Treatment of Catecholaminergic Neurodegeneration

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

This project is about treatments that may slow or prevent degeneration and loss of nerve cells (neurons) that use the catecholamines dopamine or norepinephrine as their chemical messengers (neurotransmitters). We are especially interested in testing predictions from the catecholaldehyde hypothesis, according to which 3,4-dihydroxyphenylacetaldehyde (DOPAL) and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), respective breakdown products (metabolites) of dopamine and norepinephrine, contribute to catecholaminergic neurodegeneration. (A) Alpha-Synuclein (AS) deposition in sympathetic nerves in genetic Parkinsons disease (PD): PD entails AS buildup outside the brain in nerves of the automatic nervous system (autonomic nervous system) called sympathetic nerves. In collaboration with Dr. Derek Narendra (Neurogenetics Branch, DIR, NINDS) we compared magnitudes of intra-neuronal AS deposition across genetic forms of PD. AS deposition in sympathetic nerves was measured by the AS-tyrosine hydroxylase (TH) colocalization index in skin biopsies. SNCA, DJ-1, LRRK2, and GBA mutations were found to be associated with high AS-TH colocalization indices, whereas PRKN mutations were not. Calculating AS-TH colocalization indices in skin biopsies may be informative in identifying the most appropriate candidates for experimental therapeutic trials targeting AS to treat or prevent genetic PD (PMID 34076298). (B) Animal model of the abnormal brain catecholaminergic pattern found in PD: With collaborators at the Tel Aviv University we have found preliminarily that administration of the pesticide rotenone reproduces the abnormal brain neurochemical pattern found in PD, including DOPAL buildup. We are testing whether combining monoamine oxidase (MAO) inhibition to decrease DOPAL formation with N-acetylcysteine (NAC) to decrease DOPAL-induced AS misfolding prevents the abnormal neurochemical pattern and associated neurobehavioral abnormalities in this model. (C) Differential susceptibilities of catecholamines to monoamine oxidases (MAOs): According to the catecholaldehyde hypothesis, decreasing the formation of DOPAL and DOPEGAL by inhibiting MAO should mitigate the disease process in LBDs and AD. There are two isoforms of MAO, MAO-A and MAO-B. Based on the ability to measure DOPAL and DOPEGAL we have found preliminarily that MAO-A predominates in the formation of both DOPAL from dopamine and of DOPEGAL from norepinephrine. For experimental therapeutic efforts based on the catecholaldehyde hypothesis, MAO-A seems to be the more appropriate MAO sub-type to target. (D) Sympathetic noradrenergic denervation and decreased intra-neuronal vesicular storage in pure autonomic failure (PAF): The rare Lewy body disease (LBD) pure autonomic failure (PAF) is characterized by generalized deficiency of the catecholamine norepinephrine. In a multi-tracer neuroimaging study we used 11C-methylreboxetine (11C-MRB) and 18F-dopamine positron emission tomographic (PET) scanning to evaluate cardiac sympathetic innervation and function in PAF. We obtained evidence that PAF entails a combination of a moderate amount of noradrenergic denervation with substantially reduced sequestration of catecholamines in storage vesicles in the residual nerves. This functional abnormality in dysfunctional but extent nerves is an example of the sick-but-not-dead phenomenon (PMID 32372682, 32906170). The results rationalize experimental therapeutic efforts targeting the vesicular storage defect in LBDs. (E) Computational modeling of multiple abnormalities in catecholaminergic neurons: We have constructed a computational model that incorporates harmful DOPAL-AS interactions. Preliminarily, the model predicts findings in animal models that genetically determined decreased activity of the vesicular monoamine transporter or aldehyde dehydrogenase accelerates catecholaminergic neurodegeneration, while decreased activity of MAO slows the neurodegeneration. Combining computational modeling with clinical laboratory biomarkers to detect preclinical disease may enable individualized disease-modifying treatment of LBDs. (F) Catechols in plasma after drinking caffeinated or decaffeinated coffee: Coffee contains numerous 3,4-dihydroxyphenyl compounds (catechols), such as dihydrocaffeic acid (DHCA), which is neuroprotective in cells and animal models. We have examined effects of drinking caffeinated or decaffeinated coffee on plasma free (unconjugated) catechols in healthy people. Preliminarily, within 15 minutes of drinking coffee of either type, >20 catechols are present in the plasma, with sustained increases in plasma DHCA. The results raise the possibility that extracts of decaffeinated coffee might promote resilience of catecholaminergic neurons. (G) AAV2/GDNF treatments of PD, multiple system atrophy (MSA), and Menkes disease: With other NINDS investigators we are reporting a case of PD treated with a form of gene therapy based on convection-enhanced delivery (CED) of type 2 adeno-associated virus/glial cell line-derived neurotrophic factor (AAV2/GDNF). Preliminarily, post-mortem tissues from the patient demonstrated profound dopamine depletion in the putamen (the main damaged region of the brain in PD) and norepinephrine depletion in the heart. These catecholaminergic abnormalities were associated with buildup of AS in cardiac sympathetic nerves. The neurodegenerative process in this patient may have been too advanced for AAV2/GDNF treatment to be effective. MSA is a rare disease that entails atrophy of brain centers and catecholamine deficiency. Abnormalities in glial cells (non-neuronal helper cells) likely contribute to MSA. In a multi-center collaboration we are assessing CED of AAV2/GDNF to treat MSA. So far, 3 MSA patients have undergone this treatment. A clinical trial is under development with collaborators at the Ohio State University. Menkes disease is a rare disorder of copper metabolism that usually is lethal in childhood. The enzyme that converts dopamine to norepinephrine contains and requires copper, and Menkes disease is characterized by norepinephrine deficiency in the brain and periphery. We are collaborating with investigators at the Ohio State University on animal models of gene therapy treatments for Menkes disease, with a view to a future clinical trial. (H) Atomoxetine to treat cognitive dysfunction inhibits catecholamine reuptake in the human brain: The drug atomoxetine inhibits the reuptake of norepinephrine released from neurons and is being tested in people with mild cognitive dysfunction, a risk factor for development of AD. With collaborators at Emory we have found preliminarily that atomoxetine treatment produces a cerebrospinal fluid neurochemical pattern consistent with decreased reuptake of both norepinephrine and dopamine in the brain. (I) Epidural spinal cord stimulation for low blood pressure (hypotension) in patients with spinal cord injury. In collaboration with investigators at the Univ. of Louisville we are evaluating effects of epidural stimulation on plasma levels of catecholamines and related compounds in people with hypotension after spinal cord injury. (J) LC-MS/MS for catecholamine-related compounds: Biochemical assays of DOPAL and DOPEGAL by liquid chromatography with electrochemical detection are limited technologically. To document effects of experimental therapeutic measures on DOPAL and DOPEGAL levels, liquid chromatography with tandem and time of flight mass spectrometry (LC-MS/MS) seems superior. This methodology could also be used to identify coffee-related catechols in human plasma. Under a technology transfer agreement we are exploring whether a commercially available LC-MS/MS system validly measures plasma DOPAL and DOPEGAL.