Prediagnostic Progressive Supranuclear Palsy – Insights from the UK Biobank

Abstract

Introduction: Prediagnostic features of Parkinson's Disease are well described but prediagnostic Progressive Supranuclear Palsy (PSP) is less understood. The diagnosis of PSP is delayed by an average of three years after symptom onset. Understanding the changes that occur in the prediagnostic period will aid earlier diagnosis, clarify the natural history, and may aid the design of early disease-modifying therapy trials. We set out to identify motor and cognitive markers of prediagnostic PSP, with Parkinson's disease as a comparator condition, in a large prospective cohort. Methods: Baseline UK Biobank data from 502,504 individuals were collected between 2006 and 2010. Subsequent PSP and Parkinson's disease cases were identified from primary and secondary care electronic health records' diagnostic coding data and death registry, with 5404 matched controls. Results: 176 PSP cases (time to diagnosis 7.8 ± 2.8 years) and 2526 Parkinson's disease cases (time to diagnosis 7.8 ± 2.9 years) were identified. At baseline, those later diagnosed with PSP had slower reaction times, weaker hand grip, lower fluid intelligence, prospective memory, self-rated health scores and digit recall than controls. Reaction times were correlated with time to diagnosis. The PSP group had higher mortality than both Parkinson's disease and control groups. Conclusions: Motor slowing, cognitive dysfunction, and postural instability are clinical diagnostic features of PSP that are typically symptomatic three years before diagnosis. Objective markers of these features were evident on average 7.8 years before diagnosis. Our findings suggest the existence of a long prediagnostic phase in PSP, with subtle changes in motor and cognitive function.

Pre‐diagnostic cognitive and functional impairment in multiple sporadic neurodegenerative diseases

“…As a proof-of-concept, we recently published an analysis of pre-diagnostic data on the cohort in the UK Biobank who went on to develop progressive supranuclear palsy (PSP). 19 We present an analysis of the data extracted from the UK Biobank, testing whether cognitive and functional changes are detectable in individuals who subsequently develop a neurodegenerative disease, the majority of which are sporadic. This provides an overview of the early manifestations of multiple rare and common neurodegenerative diseases.…”

“…This offers a rich data set of prospective cognitive and functional data from a large pool of individuals, some of whom have gone on to develop a neurodegenerative disease. As a proof‐of‐concept, we recently published an analysis of pre‐diagnostic data on the cohort in the UK Biobank who went on to develop progressive supranuclear palsy (PSP) 19 …”

Longitudinal Synaptic Loss in Primary Tauopathies: An In Vivo [11C]UCB‐J Positron Emission Tomography Study

“…Cognitive dysfunction is an early symptom in people with PSP/CBD, with subtle manifestations apparent 8 years before diagnosis. 18 Synaptic dysfunction is proposed as a key pathogenic mechanism underlying cognitive dysfunction, 19,20 via changes in network physiology. 21 In preclinical tauopathy models, severe synaptic loss can occur before neuronal loss.…”

“…Pathologically, PSP and CBD are associated with accumulation of hyperphosphorylated 4‐repeat tau, 8‐11 inflammation, 12‐14 and severe synaptic loss, 15‐17 ultimately all leading to neuronal loss. Cognitive dysfunction is an early symptom in people with PSP/CBD, with subtle manifestations apparent 8 years before diagnosis 18 …”

Pre-Diagnostic Cognitive and Functional Impairment in Multiple Sporadic Neurodegenerative Diseases

“…This offers a rich dataset of prospective cognitive and functional data from a large pool of individuals, some of whom have gone on to develop a neurodegenerative disease. As a proof-of-concept, we recently published an analysis of pre-diagnostic data on the cohort of people in the UK Biobank who went on to develop Progressive Supranuclear Palsy [19].…”