title: Cerebrospinal fluid biomarkers of central catecholamine deficiency in Parkinson's disease and other synucleinopathies.
abstract: Central catecholamine deficiency characterizes α-synucleinopathies such as Parkinson's disease. We hypothesized that cerebrospinal fluid levels of neuronal metabolites of catecholamines provide neurochemical biomarkers of these disorders. To test this hypothesis we measured cerebrospinal fluid levels of catechols including dopamine, norepinephrine and their main respective neuronal metabolites dihydroxyphenylacetic acid and dihydroxyphenylglycol in Parkinson's disease and two other synucleinopathies, multiple system atrophy and pure autonomic failure. Cerebrospinal fluid catechols were assayed in 146 subjects-108 synucleinopathy patients (34 Parkinson's disease, 54 multiple system atrophy, 20 pure autonomic failure) and 38 controls. In 14 patients cerebrospinal fluid was obtained before or within 2 years after the onset of parkinsonism. The Parkinson's disease, multiple system atrophy and pure autonomic failure groups all had lower cerebrospinal fluid dihydroxyphenylacetic acid [0.86 ± 0.09 (SEM), 1.00 ± 0.09, 1.32 ± 0.12 nmol/l] than controls (2.15 ± 0.18 nmol/l; P < 0.0001; P < 0.0001; P = 0.0002). Dihydroxyphenylglycol was also lower in the three synucleinopathies (8.82 ± 0.44, 7.75 ± 0.42, 5.82 ± 0.65 nmol/l) than controls (11.0 ± 0.62 nmol/l; P = 0.009, P < 0.0001, P < 0.0001). Dihydroxyphenylacetic acid was lower and dihydroxyphenylglycol higher in Parkinson's disease than in pure autonomic failure. Dihydroxyphenylacetic acid was 100% sensitive at 89% specificity in separating patients with recent onset of parkinsonism from controls but was of no value in differentiating Parkinson's disease from multiple system atrophy. Synucleinopathies feature cerebrospinal fluid neurochemical evidence for central dopamine and norepinephrine deficiency. Parkinson's disease and pure autonomic failure involve differential dopaminergic versus noradrenergic lesions. Cerebrospinal fluid dihydroxyphenylacetic acid seems to provide a sensitive means to identify even early Parkinson's disease.
authors.affiliation: Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disordersand Stroke, National Institutes of Health, Bethesda, MD 20892-1620, USA. goldsteind@ninds.nih.gov
authors.forename: David S
authors.initials: DS
authors.lastname: Goldstein
authors.forename: Courtney
authors.initials: C
authors.lastname: Holmes
authors.forename: Yehonatan
authors.initials: Y
authors.lastname: Sharabi
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000134:cerebrospinal fluid; D000368:Aged; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid*; D002395:Catecholamines / Q000097:blood / Q000134:cerebrospinal fluid / Q000172:deficiency*; D015259:Dopamine Agents / Q000627:therapeutic use; D005260:Female; D019788:Fluorodeoxyglucose F18; D005500:Follow-Up Studies; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000097:blood / Q000134:cerebrospinal fluid; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000097:blood / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging / Q000188:drug therapy; D020734:Parkinsonian Disorders / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging / Q000188:drug therapy; D049268:Positron-Emission Tomography; D054970:Pure Autonomic Failure / Q000097:blood / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging / Q000188:drug therapy; D012372:ROC Curve
chemical_list: D015415:Biomarkers; D002395:Catecholamines; D015259:Dopamine Agents; D019788:Fluorodeoxyglucose F18; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; D008734:Methoxyhydroxyphenylglycol; C010117:3,4-dihydroxyphenylglycol