α-Synuclein seed amplification assay as a diagnostic tool for parkinsonian disorders

Parkinsonian disorders consist mostly of Parkinson’s disease (PD); other forms are relatively rare, although dementia with Lewy bodies (DLB) seems to be, after Alzheimer’s disease, one of the most common causes of dementia. Atypical parkinsonisms (other than idiopathic PD) include progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD) and DLB. In addition to parkinsonism symptoms the most characteristic features of these disorders, sometimes called parkinsonism-plus syndromes, are cerebellar ataxia in MSA, apraxia in CBD, gaze palsy in PSP or early in the course of dementia in DLB, and minimal, sometimes moderate (in MSA or PSP) or complete lack (in CBD) of response to L-dopa therapy. When appraising the condition, it is vital to separate it from those conditions that mimic the appearance of PD, but that are caused by another underlying pathology. Because of the lack of biological markers, differential diagnosis has to be based mostly on clinical findings. Nevertheless, neuroimaging studies, utilizing MRI, SPECT and PET examinations, seem to be helpful in establishing diagnosis. Nuclear medicine uses different tracers, specific for the dopamine transporting system or dopamine receptor ligands, which makes it possible to differentiate presynaptic dopaminergic system involvement (seen in PD) from pre- and postsynaptic involvement in MSA or PSP. Highly asymmetric tracer uptake reflects the asymmetry of cortical-subcortical atrophy and is characteristic for CBD. All of these conditions are accompanied by different psychiatric problems. In PD, depression is the most common, followed by dementia and psychosis at late stages. In PSP, subcortical dementia is typical with frontal behavior. Dementia is less frequent and late in CBD, but usually is the first or early symptom in DLB, followed by parkinsonian features. Functional neuroimaging may be useful for assessment of the preclinical period of PD (with potential early neuroprotective therapy), the rate of progression (evaluation of the influence of drugs and stereotaxic surgery on disease progression), the role of different structures in late complications (dyskinesias, fluctuations), and differential diagnosis of PD with essential tremor and atypical parkinsonian disorders. These techniques may also be helpful for investigation of pathogenesis and pathology underlying the non-motor symptoms of PD and atypical parkinsonisms as depression, dementia and psychosis. This review summarizes recent applications of SPECT, PET, but also MRI in the study of parkinsonian disorders, in terms of differential diagnosis and understanding concomitant neuropsychiatric phenomena.

Dysarthria and dysphagia are known to occur in parkinsonian syndromes such as Parkinson disease (PD), dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). Differences in the evolution of these symptoms have not been studied systematically in postmortem-confirmed cases. To study differences in the evolution of dysarthria and dysphagia in postmortem-confirmed parkinsonian disorders. Eighty-three pathologically confirmed cases (PD, n = 17; MSA, n = 15; DLB, n = 14; PSP, n = 24; and CBD, n = 13) formed the basis for a multicenter clinicopathological study organized by the National Institute of Neurological Disorders and Stroke, Bethesda, Md. Cases with enough clinicopathological documentation for the purpose of the study were selected from research and neuropathological files of 7 medical centers in 4 countries (Austria, France, England, and the United States). Median dysarthria latencies were short in PSP and MSA (24 months each), intermediate in CBD and DLB (40 and 42 months), and long in PD (84 months). Median dysphagia latencies were intermediate in PSP (42 months), DLB (43 months), CBD (64 months), and MSA (67 months), and long in PD (130 months). Dysarthria or dysphagia within 1 year of disease onset was a distinguishing feature for atypical parkinsonian disorders (APDs) (specificity, 100%) but failed to further distinguish among the APDs. Survival time after onset of a complaint of dysphagia was similar in PD, MSA, and PSP (15 to 24 months, P =.7) and latency to a complaint of dysphagia was highly correlated with total survival time (rho = 0.88; P<.001) in all disorders. Latency to onset of dysarthria and dysphagia clearly differentiated PD from the APDs, but did not help distinguish different APDs. Survival after onset of dysphagia was similarly poor among all parkinsonian disorders. Evaluation and adequate treatment of patients with PD who complain of dysphagia might prevent or delay complications such as aspiration pneumonia, which in turn may improve quality of life and increase survival time.

Synaptic dysfunction and degeneration are central contributors to the pathogenesis and progression of parkinsonian disorders. Therefore, identification and validation of biomarkers reflecting pathological synaptic alterations are greatly needed and could be used in prognostic assessment and to monitor treatment effects. To explore candidate biomarkers of synaptic dysfunction in Parkinson's disease (PD) and related disorders. Mass spectrometry was used to quantify 15 synaptic proteins in two clinical cerebrospinal fluid (CSF) cohorts, including PD (n1 =51, n2 =101), corticobasal degeneration (CBD) (n1 =11, n2 =3), progressive supranuclear palsy (PSP) (n1 =22, n2 =21), multiple system atrophy (MSA) (n1 =31, n2 =26), and healthy control (HC) (n1 =48, n2 =30) participants, as well as Alzheimer's disease (AD) (n2 =23) patients in the second cohort. Across both cohorts, lower levels of the neuronal pentraxins (NPTX; 1, 2, and receptor) were found in PD, MSA, and PSP, compared with HC. In MSA and PSP, lower neurogranin, AP2B1, and complexin-2 levels compared with HC were observed. In AD, levels of 14-3-3 zeta/delta, beta- and gamma-synuclein were higher compared with the parkinsonian disorders. Lower pentraxin levels in PD correlated with Mini-Mental State Exam scores and specific cognitive deficits (NPTX2; rho=0.25-0.32, P < 0.05) and reduced dopaminergic pre-synaptic integrity as measured by DaTSCAN (NPTX2; rho=0.29, P=0.023). Additionally, lower levels were associated with the progression of postural imbalance and gait difficulty symptoms (All NPTX; β-estimate=-0.025 to -0.038, P < 0.05) and cognitive decline (NPTX2; β-estimate=0.32, P=0.021). These novel findings show different alterations of synaptic proteins in parkinsonian disorders compared with AD and HC. The neuronal pentraxins may serve as prognostic CSF biomarkers for both cognitive and motor symptom progression in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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.

The applause sign has been previously reported to be indicative of neurodegenerative disorders, such as progressive supranuclear palsy (PSP). In order to determine the sensitivity, specificity, and positive predictive value, we tested it in patients with PSP, Parkinson's disease (PD), multiple system atrophy (MSA), corticobasal degeneration (CBD), and Huntington's disease (HD). Subjects were asked to clap three times after demonstration by the examiner. The performance was scored as follows: 3 = claps only three times; 2 = claps four times; 1 = claps 5 to 10 times; 0 = claps >10 times. The clap test was videotaped and rated. Patients with CBD, MSA, and PSP showed significant differences in clap scores compared with normal controls. The test differentiated patients with CBD from those with PD (P < 0.005) and HD (P < 0.005), but failed to discriminate patients with PSP from other parkinsonian groups. The specificity of the applause sign is 100% in distinguishing parkinsonian patients from normal subjects with the highest sensitivity in CBD patients. We concluded that the applause sign is highly specific for parkinsonian disorders but it is not a specific sign for PSP; it appears to be most sensitive for CBD.

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.

Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), may be difficult to distinguish in early stages and are often misdiagnosed as Parkinson disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes but have not been prospectively studied. To define the distinguishing features of PSP and CBS subtypes and to assess their usefulness in facilitating early diagnosis and separation from PD. This cohort study recruited patients with APS and PD from movement disorder clinics across the United Kingdom from September 1, 2015, through December 1, 2018. Patients with APS were stratified into the following groups: those with Richardson syndrome (PSP-RS), PSP-subcortical (including PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (including PSP-frontal and PSP-CBS overlap subtypes), MSA-parkinsonism, MSA-cerebellar, CBS-Alzheimer disease (CBS-AD), and CBS-non-AD. Data were analyzed from February 1, through May 1, 2019. Baseline group comparisons used (1) clinical trajectory; (2) cognitive screening scales; (3) serum neurofilament light chain (NF-L) levels; (4) TRIM11, ApoE, and MAPT genotypes; and (5) volumetric magnetic resonance imaging measures. A total of 222 patients with APS (101 with PSP, 55 with MSA, 40 with CBS, and 26 indeterminate) were recruited (129 [58.1%] male; mean [SD] age at recruitment, 68.3 [8.7] years). Age-matched control participants (n = 76) and patients with PD (n = 1967) were included for comparison. Concordance between the antemortem clinical and pathologic diagnoses was achieved in 12 of 13 patients with PSP and CBS (92.3%) undergoing postmortem evaluation. Applying the Movement Disorder Society PSP diagnostic criteria almost doubled the number of patients diagnosed with PSP from 58 to 101. Forty-nine of 101 patients with reclassified PSP (48.5%) did not have the classic PSP-RS subtype. Patients in the PSP-subcortical group had a longer diagnostic latency and a more benign clinical trajectory than those in PSP-RS and PSP-cortical groups. The PSP-subcortical group was distinguished from PSP-cortical and PSP-RS groups by cortical volumetric magnetic resonance imaging measures (area under the curve [AUC], 0.84-0.89), cognitive profile (AUC, 0.80-0.83), serum NF-L level (AUC, 0.75-0.83), and TRIM11 rs564309 genotype. Midbrain atrophy was a common feature of all PSP groups. Eight of 17 patients with CBS (47.1%) undergoing cerebrospinal fluid analysis were identified as having the CBS-AD subtype. Patients in the CBS-AD group had a longer diagnostic latency, relatively benign clinical trajectory, greater cognitive impairment, and higher APOE-ε4 allele frequency than those in the CBS-non-AD group (AUC, 0.80-0.87; P < .05). Serum NF-L levels distinguished PD from all PSP and CBS cases combined (AUC, 0.80; P < .05). These findings suggest that studies focusing on the PSP-RS subtype are likely to miss a large number of patients with underlying PSP tau pathology. Analysis of cerebrospinal fluid defined a distinct CBS-AD subtype. The PSP and CBS subtypes have distinct characteristics that may enhance their early diagnosis.

Spontaneous and voluntary eyelid motility is often abnormal in patients with progressive supranuclear palsy. In contrast, their eyelid reflex responses are relatively preserved, and only those generated by an acoustic startle have been found absent or severely reduced. We hypothesized that, because of their relevant brainstem pathology, patients with progressive supranuclear palsy might have other brainstem reflex abnormalities which, on detection, could help with their neurophysiological characterization. In this study, we examined facial reflex responses in 14 patients with progressive supranuclear palsy, 12 patients with multisystem atrophy, 10 patients with Parkinson's disease, six patients with corticobasal ganglionic degeneration, 11 patients with various non-parkinsonian neurological illnesses and 10 normal subjects. EMG activity was simultaneously recorded from the orbicularis oculi and mentalis muscles following electrical stimulation of the median nerve at the wrist. Mentalis responses were obtained in two normal subjects and in all patients except one with Parkinson's disease, one with progressive supranuclear palsy and one with corticobasal ganglionic degeneration; there were no differences between groups of subjects regarding latency or peak amplitude. Orbicularis oculi responses were always present in control subjects and patients who exhibited mentalis responses, with the significant exception of patients with progressive supranuclear palsy, in whom only the response of mentalis was obtained. Blink-reflex responses to supraorbital nerve electrical stimuli were present at a normal latency and amplitude in all patients. An abnormally enhanced blink-reflex excitability recovery curve to paired stimuli was found in a similar percentage of patients with progressive supranuclear palsy, multisystem atrophy and Parkinson's disease, but in only two patients with corticobasal ganglionic degeneration. Patients with progressive supranuclear palsy have a functional involvement of circuits mediating orbicularis oculi responses to median nerve electrical stimuli, that is a distinctive feature with respect to other parkinsonian syndromes.

Assessment of APOE in atypical parkinsonism syndromes

Multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) are the most common atypical parkinsonism (AP) syndromes. They are clinically characterized by varying combinations of levodopa-poorly responsive parkinsonism, motor, cerebellar, and other signs. They are associated with a wide spectrum of non-motor symptoms, including prominent cognitive impairment such as global cognitive deficits, memory, executive, attentional, visuospatial, language, and non-verbal reasoning dysfunctions. Within the APs, their cognitive functioning is distributed along a continuum from MSA with the least impaired cognitive profile (similar to Parkinson's disease) to PSP and CBD with the greatest decline in global cognitive and executive domains. Although their pathological hallmarks are different-MSA α-synucleinopathy, CBD, and PSP 4-repeat tauopathies-cognitive dysfunctions in APs show both overlaps and dissimilarities. They are often preceding and anticipate motor dysfunctions, finally contributing to reduced quality of life of patients and caregivers. The present paper will review the current evidence of the prevalence and type of cognitive impairment in these AP syndromes, their neuroimaging, pathogenic backgrounds, and current management options based on extensive literature research. Cognitive dysfunctions in APs are due to disruption of prefronto-subcortical and striato-thalamo-cortical circuitries and multiple essential brain networks. This supports the concept that they are brain network disorders due to complex pathogenic mechanisms related to the basic proteinopathies that are still poorly understood. Therefore, the pathophysiology and pathogenesis of cognitive impairment in APs deserve further elucidation as a basis for early diagnosis and adequate treatment of these debilitating comorbidities.

Positron emission tomography (PET) and magnetic resonance imaging (MRI) are imaging techniques providing the foundation for the study of neurochemical, functional, and structural abnormalities associated with the pathology of movement disorders. The availability of several PET radioligands for imaging the monoaminergic systems in Parkinson’s disease (PD) and related disorders has provided the opportunity to apply different tools to support the diagnosis of degenerative parkinsonism and to examine the link between dopaminergic or serotoninergic dysfunction and motor symptoms, cognitive function, behavior, and depression. FDG-PET is at present acknowledged as imaging tool to support the differential diagnosis between PD and atypical parkinsonian disorders, and D2 receptor imaging with PET can also represent a useful imaging tool in this context. MRI techniques have also a major role in the diagnostic workup of patients with parkinsonism. Structural MRI is a cornerstone for the assessment of patients with atypical parkinsonism and to rule out possible secondary causes of parkinsonism. Diffusion-weighted MRI has gained increasing attention because of the possibility to examine the diffusivity of water molecules in relation of neurodegenerative processes at the level of the basal ganglia or other subcortical structures. Functional MRI, although mostly a research tool, can provide valuable information to examine patterns of functional activation and brain connectivity that can be associated to specific motor, cognitive, or behavioral symptoms of different parkinsonian disorders. PET and MRI have so far been used separately or in a complementary fashion, but the recent development of hybrid PET/MR systems possesses a relevant question about the advantages of combined imaging in the area of movement disorders. In this chapter the role of each imaging modality will be summarized with regard to clinical and research applications in PD patients and in patients with related parkinsonian disorders. The chapter will focus on PD and atypical parkinsonian disorders, such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Potential synergies between the two imaging modalities will be discussed to identify potential advantages of combined or simultaneous PET/MRI and future applications.

Background: Semi-quantitative electroencephalogram (EEG) analysis is easy to perform and has been used to differentiate dementias, as well as idiopathic and vascular Parkinson's disease.Purpose: To study whether a semi-quantitative EEG analysis can aid in distinguishing idiopathic Parkinson's disease (IPD) from atypical parkinsonian disorders (APDs), and furthermore, whether it can help to distinguish between APDs.Materials and Methods: A comprehensive retrospective review of charts was performed to include patients with parkinsonian disorders who had at least one EEG recording available. A modified grand total EEG (GTE) score evaluating the posterior background activity, and diffuse and focal slow wave activities was used in further analyses.Results: We analyzed data from 76 patients with a final diagnosis of either IPD, probable corticobasal degeneration (CBD), multiple system atrophy (MSA), or progressive supra-nuclear palsy (PSP). IPD patients had the lowest mean GTE score, followed those with CBD or MSA, while PSP patients scored the highest. However, none of these differences were statistically significant. A GTE score of ≤9 distinguished IPD patients from those with APD (p < 0.01) with a sensitivity of 100% and a specificity of 33.3%.Conclusion: The modified GTE score can distinguish patients with IPD from those with CBD, PSP or MSA at a cut-off score of 9 with excellent sensitivity but poor specificity. However, this score is not able to distinguish a particular form of APD from other forms of the disorder.

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

The early pathogenesis of Parkinson's disease (PD) and the atypical parkinsonian disorders multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) is poorly understood, but presynaptic and axonal dysfunction are hypothesized to play a prominent role. To identify synapse- and/or axonal dysfunction as indicated by cerebrospinal fluid (CSF) biomarker profiles and their clinical correlates in early-stage PD, MSA, and PSP. Liquid chromatography mass spectrometry and enzyme-linked immunosorbent assay analyses of CSF samples from patients with early-stage PD (n=38), MSA (n=21), or PSP (n=19), and age-matched, neurologically healthy controls (n=30). Compared to controls, patients with early parkinsonian disorders had significantly reduced CSF levels of the synapse-associated proteins neuronal pentraxin-1 (NPTX1), amyloid precursor protein, and β-amyloid 42 (Aβ42), as well as the neurosecretory granin-derived proteins secretogranin-II, chromogranin-A, and secretogranin-VII. Among these, synapse-associated proteins correlated with non-motor features, while none correlated with age. CSF levels of the predominantly axonal proteins neurofilament light (NfL) and tau were elevated in patients with MSA or PSP. Reduced NPTX1 and Aβ42 distinguished PD from PSP, while elevated NfL and tau distinguished PSP and/or MSA from PD. Low CSF levels of biomarkers associated with synaptic and neurosecretory function (e.g., NPTX1) implicate age-independent synaptic dysfunction as a shared, early feature in the pathogenesis of PD, MSA, and PSP. Such biomarkers may be particularly sensitive correlates of early non-motor dysfunction. Early axonal dysfunction is more pronounced in PSP and MSA than in PD.

Redefining Bradykinesia.