Computational modeling reveals multiple abnormalities of myocardial noradrenergic function in Lewy body diseases

Goldstein, David S.; Pekker, Mark J.; Eisenhofer, Graeme; Sharabi, Yehonatan

doi:10.1172/jci.insight.130441

Cited by 25 publications

(41 citation statements)

References 44 publications

(62 reference statements)

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“…20 Outside the brain, in PD there is very prominent loss of NE in the left ventricular myocardium. [21][22][23] The extent of decrease in PD-90 to 99%-is similar to that of putamen dopamine. Several in vivo neuroimaging studies have indicated that in PD noradrenergic deficiency is cardioselective [24][25][26][27] ; however, postmor-tem NE tissue contents in extracardiac regions in PD have not yet been reported.…”

Section: Catecholamine Depletion In Neurodegenerative Diseasesmentioning

confidence: 69%

“…We have introduced the term "sick-but-not-dead" to refer to the occurrence of functional abnormalities in extant residual catecholaminergic neurons in diseases involving catecholaminergic neurodegeneration. 23 The following discussion describes examples of the sick-but-not-dead phenomenon in catecholaminergic neurons in the brain or heart in Lewy body diseases.…”

Section: Catecholamine Depletion In Neurodegenerative Diseasesmentioning

confidence: 99%

“…[64][65][66][67][68][69] Several in vivo and postmortem studies have indicated an analogous vesicular storage defect in residual myocardial sympathetic noradrenergic neurons in Lewy body diseases. [21][22][23]59,61 Another functional abnormality contributing to putamen dopamine deficiency in PD is decreased dopamine biosynthesis from 3,4-dihydroxyphenylalanine (DOPA) via L-aromatic-amino-acid decarboxylase (LAAAD). 9,70 Decreased LAAAD activity has also recently been reported in residual cardiac sympathetic nerves in PD.…”

Section: Catecholamine Depletion In Neurodegenerative Diseasesmentioning

confidence: 99%

“…9,70 Decreased LAAAD activity has also recently been reported in residual cardiac sympathetic nerves in PD. 23 A third functional abnormality in putamen dopaminergic terminals is decreased activity of aldehyde dehydrogenase (ALDH). ALDH is gaining increasing attention as a factor relevant to PD pathogenesis.…”

Section: Catecholamine Depletion In Neurodegenerative Diseasesmentioning

confidence: 99%

“…21,22,96 As for putamen dopamine, one might presume that myocardial NE depletion in Lewy body diseases reflects denervation; however, studies using immunoreactive TH as a marker of myocardial noradrenergic innervation have noted about a 75% average decrease in PD, [97][98][99][100][101][102] whereas the extent of decrease in tissue NE content is in the range of 90 to 99%. [21][22][23] The greater magnitude of NE depletion than of loss of sympathetic noradrenergic innervation indicates the sickbut-not-dead phenomenon in residual myocardial noradrenergic nerves in Lewy body diseases.…”

Section: Catecholamine Depletion In Neurodegenerative Diseasesmentioning

confidence: 99%

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The “Sick-but-not-Dead” Phenomenon Applied to Catecholamine Deficiency in Neurodegenerative Diseases

Goldstein

2020

Semin Neurol

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The catecholamines dopamine and norepinephrine are key central neurotransmitters that participate in many neurobehavioral processes and disease states. Norepinephrine is also the main neurotransmitter mediating regulation of the circulation by the sympathetic nervous system. Several neurodegenerative disorders feature catecholamine deficiency. The most common is Parkinson's disease (PD), in which putamen dopamine content is drastically reduced. PD also entails severely decreased myocardial norepinephrine content, a feature that characterizes two other Lewy body diseases—pure autonomic failure and dementia with Lewy bodies. It is widely presumed that tissue catecholamine depletion in these conditions results directly from loss of catecholaminergic neurons; however, as highlighted in this review, there are also important functional abnormalities in extant residual catecholaminergic neurons. We refer to this as the “sick-but-not-dead” phenomenon. The malfunctions include diminished dopamine biosynthesis via tyrosine hydroxylase (TH) and L-aromatic-amino-acid decarboxylase (LAAAD), inefficient vesicular sequestration of cytoplasmic catecholamines, and attenuated neuronal reuptake via cell membrane catecholamine transporters. A unifying explanation for catecholaminergic neurodegeneration is autotoxicity exerted by 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate intermediate in cytoplasmic dopamine metabolism. In PD, putamen DOPAL is built up with respect to dopamine, associated with a vesicular storage defect and decreased aldehyde dehydrogenase activity. Probably via spontaneous oxidation, DOPAL potently oligomerizes and forms quinone-protein adducts with (“quinonizes”) α-synuclein (AS), a major constituent in Lewy bodies, and DOPAL-induced AS oligomers impede vesicular storage. DOPAL also quinonizes numerous intracellular proteins and inhibits enzymatic activities of TH and LAAAD. Treatments targeting DOPAL formation and oxidation therefore might rescue sick-but-not-dead catecholaminergic neurons in Lewy body diseases.

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Section: Catecholamine Depletion In Neurodegenerative Diseasesmentioning

confidence: 69%

Section: Catecholamine Depletion In Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Catecholamine Depletion In Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Catecholamine Depletion In Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Catecholamine Depletion In Neurodegenerative Diseasesmentioning

confidence: 99%

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The “Sick-but-not-Dead” Phenomenon Applied to Catecholamine Deficiency in Neurodegenerative Diseases

Goldstein

2020

Semin Neurol

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Cardiac sympathetic innervation and vesicular storage in pure autonomic failure

Goldstein

Isonaka

Holmes

et al. 2020

Ann Clin Transl Neurol

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Objective: Pure autonomic failure (PAF) is a rare disease characterized by neurogenic orthostatic hypotension (nOH), absence of signs of central neurodegeneration, and profound deficiency of the sympathetic neurotransmitter norepinephrine. Reports have disagreed about mechanisms of the noradrenergic lesion. Neuropathological studies have highlighted denervation, while functional studies have emphasized deficient vesicular sequestration of cytoplasmic catecholamines in extant neurons. We examined both aspects by a combined positron emission tomographic (PET) neuroimaging approach using 11 Cmethylreboxetine (11 C-MRB), a selective ligand for the cell membrane norepinephrine transporter, to quantify interventricular septal myocardial noradrenergic innervation and using 18 F-dopamine (18 F-DA) to assess intraneuronal vesicular storage in the same subjects. Methods: Seven comprehensively tested PAF patients and 11 controls underwent 11 C-MRB PET scanning for 45 minutes (dynamic 5X1', 3X5', 1X10', static 15 minutes) and 18 F-DA scanning for 30 minutes (same dynamic imaging sequence) after 3-minute infusions of the tracers on separate days. Results: In the PAF group septal 11 C-MRB-derived radioactivity in the static frame was decreased by 26.7% from control (p = 0.012). After adjustment for nonspecific binding of 11 C-MRB, the PAF group had a 41.1% mean decrease in myocardial 11 C-MRB-derived radioactivity (p = 0.015). The PAF patients had five times faster postinfusion loss of 18 F-DA-derived radioactivity (70 AE 3% vs. 14 AE 8% by 30 minutes, p < 0.0001). At all time points after infusion of 18 F-DA and 11 C-MRB mean 18 F/ 11 C ratios in septal myocardium were lower in the PAF than control group. Interpretation: PAF entails moderately decreased cardiac sympathetic innervation and a substantial vesicular storage defect in residual nerves.

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Cardioselective peripheral noradrenergic deficiency in Lewy body synucleinopathies

Lamotte

Holmes

Sullivan

et al. 2020

Ann Clin Transl Neurol

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Objective: Lewy body (LB) synucleinopathies such as Parkinson's disease (PD) entail profound cardiac norepinephrine deficiency. The status of sympathetic noradrenergic innervation at other extracranial sites has been unclear. Although in vivo neuroimaging studies have indicated a cardioselective noradrenergic lesion, no previous study has surveyed peripheral organs for norepinephrine contents in LB diseases. We reviewed 18 F-dopamine (18 F-DA) positron emission tomographic images and postmortem neurochemical data across several body organs of controls and patients with the LB synucleinopathies PD and pure autonomic failure (PAF) and the non-LB synucleinopathy multiple system atrophy (MSA). Methods: 18 F-DA-derived radioactivity in the heart, liver, spleen, pancreas, stomach, kidneys, thyroid, and submandibular glands were analyzed from 145 patients with LB synucleinopathies (112 PD, 33 PAF), 74 controls, and 85 MSA patients. In largely separate cohorts, postmortem tissue norepinephrine data were reviewed for heart, liver, spleen, pancreas, kidney, thyroid, submandibular gland, and sympathetic ganglion tissue from 38 PD, 2 PAF, and 5 MSA patients and 35 controls. Results: Interventricular septal 18 F-DA-derived radioactivity was decreased in the LB synucleinopathy group compared to the control and MSA groups (P < 0.0001 each). The LB and non-LB groups did not differ in liver, spleen, pancreas, stomach, or kidney 18 F-DA-derived radioactivity. The LB synucleinopathy group had markedly decreased apical myocardial norepinephrine, but normal tissue norepinephrine in other organs. The MSA group had normal tissue norepinephrine in all examined organs. Interpretation: By in vivo sympathetic neuroimaging and postmortem neurochemistry peripheral noradrenergic deficiency in LB synucleinopathies is cardioselective. MSA does not involve peripheral noradrenergic deficiency.

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Computational modeling reveals multiple abnormalities of myocardial noradrenergic function in Lewy body diseases

Cited by 25 publications

References 44 publications

The “Sick-but-not-Dead” Phenomenon Applied to Catecholamine Deficiency in Neurodegenerative Diseases

The “Sick-but-not-Dead” Phenomenon Applied to Catecholamine Deficiency in Neurodegenerative Diseases

Cardiac sympathetic innervation and vesicular storage in pure autonomic failure

Cardioselective peripheral noradrenergic deficiency in Lewy body synucleinopathies

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