Evolution of prodromal Parkinson’s disease and dementia with Lewy bodies: a prospective study

Abstract

Parkinson’s disease has a long prodromal stage with various subclinical motor and non-motor manifestations; however, their evolution in the years before Parkinson’s disease is diagnosed is unclear. We traced the evolution of early motor and non-motor manifestations of synucleinopathy from the stage of idiopathic rapid eye movement (REM) sleep behaviour disorder until defined neurodegenerative disease. During 2004–16, we recruited and then annually followed 154 polysomnography-proven patients with idiopathic REM sleep behaviour disorder, of whom 55 phenoconverted to defined parkinsonism or dementia. Longitudinal data on multiple prodromal features, including the Unified Parkinson’s Disease Rating Scale parts I–III, quantitative motor tests, olfaction, colour vision, cognition, and autonomic functions were gathered annually (average = five follow-up visits, range: 2–12 years). The same measures were also assessed in 102 age- and sex-matched healthy control subjects. By looking backward from the time of dementia or parkinsonism diagnosis, we examined trajectories of each prodromal feature using mixed effect models. Based on analysis, olfactory loss was first to develop, with predicted onset >20 years before phenoconversion. This was followed by impaired colour vision, constipation, and erectile dysfunction, starting 10–16 years prior to phenoconversion. At 7–9 years before phenoconversion, slight urinary dysfunction and subtle cognitive decline could be detected. Among motor symptoms altered handwriting, turning in bed, walking, salivation, speech, and facial expression began to be disrupted starting 7–11 years prior to parkinsonism diagnosis, but remained mild until soon before phenoconversion. Motor examination abnormalities began 5–7 years before phenoconversion, with the alternate tap test having the longest interval (8 years before phenoconversion). Among cardinal motor phenotypes, bradykinesia appeared first, ∼5–6 years prior to phenoconversion, followed by rigidity (Year −3) and tremor (Year −2). With direct prospective evaluation of an idiopathic REM sleep behaviour disorder cohort during phenoconversion, we documented an evolution of prodromal manifestations similar to that predicted by pathological staging models, with predicted prodromal intervals as long as 20 years.

Research criteria for the diagnosis of prodromal dementia with Lewy bodies

“…58 However, because there are many other causes for autonomic dysfunction in older people, these symptoms, either alone or in combination, have low positive predictive value. 59 The situation is similar for hyposmia, which also frequently occurs early in prodromal DLB and PD, 42 but which can have many other causes in this age group.…”

“…e29 Other direct or indirect biomarker candidates that may occur early include identification of phosphorylated α-synuclein deposits in peripheral nervous tissue from skin biopsy, 40 gait analysis, e30 and abnormalities in color vision discrimination. 41,42 Figure shows a framework for considering a wider range of biomarkers in the setting of prodromal DLB determining the extent to which AD-related pathology is contributing to the dementia syndrome and influencing clinical trajectories in these patients. 43,44,e31,e32 Aβ42 declines earlier in AD than DLB, whereas Aβ40 levels increase alone in AD.…”

“…Although idiopathic RBD is a useful model to study the early stages of LB disease progression, it is not necessarily representative of the whole spectrum of patients with PD and DLB, a significant minority of whom do not have RBD. 42 Autonomic dysfunction/anosmia and other nonspecific prodromal LB disease symptoms Patients with DLB frequently report a history of autonomic dysfunction at first clinic attendance, with 25%-50% complaining of one of more among constipation, orthostatic dizziness, urinary incontinence, erectile dysfunction, increased sweating, or increased saliva. 56,57 In a cohort of patients with pure autonomic failure, 34% converted to an overt α-synucleinopathy over 6 years of follow-up; this was to DLB (52%), PD (24%), or MSA (24%).…”

Continuous Real-World Gait Monitoring in Idiopathic REM Sleep Behavior Disorder

“…This period has been estimated, by retrospective and prospective studies, to vary between three to more than 20 years [2,5,6]. If we wish to address disease modification, early intervention during the prodromal period would be ideal to slow or halt ongoing degeneration of neurons.…”

White Matter Hyperintensities Mediate Impact of Dysautonomia on Cognition in Parkinson's Disease

“…1 Dysautonomia has been found to manifest during the prodromal stage of parkinsonism, years before phenoconversion to PD. [2][3][4] The prevalence of autonomic features is associated with disease duration and severity as well as some PD medications. 5,6 More severe autonomic dysfunction has also been shown to be associated with increased cognitive impairment.…”