Thinking Outside the Brain for a Parkinson's Cure : By Dr. De Leon

I don’t think inside the box, I don’t think OUTSIDE the box, I don’t EVEN KNOW where the box is!”- unknown

The other day while I was giving a talk about how to diagnose PD, I was giving my usual spill about ” in the hands of a specialist like myself- accuracy is 95%,” when someone in the audience asked me a very thought provoking question. So, how early can you diagnose with such certainty? Therein lies the BIG Problem in why we need biomarkers and be able to think outside of our current diagnostic criteria!

In reality, I told her it is still very accurate above 90% for someone that has a lot of experience -that’s where art meets medicine …you get your “intuition” about things based on past knowledge and experience and are able to predict with fair accuracy and since at this point there is NO difference in treatment really between one type of Parkinson syndrome or another it does not much matter at the beginning…However, where it becomes a problem is being able to predict outcome and assign patients to studies because you have to follow strict criteria and even if you just KNOW that someone has Parkinson’s or an atypical variant you have to back it up…and as you all know EVERYONE is different so it may take some one ten years to develop all 4 cardinal symptoms of Parkinson’s while someone else only 2. So, it is hard to at present time to make a lot of head way in the discovery of new medications that might be beneficial to slow or stop the progression of early stage of Parkinson’s because unfortunately there is still a lot of variability in early diagnostic accuracy depending on the field. Even among neurologist not Parkinson’s specialist, a published study indicated that for PD patients who had symptoms less than 5 years, they were wrong 50% of the time. These patients turned up to have another reason for their Parkinsonism which translates to automatic failure of any drug being studied since 50% of the patients in any given trial of early PD may not even respond because they don’t have the right diagnosis!

So, I realized that in order for us to start thinking OUTSIDE the BOX we need to FIRST get a CLUE of where the BOX is – what Parkinson’s looks like- acts like, presents like so THAT EVERYONE IS on the same page and able to diagnose with same degree of accuracy!!! This needs of course to go back to medical school, residency and communities and we all as PD advocates can play a role in educating health staff and other health professionals about Parkinson’s. The better we are at recognizing early symptoms the better chance we have for participating in neuro-protective trials as well as be able to determine biomarkers early on.

A lot of money and research is being channeled to the finding of these biomarkers in the recent years. According to research initiated by the MJFOX foundation, we may have insight into possible new biomarkers coming from the retina, colon, or skin which could lead to not early detection but a cure for PD.

For a number of years, neuroscientist have known that alpha-synuclein the abnormal protein seen in Parkinson’s is also found outside of the central nervous system. This protein is a major constituent of Lewy body disease another Parkinson’s like disease. However, alpha-synuclein which is located largely at the ends of neurons plays a part in both familial and sporadic Parkinson’s disease as well.

Through the usage of very powerful machines and equipment known as optical coherence tomography (OCT) which takes high resolution pictures of the retina, scientists and doctors have found that PD patients have thinner retinas compared to healthy individuals.
At this point, they are not sure if there is enough evidence to use as a biomarker because they are not certain how specific it is to Parkinson’s since it also has been seen in Alzheimer’s patients who had Parkinson’s as a co-morbidity.
Alpha-synuclein is normally present in several types of retinal cells…so the possibility of serving as a biomarker exists either by accumulation or (absence) at this time no cells have been found in PD patients.

Another place that accumulates alpha-synuclein outside the brain is the colon. Published studies have revealed that immunostaining for Alpha-synuclein in living Parkinson’s individuals results in a positive outcome in 69-100% of the time but not seen in MSA ( multi -system atrophy) patients. Another study showed that these findings preceded the clinical motor symptoms. So far, results which are small have been mixed. They are easy to attain because of flexible sigmoidoscopy can access distal colon easily plus screening is required of all over 50 years of age. However, not all pd people showed pathology. Some explanations have been given which include variation of tissue involvement, change in pathology over time and perhaps unsuitability of this being used as a biomarker.

The third place where scientists are looking for a possible biomarker outside the central nervous system which is also full of alpha -synuclein is the skin. One reason, people are interested in this area is because of the new wave of knowledge and thinking about the etiology of Parkinson’s. Since, we now know that there is a prodrome period of non- motor & autonomic symptoms that precede the development of the motor symptoms, researchers believe that perhaps alpha-synuclein pathology starts outside the brain and migraines to the brainstem.
Also, studies have suggested that peripheral nervous system is equally involved in Parkinson’s. Evidence of this was suggested in an issue of Brain in 2008 where Parkinson’s patients were found to have cutaneous denervation resulting in higher threshold for heat and touch but decrease for pain.

Because the skin is not only easily accessible but also has a plethora of autonomic involvement, and many autonomic nerves making it a great candidate for study.
A study in the Journal of Neuropathology & Experimental Neurology proposed that the skin may be a beneficial site for diagnostic predictability since 70% of PD cases and 40% of PD with dementia revealed positive alpha-synuclein immunoreactivity while absent in other Parkinson plus syndromes like MSA ( multisystem atrophy) , PSP( Progressive supranuclear palsy), & CBGD (Cortico-basal-ganglia-degeneration). The results are very promising but still need to be validated and compared longitudinally and with autopsy confirmed cases of PD.

Out of all these the most promising is the skin biopsies as a possible biomarker..easy and readily accessible and this far able to differentiate between Parkinson’s and other Parkinson’s plus syndromes.
For more information on the topic: MJFOX research on biomarkers
Haugh, Zac., Movement Disorder Focus: Alpha-synuclein :Thinking Outside the Brain. Practical Neurology. Vol. 13, No.2, March 2014

Dr. M. De Leon is a movement disorder specialist on sabbatical, PPAC member and research advocate for PDF (Parkinson’s Disease Foundation); Texas State Assistant Director for PAN (Parkinson’s Action Network). You can learn more about her work at you can also learn more about Parkinson’s disease at or at;,

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