Fluid and Biopsy Based Biomarkers in Parkinson's Disease

Abstract

Several advances in fluid and tissue-based biomarkers for use in Parkinson's disease (PD) and other synucleinopathies have been made in the last several years. While work continues on species of alpha-synuclein (aSyn) and other proteins which can be measured from spinal fluid and plasma samples, immunohistochemistry and immunofluorescence from peripheral tissue biopsies and alpha-synuclein seeding amplification assays (aSyn-SAA: including real-time quaking induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA)) now offer a crucial advancement in their ability to identify aSyn species in PD patients in a categorical fashion (i.e., of aSyn + vs aSyn -); to augment clinical diagnosis however, aSyn-specific assays that have quantitative relevance to pathological burden remain an unmet need. Alzheimer's disease (AD) co-pathology is commonly found postmortem in PD, especially in those who develop dementia, and dementia with Lewy bodies (DLB). Biofluid biomarkers for tau and amyloid beta species can detect AD co-pathology in PD and DLB, which does have relevance for prognosis, but further work is needed to understand the interplay of aSyn tau, amyloid beta, and other pathological changes to generate comprehensive biomarker profiles for patients in a manner translatable to clinical trial design and individualized therapies.

Keywords: Alpha-synuclein; Biopsy; Immunofluorescence; Parkinson’s disease; Protein misfolding cyclic amplification; Real-time quaking induced conversion.

Fig. 1

aSyn-SAA metrics. Tissue or fluid samples are analyzed with fluorescence measurements read at given intervals which can be used to establish curves shown in (a). From these curves, a variety of metrics can be derived including maximum fluorescence, time to threshold (or time lag), time to 50% of maximum fluorescence (T50) or area under the curve calculations; however, these metrics have not consistently been shown to relate to clinical characteristics or pathological burden within PD patients. If a sample undergoes serial dilution and is analyzed at these different dilutions as shown in (b), the dilution at which 50% of well remain positive can be used to estimate the SD50 which may have more relevance to disease activity in some studies. In this example the estimated -log(SD50) = 7. Created with Biorender.com

Fig. 2

aSyn assays from biofluids and tissue. Summary of static aSyn assessments, peripheral tissue immunohistochemistry, immunofluorescence and aSyn-SAA assays in different tissues and fluids studied currently with spinal fluid aSyn-SAA and skin aSyn-SAA and immunofluorescence assays showing the greatest accuracy to date but with many other assays still in development. Created with Biorender.com