Biomarkers of Catecholaminergic Neurodegeneration

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(A) NINDS PDRisk study: In the intramural NINDS PDRisk study (NIH Clinical Protocol 09N0010, NCT NCT00775853 ) we are following individuals at risk for developing Parkinsons disease (PD) based on genetics, dream enactment behavior, decreased sense of smell, and a fall in blood pressure during standing (orthostatic hypotension, OH). A sufficient number of participants have completed 5 1.5-year follow-up evaluations to begin to draw conclusions about the positive and negative predictive values of having biomarkers of catecholamine deficiency in the brain or heart. Preliminarily, all of 8 catecholaminergic biomarkers distinguish the group that develops PD from the group that does not. The negative predictive value of the absence of these biomarkers may be as high as 100%. Therefore, biomarkers of catecholamine deficiency seem to identify efficiently at-risk individuals who go on to develop PD. (B) Alpha-synuclein (AS) deposition in sympathetic nerves in skin, submandibular gland (SMG), and heart in PD: A post-mortem observational study: The pathophysiological significance of AS deposition in catecholaminergic neurons, although widely suspected, has been poorly understood. In a post-mortem study we quantified the amounts of immunoreactive AS and tyrosine-hydroxylase (TH, a marker of catecholaminergic neurons) and concurrently assayed norepinephrine contents in three sympathetic noradrenergically innervated structures--skin, SMG, and myocardum--from patients with autopsy-proven PD. In all three tissues PD patients had increased AS deposition compared to age-matched controls. Unexpectedly, norepinephrine and TH contents in skin and SMG were normal in PD patients, whereas in the heart PD patients had severe norepinephrine deficiency and decreased TH. These findings suggest that in skin and SMG AS deposition may be a non-pathogenic biomarker, whereas in the heart AS in sympathetic nerves may be toxic (PMID 35260194). (C) Computational modeling reveals tri-phasic progression of LBDs: By the time a patient develops symptoms of a LBD, there is already substantial loss of catecholaminergic neurons. Identifying biomarkers of preclinical LBDs may be crucial for maximizing the effectiveness of disease-modifying treatments. The pattern of progression of catecholaminergic neurodegeneration in preclinical LBDs, however, has been unknown. We extended on a previously published computational model that incorporates harmful interactions of the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) with AS. The modeling indicated tri-phasic loss of catecholamine contents, from homeostasis in the first phase to dyshomeostasis and rapid catecholamine depletion in the second phase to slow further loss in the symptomatic third phase. Empirical longitudinal neuroimaging data in both the heart and putamen of LBD patients fit with this tri-phasic pattern. Combining computational modeling with clinical laboratory biomarkers to detect preclinical disease may enable individualized predictions about disease progression and target specific intra-neuronal dysfunctions for experimental therapeutic trials in LBDs (PMID 35621196). (D) Alpha-Synuclein deposition in sympathetic nerves in genetic PD: Cytoplasmic inclusions of AS in brainstem neurons are characteristic of idiopathic PD. PD also entails AS buildup in sympathetic nerves. Among genetic forms of PD, the relative extents of sympathetic intra-neuronal accumulation of AS have not been reported. In a cross-sectional observational study we compared magnitudes of intra-neuronal AS deposition in common and rare genetic forms of PD by applying a validated method, calculation of AS-tyrosine hydroxylase colocalization indexes. Intra-neuronal AS deposition varied as a function of genotype, above the control range in 100% of subjects with SNCA or LRRK2 mutations, 95% with idiopathic PD, 83% with GBA mutations, and 0% with biallelic PRKN mutations. Individuals with SNCA, LRRK2, or GBA mutations therefore have substantial intra-neuronal AS deposition in sympathetic noradrenergic nerves in skin biopsies, whereas those with biallelic PRKN mutations do not. These findings have important implications for diagnosing LBDs in living patients via AS-TH colocalization indexes (PMID 34076298). (E) Liquid chromatography with tandem and time of flight mass spectrometry (LC-MS/MS) to assay catecholamines and related compounds in clinical biofluids and tissues: Assays of catecholamines and related compounds by liquid chromatography with electrochemical detection are limited technologically. With collaborators we are exploring LC-MS/MS using a commercially available system.