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Background: 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. Objective: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Background: 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.

Objective: To explore candidate biomarkers of synaptic dysfunction in Parkinson's disease (PD) and related disorders.

Methods: 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.

Results: 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).

Conclusions: 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.