Objective: The aim of this multicenter study was to investigate potential alterations of CSF protein levels associated with overall and domain-specific cognitive performance in early PD patients.

Background: Cognitive impairment is a common feature in Parkinson’s disease (PD). Two distinct subtypes of cognitive dysfunction have been suggested in PD, including frontal executive dysfunction associated with dopaminergic loss, and the posterior/temporal subtype that affects visuospatial and semantic fluency function and correlates with cholinergic loss. Reduced cerebrospinal fluid (CSF) levels of alpha synuclein (α-syn), and increased plasma levels of soluble tumor necrosis factor and higher frequency of the apolipoprotein E e4 allele carriership have been associated with executive dysfunction in PD. Visuospatial and semantic fluency deficit is associated with tau pathology, and has a predictable progress that eventually leads to PD dementia.

Method: In total, 405 individuals were recruited in the PD-cohort of the AETIONOMY project. Idiopathic PD patients with available CSF (n=74) were included in the analyses. A suspension bead array procedure was performed utilizing polyclonal rabbit antibodies generated within the Human Protein Atlas project (www.proteinatlas.org) targeting 216 proteins. Cognitive function was assessed with Repeatable Battery for the Assessment of the Neuropsychological Status (RBANS). RBANS total index score was dichotomized at the level of 90.

Results: RBANS score was available in 69 of 74 patients; 34 (49%) had high (≥90) and 35 (51%) had low RBANS total score (<90). Age at PD-diagnosis, disease-duration and sex distribution were similar in the two groups. Protein profiling was performed and 14 proteins were found at altered levels in patients with high vs. low RBANS score after adjustment for multiple comparisons. In logistic regression analysis, increased kininogen 1 (KNG1), validated with several antibodies, and kallikrein 6 (KLK6) were independently associated with low RBANS total score after adjustment for confounders including sex, disease duration and confounders including environmental factors, anxiety, and hyposmia.

Conclusion: In our study, CSF levels of KNG1 and KLK6 were associated with cognitive performance of PD patients without overt dementia. Further, longitudinal studies with serial cognitive assessments and lumbar punctures are necessary to further explore the nature of this correlation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cerebrospinal-fluid-protein-markers-of-cognition-in-early-parkinsons-disease/