Redefining Parkinson’s research: Study takes stock of challenges, suggests new criteria
The current climate of Parkinson’s research is much like it was for Alzheimer’s disease before there was a clear way forward toward pathological detection. Complex clinical features, genetics and molecular drivers of the disease in all its various forms make it exceedingly difficult to standardize research and therefore screening and diagnosis, but a new framework for research is being presented, according to a perspective piece published online April 11 by The Lancet.
Daniela Berg, MD, from the department of neurodegeneration at the Hertie-Institute of Clinical Brain Research, University of Tubingen, and German Center for Neurodegenerative Diseases (DZNE) in Tubingen, Germany, and colleagues discussed a protocol for future Parkinson’s study based on three major areas of interest: molecular mechanisms and genetics, histopathological data and clinical findings.
Some of the complications involved in pinning down Parkinson’s disease include the heterogeneity of its pathology. As in Alzheimer’s disease, the beginning stages are subtle and protracted and silent developement can go on for years if not decades before the presentation of clear motor-system symptoms and progression of disease can be very inconsistent. Standardization is made difficult when Parkinson’s disease is diagnosed without the presence of classic Lewy body involvement, such as those based on genetic factors.
“All these limitations suggest that attempting to conclusively redefine the clinical diagnosis of Parkinson’s disease at this moment in time might be premature,” wrote Berg et al. “In this Personal View, we argue that there are three major areas of research—clinical features, neuropathology, and genetics (which includes molecular pathology, because genetic findings are at present the only reliable entry point into the discovery of the molecular pathways)—that, on the one hand, have led to a broader understanding of the disease but, on the other, have provided findings that are not always compatible with the present clinical diagnosis of Parkinson’s disease.”
Areas of concern with clinical diagnoses are those based on motor symptoms including Bradykinesia, defined as “slowness of initiation of voluntary movement with progressive reduction in speed and amplitude of repetitive actions,” plus rigidity and resting tremor, but these can be present in other diseases that exhibit parkinsonism. The authors mentioned that this can be improved with the inclusion of features like asymmetry and significant response to therapy with levodopa.
New criteria for diagnosis by the UK Parkinson’s Disease Society Brain Bank was found to be comprehensive with three steps of clinical evaluation, including the previously mentioned features and postural instability that is not due to a number of disorders, including vestibular, proprioceptive and cerebellar dysfunction. This first step is followed by a rundown of exclusions including history of strokes and head injury, familial Parkinson’s disease and severe dementia with memory and language difficulty. The third step for diagnoses includes a comprehensive “prospective-positive criteria” for ruling-in Parkinson’s rather than ruling it out. These three steps of clinical criteria have been found in studies to have a detection specificity of anywhere from 76 to more than 90 percent as the method develops and depending on the expertise of the clinician.
A major limitation is that motor symptoms are made manifest after substantial contralateral substantia nigra pars compacta cell death, reaching an estimated 40-50 percent with depletion of striatal dopamine of approximately 60-70 percent. Further complicating matters is the fact that compensating nigrostriatal networks can hide this for years. Researchers recommended the use of quantitative assessment, including the so-called alternate tap test, timed-up-and-go test and the Purdue peg board test, which could provide meaningful information about early disease development six to nine years ahead of time, but there is a real push to extend this even further with neuroimaging and novel biomarkers to be used with modalities such as PET and SPECT.
“So far, the only reliable test to separate first motor signs of Parkinson’s disease from those of these other disorders is nigrostriatal dopamine imaging,” wrote the authors. “In contrast to findings obtained by assessment of the clinical phenotype, functional neuroimaging data might be less influenced by compensatory mechanisms and therefore might enable earlier diagnosis,” they added.
Non-motor features need to be taken into account, especially those related to mood disorders and sleep problems and sensory dysfunction such as that of olfactory dysfunction and defects in color vision, which are thought to develop much sooner than other symptoms. Depression was found to increase Parkinson’s risk as much as two to three times that of patients with no history of mood disorder. Sleep disorders in particular are of interest, as prospective studies of REM sleep disturbance suggest that 5-year risk of neurodegenerative development including synucleino pathology including Lewy bodies spans 18 to 45 percent and rises 40 to 65 percent at the 10-year mark.
“This specificity is by far the highest of any known clinical marker, suggesting that patients with REM sleep behavior disorder might be ideal candidates to assess development of defined neurodegenerative diseases from prodromal stages,” wrote the researchers.
Parkinson’s or no Parkinson’s is the question when it comes to Lewy bodies. When motor symptoms first become apparent, cognitive impairment rules out Parkinson’s and points toward dementia with Lewy bodies, but this is currently under debate. Lewy body dementia involves more beta amyloid deposition, but researchers are now questioning whether dementia with Lewy bodies, a-synuclein pathology and Parkinson’s could rather be redefined as points of development along the spectrum of a single disorder, rather than two separate diseases.
Parkinson’s disease brought on by LRRK2, PINK1 and DJ1 mutations without the presence of Lewy bodies and the presence of Lewy bodies in healthy adults further demonstrates how the criteria for diagnoses should be more inclusive. A recent study of 744 patients showed post-mortem evidence of Lewy bodies in 17 percent of subjects. Researchers suggest using a multi-tier system of clinical diagnoses that allows for all of these varying circumstances.
“An individual would fulfill criteria of different accuracy within each tier,” concluded the authors. “This approach allows flexibility in a way that present research criteria do not. There are no preconceived notions (e.g. the necessity of having Lewy bodies) that limit the construct of Parkinson’s disease using this approach. Moreover, using the tier approach will enable expansion of new knowledge as it becomes available and helps to set the priorities for filling knowledge gaps. An important contribution to improve diagnostic accuracy within each tier and to bridge the tiers will need to come from the development of valid neuroimaging and biochemical markers."