Experts believe that early diagnosis of Parkinson disease and the initiation of neuroprotective treatment may alter the disease course, improving the quality of life for patients. Neuronal degeneration is believed to begin years before clinical symptoms manifest. And there is evidence that a prodromal phase, which occurs after the preclinical phase, is characterized by early non-motor signs, imaging changes, and possibly other markers that emerge before the onset of the classical clinical symptoms of Parkinson disease. Yet, identifying prodromal markers in Parkinson disease has been a challenge.
Etienne Hirsch, PhD, from France, one of the conference presenters at the International Congress of Parkinson Disease and Movement Disorders says that the Parkinson and Movement Disorders Society has defined the research criteria for prodromal Parkinson disease as follows: “Prodromal disease refers to the stage wherein early symptoms or signs of PD neurodegeneration are present, but classic clinical diagnosis based on fully evolved motor parkinsonism is not yet possible.”
Dr. Hirsch explains that this stage has the following characteristics:
• Developed for research purposes only
• Based upon the likelihood of prodromal disease being present
• Calculated by adding diagnostic information, expressed as likelihood ratios
• Combines estimates of background risk (from environmental risk factors and genetic findings) and results of diagnostic marker testing
• They include motor and non-motor clinical symptoms, clinical signs, and ancillary diagnostic tests
Prodromal markers in Parkinson disease
A number of markers for prodromal Parkinson disease have been suggested, including rapid eye movement (REM) sleep behavior disorder, diminished olfactory function, constipation, autonomic dysfunction, and alternations on brain imaging studies reflecting changes in the structure or function of the substantia nigra. It is not certain how predictive, sensitive, or specific these early signs are, and there is a range in the time between the onset of prodromal signs and the diagnosis of Parkinson disease, which can vary from 5 to 20 years.1
Another interesting and recently emerging potential biomarker of prodromal Parkinson disease includes changes in the gut microbiome. Recent studies have identified some alterations in intestinal bacteria, as well as antibody markers in patients who have REM sleep behavior disorder or Parkinson disease.2 Researchers suggest that the intestinal flora may change as early as the prodromal phase of Parkinson disease, making this a possible area of future research.
Early imaging changes outside the substantia nigra
Headmann and colleagues,3 researchers at the University of Lübeck in Germany, conducted a study that included 29 individuals who were defined as “at risk” of Parkinson disease and 28 controls. None of the participants had clinical symptoms of Parkinson disease. The “at risk” individuals had hyposmia and/or an increased hyperechogenicity in the substantia nigra, two of the markers that are considered possible indicators of prodromal Parkinson disease.
The researchers reported that diffusion-weighted imaging mean diffusivity was increased in the left posterior thalamus, inferior longitudinal fasciculus, fornix, and corticospinal tract among the Parkinson disease risk group. This evidence of microstructural white matter changes in the absence of symptoms differentiated the at-risk group from the control group, suggesting that these early changes are part of the prodromal Parkinson disease phase.
Current limitations and future challenges
While the understanding of prodromal Parkinson disease is improving, there is still work that needs to be done. Deciding who should be screened and with which tests, when screening should take place, whether negative or positive tests should be repeated, determining the sensitivity and specificity of prodromal Parkinson disease markers, and deciding on the optimal next steps, are all among the issues that will accompany this area of research.
There are several limitations in defining early markers and prodromal signs in Parkinson disease. Heinzel and colleagues,4 a research group in Germany, evaluated 35 longitudinal studies that reported on prodromal symptoms of Parkinson disease. The researchers found heterogeneity among the studies, which can limit the utility of the results. They proposed the use of a formal core data set to be used in future studies. They also proposed several strategies for future research, including:
• Distinguishing between stable and changing markers
• Following patients after they are diagnosed with Parkinson disease to confirm the diagnosis and identify subgroups
• Using enriched cohorts at risk of developing Parkinson disease in the studies
Recently the Movement Disorders Society (MDS) research criteria for prodromal PD was applied to a prospective population-based study, and cases of Parkinson disease were identified at follow up.5 Patients who had a baseline status of probable prodromal Parkinson disease using the research criteria had 98.8% specificity for a Parkinson disease diagnosis, 66.7% senstivity, and a positive predictive value of 40.0% over the first 3 years. Specificity remained stable with time, while the sensitivity decreased and positive predictive value increased.
These results are promising in terms of using criteria to identify prodromal Parkinson disease with possible earlier initiation of treatment.
Three presentations about prodromal Parkinson disease are scheduled at the International Parkinson and Movement Disorder Society Conference in Hong Kong. Daniela Berg, MD, from Germany will talk about the biological basis of prodromal Parkinson disease and Jean-Christophe Corvol, MD, PhD, from France will give a presentation about the how to modify the course of Parkinson’s disease.
Dr Hirsch says,
I will discuss the appearance of the non-motor symptoms such as constipation, anosmia, and sleep disorders. I will show that they are correlated with the deposition of alpha-synuclein in the periphery, olfactory bulb and lower brainstem. Then, I will show that when this pathology is reproduced in animal models it can provoke the symptoms. This will provide strong evidence that these early non-motor symptoms are due to specific and localized pathology developing before the loss of neurons in the substantia nigra.
1. Postuma RB, Berg D. Advances in markers of prodromal Parkinson disease. Nat Rev Neurol. 2016;12:622-634.
2. Bedarf JR, Hildebrand F, Goeser F, et al. The gut microbiome in Parkinson disease. Nervenarzt. August 31, 2018; E-pub ahead of print.
3. Heldmann M, Heeren J, Klein C, et al. Neuroimaging abnormalities in individuals exhibiting Parkinson's disease risk markers. Mov Disord. May 14, 2018; E-pub ahead of print.
4. Heinzel S, Roeben B, Ben-Shlomo Y, et al. Prodromal markers in Parkinson disease: limitations in longitudinal studies and lessons learned. Front Aging Neurosci. 2016;8:147.
5. Mahlknecht P, Gasperi A, Djamshidian A. Performance of the Movement Disorders Society criteria for prodromal Parkinson disease: a population-based 10-year study. Mov Disord. 2018;33:405-413.