Prodromal Parkinson's Disease: The Decade Past, the Decade to Come

Abstract

The past decade has seen a dramatic expansion of the field of prodromal PD. Ten years ago, there were only six known prodromal markers of disease, none of which had more than two studies documenting diagnostic value. We now have at least 16 markers, with as many as 10 prospective studies for a single marker. This review summarizes the major advances over the last decade and speculates about the advances we will see in the decade to come. The most notable advances over the last decade came through the study of high‐risk cohorts (REM sleep behavior disorder and later genetic and autonomic cohorts), the generation of more representative population‐based cohorts for studying prodromal PD, major advances in neuroimaging of early disease stages, the emerging likelihood that tissue biopsy will be able to diagnose prodromal PD, and the coalescence of prodromal markers into discrete criteria. As the next decade dawns, we await increasing precision of sensitivity and specificity estimates of known markers, the discovery of new biomarkers of prodromal disease, improvements in diagnosis using combined methods/criteria (with increasing recognition of prodromal PD as one stage of the full PD spectrum), and ultimately the development of neuroprotective therapy that can be provided at the earliest stages of disease. © 2019 International Parkinson and Movement Disorder Society

If not salivary alpha-synuclein, then what? A look at potential Parkinson’s disease biomarkers

“…Most of these studies have shown high specificity/positive predictive values for conversion to PD. Sensitivity was variable and depended almost entirely upon the depth of marker assessment [3].…”

The Challenge and Opportunity to Diagnose Parkinson's Disease in Midlife

“…In addition to motor impairments, symptoms of PD typically involve a plethora of non-motor features that range from sensory disturbances, to neuropsychiatric and cognitive symptoms, to sleep disorders, and to autonomic dysfunction (39)(40)(41). Olfactory impairment/hyposmia, rapid-eye movement sleep behavior disorder (RBD), constipation, impairments in memory retrieval and decision making as well as depression (42)(43)(44)(45) often have a greater impact on the patient's quality of life than motor deficits (46). A number of these symptoms precede motor deficits by years or even decades (Figure 1) (23,(47)(48)(49), but due to the lack of specificity, diagnostic possibilities based on these markers are still limited (19).…”

α-Synuclein-induced Kv4 channelopathy in mouse vagal motoneurons causes non-motor parkinsonian symptoms

“…However, the lessons from Alzheimer's disease clinical trials targeting beta-amyloids with similar strategies (Selkoe, 2019) indicated that early detection before manifestation of clinical core symptom might also be essential for PD (Brundin et al, 2017;Lang and Espay, 2018). Therefore, for future disease-modifying therapies to be successful they will require early detection of the a-synucleinopathies, which in most (but not all) cases appear in the brainstem years before clinical diagnosis (Arnaldi et al, 2019;Lim et al, 2009;Mahlknecht et al, 2016;Postuma and Berg, 2019). During this prodromal period, future PD patients already begin to suffer from a variety of non-motor symptoms (NMS), which can precede clinical diagnosis by decades (Postuma and Berg, 2019).…”

“…Therefore, for future disease-modifying therapies to be successful they will require early detection of the a-synucleinopathies, which in most (but not all) cases appear in the brainstem years before clinical diagnosis (Arnaldi et al, 2019;Lim et al, 2009;Mahlknecht et al, 2016;Postuma and Berg, 2019). During this prodromal period, future PD patients already begin to suffer from a variety of non-motor symptoms (NMS), which can precede clinical diagnosis by decades (Postuma and Berg, 2019). It stands to reason that particular NMS are associated with the appearance of LPs in particular anatomical regions.…”