The association of cerebrospinal fluid α-synuclein, level of olfactory disability, and enteric nervous system dysfunction with motor disability, cognitive deficits, and anxiety in Parkinson’s Disease

Abstract

Thesis Overview Parkinsons disease (PD) is a complex neurodegenerative disorder with clinical symptoms of motor and non-motor dysfunction (1,2) including pathological findings of α-synuclein (SYN) aggregates within the brain (3). Synuclein aggregates are particularly prominent in the substantia nigra, a structure that has dopamine projections to the striatum. The reduction in dopamine in the striatum is thought to underlie the motor deficits in PD (3). Aggregated forms of SYN coalesce within Lewy bodies with inclusions containing misfolded SYN protein which cause subsequent neuronal dysfunction(4). The range of motor symptoms include bradykinesia, resting tremor, rigidity, and postural instability. In regard to non-motor symptoms: olfactory dysfunction, cognitive dysfunction, neuropsychiatric phenotypes, sleep disturbances, and autonomic impairment including constipation are typically observed (2). It is important to note that PD dementia is the second most frequent cause of cognitive impairment after Alzheimer’s Disease and for this reason, we have selected this as one of the primary clinical outcomes for biomarker analysis. In testing potential new therapies for treatment of PD in clinical trials, there is a critical need for new prognostic biomarkers to determine propensity for patients to develop both motor and non-motor symptoms. However, current biomarkers, including dopamine uptake on PET and SPECT imaging, only weakly correlate with motor symptoms and do not predict progression of non-motor symptoms reliably. Biochemical measurements of biofluids are promising and have proven useful in other neurodegenerative disorders but have not been well-validated in PD. We therefore conceived our project in an attempt to find a better set of prognostic biomarkers to help clinicians identify patients most at risk for severe pathology and adjust their treatment regimen accordingly. In order to accomplish this goal, we chose the Michael J. Fox Foundation Parkinsons Progressive Marker Initiative (PPMI) cohort study to evaluate a number of potential biomarkers, both for motor and non-motor symptoms in PD. The PPMI contains one of the largest clinical databases, which was specifically designed for testing and validation biomarkers in PD. This thesis will report results that provides plausible mechanism-based connections between biomarkers (synuclein, olfaction, and enteric nervous system dysfunction) and anxiety and cognitive impairment, which are non-motor symptoms that are a major source of disability for PD patients. Thematic Linkage Thesis Part 1 and 2 Thesis work is separated into Parts 1 and 2, each of which carries a common theme of testing of a proteomic biomarker (SYN) for motor and cognitive disability (Part 1) and testing of early non-motor symptoms (olfaction and constipation) as predictors of cognitive impairment and moderate to severe anxiety (Part 2) in PD. Additionally, a secondary aim of our research is to determine the mechanistic routes of SYN mediated synucleinopathies. It has recently been reported that PD may be due to the spread of SYN via two distinct mechanisms known as the brain initiated or body-initiated routes (4). These mechanisms of synucleinopathy may function separately or simultaneously with body route pathology beginning in the enteric nervous system and spreading upward similar to a prion via the dorsal vagus to through the brain stem to the central nervous system (CNS). The “brain-first” mechanism begins with the SYN seeding event occurring in the olfactory-amygdala system and spreading across the CNS and downward to the enteric nervous system through the dorsal motor vagus (4). If SYN spreads in a brain route, there should be early involvement of the amygdala and possibly dysfunction of the olfactory circuit. PD patients frequently lose partial sense of smell (hyposmia) or all sense of smell (anosmia) years prior to significant motor dysfunction, fitting with this “brain-first” pathway (4) . In contrast, the “body-first” mechanism proposes to explain early enteric nervous system dysfunction as manifested by constipation, which can also precede a clinical diagnosis of PD by years (4). We believe that our thesis work can contribute to the understanding of the genesis of PD disability. In order to accomplish our goals, Part 1 thesis work was specifically designed to determine if motor dysfunction symptoms as well as cognition were associated with a PD patient’s association of total α-SYN in cerebrospinal fluid. Part 2 thesis was designed to determine if the olfactory circuit and/or enteric nervous dysfunction were associated with PD non-motor symptoms of cognitive impairment and severity of anxiety. If results from part 1 are clinically significant (SYN soluble biomarker), our goal was to then to combine this data with results from Part 2 to potentially construct an overall prognostic model of PD disease progression. Our goals were to begin to provide the beginnings of an integrated model of disease progression that could be used by clinicians and researchers alike. The titles of Part 1 and 2 are described below: Title Part 1: A study to determine the strength of association of Cerebrospinal Fluid Levels of α-Synuclein in Parkinsons Disease patients with motor disability and cognitive deficits using prospective biomarker data from the Parkinsons Progressive Marker Initiative (PPMI). Title Part 2: A study to determine the association olfactory and enteric nervous system dysfunction with cognitive impairment and severity of anxiety in Parkinsons Disease (PD) Patients. The potential role of olfaction and constipation as part of a prognostic disease model for predicting cognitive deficits and anxiety in PD patients, using prospective biomarker data from the 'Parkinsons Progressive Marker Initiative (PPMI).