Date: February 2019
Prepared by SIC member: Susanne A. Schneider, MD
Authors: Susanne Schneider, MD; Ron Postuma, MD; Daniela Berg, MD
Editor: Stella Papa, MD
Parkinson’s disease is a neurodegenerative disease with variable clinical presentation - including slowly and more rapidly progressing variants. By the time of manifestation of the typical motor symptoms, a substantial proportion of neurons have already been lost, but potential neuroprotective therapies are most effective before reaching that stage. Therefore, major efforts are directed to identify markers that reliably reflect the disease evolution, i.e. markers that can either provide early detection or predict conversion to disease. These include clinical, imaging, pathological and biochemical markers. We are witnessing a growing number of publications in this important area and have asked two experts, Dr. Berg and Dr. Postuma, to discuss the current state of the art in best early-stage predictors of PD development and disease evolution.
How is PD diagnosed? What are the most reliable markers and how early can we diagnose it?
For diagnosis of clinical PD, not that much has changed; diagnosis is still mostly based upon the clinical history and examination. We look for parkinsonism (fatiguing bradykinesia plus rigidity and/or rest tremor). Then we decide, mostly based upon clinical signs, whether this is likely to be PD or another cause. Some specifics have changed; for example, early severe orthostatic hypotension no longer means only MSA, dementia does not exclude PD diagnosis (even in a patient already with DLB), and familial PD is increasingly recognized. We have some new diagnostic tests (e.g. olfaction, MIBG scintigraphy), which can be used to support PD diagnosis. Still, the procedure in most patients looks familiar.
The big changes come with the diagnosis of earlier stages, which is a field still in its infancy. We are now able to reliably detect prodromal PD (which is true PD, just at an earlier stage) by combining clinical symptoms, especially REM sleep behavior disorder, olfactory loss, pure autonomic failure, constipation, etc. We have neuroimaging biomarkers such as DAT-SPECT, MIBG scintigraphy and some new MRI markers that can identify prodromal PD. Moreover, we almost certainly can diagnose many cases of prodromal (and clinical) PD cases during life with tissue biopsy, particularly salivary glands or skin. These are all included in the MDS prodromal PD criteria, an updated version of which will be published soon. So far prodromal PD diagnosis is mainly performed in research settings; there are not enough therapeutic implications of an earlier diagnosis to warrant large-scale screening. However, once neuroprotective therapy is developed, finding patients with prodromal PD will become a critical clinical issue.
What do we know about markers of disease evolution of PD? Can we predict who will have a milder or more aggressive type of disease?
We do know that the clinical phenotype as well as the underlying pathology including spreading of neurodegeneration is very heterogenous in PD. An MDS task force on PD subtypes is currently striving to figure out whether we have sufficient data to define clear clinical subtypes.
Still, from clinical practice and the literature there seem to be some indicators for different forms of progression predicting the disease course early on. In this respect there is growing evidence suggesting that RBD is associated with greater disease burden, increased risk of mortality and relatively poor prognosis. A recent large neuropathologically confirmed investigation supports this notion and extends the prediction of individual progression by stratifying patients according to the presence and severity of motor, non-motor, cognitive functions and RBD at the time of diagnosis (De Pablo-Fernández et al., JAMA Neurol 2019). Using a four point semiquantitative scale and the 75% percentile as cut-off a prediction is suggested according to three groups. mild-motor predominant – motor and all non-motor scores less than the 75th percentile, diffuse malignant – either motor score greater than the 75th percentile and at least 1 non-motor score greater than the 75th percentile or all 3 non-motor scores greater than the 75th percentile and intermediate –all others. Additionally we know that genetically determined subtypes of PD present with different forms of progression. GBA-PD for example is often associated with a more rapid progression and an earlier and more severe appearance of autonomic symptoms and cognitive impairment whereas LRRK2-mutation carriers frequently have a milder progression of the disease.
What do we know about RBD as risk factor for PD and also other neurodegenerative disorders?
RBD is strongly associated with neurodegenerative diseases, primarily with Parkinson’s disease but also other neurodegenerative diseases. A recent meta-analysis yielded that RBD patients carry 33%-risk at five years follow-up, 82%-risk at 10 years, and 96%-risk at 14 years for developing neurodegenerative diseases. While the majority of RBD patients converted to PD (43%), Dementia with Lewy Bodies (25%) or other types of dementia (13%, including Alzheimer’s disease and mild cognitive impairment or not further specified dementia types) were also common (Galbiati et al. 2019).
Is RBD associated with synucleinopathies rather than taupoathies? How specific is RBD regarding PD vs other syncleinopathies? Do we know about risk factors for RBD?
Without question there is a very strong connection between RBD and synculeinopathy. It is important to note that this is not absolute - RBD can occur in non-synculeinopathy diseases; however, it just does so much less often and will generally occur later, when the disease causes broad brainstem degeneration. The best evidence for this comes from a 2013 pathological study led by Brad Boeve, in which 98% of those with polysomnographic-proven RBD had synuclein deposition on autopsy. This finding has been incorporated into the new DLB consensus criteria - now, a PSG-confirmed diagnosis in a dementia patient is sufficient to make the diagnosis of DLB by itself (in other words, PSG-proven RBD is actually now incompatible with a clinical diagnosis of AD alone).
The RBD-synuclein relationship is especially strong in early stages, that is in the ‘idiopathic’ RBD stage. Here, well over 95% of patients who develop a neurodegenerative disease will develop a synucleinopathy. The strongest evidence here comes from a study just published (March 2019) by the International RBD study group- this included 1280 patients, and all of those who developed a defined neurodegenerative syndrome had a clinical diagnosis of synucleinopathy.
The risk factors for RBD are somewhat unusual. Some are similar to PD, like pesticide use. Others are notably different; for example, studies seem to consistently find that RBD patients are more likely to smoke (opposite of PD) and have a lower education level. Genes are clearly important as well - the commonest known genetic risk factor is GBA, which carries a mutation in about 14% of patients. That is actually a higher rate than in PD. It is also notable that the GBA clinical phenotype is quite similar to the clinical subtype associated with RBD (faster progression, more dementia, more autonomic loss).
What do you tell your RBD patients with regard to their risk of developing PD, and are we close to have a neuroprotective treatment for these patients?
As to what to tell the patient, this is a difficult issue. Clearly everyone has a right to be fully informed, but people vary a lot in how much information they want to hear (some of my patients really do not want to hear much about it at all). So there is no ‘one size fits all’ approach, and clinicians need have subtlety and flexibility in providing the depth of information needed/desired by each patient. There is no neuroprotective therapy yet, but there is clearly a huge potential to test these therapies in those who are early enough in the disease course to maximally benefit.
First, I try to sense whether an individual wants to hear about the risk imminent in the diagnosis of RBD. We need to be aware that there are cultural differences in dealing with this kind of far reaching questions. In our country (Germany) most of the patients want to know. I then describe the long prodromal period, lasting years to decades, which mirrors the extremely slow neurodegeneration. This usually leads to the question: What can be done to stop/slow down progression? Here the answer is twofold. First, I describe the worldwide effort to find therapies modulating progression of neurodegeneration, exemplified with several of the currently ongoing studies in early PD. Most individuals are grateful to see what is being done and to know that the neurodegenerative process is very slow. However, I never end before emphasizing the second point: Although there is no neuroprotective medication available, yet, it is well known that physical activity and specific nutritional elements (rather Mediterranean diet rich in vitamins and polyphenols including coffee and black/green tea) can have a positive influence. This gives people the opportunity to contribute themselves to their own health, which is of great importance to many. All are invited for regular follow-ups to see whether new symptoms occur and to have a chance to talk and know the latest advances in science, and finally to search themselves for new developments.