Assistant Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Sarva reports no financial relationships relevant to this field of study.

SYNOPSIS: In this review of the common prodromal symptoms of α-synucleinopathies, such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, the authors provided a potential framework for a timeline of the development of these conditions, starting with these prodromal symptoms.

SOURCE: Savica R, Bradley BF, Mielke MM. When do α-synucleinopathies start? An epidemiological timeline: A review. JAMA Neurol 2018;75:503-509.

Alpha-synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are chronic progressive neurodegenerative conditions that result from abnormal deposition of misfolded α-synuclein into neurons, and in the case of MSA, into oligodendrocytes. Although pathological hallmarks begin many years before their clinical diagnoses, several prodromal features have been described in various studies. Neuropathological and functional imaging studies suggest the development of a premotor stage of at least five years before the clinical diagnosis of PD. Common prodromal symptoms described in the literature include olfactory dysfunction, constipation and dysautonomia, anxiety and depression, and REM-sleep behavior disorder. Two epidemiological studies have shown that anosmia can be predictive of Lewy body pathology and DaTscan positivity. Constipation is among the most commonly reported symptoms and, on average, can predate the clinical features of PD by at least 10 years. Anxiety and depression are also very common and may predate PD motor symptoms by 20 years. REM-sleep behavior disorder, another
very common premotor symptom, may assist in predicting conversion to clinical features of PD. New studies indicate a median conversion of 7.5 years to PD, DLB, or MSA. Because of the lack of concrete predictive value of any of these prodromal symptoms, Savica et al proposed a three-stage representation: Stage 1 begins with neuropathology and early manifestations such as anosmia; Stage 2 consists of anxiety and RBD; and Stage 3 involves the striatum and presentation of parkinsonian symptoms.

COMMENTARY

Although various prodromal symptoms have been identified and have expanded our knowledge about the pathology and clinical phenomena of α-synucleinopathies, there is still a gap in predicting the development of specific types of disorders based on these early manifestations. Further complicating the issue is that PD itself is not a single disorder and has multiple subtypes. Thus, while having several prodromal features simultaneously may increase predictability, exactly which subtype of PD will develop is difficult to determine. In addition, exactly how the α-synuclein pathology propagates is unclear despite Braak’s work and as shown by the clinical manifestations of DLB. The role of genetic and epigenetic factors in the development of these conditions is not understood entirely. Lastly, much of the work on prodromal features of these conditions has been performed on patients with PD and cannot be generalizable to atypical parkinsonisms, which are rare. The high misdiagnosis rate between PD and parkinsonisms further complicates the predictability of these prodromal symptoms. Thus, large-scale epidemiological studies of at least five years with radiological and biological specimens are needed to aid not only in the development of good biomarkers but also in assisting in better using these prodromal features to predict the diverse forms of these neurodegenerative disorders.