What if it is not the dopamine?
 

I know that this is a little absurd at first glance, but what if Sinemet and maybe even the agonists are not easing symptoms for the reasons everyone assumes but for another reason altogether.

I got to wondering about this when I came across a study which showed a dramatic temporary drop in cortisol when one takes Ldopa. Other studies show that PWP have high cortisol levels, so a drop might be welcome news while it lasted. And we all know that when the change is in the other direction, all hell breaks loose. Does it seem unreasonable that a drop would improve function?

Another thing I have wonderred about is that I can crawl to bed completely shot. The last med several hours in my past and the next one hours in my future. Yet, if I wake up in the night, I'm not surprised to find that I am in pretty good shape. And the degree of improvement is related to when I wake up, 1:00 AM is different than 5:00 AM. But if I stay up then it isn't long before symptoms start. I have used up the dopamine that accumulated while I slept. Or had I? What if the explanation was that my cortisol levels rose instead?

Worth a thought....

Clin Neuropharmacol. 2007 Mar-Apr;30(2):101-6.
Acute levodopa intake and associated cortisol decrease in patients with Parkinson disease.

Müller T, Muhlack S.

Department of Neurology, St Josef Hospital, Ruhr University Bochum, Germany. thomas.mueller@ruhr-uni-bochum.de

Levodopa application improves motor symptoms in patients with Parkinson disease (PD). Levodopa induces lower cortisol plasma levels and decreases serotonergic activity in certain brain areas of fish. The objectives of this study were to perform repeat cortisol concentration measurements before and after the administration of soluble levodopa/benserazide (dose, 200 mg) in 32 patients with PD during an interval of 150 minutes. The cortisol concentrations significantly decreased after levodopa intake, particularly in the patients with more advanced stage of PD, but not in the less affected patients. There were significantly lower cortisol levels in the patients at the advanced stage of PD compared with those of the earlier patients with PD, particularly at -30, 0, and 90 minutes before/after levodopa application. Significant inverse relations were found between the cortisol levels and the Unified Parkinson Disease Rating Scale total score, particularly at 60 and 90 minutes after levodopa intake. Neurodegeneration occurs in striatal regions and in the brain stem of patients with PD. The 5-HT-containing neuronal terminals of the brain stem hypothetically mediate the cortisol level decrease after levodopa intake because these cells contain an important fraction of amino acid decarboxylase. Therefore, this compartment may be the site of enzymatic conversion of superfluous, exogenous levodopa to dopamine. Consequently, short-term levodopa administration also leads to levodopa uptake in these 5-HT-metabolizing neurons, which interferes with the 5-HT synthesis and may cause a decrease of 5-HT levels. These lower 5-HT levels reduce the hypothalamic function and, via the corticotropin axis, the subsequent peripheral cortisol release. Thus, levodopa-induced cortisol decrease may be related to PD progression.

PMID: 17414942 [PubMed - indexed for MEDLINE]

what"???
 

I thought cortisol was bad? The last sentence seems to say that decreasing cortisol, which I thought would be a good thing (higher cortisol = worse symptoms) actually makes the PD progress. Did I get this right?

It isn't clear from the abstract and if anyone can get a pdf I would sure like to have it. I suspect that advanced PWP had higher levels at baseline and higher changes as well.

REM sleep disorders caused by acetylcholine and cortisol?
 

cortisol and acetylcholine work together. even as we sleep.

http://grande.nal.usda.gov/ibids/ind...&therow=225891

http://www.sleepdisorderchannel.com/rem/index.shtml
http://learnmem.cshlp.org/content/11/6/671.full

REM - normal
SWS - slow wave sleep - normal
RBD - REM Behavior Disorder - abnormal -acting out dreams, yelling, acetycholine and cortisol are unblocked


In a normal person
Sleep Paralysis
The basic mechanism for REM sleep paralysis is found in the brainstem. Neurotransmitters, particularly the monoamines (largely serotonin [5-HT] and norepinephrine [NE]) and acetylcholine, play a critical role in switching the brain from one sleep stage to another. REM sleep occurs when activity in the aminergic system has decreased enough to allow the reticular system to escape its inhibitory influence (Hobson et al. 1975, 1998).

The release from aminergic inhibition stimulates cholinergic reticular neurons in the brainstem and switches the sleeping brain into the highly active REM state, in which acetylcholine levels are as high as in the waking state. 5-HT and NE, on the other hand, are virtually absent during REM. SWS, conversely, is associated with an absence of acetylcholine and nearly normal levels of 5-HT and NE (Hobson and Pace-Schott 2002).


Physicians and sleep technicians hypothesize that the brain naturally and purposely prevents motor activity during REM sleep to ensure restful, inactive sleep during the most electrically active stage of sleep. In this context, sleep paralysis describes a normal state of sleep, unlike sleep paralysis experienced in narcolepsy, which affects people while they are trying to stay awake.

Motor Activity and REM Sleep not normal
In RBD, neurotransmitters are not blocked, and the voluntary muscles become tonic, or tensely contracted, allowing a sleeping person to move his or her muscles during REM
~
This is considered a possible pre-motor pd symptom.

another 'It adds up".
paula

Hi Rick,
Just thinking aloud,
Firstly, does cortisol, (which is made in the blood) cross the BBB into the brain? If it doesn't, and it seems as though it doesn't, it presumably can't affect PD symptoms?
http://www.ncbi.nlm.nih.gov/pubmed/1...m&ordinalpos=7
"entry of cortisol to the brain of these animals is limited at the blood-brain barrier (BBB)"
This is complicated though, since cortisol is released by stress, which also dramatically increases the permeability of the BBB, (and of course increase PD symptoms) Stress may widen the BBB enough to permit passage of cortisol, even though the level is reduced.
However, low cortisol from other causes should show improved PD symptoms if you are correct. What are other causes of higher cortisol levels,(other than stress) and do they cause a worsening of symptoms?

See http://www.ehow.com/about_5184651_ef...l-levels_.html
"Some medications can block the synthesis of cortisol."
So presumably other compounds besides levodopa can cause low cortisol.
I have not had time to find all of them, but one I found was

"One of the best known and most effective ways to lower excess
cortisol levels is with the nutrient Phosphatidylserine"
See http://answers.google.com/answers/th...id/757599.html
I think this is a supplement used to treat PD, so that supports your idea. I must do a search on the others.

A fascinating idea Rick. I wonder what can cause dyskinesia after prolonged use of levodopa. Could a lowering of cortisol be a possible cause?
Dyskinesia must be due to one of the side effects of levodopa. Your reference says,
"
The cortisol concentrations significantly decreased after levodopa intake, particularly in the patients with more advanced stage of PD, but not in the less affected patients. There were significantly lower cortisol levels in the patients at the advanced stage of PD"

Dyskinesia only occurs in advanced patients when levodopa is administered.
I never get diskinesia when I am off and have not taken any levodopa for a long period. So dyskinesia must be a function of taking levodopa. Nothing else causes it.
Sorry if this rambles somewhat.
Ron

As you say, Ron, complicated
 

But worth considering. I don't think we can talk about any of it in isolation. We know there is an inflammatory factor, a stress factor, and a BBB factor working simultaneously and feeding back into one another. Inflammation opens the BBB. The body produces cortisol to quell inflammation and presumably closes the BBB. But how fast it closes and what amount of cortisol gets into the brain in the process I don't know. Our symptoms don't come and go suddenly so it's probably transitional. Found this-

1. Cell Mol Neurobiol. 2001 Dec;21(6):675-91.

Frequent blood-brain barrier disruption in the human cerebral cortex.

Tomkins O, Kaufer D, Korn A, Shelef I, Golan H, Reichenthal E, Soreq H, Friedman
A.

Department of Physiology and Neurosurgery, Soroka University Hospital, Zlotowski
Center of Neuroscience, Ben-Gurion University, Beersheva, Israel.

1. The blood-brain barrier (BBB) protects the brain from circulating xenobiotic
agents. The pathophysiology, time span, spatial pattern, and pathophysiological
consequences of BBB disruptions are not known. 2. Here, we report the
quantification of BBB disruption by measuring enhancement levels in computerized
tomography brain images. 3. Pathological diffuse enhancement associated with
elevated albumin levels in the cerebrospinal fluid (CSF) was observed in the
cerebral cortex of 28 out of 43 patients, but not in controls. Four patients
displayed weeks-long focal BBB impairment. In 19 other patients, BBB disruption
was significantly associated with elevated blood pressure, body temperature,
serum cortisol, and stress-associated CSF 'readthrough" acetylcholinesterase.
Multielectrode electroencephalography revealed enhanced slow-wave activities in
areas of focal BBB disruption. Thus, quantification of BBB disruption using
minimally invasive procedures, demonstrated correlations with molecular,
clinical, and physiological stress-associated indices. 4. These sequelae
accompany a wide range of neurological disorders, suggesting that persistent,
detrimental BBB disruption is considerably more frequent than previously assumed.

PMID: 12043841 [PubMed - indexed for MEDLINE]

Paula,

This is a find! I have been wondering about this phenomenon which is part of that weird thing going on referred to as paradoxical movement. A PD person who is normally bradykinetic or akinetic, will, upon an emergency, move like there's no tomorrow. I think it's just as fascinating that those PWP who do have REM Sleep Disorder, move with ease, and most importantly they are completely fluid - the movements in REM do not look Parkinsonian!

What gives? If we have too much poorly modulated (dopamine is the modulator) acetylcholine, in our normal day, we then end up dystonic. Why then don't we end up a ball of spasm if the acetylcholine is not at all being held in check? This leaves me with the big question that perhaps dopamine is playing a bigger part here and if we could harness why, all of a sudden, things flow for us, could we possibly have new treatments?

One other thing...can we also start looking at having too much acetylcholine as a basis for having PD subtypes? In other words, does the akinetic-rigid type have more of an acetylcholine imbalance than tremor dominant?

Thanks for sharing

Laura

I think subtypes will soon be in play
 

the concern is that they will neglect the advanced pwp and use younger participants when developing treatments.

Here's an NIH study.
Biomarkers of Risk of Parkinson Disease

The point i noticed here is that they acknowledge pwp lack norepinephrine and of course dopamine. No mention of pwp needing acetylcholine. Or having too much.

https://pdrisk.ninds.nih.gov/AboutThisStudy.aspx
https://pdrisk.ninds.nih.gov/Welcome.aspx

here are some clinical trials on the subjects
http://www.clinicaltrial.gov/ct2/res...on%27s+disease

http://www.clinicaltrial.gov/ct2/res...on%27s+disease

http://www.clinicaltrial.gov/ct2/res...+parkinson%27s

here's one on RBD sleep disorder and chemical changes
http://clinicaltrials.gov/ct2/show/N...r=Open&rank=16