TY - JOUR
T1 - Differential abnormalities of cerebrospinal fluid dopaminergic versus noradrenergic indices in synucleinopathies
AU - Goldstein, David S.
AU - Sullivan, Patti
AU - Holmes, Courtney
AU - Lamotte, Guillaume
AU - Lenka, Abhishek
AU - Sharabi, Yehonatan
N1 - Publisher Copyright:
© 2021 The Authors. This article is a U.S.Government work and is in the public domain in the USA.
PY - 2021/7
Y1 - 2021/7
N2 - The synucleinopathies Parkinson's disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) are characterized by intra-cytoplasmic deposition of the protein alpha-synuclein and by catecholamine depletion. PAF, which manifests with neurogenic orthostatic hypotension (nOH) and no motor signs of central neurodegeneration, can evolve into PD+nOH. The cerebrospinal fluid (CSF) levels of catecholamine metabolites may indicate central catecholamine deficiency in these synucleinopathies, but the literature is inconsistent and incomplete. In this retrospective cohort study we reviewed data about CSF catecholamines, the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the norepinephrine metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG). The compounds were measured in 36 patients with PD, 37 patients with MSA, and 19 patients with PAF and in 38 controls. Compared to the control group, the PD, MSA, and PAF groups had decreased CSF MHPG (p <.0001 each by Dunnett's post hoc test), DHPG (p =.004; p <.0001; p <.0001) and norepinephrine (p =.017; p =.0003; p =.044). CSF HVA and DOPAC were decreased in PD (p <.0001 each) and MSA (p <.0001 each) but not in PAF. The three synucleinopathies therefore have in common in vivo evidence of central noradrenergic deficiency but differ in the extents of central dopaminergic deficiency—prominent in PD and MSA, less apparent in PAF. Data from putamen 18F-DOPA and cardiac 18F-dopamine neuroimaging in the same patients, post-mortem tissue catecholamines in largely separate cohorts, and review of the neuropathology literature fit with these distinctions. The results suggest a ‘norepinephrine first’ ascending pathogenetic sequence in synucleinopathies, with degeneration of pontine locus ceruleus noradrenergic neurons preceding the loss of midbrain substantia nigra dopaminergic neurons. (Figure presented.).
AB - The synucleinopathies Parkinson's disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) are characterized by intra-cytoplasmic deposition of the protein alpha-synuclein and by catecholamine depletion. PAF, which manifests with neurogenic orthostatic hypotension (nOH) and no motor signs of central neurodegeneration, can evolve into PD+nOH. The cerebrospinal fluid (CSF) levels of catecholamine metabolites may indicate central catecholamine deficiency in these synucleinopathies, but the literature is inconsistent and incomplete. In this retrospective cohort study we reviewed data about CSF catecholamines, the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the norepinephrine metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG). The compounds were measured in 36 patients with PD, 37 patients with MSA, and 19 patients with PAF and in 38 controls. Compared to the control group, the PD, MSA, and PAF groups had decreased CSF MHPG (p <.0001 each by Dunnett's post hoc test), DHPG (p =.004; p <.0001; p <.0001) and norepinephrine (p =.017; p =.0003; p =.044). CSF HVA and DOPAC were decreased in PD (p <.0001 each) and MSA (p <.0001 each) but not in PAF. The three synucleinopathies therefore have in common in vivo evidence of central noradrenergic deficiency but differ in the extents of central dopaminergic deficiency—prominent in PD and MSA, less apparent in PAF. Data from putamen 18F-DOPA and cardiac 18F-dopamine neuroimaging in the same patients, post-mortem tissue catecholamines in largely separate cohorts, and review of the neuropathology literature fit with these distinctions. The results suggest a ‘norepinephrine first’ ascending pathogenetic sequence in synucleinopathies, with degeneration of pontine locus ceruleus noradrenergic neurons preceding the loss of midbrain substantia nigra dopaminergic neurons. (Figure presented.).
KW - HVA
KW - MHPG
KW - Parkinson
KW - multiple system atrophy
KW - norepinephrine
KW - pure autonomic failure
UR - http://www.scopus.com/inward/record.url?scp=85106337482&partnerID=8YFLogxK
U2 - 10.1111/jnc.15371
DO - 10.1111/jnc.15371
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C2 - 33894018
AN - SCOPUS:85106337482
SN - 0022-3042
VL - 158
SP - 554
EP - 568
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 2
ER -