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Saturday, October 8, 2016

Little known facts about Parkinson's disease

An exciting new treatment involves electrical stimulation instead of L-DOPA.


T he third video from Dr Ted Noel, where he presents more evidence that Hillary Clinton has Parkinson's disease, is the most convincing yet. He showed clips of the first debate where she exhibits an obvious hand tremor, which he calls ‘pill-rolling rest tremor.’ Many others have commented on her drugged or ‘stoned’ appearance as well.

If true, it's possible we might have for the first time a president who suffers from a neurodegenerative disorder while in office. If so, we need to know what to expect. Politically, it would be devastating. If the Democratic party is revealed to have concealed something of this magnitude about their candidate, they may discover that there really is such a thing as a line that one is not entitled to cross.

But I'd like to stay away from politics here. These could be exciting times for neuroscientists. Believe me you, we don't get too many of those. It hasn't been this exciting—and not in a good way—since that time we got a chance to talk about anthrax toxin.

Harmful substances like bacterial toxins are valuable because they tell us a lot about how our cells work. And so do diseases. Of course they are terrible things in themselves: dragons to be slain. But Alzheimer's disease has much to teach us about how memory works, and Parkinson's disease will teach us a lot about how we control our movements.

What other famous people have had Parkinson's disease? Michael J. Fox, Janet Reno, Linda Ronstadt, Mohammed Ali, Jim Backus (from Gilligan's Island), Johnny Cash, Salvador Dali, Deng Xiaoping, Francisco Franco, and Adolf Hitler all had it. (Some sites also claim Robin Williams, but he actually had Lewy body dementia, which is slightly different.)

As many people probably know, Parkinson's disease, or PD, happens when the cells in a part of the brain called the substantia nigra die. These cells produce dopamine, which is needed by other brain regions, mainly the striatum. The two characteristic signs of PD are tremor and a shuffling gait. But there are a lot of other strange phenomena that occur in PD that many people don't know about.

Dyskinesia

The standard treatment for PD is levodopa, or L-DOPA, which replaces the lost dopamine. But it's nasty stuff. It causes adverse events, including dyskinesia, in 50% of the patients.[1] Parkinson's patients typically have some kind of dyskinesia. There are three kinds:

  1. Chorea and choreoathetosis (involuntary, rapid, uncoordinated movements, such as flailing arm movements).
  2. Dystonia (sustained, painful muscle contractions, such as twisting of the leg on walking).
  3. Akathasia (excessive motor restlessness, such as a high-stepped overshooting gait).

Which kind they get depends to a large degree on their L-DOPA levels. During peak doses, they get chorea, while in the ‘off’ state when L-DOPA levels are low they get mostly dystonia. Dyskinesia is not to be confused with tarditive dyskinesia, which results from prolonged treatment with antipsychotics such as haloperidol. But haloperidol blocks dopamine receptors, so there must be some similarity.

Gambling

For reasons not fully understood, pathological gambling is higher in PD. Patients who gamble tend to be younger, with more novelty-seeking traits, and have a history of alcohol addiction. Scientists speculate that the gambling is associated with genetic mutations in molecules involved in dopamine metabolism (DRD3, 5-HTTLPR, and GRIN2B).[2]

Hallucinations and psychosis

About one fourth to one half of PD patients get hallucinations. Although they're not as awful as the disturbing hallucinations seen in Lewy body dementia, they're qualitatively similar: patients typically sense the presence of a person or an animal. The hallucinations used to be considered to be a side effect of drug treatment, but nowadays they are recognized as part of the disease.[3][11] In one in three patients, hallucinations and delusions are serious enough to be called psychosis. This seems to be related to Lewy body formation, and it's different from regular psychosis.[4]

Deep Brain Stimulation

A new treatment for PD involves electrical stimulation of the subthalamic nucleus, also called deep brain stimulation. Doctors surgically implant electrodes into the brain and attach them to a pulse generator. The idea is to replace the signals from the neurons that have died.

The electrical stimulator dramatically reduces the amount of dyskinesia, but because it's still mostly experimental it's mostly done on advanced patients who require help with daily living when not taking medication. Some studies say it gives a 24–38% improvement in scores for mobility and well being.[5] In one study it reduced the scores on UPDRS-III, a test of PD severity, from 48±12 to 28±15. And, most dramatically, it reduced the hours per day that the patients were immobile from 6.2 to 2.0.

Deep brain stimulation also increases the risk of serious adverse events to 13%.[5] These include an increase in gambling behavior,[6] increased risk of suicide,[7] and even fatal intracerebral hemorrhage. If the stimulator gets accidentally switched off, the patient will fall and be injured.[8]

What causes Parkinson's disease?

The cause of PD is not known, but there is strong circumstantial evidence for an environmental cause. The incidence of PD varies enormously (by a factor of 100 or more) in different countries. The incidence is also higher in rural areas. These factors strongly suggest something in the environment, diet, air, or in our behavior.

There's also some role for interactions between the dopamine and acetylcholine systems, since one risk factor for PD is exposure to organochlorine insecticides such as chlorpyrifos (which inhibits acetylcholinesterase, thereby increasing acetylcholine levels), while smoking tobacco seems to slightly reduce the risk. Nicotine mimics the effects of having more acetylcholine by activating one type of acetylcholine receptor called the nicotinic receptor. This might mean that the toxin, whatever it is, also binds to nicotinic receptors, and that cigarette smoking makes it so the toxin can't do that.

Some herbicides like paraquat, which produces lots of free radicals, the pesticide rotenone, which is used to kill fish and insects, and some metals like manganese, increase the risk.[13] There is also a hereditary form of PD which has an earlier onset. And there are certain poisonous chemicals like 6-hydroxydopamine that reliably induce PD in experimental animals.

The most potent of these is MPTP. MPTP was accidentally invented by drug pushers attempting to synthesize a narcotic similar to meperidine. It produces rapid, irreversible paralysis in humans that resembles advanced PD. Scientists discovered that it gets converted to 1-methyl-4-phenylpyridinium, or MPP+, by monoamine oxidase, which is the enzyme that degrades dopamine and other monoamine neurotransmitters[12].

Bacteria

A famous outbreak of a disease called amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson-dementia complex (or ALS-PDC for short) in Guam was traced to an unusual amino acid called beta-N-methylamino-L-alanine, or BMAA, which is produced by cyanobacteria.[9] There are also several reports linking Helicobacter pylori, the bacterium that causes peptic ulcers, to PD.[10] The idea is not so much that the bacteria cause the disease (although that hasn't been ruled out), but that they can make the symptoms worse by interfering with the absorption of levodopa.

None of this means that anybody really thinks PD is caused by bacteria, but it does show that it's possible for something in our food or water to cause Parkinson's like symptoms. And that's a big clue for scientists.


1. Thanvi B, Lo N, Robinson T. (2007). Levodopa-induced dyskinesia in Parkinson's disease: clinical features, pathogenesis, prevention and treatment. Postgrad Med J. Jun;83(980):384–388. Link

2. Heiden P, Heinz A, Romanczuk-Seiferth N. (2016). Pathological gambling in Parkinson's disease: what are the risk factors and what is the role of impulsivity? Eur J Neurosci. Sep 13. Link

3. Hallucinations in Parkinson's disease: prevalence, phenomenology and risk factors. Fénelon G, Mahieux F, Huon R, Ziégler M. Brain. 2000 Apr;123 ( Pt 4):733–745. Link

4. Ravina B, Marder K, Fernandez HH, Friedman JH, McDonald W, Murphy D, Aarsland D, Babcock D, Cummings J, Endicott J, Factor S, Galpern W, Lees A, Marsh L, Stacy M, Gwinn-Hardy K, Voon V, Goetz C. (2007). Diagnostic criteria for psychosis in Parkinson's disease: report of an NINDS, NIMH work group. Mov Disord. Jun 15;22(8):1061–1068. Link

5. Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schäfer H, Bötzel K, Daniels C, Deutschländer A, Dillmann U, Eisner W, Gruber D, Hamel W, Herzog J, Hilker R, Klebe S, Kloss M, Koy J, Krause M, Kupsch A, Lorenz D, Lorenzl S, Mehdorn HM, Moringlane JR, Oertel W, Pinsker MO, Reichmann H, Reuss A, Schneider GH, Schnitzler A, Steude U, Sturm V, Timmermann L, Tronnier V, Trottenberg T, Wojtecki L, Wolf E, Poewe W, Voges J; German Parkinson Study Group, Neurostimulation Section (2006). A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med. Aug 31;355(9):896–908. Link

6. Rogers RD, Wielenberg B, Wojtecki L, Elben S, Campbell-Meiklejohn D, Schnitzler A. (2011). Deep brain stimulation of the subthalamic nucleus transiently enhances loss-chasing behaviour in patients with Parkinson's disease. Exp Neurol. Sep;231(1):181–189. Link

7. Voon V, Krack P, Lang AE, Lozano AM, Dujardin K, Schüpbach M, D'Ambrosia J, Thobois S, Tamma F, Herzog J, Speelman JD, Samanta J, Kubu C, Rossignol H, Poon YY, Saint-Cyr JA, Ardouin C, Moro E. (2008). A multicentre study on suicide outcomes following subthalamic stimulation for Parkinson's disease. Brain Oct;131(Pt 10):2720–2728. Link

8. Tousi B, Wilson K. (2013). Falls related to accidental deactivation of deep brain stimulators in patients with Parkinson's disease living in long term care facilities. Am Med Dir Assoc. Jan;14(1):58–59. Link

9. Arif M, Kazim SF, Grundke-Iqbal I, Garruto RM, Iqbal K. (2014). Tau pathology involves protein phosphatase 2A in parkinsonism-dementia of Guam. Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):1144–1149. Link

10. Camci G, Oguz S. (2016). Association between Parkinson's Disease and Helicobacter Pylori. J Clin Neurol. Apr;12(2):147–150. Link

11. Ibarretxe-Bilbao N, Junque C, Marti MJ, Tolosa E. (2011). Cerebral basis of visual hallucinations in Parkinson's disease: structural and functional MRI studies. Neurol Sci. 2011 Nov 15;310(1-2):79–81. Link

12. MPTP-Induced Parkinsonian Syndrome. In Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Siegel GJ, Agranoff BW, Albers RW, et al., editors. Philadelphia: Lippincott-Raven; 1999. Link

13. Tanner CM, Kamel F, Ross GW, Hoppin JA, Goldman SM, Korell M, Marras C, Bhudhikanok GS, Kasten M, Chade AR, Comyns K, Richards MB, Meng C, Priestley B, Fernandez HH, Cambi F, Umbach DM, Blair A, Sandler DP, Langston JW (2011). Rotenone, Paraquat, and Parkinson's Disease. Environ Health Perspect 119:866–872.

Last edited oct 08 2016, 6:46 pm

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