Cerebrospinal Fluid Biomarkers of Synaptic Dysfunction are Altered in Parkinson's Disease and Related Disorders

Johanna Nilsson; Julius Constantinescu; Bengt Nellgård; Protik Jakobsson; Wagner S Brum; Johan Gobom; Lars Forsgren; Keti Dalla; Radu Constantinescu; Henrik Zetterberg; Oskar Hansson; Kaj Blennow; David Bäckström; Ann Brinkmalm

doi:10.1002/mds.29287

Cerebrospinal Fluid Biomarkers of Synaptic Dysfunction are Altered in Parkinson's Disease and Related Disorders

Mov Disord. 2023 Feb;38(2):267-277. doi: 10.1002/mds.29287. Epub 2022 Dec 12.

Authors

Johanna Nilsson¹, Julius Constantinescu², Bengt Nellgård³, Protik Jakobsson⁴, Wagner S Brum^{1

5}, Johan Gobom^{1

6}, Lars Forsgren⁴, Keti Dalla³, Radu Constantinescu², Henrik Zetterberg^{1

6

7

8

9}, Oskar Hansson^{10

11}, Kaj Blennow^{1

6}, David Bäckström⁴, Ann Brinkmalm^{1

6}

Affiliations

¹ Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
² Department of Neurology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
³ Department of Anesthesiology and Intensive Care, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
⁴ Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
⁵ Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
⁶ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁷ UK Dementia Research Institute at UCL, London, United Kingdom.
⁸ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
⁹ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
¹⁰ Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.
¹¹ Memory Clinic, Skåne University Hospital, Malmö, Sweden.

PMID: 36504237
DOI: 10.1002/mds.29287

Abstract

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. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; biomarkers; multiple system atrophy; progressive supranuclear palsy; synaptic dysfunction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / complications
Biomarkers / cerebrospinal fluid
Humans
Multiple System Atrophy* / diagnosis
Parkinson Disease* / complications
Parkinsonian Disorders* / pathology
Supranuclear Palsy, Progressive* / diagnosis

Substances

Biomarkers