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

Nilsson, Johanna ; Constantinescu, Julius ; Nellgård, Bengt ; Jakobsson, Protik ; Brum, Wagner S. ; Gobom, Johan ; Forsgren, Lars ; Dalla, Keti ; Constantinescu, Radu and Zetterberg, Henrik LU , et al. (2023) In Movement Disorders 38(2). p.267-277
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)... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
biomarkers, multiple system atrophy, Parkinson's disease, progressive supranuclear palsy, synaptic dysfunction
in
Movement Disorders
volume
38
issue
2
pages
267 - 277
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:36504237
  • scopus:85144096881
ISSN
0885-3185
DOI
10.1002/mds.29287
language
English
LU publication?
yes
id
e4345ed2-f2e0-48e4-b065-45728ba0ec39
date added to LUP
2023-01-26 16:08:11
date last changed
2024-06-13 15:29:26
@article{e4345ed2-f2e0-48e4-b065-45728ba0ec39,
  abstract     = {{<p>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 (n<sub>1</sub> = 51, n<sub>2</sub> = 101), corticobasal degeneration (CBD) (n<sub>1</sub> = 11, n<sub>2</sub> = 3), progressive supranuclear palsy (PSP) (n<sub>1</sub> = 22, n<sub>2</sub> = 21), multiple system atrophy (MSA) (n<sub>1</sub> = 31, n<sub>2</sub> = 26), and healthy control (HC) (n<sub>1</sub> = 48, n<sub>2</sub> = 30) participants, as well as Alzheimer's disease (AD) (n<sub>2</sub> = 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 &lt; 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 &lt; 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.</p>}},
  author       = {{Nilsson, Johanna and Constantinescu, Julius and Nellgård, Bengt and Jakobsson, Protik and Brum, Wagner S. and Gobom, Johan and Forsgren, Lars and Dalla, Keti and Constantinescu, Radu and Zetterberg, Henrik and Hansson, Oskar and Blennow, Kaj and Bäckström, David and Brinkmalm, Ann}},
  issn         = {{0885-3185}},
  keywords     = {{biomarkers; multiple system atrophy; Parkinson's disease; progressive supranuclear palsy; synaptic dysfunction}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{267--277}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Movement Disorders}},
  title        = {{Cerebrospinal Fluid Biomarkers of Synaptic Dysfunction Are Altered in Parkinson's Disease and Related Disorders}},
  url          = {{http://dx.doi.org/10.1002/mds.29287}},
  doi          = {{10.1002/mds.29287}},
  volume       = {{38}},
  year         = {{2023}},
}