34 pts with certain diagnosis (17 MSA and 17 PD) whose f-up was completed, were significantly different from those of HS. VLFpower and recurrence plot parameters calculated during active wakefulness were different (p&amp;lt;0.05) between MSA and PD, and correctly classified them with 88,2% predictive accuracy (PA) at DA, according to the formula: F1 = (vlfpw%ar* − 0,087) + (rprec* − 0,319) + (rpshen*10.81) + (−20,53) Comparative classification accuracy of HRVa, Ewing score, UPDRS and Hoehn/Yahr scales is shown in Table 1. Attempting prognostic risk assessment by applying F1 to HRV data of pts with PD-AI and of pts with UP, those classified as MSA according to F1 showed the worst clinical outcome during the f-up. Conclusions This study confirms that a higher degree of prevailing sympathetic ASNd in MSA compared to PD can be identified by a combination of Linear and NL HRV parameters, and correctly differentiate with high (88,2%) predictive accuracy all pts with certain diagnosis verified during prolonged f-up. Moreover, HRVa might be useful for earlier prognostic stratification of pts with parkinsonian symptoms of uncertain nature and to improve clinical and pharmacological management. Funding Acknowledgement Type of funding sources: None.

Background:Both Parkinson's disease (PD) and multiple system atrophy (MSA) have associated sleep disorders related to the underlying neurodegenerative pathology. Clinically, MSA with predominant parkinsonism (MSA-P) resembles PD in the manifestation of prominent parkinsonism. Whether the amount of rapid eye movement (REM) sleep without atonia could be a potential marker for differentiating MSA-P from PD has not been thoroughly investigated. This study aimed to examine whether sleep parameters could provide a method for differentiating MSA-P from PD.Methods:This study comprised 24 MSA-P patients and 30 PD patients, and they were of similar age, gender, and REM sleep behavior disorder (RBD) prevalence. All patients underwent clinical evaluation and one night of video-polysomnography recording. The tonic and phasic chin electromyogram (EMG) activity was manually quantified during REM sleep of each patient. We divided both groups in terms of whether they had RBD to make subgroup analysis.Results:No significant difference between MSA-P group and PD group had been found in clinical characteristics and sleep architecture. However, MSA-P patients had higher apnea-hypopnea index (AHI; 1.15 [0.00, 8.73]/h vs. 0.00 [0.00, 0.55]/h, P = 0.024) and higher tonic chin EMG density (34.02 [18.48, 57.18]% vs. 8.40 [3.11, 13.06]%, P < 0.001) as compared to PD patients. Subgroup analysis found that tonic EMG density in MSA + RBD subgroup was higher than that in PD + RBD subgroup (55.04 [26.81, 69.62]% vs. 11.40 [8.51, 20.41]%, P < 0.001). Furthermore, no evidence of any difference in tonic EMG density emerged between PD + RBD and MSA - RBD subgroups (P > 0.05). Both disease duration (P = 0.056) and AHI (P = 0.051) showed no significant differences during subgroup analysis although there was a trend toward longer disease duration in PD + RBD subgroup and higher AHI in MSA - RBD subgroup. Stepwise multiple linear regression analysis identified the presence of MSA-P (β = 0.552, P < 0.001) and RBD (β = 0.433, P < 0.001) as predictors of higher tonic EMG density.Conclusion:Tonic chin EMG density could be a potential marker for differentiating MSA-P from PD.

Loss of medullary serotonin (5-hydroxytryptamine) neurons has been linked to respiratory disturbances in multiple system atrophy (MSA). Broader 5-hydroxytryptamine dysfunction may contribute to additional motor/nonmotor symptoms in MSA. The objective of this study was to compare brain 5-hydroxytryptamine1A receptor binding between MSA and healthy controls. Secondary objectives were to compare 5-hydroxytryptamine1A receptor binding between MSA and Parkinson's disease (PD) and to assess potential associations with motor/nonmotor symptoms in MSA. 2'-Methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine positron emission tomography was performed in matched MSA patients (n = 16), PD patients (n = 15), and healthy controls (n = 18). 2'-Methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine distribution volume ratios were lower in MSA patients versus healthy controls in several brain regions including the caudate, raphe nuclei, thalamus, and brain stem. Distribution volume ratios were also lower in brain stem and amygdala in MSA versus PD. Moderate associations were found between 2'-methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine distribution volume ratios and fatigue, pain, and apathy in MSA. Our results demonstrate 5-hydroxytryptamine dysfunction in several brain regions in MSA, which may contribute to fatigue, pain, and apathy. © 2020 International Parkinson and Movement Disorder Society.

Objectives To assess the value of external anal sphincter electromyography (EASEMG) in evaluating the related autonomic dysfunction in Parkinson's disease ( PD), parkinsonism dominant multiple system atrophy (MSA-P) and progressive supranuclear palsy (PSP). Methods From the records of EAS-EMG collected in our lab (total 562 cases), 60 PD (male 41, female 19), 68 MSA-P (male 35,female 33) and 13 PSP (male 10, female 3) were included in the analysis in this study. Mean duration,polyphasic ratio and satellite potential occurrence rate were comparable among the groups. Mean duration prolongation were graded as normal ( ＜ 10.0 ms), mild ( 10.0-11.9 ms), moderate ( 12.0-13.9 ms)and severe ( ≥ 14.0 ms). Results Among all related autonomic symptoms, the occurrence rate of constipation, urinary incontinence, urgency and frequency in patients with MSA-P(95.8% (23/24) ,94.6% (53/56) ,87.7% ( 50/57 ), 85.7% (42/49), 76.5% ( 39/51 ) ) were higher than that of PD ( 61.5%(16/26), 62.3% (33/53), 30.6% (15/49), 46.2% (24/52), 45.7% (21/46)) and PSP (75.0%(3/4) , 62.5% (5/8), 50.0% (4/8), 42.9% (3/7), 42.9% (3/7)). The abnormal rate of EAS-EMG in PD, MSA-P and PSP were 60.0%, 94.2% and 84.6%, accordingly. Mean duration ( PD ( 12.0 ± 1.6)ms, MSA-P (15.4±3.0) ms, PSP (13.8±1.8) ms), polyphasic ratio (PD 46.2% ±19.2%, MSA-P 63.9% ± 15.8%, PSP 51.5% ± 12.1% ) and satellite potential occurrence rate ( PD 9.5% ± 8.3%,MSA-P 26.5% ± 15.9%, PSP 19.2% ± 12.5% ) varied significantly different among the groups ( F =31.724, F = 17.412, x2 =45. 335, all P ＜0.01 ). Severe mean duration prolongation was overwhelming in MSA-P (66.2% ) , compared with mild 10.3% and moderate 23.5%. The predominant prolongation degree was moderate in PSP (61.5%, mild 7.7%, severe 30.8% ), and mild in PD (36.7%, moderate 36.7% ,severe 11.7%, normal 15.0% ). Conclusions EAS-EMG could play a role in evaluating the related autonomic dysfunctions in PD, MSA-P and PSP. The EAS-EMG impairment was severe and frequent in MSA-P, mild and infrequent in PD, moderate in PSP. The spectrum of mean duration prolongation suggested the possibility of Onuf's nucleus involvement in these diseases. Key words: Parkinson disease; Multiple system atrophy; Supranuelear palsy progressive; Anal canal; Electromyography; Autonomic nervous system

Cerebrospinal fluid cytokines in multiple system atrophy: A cross-sectional Catalan MSA registry study

Multiple system atrophy (MSA) is a predominantly sporadic, adult-onset, fatal neurodegenerative disease of unknown etiology. MSA is characterized by autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia and pyramidal signs in any combination. MSA belongs to a group of neurodegenerative disorders termed α-synucleinopathies, which also include Parkinson's disease and dementia with Lewy bodies. Their common pathological feature is the occurrence of abnormal α-synuclein positive inclusions in neurons or glial cells. In MSA, the main cell type presenting aggregates composed of α-synuclein are oligodendroglial cells . This pathological hallmark, also called glial cytoplasmic inclusions (GCIs) , is associated with progressive and profound neuronal loss in various regions of the brain. The development of animal models of MSA is justified by the limited understanding of the mechanisms of neurodegeneration and GCIs formation, which is paralleled by a lack of therapeutic strategies. Two main types of rodent models have been generated to replicate different features of MSA neuropathology. On one hand, neurotoxin-based models have been produced to reproduce neuronal loss in substantia nigra pars compacta and striatum. On the other hand, transgenic mouse models with overexpression of α-synuclein in oligodendroglia have been used to reproduce GCIs-related pathology. This chapter gives an overview of the atypical Parkinson's syndrome MSA and summarizes the currently available MSA animal models and their relevance for pre-clinical testing of disease-modifying therapies.

Magnetic resonance imaging (MRI) paired with appropriate disease-specific machine learning holds promise for the clinical differentiation of Parkinson disease (PD), multiple system atrophy (MSA) parkinsonian variant, and progressive supranuclear palsy (PSP). A prospective study is needed to test whether the approach meets primary end points to be considered in a diagnostic workup. To assess the discriminative performance of Automated Imaging Differentiation for Parkinsonism (AIDP) using 3-T diffusion MRI and support vector machine (SVM) learning. This was a prospective, multicenter cohort study conducted from July 2021 to January 2024 across 21 Parkinson Study Group sites (US/Canada). Included were patients with PD, MSA, and PSP with established criteria and unanimous agreement in the clinical diagnosis among 3 independent, blinded neurologists who specialize in movement disorders. Patients were assigned to a training set or an independent testing set. MRI. Area under the receiver operating characteristic curve (AUROC) in the testing set for primary model end points of PD vs atypical parkinsonism, MSA vs PSP, PD vs MSA, and PD vs PSP. AIDP was also paired with antemortem MRI to test against postmortem neuropathology in a subset of autopsy cases. A total of 316 patients were screened and 249 patients (mean [SD] age, 67.8 [7.7] years; 155 male [62.2%]) met inclusion criteria. Of these patients, 99 had PD, 53 had MSA, and 97 had PSP. A retrospective cohort of 396 patients (mean [SD] age, 65.8 [8.9] years; 234 male [59.1%]) was also included. Of these patients, 211 had PD, 98 had MSA, and 87 had PSP. Patients were assigned to the training set (78%; 104 prospective, 396 retrospective) or independent testing set, which included 145 (22%; 60 PD, 27 MSA, 58 PSP) prospective patients (mean age, 67.4 [SD 7.7] years; 95 male [65.5%]). The model was robust in differentiating PD vs atypical parkinsonism (AUROC, 0.96; 95% CI, 0.93-0.99; positive predictive value [PPV], 0.91; negative predictive value [NPV], 0.83), MSA vs PSP (AUROC, 0.98; 95% CI, 0.96-1.00; PPV, 0.98; NPV, 0.81), PD vs MSA (AUROC, 0.98; 95% CI, 0.96-1.00; PPV, 0.97; NPV, 0.97), and PD vs PSP (AUROC, 0.98; 95% CI, 0.96-1.00; PPV, 0.92; NPV, 0.98). AIDP predictions were confirmed neuropathologically in 46 of 49 brains (93.9%). This prospective multicenter cohort study of AIDP met its primary end points. Results suggest using AIDP in the diagnostic workup for common parkinsonian syndromes.

Loss of nigrosome-1 on 3T and 7T magnetic resonance imaging (MRI) is a recently explored imaging biomarker in the diagnosis of neurodegenerative parkinsonism. This study was undertaken to evaluate the utility of imaging of nigrosome in the diagnosis of neurodegenerative parkinsonism on 3T MRI. An institution-based prospective case-control study was conducted at a tertiary care center in North India. 3T venous blood oxygen level-dependent (VenoBOLD) and high-resolution susceptibility-weighted imaging (SWI) imaging sequences in MRI were performed in 100 patients with parkinsonism (56 with idiopathic Parkinson's disease [IPD], 30 with young onset Parkinson's disease [YOPD], 12 with progressive supranuclear palsy, and 2 patients with multiple system atrophy) and 15 controls. Grading of nigrosome was done in both the sequences. Each patient underwent 18F-DOPA positron emission tomography (PET), detailed neurological examination including Hoen and Yahr (H&Y) staging and Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scoring. The diagnostic sensitivity and specificity of the detection of loss of nigrosome-1 on VenoBOLD and SWI sequence at 3T MR imaging were 90% and 66.7% and 94% and 80%, respectively. A weak negative correlation was found between the grading of the nigrosome and clinical parameters (H&Y and UPDRS III). There was no correlation between the side of nigrosome loss and clinical asymmetry. However, nigrosome imaging was not able to differentiate between Parkinson's disease and atypical parkinsonism. The loss of nigrosome-1 on 3T MRI on SWI and VenoBOLD sequences may serve as a potential imaging marker in the diagnosis of degenerative parkinsonian syndromes. However, it cannot differentiate between idiopathic Parkinson's disease and atypical parkinsonian syndromes.