Biomarkers of Catecholaminergic Neurodegeneration

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

(A) NINDS PDRisk study: In the intramural NINDS PDRisk study (NIH Clinical Protocol 09N0010) we are following individuals at risk for developing Parkinson's 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 have distinguisehd the group that has developed PD from the group that has not. The negative predictive value of the absence of these biomarkers is 100%. Therefore, biomarkers of catecholamine deficiency may identify at-risk individuals who go on to develop PD years later. (B) Alpha-Synuclein (AS) deposition in sympathetic nerve fibers in skin and submandibular gland (SMG) in PD: There is great interest in determining whether analyses of potentially biopsiable tissues such as skin and submandibular gland (SMG) for deposition of the protein AS can provide a biomarker of pre-symptomatic PD. We recently completed a post-mortem study in which we quantified the amount of AS deposition in norepinephrine-producing (noradrenergic) nerve fibers in skin and SMG samples from patients with autopsy-proven PD and from age-matched controls. Preliminarily, in both skin and SMG, PD patients have increased AS deposition in noradrenergic nerves. Unexpectedly, the patients do not have evidence for either loss or dysfunction of noradrenergic nerves in the same samples. Therefore, intra-neuronal AS accumulation in biopsies of skin or SMG may provide biomarkers of PD, but the increased AS deposition does not appear to be damaging in these organs. The situation seems to be quite different in the heart, where the same patients have AS buildup associated with severe norepinephrine deficiency and evidence for loss of noradrenergic nerves. (C) Cardioselective noradrenergic deficiency in Lewy body diseases (LBDs): We reviewed 18F-dopamine positron emission tomographic (PET) scanning images and post-mortem neurochemical data across several body organs of patients with the LBDs PD or pure autonomic failure (PAF). We found that by both in vivo sympathetic neuroimaging and post-mortem neurochemistry, peripheral noradrenergic deficiency in LBDs is cardioselective (PMID 33216462). Neuroimaging biomarkers of catecholamine deficiency in the heart seem especially valuable for identifying LBDs. (D) 18F-Dopamine cardiac sympathetic neuroimaging to diagnose PD with orthostatic hypotension (PD+OH) differentially from the parkinsonian form of multiple system atrophy (MSA-P): PD+OH can be difficult to distinguish clinically from MSA-P. We investigated the utility of cardiac sympathetic neuroimaging by 18F-dopamine PET scanning for separating PD+OH from MSA-P. Cardiac 18F-dopamine scanning distinguished the PD+OH from the MSA-P group with sensitivity 92% and specificity 96%. Cardiac 18F-dopamine scanning provides a powerful biomarker for diagnosing PD+OH differentially from MSA-P (PMID 33981791). (E) Long-term trends in cardiac sympathetic innervation and function in LBDs: In LBDs, the rate of loss of 18F-dopamine-derived radioactivity across imaging frames within a scanning session is already increased upon initial testing, even in patients who have normal 18F-dopamine uptake. Neuroimaging evidence for decreased retention of 18F-dopamine-derived radioactivity may provide a biomarker of early disease in LBDs (PMID 31621602). (F) Sympathetic noradrenergic denervation and decreased intra-neuronal vesicular storage in pure autonomic failure (PAF): In the rare LBD PAF it has been presumed that loss of norepinephrine-containing sympathetic nerves throughout the body causes generalized noradrenergic deficiency and OH. In a multi-tracer neuroimaging study we used 11C-methylreboxetine and 18F-dopamine PET scanning to evaluate separately loss of cardiac sympathetic noradrenergic nerves and impaired vesicular storage function in residual nerves in PAF. We obtained evidence that PAF entails a combination of moderate denervation with substantially reduced vesicular storage of catecholamines, an example of the sick-but-not-dead phenomenon (PMID 32372682, 32906170). Multi-tracer cardiac neuroimaging may be a means to identify LBDs early in the disease course. (G) Differential abnormalities of cerebrospinal fluid (CSF) dopaminergic vs. noradrenergic indices in synucleinopathies: PD, MSA, and PAF are characterized by intracellular deposition of AS and are considered to be forms of synucleinopathy. The three diseases also entail catecholamine depletion in the brain. CSF levels of catecholamine metabolites may provide neurochemical biomarkers of central catecholamine deficiency in these synucleinopathies. We obtained evidence that the three diseases have in common in vivo evidence for central noradrenergic deficiency, which can be explained by degeneration of brainstem noradrenergic neurons. Neurochemical evidence for central dopamine deficiency, on the other hand, was obtained in PD and MSA but not in PAF. The results support the use of CSF catecholamine neurochemistry to identify differential abnormalities of central catecholaminergic neurons in synucleinopathies (PMID 33894018). (H) Computational modeling reveals tri-phasic progression of LBDs: To investigate the progression of catecholamine deficiency in LBDs we have constructed a computational model that incorporates harmful interactions of the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) with AS. Preliminarily, the model predicts a tri-phasic loss of neuronal norepinephrine stores, with a long period where norepinephrine stores are maintained, then rapid loss of those stores, and finally a slow further loss. Empirical longitudinal neuroimaging data in the heart and putamen of LBD patients fit this 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. (I) Collaborations: (1) With Dr. Derek Narendra (Neurogenetic Branch, DIR, NINDS) we published a genotype-phenotype study about AS-tyrosine hydroxylase (TH) colocalization in skin biopsies from patients with genetic forms of PD. Individuals with SNCA, DJ-1, LRRK2, or GBA mutations had increased AS-TH colocalization indices in sympathetic noradrenergic nerves, whereas those with biallelic PRKN mutations did not. Measuring AS-TH colocalization indices in skin biopsies may provide a biomarker of Lewy body forms of genetic PD (PMID 34076298). Also with Dr. Narendra we are assessing autonomic correlates of genetic PD. Preliminarily, PD from SNCA, LRRK2, or GBA mutations entails baroreflex-sympathoneural failure and cardiac noradrenergic deficiency, whereas PD from PRKN mutations does not. (2) In collaboration with investigators at the Univ. of Texas we assessed sympathetic innervation of the kidneys based on 11C-methylreboxetine and 18F-dopamine PET scanning. This multi-tracer neuroimaging approach seems to provide a quantitative biomarker of renal innervation (PMID 33677553). (3) According to the catecholaldehyde hypothesis, DOPAL and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) cause or contribute to catecholaminergic neurodegeneration in LBDs. Assays of DOPAL and DOPEGAL by liquid chromatography with electrochemical detection are limited technologically. With collaborators we are exploring liquid chromatography with tandem and time of flight mass spectrometry using a commercially available system.