Manne, Sireesha

Pick’s disease (PiD) is a devastating neurodegenerative disease that is characterized by dementia, frontotemporal lobar degeneration, and the aggregation of 3R tau in pathognomonic inclusions known as Pick bodies. The term PiD has adopted many meanings since its conception in 1926, but it is currently used as a strictly neuropathological term, since PiD patients cannot be diagnosed during life. Due to its rarity, PiD remains significantly understudied, and subsequently, the etiology and pathomechanisms of the disease remain to be elucidated. The study of PiD and the preferential 3R tau accumulation that is unique to PiD is imperative in order to expand the current understanding of the disease and inform future studies and therapeutic development, since the lack of intervention strategies for tauopathies remains an unmet need. Yet, the lack of an antemortem diagnostic test for the disease has further complicated the study of PiD. The development of a clinical diagnostic assay for PiD will be a vital step in the study of the disease that will greatly contribute to therapeutic research, clinical trial design and patient recruitment and ultimately improve patient outcomes. Seed aggregation assays have shown great promise for becoming ante mortem clinical diagnostic tools for many proteinopathies, including tauopathies. Future research on adapting and optimizing current seed aggregation assays to successfully detect 3R tau pathogenic forms from PiD samples will be critical in establishing a 3R tau specific seed aggregation assay that can be used for clinical diagnosis and treatment evaluation.

ABSTRACT Background An unmet clinical need in Parkinson's disease (PD) is to identify biomarkers for diagnosis, preferably in peripherally accessible tissues such as skin. Immunohistochemical studies have detected pathological α‐synuclein (αSyn) in skin biopsies from PD patients albeit sensitivity needs to be improved. Objective Our study provides the ultrasensitive detection of pathological αSyn present in the skin of PD patients, and thus, pathological αSyn in skin could be a potential biomarker for PD. Methods The real‐time quaking‐induced conversion assay was used to detect pathological αSyn present in human skin tissues. Further, we optimized this ultra‐sensitive and specific assay for both frozen and formalin‐fixed paraffin‐embedded sections of skin tissues. We determined the seeding kinetics of the αSyn present in the skin from autopsied subjects consisting of frozen skin tissues from 25 PD and 25 controls and formalin‐fixed paraffin‐embedded skin sections from 12 PD and 12 controls. Results In a blinded study of skin tissues from autopsied subjects, we correctly identified 24/25 PD and 24/25 controls using frozen skin tissues (96% sensitivity and 96% specificity) compared to 9/12 PD and 10/12 controls using formalin‐fixed paraffin‐embedded skin sections (75% sensitivity and 83% specificity). Conclusions Our blinded study results clearly demonstrate the feasibility of using skin tissues for clinical diagnosis of PD by detecting pathological αSyn. Moreover, this peripheral biomarker discovery study may have broader translational value in detecting misfolded proteins in skin samples as a longitudinal progression marker. © 2020 International Parkinson and Movement Disorder Society