Parkinson disease and the gut: new insights into pathogenesis and clinical relevance

Two mutations in the gene encoding alpha-synuclein have been linked to early-onset Parkinson's disease (PD). alpha-Synuclein is a component of Lewy bodies, the fibrous cytoplasmic inclusions characteristic of nigral dopaminergic neurons in the PD brain. This connection between genetics and pathology suggests that the alpha-synuclein mutations may promote PD pathogenesis by accelerating Lewy body formation. To test this, we studied alpha-synuclein folding and aggregation in vitro, in the absence of other Lewy body-associated molecules. We demonstrate here that both mutant forms of alpha-synuclein (A53T and A30P) are, like wild-type alpha-synuclein (WT), disordered in dilute solution. However, at higher concentrations, Lewy body-like fibrils and discrete spherical assemblies are formed; most rapidly by A53T. Thus, mutation-induced acceleration of alpha-synuclein fibril formation may contribute to the early onset of familial PD.

Parkinson's disease varies widely in clinical manifestations, course of progression and biomarker profiles from person to person. Identification of distinct Parkinson's disease subtypes is of great priority to illuminate underlying pathophysiology, predict progression and develop more efficient personalized care approaches. There is currently no clear way to define and divide subtypes in Parkinson's disease. Using data from the Parkinson's Progression Markers Initiative, we aimed to identify distinct subgroups via cluster analysis of a comprehensive dataset at baseline (i.e. cross-sectionally) consisting of clinical characteristics, neuroimaging, biospecimen and genetic information, then to develop criteria to assign patients to a Parkinson's disease subtype. Four hundred and twenty-one individuals with de novo early Parkinson's disease were included from this prospective longitudinal multicentre cohort. Hierarchical cluster analysis was performed using data on demographic and genetic information, motor symptoms and signs, neuropsychological testing and other non-motor manifestations. The key classifiers in cluster analysis were a motor summary score and three non-motor features (cognitive impairment, rapid eye movement sleep behaviour disorder and dysautonomia). We then defined three distinct subtypes of Parkinson's disease patients: 223 patients were classified as 'mild motor-predominant' (defined as composite motor and all three non-motor scores below the 75th percentile), 52 as 'diffuse malignant' (composite motor score plus either ≥1/3 non-motor score >75th percentile, or all three non-motor scores >75th percentile) and 146 as 'intermediate'. On biomarkers, people with diffuse malignant Parkinson's disease had the lowest level of cerebrospinal fluid amyloid-β (329.0 ± 96.7 pg/ml, P = 0.006) and amyloid-β/total-tau ratio (8.2 ± 3.0, P = 0.032). Data from deformation-based magnetic resonance imaging morphometry demonstrated a Parkinson's disease-specific brain network had more atrophy in the diffuse malignant subtype, with the mild motor-predominant subtype having the least atrophy. Although disease duration at initial visit and follow-up time were similar between subtypes, patients with diffuse malignant Parkinson's disease progressed faster in overall prognosis (global composite outcome), with greater decline in cognition and in dopamine functional neuroimaging after an average of 2.7 years. In conclusion, we introduce new clinical criteria for subtyping Parkinson's disease based on a comprehensive list of clinical manifestations and biomarkers. This clinical subtyping can now be applied to individual patients for use in clinical practice using baseline clinical information. Even though all participants had a recent diagnosis of Parkinson's disease, patients with the diffuse malignant subtype already demonstrated a more profound dopaminergic deficit, increased atrophy in Parkinson's disease brain networks, a more Alzheimer's disease-like cerebrospinal fluid profile and faster progression of motor and cognitive deficits.

Although still considered a paradigmatic movement disorder, Parkinson's disease (PD) is associated with a broad spectrum of non-motor symptoms. These include disorders of mood and affect with apathy, anhedonia and depression, cognitive dysfunction and hallucinosis, as well as complex behavioural disorders. Sensory dysfunction with hyposmia or pain is almost universal, as are disturbances of sleep-wake cycle regulation. Autonomic dysfunction including orthostatic hypotension, urogenital dysfunction and constipation is also present to some degree in a majority of patients. Whilst overall non-motor symptoms become increasingly prevalent with advancing disease, many of them can also antedate the first occurrence of motor signs - most notably depression, hyposmia or rapid eye movement sleep behaviour disorder (RBD). Although exact clinicopathological correlations for most of these non-motor features are still poorly understood, the occurrence of constipation, RBD or hyposmia prior to the onset of clinically overt motor dysfunction would appear consistent with the ascending hypothesis of PD pathology proposed by Braak and colleagues. Screening these early non-motor features might, therefore, be one approach towards early 'preclinical' diagnosis of PD. This review article provides an overview of the clinical spectrum of non-motor symptoms in PD together with a brief review of treatment options.