Biomarkers to detect central dopamine deficiency and distinguish Parkinson disease from multiple system atrophy

Abstract

Objective-Biomarkers are increasingly important to diagnose and test treatments of neurodegenerative diseases such as Parkinson disease (PD). This study compared neuroimaging, neurochemical, and olfactory potential biomarkers to detect central dopamine (DA) deficiency and distinguish PD from multiple system atrophy (MSA).Methods-In 77 PD, 57 MSA, and 87 control subjects, radioactivity concentrations in the putamen (PUT), caudate (CAU), occipital cortex (OCC), and substantia nigra (SN) were measured 2 hours after 6-[ 18 F]fluorodopa injection, septal myocardial radioactivity measured 8 minutes after 6-[ 18 F] fluorodopamine injection, CSF and plasma catechols assayed, or olfaction tested (University of Pennsylvania Smell Identification Test (UPSIT)). Receiver operating characteristic curves were constructed, showing test sensitivities at given specificities.Results-PUT:OCC, CAU:OCC, and SN:OCC ratios of 6-[ 18 F]fluorodopa-derived radioactivity were similarly low in PD and MSA (p<0.0001, p<0.0001, p=0.003 compared to controls), as were CSF dihydroxyphenylacetic acid (DOPAC) and DOPA concentrations (p<0.0001 each). PUT:SN and PUT:CAU ratios were lower in PD than in MSA (p=0.004; p=0.005). CSF DOPAC correlated positively with PUT:OCC ratios (r=0.61, p<0.0001). Myocardial 6-[ 18 F]fluorodopamine-derived radioactivity distinguished PD from MSA (83% sensitivity at 80% specificity, 100% sensitivity among patients with neurogenic orthostatic hypotension (NOH)). Only PD patients were anosmic; only MSA patients had normal olfaction (61% sensitivity at 80% specificity).Conclusions-PD and MSA feature low PUT:OCC ratios of 6-[ 18 F]fluorodopa-derived radioactivity and low CSF DOPAC and DOPA concentrations, cross-validating the neuroimaging and neurochemical approaches but not distinguishing the diseases. PUT:SN and PUT:OCC ratios of Corresponding author: David S. Goldstein, MD PhD, Clinical Neurocardiology Section, NINDS, NIH, 10 Center Drive MSC-1620, Building 10 Room 6N252, Bethesda, MD 20892-1620 USA, Phone: 301-496-2103, Fax: 301-402-0180, Blackberry: 301-675-1110 goldsteind@ninds.nih.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Loss of sense of smell in PD has been associated with neuroimaging evidence of both central DA deficiency [22] and cardiac noradrenergic denervation [23]. Decreased olfaction also can occur in MSA [24,25], and it has been unclear how efficiently olfactory testing separates PD from MSA. NIH Public AccessThe main purpose of this study was to identify biomarkers that detect central DA deficiency and distinguish PD from MSA. Because of the impo...

Preclinical Biomarkers of Parkinson Disease

“…26 These results suggest that olfactory loss can predate the development of clinical PD by 2 to 7 years. The mechanism of olfactory loss in PD is not well understood, but it appears to be of central origin rather than due to damage to the olfactory epithelium.…”

2.112 the Odor Stick Identification Test for Japanese Differentiates Parkinson's Disease From Multiple System Atrophy and Progressive Supra Nuclear Palsy

“…Progressive supranuclear palsy (PSP) and parkinsonian variant of multiple system atrophy (MSA-P) are neurodegenerative disorders that are clinically difficult to differentiate from idiopathic PD, particularly in the early stages of the disease, when the typical clinical signs are not clearly evident [10]. Previous reports indicated that the olfactory function is relatively intact or slightly reduced in patients with PSP and MSA-P [11][12][13][14][15], suggesting that OSIT-J may be useful in the differential diagnosis of early-stage PD from MSA-P and PSP [15,16]. To our knowledge, there is no information on the sensitivity and specificity of OSIT-J in the diagnosis of parkinsonian syndromes such as PSP and MSA-P.…”

Survival in synucleinopathies

“…Second, for assessing survival rates in these diseases, accurate diagnostic assignments are essential, and differential diagnosis among these diseases by clinical criteria alone is imperfect. 5 Third, although testing of central and peripheral catecholaminergic innervation can aid the differential diagnosis of autonomic synucleinopathies, 6 this is not done routinely at most centers.…”

“…In addition, the findings of normal or only slightly decreased olfactory function by the University of Pennsylvania Smell Identification Test and normal myocardial 18 F-dopamine-derived radioactivity were taken as supportive of MSA as opposed to PD. 6 Patients with MSA and both parkinsonism and cerebellar ataxia were considered to have MSA-P.…”

“…In addition, the findings of anosmia by the University of Pennsylvania Smell Identification Test and low myocardial 18 F-dopamine-derived radioactivity were taken as supportive of PD as opposed to MSA. 6 A diagnosis of PAF was assigned based on chronic, persistent, consistent OH, identified as neurogenic by clinical laboratory testing, 9 without an identified cause (e.g., diabetic autonomic neuropathy, autoimmune autonomic ganglionopathy) and by clinical laboratory evidence of loss of sympathetic noradrenergic innervation (low myocardial 18 F-dopamine-derived radioactivity, low plasma levels of 3,4-dihydroxyphenylglycol, or both 10 ). OH was defined by a decrease in systolic blood pressure of at least 20 mm Hg or in diastolic pressure at least 10 mm Hg between supine rest for at least 15 minutes and upright posture for 5 minutes (unless symptomatic or rapid hypotension necessitated return to the supine position before 5 minutes upright).…”