Biomarkers of Catecholaminergic Neurodegeneration

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This summary highlights recent advances from the Autonomic Medicine Section (AMS) in the area of biomarkers of catecholaminergic neurodegeneration. (1) In the unique intramural NINDS PDRisk study, a prospective, longitudinal, cohort study of individuals with multiple risk factors for Parkinson disease (PD), we have been assessing whether biomarkers of catecholaminergic neurodegeneration in the brain or heart predict PD development during up to 7.5 years of follow-up. We have found that among groups with equal statistical risk factors, biomarkers of central dopamine and cardiac norepinephrine deficiency predict PD (Goldstein et al., Park Rel Dis 2018;50:108-112; Goldstein et al., Park Rel Dis 2018;52:90-93). The study is almost completed, and preliminarily the negative predictive value of NOT have biomarkers of catecholaminergic neurodegeneration is 100%. (2) We found that increased colocalization of alpha-synuclein (AS) with tyrosine hydroxylase (TH), a marker of catecholaminergic neurons, in sympathetic noradrenergically innervated skin constituents efficiently separates Lewy body from non-Lewy body forms of neurogenic orthostatic hypotension (nOH) (Isonaka et al., Hypertension 2019;73:910-918). With this study as a foundation we are assembling data to propose that quantitative immunofluorescence microscopy can identify Lewy body diseases in living patients. (3) We published a study about long-term trends in indices of cardiac sympathetic innervation and function in synucleinopathies and found that in Lewy body forms of synucleinopathy, even upon initial testing, the rate of loss of radioactivity after 18F-dopamine uptake was already increased. The results suggest that decreased vesicular sequestration of cytoplasmic catecholamines precedes loss of cardiac sympathetic neurons in these diseases. We call this the sick-before-dead phenomenon (Lamotte et al., Park Rel Dis 2019;67:27-33). (4) In a unique multi-tracer sympathetic neuroimaging study, 11C-methylreboxetine (11C-MRB) and 18F-dopamine were used to evaluate cardiac sympathetic innervation and intra-neuronal vesicular storage in pure autonomic failure (PAF), a rare but scientifically important disease that can evolve from isolated neurogenic orthostatic hypotension to PD or dementia with Lewy bodies. It has been thought that PAF directly reflects sympathetic noradrenergic denervation. The results of this sutyd, however, indicate that PAF entails a combination of moderate myocardial sympathetic denervation with markedly reduced vesicular sequestration of cytoplasmic catecholamine in residual noradrenergic nerves, providing graphic visualization of the sick-but-not-dead phenomenon (Goldstein et al., Ann Clin Transl Neurosci, in press). (5) We have found preliminarily that in vivo myocardial 18F-dopamine-derived radioactivity correlates positively with post-mortem TH (r=0.80) and norepinephrine (r=0.82) contents in the same patients. These data validate 18F-dopamine scanning as a biomarker to assess the status of cardiac sympathetic innervation. (6) Collaborations: (a) In collaboration with Dr. Derek Narendra (NINDS) we completed a genotype-phenotype study of AS-TH colocalization in skin biopsies from individuals at genetic risk of PD. We published that in PD from DJ-1 mutation (PARK7) there is increased AS-TH colocalization, providing the first evidence for peripheral intra-neuronal synucleinopathy in this disease (Narendra et al., Neurology 2019;92:1113-1115). Preliminarily, increased AS-TH colocalization characterizes genetic synucleinopathies, glucocerebrosidase gene mutation, and LRRK2 mutation but not parkin gene mutation (Isonaka et al., unpublished observations). (b) In a collaborative study with investigators at Harvard we found an association between innervation-adjusted AS in arrector pili muscles and cardiac noradrenergic deficiency in autonomic synucleinopathies (Isonaka et al., Clin Auton Res 2019;29:587-593). (c) With collaborators at the Univ. of Texas, Applying renal 11C- MRB scanning we obtained the first evidence that a chemical denervation procedure actually decreases local sympathetic innervation in humans (Hearon et al., unpublished observations). (d) COVID-19-related biomarkers testing: The pandemic viral illness COVID-19 is especially life-threatening in the elderly and in those with any of a variety of chronic medical conditions. We explored the possibility that the heightened risk may involve activation of the extended autonomic system (EAS). Traditionally the autonomic nervous system has been viewed as consisting of the sympathetic nervous system, the parasympathetic nervous system, and the enteric nervous system. Over the past century, however, neuroendocrine and neuroimmune systems have come to the fore, justifying expansion of the meaning of autonomic. Additional facets include the sympathetic adrenergic system, for which adrenaline is the key effector; the hypothalamic-pituitary-adrenocortical axis; arginine vasopressin (synonymous with anti-diuretic hormone); the renin-angiotensin-aldosterone system, with angiotensin II and aldosterone the main effectors; and cholinergic anti-inflammatory and sympathetic inflammasomal pathways. A hierarchical brain networkthe central autonomic networkregulates these systems; embedded within it are components of the Chrousos/Gold stress system. Acute, coordinated alterations in homeostatic settings (allostasis) can be crucial for surviving stressors such as traumatic hemorrhage, asphyxiation, and sepsis, which throughout human evolution have threatened homeostasis; however, intense or long-term EAS activation may cause harm. While required for appropriate responses in emergencies, EAS activation in the setting of chronically decreased homeostatic efficiencies (dyshomeostasis) may reduce thresholds for induction of destabilizing, lethal vicious cycles. Testable hypotheses derived from these concepts are that biomarkers of EAS activation correlate with clinical and pathophysiologic data and predict outcome in COVID-19 (Goldstein, Clin Auton Res 2020; 2020;22:1-17).