An Advance in the Search for Parkinson's Disease Biomarkers
An Advance in the Search for Parkinson's Disease Biomarkers
Abstract & Commentary
By Claire Henchcliffe, MD, Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Henchcliffe reports she is on the speakers bureau and advisory board for Allergan and Teva; speakers bureau for Boehringer-Ingelheim, GlaxoSmithKline, and Novartis; advisory board for Merz; and is a consultant for Gerson Lehman Group and Guidepoint Global.
Synopsis: Changes in CSF metabolites reflect dopamine and norepinephrine deficiency in Parkinson's disease, and may be sensitive in early identification.
Source: Goldstein DS, et al. Cerebrospinal fluid biomarkers of central catecholamine deficiency in Parkinson's disease and other synucleinopathies. Brain 2012;135:1900-1913.
Parkinson's disease (PD), and the less common disorders Multiple System Atrophy (MSA) and Pure Autonomic Failure (PAF), are related by pathology involving the protein a-synuclein, and all involve central catecholamine deficiency with well-established decreases in dopamine and norepinephrine. In this study, cerebrospinal fluid (CSF) levels of dopamine and its metabolite, dihydroxyphenylacetic acid (DOPAC), and norepinephrine and its metabolite, dihydroxyphenylglycol (DHPG), were quantitated in individuals with PD (n = 34), MSA (n = 54), PAF (n = 20), and control subjects (n = 38). Ages in the PD, MSA, and PAF groups were similar (63 ± 2, 60 ± 1, and 61 ± 3 years, respectively). Controls comprised three groups: volunteers from the NIH Clinical Center (50 ± 2 years), individuals judged not to have chronic autonomic failure or central neurodegeneration (53 ± 3 years), and volunteers at the University of Washington (> 70 years). More men than women were recruited in the patient groups, but gender ratio was not stated for the control group. DOPAC levels were significantly lower in CSF from those with PD, MSA, and PAF (0.86 ± 0.09, 1.00 ± 0.09, and 1.32 ± 0.12 nM, respectively) compared with controls (2.15 ± 0.18 nM), as were DHPG levels (PD: 8.82 ± 0.44 nM; MSA: 7.75 ± 0.42 nM; PAF 5.82 ± 0.65 nM; control 11.0 ± 0.62 nM). Moreover, DOPAC levels could distinguish cases of parkinsonism from controls with 100% sensitivity and 89% specificity. Although DOPAC levels could not distinguish PD from MSA, PD differed from PAF in measures of lower CSF DOPAC and higher CSF DHPG.
Commentary
Diagnosis of PD and related disorders remains clinical, and although 123I-ioflupane SPECT (DaTscan®) scans were recently approved as adjunctive testing for parkinsonism, there remains a critical need for biomarker development to aid diagnosis, tracking progression, and evaluating treatment response. Measuring CSF catecholamines and their metabolites, although indirect, is attractive based on a strong scientific rationale, but previous studies have failed to yield definitive answers. Now, the authors present compelling data that measures of DOPAC and DHPG, major metabolites of dopamine and norepinephrine, are decreased in CSF of PD, MSA, and PAF, and hold promise as potential future tests and measures of neurodegeneration. The strength of this study is in sophisticated technology using liquid chromatography with electrochemical detection, and although not widely available, the authors state there is an effort to make this resource available for clinicians and researchers. Potential confounders include medications taken by the subjects, which were very different between groups, and it is also difficult to tell from data presented how well the control group was matched for age and gender. Furthermore, patients referred to the NIH, as in this study, may not represent the "typical" cohort we see in clinical practice. Indeed, one had a rare a-synuclein gene triplication leading to PD, seven of 34 PD subjects initially had been diagnosed with MSA or PAF due to prominent dysautonomia, and almost a quarter of PD subjects were taking midodrine and fludrocortisone (presumably for blood pressure support). The study highlights how important developing standardized biosample collections has become, both in discovery and validation phases of test development, and efforts such as the international Parkinson's Progression Markers Initiative (NCT01140123) have now evolved to fill this need. It is critically important that we see these measures validated in an independent cohort, as these results hold as potential biomarkers of pathway-specific neurodegenerative processes.
Changes in CSF metabolites reflect dopamine and norepinephrine deficiency in Parkinson's disease, and may be sensitive in early identification.Subscribe Now for Access
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