What can biomarkers tell us about cognition in Parkinson's disease?

Abstract

Cognitive decline is common in Parkinson's disease (PD), even in the early motor stage, and this non-motor feature impacts quality of life and prognosis tremendously. In this article, we discuss marker candidates for cognitive decline in PD from different angles, including functional and structural imaging techniques, biological fluid markers in cerebrospinal fluid, and blood genetic predictors, as well as gait as a surrogate marker of cognitive decline. Specifically, imaging-based markers of cognitive impairment in PD include cortical atrophy, reduced cortical metabolism, loss of cortical cholinergic and frontal dopaminergic function, as well as an increased cortical amyloid load. Reduced β-amyloid(1-42) in cerebrospinal fluid and lower plasma levels of epidermal growth factor are predictors for cognitive decline in PD. In addition, genetic variation in the apolipoprotein E (APOE), catechol-O-methyltransferase (COMT), microtubule-associated protein tau (MAPT), and glucocerebrosidase (GBA) genes may confer risk for cognitive impairment in PD; and gait disturbance may also indicate an increased risk for dementia. Other marker candidates have been proposed and are discussed. All of the current studies are hampered by gaps in our knowledge about the molecular causes of cognitive decline, which will have to be considered in future biomarker studies.

Keywords: Parkinson's disease; biomarker; blood; cerebrospinal fluid; dementia; gait; genetics; imaging.

FIG. 1

(11)C-labeled Pittsburgh Compound B (11C-PIB) positron emission tomography images are normal (left) in a patient who has Parkinson's disease with dementia (PD1dem) but show raised amyloid levels (right) in a patient who has dementia with Lewy bodies (DLB).

FIG. 2

Schematic summary (modified from Weinrich et al.) of the most frequent and known pathomorphologic characteristics of Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease with dementia (PDD) shown with the respective patterns in cerebrospinal fluid (CSF) and with β-amyloid (Aβ) nuclear imaging. Shown are neurofibrillary tangle (top left) (immunohistochemistry reaction with the antibody AT-8 against hyper-phosphorylated tau protein), amyloid plaque (middle left) (Bielchowsky staining), and Lewy body (bottom left) (immunohistochemistry reaction with antibody LB-509 against α-synuclein [αSyn]). PD-MCI indicates Parkinson's disease with mild cognitive impairment.

FIG. 3

Changes in the power of attention (PoA) over 18 months (a positive value means attention has worsened) since diagnosis are illustrated in 58 patients with idiopathic Parkinson's disease (mean age 6 standard deviation, 67.4 ± 10.6 years; 31 males, 21 females; Unified Parkinson's Disease Rating Scale motor part score [mean ± standard deviation], 10.6 ± 9.8; tested at peak dose of levodopa medication [controlling for baseline attention]). A slow walking speed at baseline predicted greater worsening of attention 18 months later, particularly for those who walked slowly (less than 1 ms⁻¹) (from Lord et al., 2013).