In pursuit of prodromal Parkinson's disease

In The Lancet Neurology, Anette Schrag and colleagues1Schrag A Horsfall L Walters K Noyce A Petersen I Prediagnostic presentations of Parkinson's disease in primary care: a case-control study.Lancet Neurol. 2014; (published online Nov 27.)http://dx.doi.org/10.1016/S1474-4422(14)70287-XGoogle Scholar provide a valuable contribution to the pursuit of prodromal Parkinson's disease. Why is this important? Many clinical trials involving thousands of patients and millions of dollars have assessed a range of drugs for their putative neuroprotective effects in Parkinson's disease.2Aldakheel A Kalia LV Lang AE Pathogenesis-targeted, disease-modifying therapies in Parkinson disease.Neurotherapeutics. 2014; 11: 6-23Google Scholar These drugs have targeted several different pathophysiological processes, including oxidative stress, mitochondrial dysfunction, apoptosis, excitotoxicity, inflammation, and failure of trophic support. Despite impressive preclinical effects, none of these agents has modified disease progression in patients with Parkinson's disease. The many possible reasons for these failures include poor target engagement, inappropriate dose, and targeting of the wrong biological pathways, further exacerbated by inadequate animal models that might not represent the pathogenesis of the human disease. However, an important concern that applies to the discovery of effective neuroprotective therapy in all neurodegenerative diseases is the possibility that these treatments have been administered too late in the degenerative process. Patients participating in such trials for Parkinson's disease have previously been viewed as having early disease, since they are generally enrolled within months to 2–3 years of the onset of their motor symptoms. However, it is now increasingly acknowledged that at this so-called early clinical stage the disease has become well entrenched and potentially advanced beyond a point at which such treatments could be expected to have a substantial clinical effect, especially when given alone and directed towards only one pathogenic mechanism or pathway.3Lang AE Clinical trials of disease-modifying therapies for neurodegenerative diseases: the challenges and the future.Nature Med. 2010; 16: 1223-1226Google Scholar In support of this concern, such patients diagnosed as having early Parkinson's disease are known to have a greater than 50–60% deficit in the dopaminergic nigrostriatal pathway.4Bernheimer H Birkmayer W Hornykiewicz Jellinger K Seitelberger F Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations.J Neurol Sci. 1973; 20: 415-455Google Scholar Consequently, interest has grown into the possibility of defining earlier stages of the disorder based on the understanding that the disease might actually begin in the peripheral autonomic nervous system and the olfactory bulb and spread from there to the CNS, typically affecting lower brainstem structures well before the involvement of the substantia nigra.5Braak H Tredici KD Rub U De Vos RA Jansen Steur EN Braak E Staging of brain pathology related to sporadic Parkinson's disease.Neurobiol Aging. 2003; 24: 197-211Google Scholar Substantial evidence supports the occurrence of various symptoms many years before the development of classical motor parkinsonism. Increased attention to the issues of where the disease process begins, how it spreads through the nervous system, and how it can be diagnosed at earlier prodromal stages has encouraged active discussions about the need to redefine Parkinson's disease6Berg D Lang AE Postuma RB et al.Changing the research criteria for the diagnosis of Parkinson's disease: obstacles and opportunities.Lancet Neurol. 2013; 12: 514-524Google Scholar and establish new research criteria7Berg D Postuma RB Bloem B et al.Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson's disease.Mov Disord. 2014; 29: 454-462Google Scholar that can be applied in future clinical trials of disease-modifying therapies. Schrag and colleagues now describe the largest and most comprehensive assessment of the prediagnostic features of Parkinson's disease reported so far.1Schrag A Horsfall L Walters K Noyce A Petersen I Prediagnostic presentations of Parkinson's disease in primary care: a case-control study.Lancet Neurol. 2014; (published online Nov 27.)http://dx.doi.org/10.1016/S1474-4422(14)70287-XGoogle Scholar By using data recorded in The Health Improvement Network UK primary care database, they were able to compare the incidence of symptoms in up to 8166 individuals with Parkinson's disease and 46 755 without the disease at 2, 5, and 10 years before the diagnosis. 2 years before clinical diagnosis, many patients may have had overt but unappreciated clinical features of Parkinson's disease. However, 5 years before the diagnosis of the disease, patients who went on to develop Parkinson's disease had a higher incidence of several symptoms than did control participants, including tremor, balance problems, depression, anxiety, constipation, postural hypotension, dizziness, erectile dysfunction, fatigue, and urinary dysfunction. At 10 years before disease onset, the incidence of constipation (risk ratio 2·01, 95% CI 1·62–2·49) and tremor (7·59, 1·11–44·83) were higher in those who went on to develop the disease than in controls. Although this study largely confirms previous findings, such as those from the Honolulu-Asia Aging Study8Abbott RD Petrovitch H White LR et al.Frequency of bowel movements and the future risk of Parkinson's disease.Neurology. 2001; 57: 456-462Google Scholar and from the Mayo Clinic,9Shiba M Bower JH Maraganore DM et al.Anxiety disorders and depressive disorders preceding Parkinson's disease: a case-control study.Mov Disord. 2000; 15: 669-677Google Scholar its size is impressive and the data were collected prospectively in the course of routine primary care, without recall or selection bias towards the diagnosis of Parkinson's disease. The findings further emphasise the frequency and complexity of the early premotor or prodromal phase of the disorder. Unfortunately, the study design did not allow the investigators to calculate relative risks for combinations of clinical features. Indeed, without a reliable diagnostic biomarker, we will probably need such information if patients who are presumed to have prodromal Parkinson's disease are ever to be enrolled in neuroprotective trials in the future. An important limitation of this type of study is the uncertainty of the accuracy of the diagnosis of Parkinson's disease. In a similar population with older disease onset, Adler and colleagues10Adler CH Beach TG Hentz JG et al.Low clinical diagnostic accuracy of early vs advanced Parkinson disease: clinicopathologic study.Neurology. 2014; 83: 406-412Google Scholar reported only 26% accuracy for the clinical diagnosis of Parkinson's disease in untreated patients or those not clearly responsive to treatment, and only 53% accuracy in early (<5 years' duration) Parkinson's disease responsive to medication. Therefore, many patients diagnosed with Parkinson's disease in Schrag and colleagues' study might not have actually had the disease of interest. This possibility emphasises the crucial need for reliable and widely applicable diagnostic biomarkers. When these become available, they will probably be applied first to populations enriched for the clinical symptoms emphasised in the present study, as well as other features known to be associated with α-synuclein pathology, such as olfactory dysfunction,11Ross GW Petrovitch H Abbott RD et al.Association of olfactory dysfunction with risk for future Parkinson's disease.Ann Neurol. 2008; 63: 167-173Google Scholar rapid eye movement sleep behaviour disorder,12Postuma RB Gagnon JF Vendette M Fantini ML Massicotte-Marquez J Montplaisir J Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder.Neurology. 2009; 72: 1296-1300Google Scholar and selected genetic factors,13Bonifati V Genetics of Parkinson's disease—state of the art, 2013.Parkinsonism Relat Disord. 2014; 20: S23-S28Google Scholar in hope of defining those patients who are most likely to benefit from the early application of effective neuroprotective strategies. I declare no competing interests. Prediagnostic presentations of Parkinson's disease in primary care: a case-control studyA range of prediagnostic features can be detected several years before diagnosis of Parkinson's disease in primary care. These data can be incorporated into ongoing efforts to identify individuals at the earliest stages of the disease for inclusion in future trials and to help understand progression in the earliest phase of Parkinson's disease. Full-Text PDF Open Access

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