I am just pulling out a discussion started in a rather long thread as it seems we might be able to get a little more input in doing this.

Rick suggested that PD may indeed start out as an endocrine disorder and based on what I have been reading I am inclined to agree. Thyroid dysfunction was broached, and I immediately started reading up on parathyroidism. The paraythyroid is very interesting because it acts independently of our thyroid and its entire purpose is to modulate calcium in our systems. Vitamin D is often found to be at insufficient levels when there is a parathyroid dysfunction, but from what I have read, supplementing with more Vitamin D may not always be the answer as it can cause even higher levels of circulating calcium in our systems.

So we know that many of us show Vitamin D deficiencies. Where does calcium come into play and what does it all have to do with PD. Obviously, I don't know the answers, but there are some interesting links and hints out there.The main thing to know is that any sort of parathyroid dsyfunction results in dysregulation between calcium, Vitamin D, and phosphate in the blood stream. It often is not detected by common blood tests run by doctor. Longstanding and untreated it has shown in some rare cases to result in Parkinsonism. I am not saying that this is concomitant in us but am feeling there are very strong connections to PD.

Calcium is a neuromodulator controlling electrical signaling and it is hypothesized that calcium meets up with oxidative stress and cell system failure = what looks like idiopathic PD. <A really great interactive model here> Note that PD has shown some response to ECD (Electro-convulsive Therapy).

People with hypoparathryoidism have increased chance of getting Addison's or Parkinson's Disease- the symptom/features of Addison's (result is body's inability to produce enough steroid hormones)- these may mimic some symptoms of PD as well: the key thing is that the parathyroid impairs the nervous system and muscles so obvious to see it as a link to a movement disorder. How so? Parathyroid problems lead to calcium dysregulation- calcium is vital to us as it helps conduct electrical impulses and energy for muscular control. When the parathyroid can't produce the right levels of Parathyroid Hormones (PTH); note this often happens as an autoimmune and inflammatory response. I wonder if PD doesn't begin somewhere in the endocrine system for us? This impaired PTH production; PD aside, results in hypocalcemia and too much phosphate in our system and has manifested with both symptoms of PD, cognitive impairment, and dementia.

Calcium Disorders. Disorders of calcium metabolism may occur in association with parkinsonism. Hypoparathyroidism has been reported to cause parkinsonism both in the presence and absence of basal ganglia calcifications. It may occur as a late complication after thyroidectomy[5] and may be responsive to levodopa in some cases.[6] Pseudohypoparathyroidism, characterized by end-organ resistance to normal endogenous parathyroid hormone, may be associated with parkinsonism in up to 4 to 12% of patients, either with or without evidence of basal ganglia calcifications,[7] and may respond partly to normalization of serum calcium.[8] Hyperparathyroidism due to parathyroid adenomas can rarely cause parkinsonism, which is reversible after surgical removal of the tumor.[9] Bilateral subcortical calcification involving the basal ganglia and cerebellum, often labeled as Fahr's disease, represents a heterogeneous collection of disorders that are not associated with a known disorder of calcium metabolism. Movement disorders in Fahr's disease most commonly present as parkinsonism (55%), often in association with dementia, cerebellar signs, or other hyperkinetic movements including chorea, tremor, and dystonia.[10]

Please register at Medscape and read the full article "Movement Disorders caused by Medical Diseases: Parkinsonism"

Hypoparathyroidism hallmarks include low Vita D and the main thing is not enough calcium in the system. Here are two case studies of note; one involves the pseudo version and the other straight on thyroid disorder. I love a good puzzle, but know that there is more than simple links. Anyone else have anything to go on...where does the fight or flight and stress fit into all this. It is noted that hypoparathyroidism and Addison's Disease (absence of steroid hormones also linked to thyroid disorder) are both negatively impacted by stress.

Case studies:


Pseudohypoparathyroidism, Parkinsonian Syndrome, with No Basal Ganglia Calcification Jounal of Neurology...1988.

Idiopathic Hypoparathyroidism Presenting as Dementia. British Medical Journal...1974.


Last interesting thing, it is now considered common for parathyroid dysfunction to occur as result of pregnancy, and is often invisible as symptoms mimic hormonal changes. It looks like it can be a permanent condition or just make an appearance in times of stress? Just what Rick and some of us have been looking at...so clearly our chronic lower level stress I'm sure would also play a part.

Just how does this fit together? Why is dopamine and basal ganglia the hardest hit neuro aspect? Anyone have any insights? I feel like I am just either putting together the obvious for any doctor or scientist, so maybe there is nothing more to all this. Just feel there has got to be some sort of major connection or maybe common pathway. Would all this further indicate that the autoimmune system does have a role in PD. BTW, it is noted that pseudohypoparathryoid causes anosmia or the impaired sense of smell many PD people have.

Laura

This is excellent, thanks for sharing. I have to add, perhaps this is also why calcium channel blockers have indicated some success, they are looking at this at Northwestern and we got one of our docs to script us for Dynacirc which is the calcium channel blocker they are using in the trial (I think isradipine is another name for it). Who knows, but I'm not seeing a one pill fits all for PD, there are just too many variations on a theme as we all know all too well.

We sure have some excellent minds here. I'm so grateful.

No, Laura, you are not putting together the obvious. This is a tangled knot that we are tugging on. What do we know? In particular, what do we know as patients that researchers may not? Or it is known but dismissed or simply not explained?

One is the knowledge of just how involved emotion is in PD. Emotion generates stress, both good and bad. It is said that we don't seek out novelty, or take risks, or show emotion like normal folk. Is it true? In my case it is, sort of. I enjoy novelty but not for novelty's sake. I take risks but I do my homework to minimize them. I don't show my emotions I must admit. Why? I don't know, but I have a suspicion.

I suspect that we, for whatever reason, cling to stability at all levels. It is a way to minimize stress.

Thanks, Lurking for adding the calcium channel blocker connection; this is a biggie! I just learned that not only is the protein CACN1S (this is key in Isradipine therapeutics for PD) linked to schizophrena...and the other team of scientists and researchers who can't get past dopamine. In other words, schizophrenia, long touted as result of excess dopamine, and its opposite manifesting as PD, are both perhaps channelopathies.

Interestingly, only the "L Type" Calcium Channel blockers may be neuroprotective (this is Isradipine). Other old school channel blockers like Verapimil actually have induced Parkinsonism! I have no idea why only the L Type seems to be our friend.

Rick, I just ran across this morsel when researching L type calcium dealies. Apparently, a certain receptor protein is essential for proper function of L type. It is known impacted by the gene CLCNL1A3

From Wikipedia:
This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility.[1]

Rick- if you have haven't run across the Thyrotoxic Periodic Paralysis info, please connect to a brief NYT article- it sounds alarmingly familiar! Even lists salty foods as a possible trigger.

Next up:

Moreover, rom the ER that consistently induced mitochondrial Ca2+ uptake, with a rise of mitochondrial matrix free Ca2+. In other words...too many free radical Ca2+ cells resulting in toxicity.

I sure wish we could put all these pieces together into actually beginning to make sense of how the substantia nigra ends up taking the biggest hit for us. I also wonder if this model of how PD might originate allows for potential autoimmune role and my hope for a vaccine.

From: http://www.answers.com/topic/channelopathy

"Cells of the body, including nerve and muscle cells, are surrounded by thin coverings called membranes. Embedded in these membranes are a large and varied set of proteins that control the movement of materials across the membrane, in and out of the cell. One major type of material that crosses through such proteins are called ions, and the proteins that transport them are called ion channels.

Ions perform many different functions in cells. In neurons (nerve cells), they help transmit the electrical messages that allow neurons to communicate with each other, and with muscle cells. In muscle cells, they allow the muscle to contract. When the ion channels are defective, these activities may be disrupted."

<Think of ion channels as the port holes in a great ocean liner and pretend they are the only way to pass stuff onto or off of the ship. Suppose you are going to load a shipment of beach balls 18"in diameter through ports that the ship specs say are 19" in diam. No problem. But you find that due to a mutation that the ports are actually 17" in diam. That is a channelopathy. You may still be able to squeeze the beach balls through the port, but it will be slower, some will be damaged, etc. Things won't work right.>

From http://www.kcnq.org/health/channelopathies.php

"When an ion channel goes wrong or does not function as it should, it may produce a disease in an individual. Certain forms of skeletal and cardiac muscle and brain diseases such as the myotonias, epilepsies, migraine or arrhythmias are due to pathological alterations in channel proteins and thus, can be considered as "Channelopathies".

" Another important cause of channelopathies is auto-immune attack. However, mutations in associated proteins, alterations in the expression of ion channels, and changes in the activity of
non-mutated channel genes or associated proteins can also produce what are known as acquired channelopathies. Such acquired channelopathies may occur as a result of nerve-injury or after drug treatments that perturb cellular function.
This huge variety in the causes of channelopathies, as varied as the diseases themselves, not only makes it difficult to study these diseases but it often makes the clinical diagnosis of these diseases problematic. "

"As stated, Channelopathies may also be due to the body producing antibodies that destroy specific ion channel proteins. These types of disease are known as autoimmune channelopathies of which myasthenia gravis and neuromyotonia are good examples. In these diseases, the antibodies mainly affect the function of the nicotinic acetylcholine receptors at the endplate and dendrotoxin-sensitive potassium channels, respectively. "

From http://www.associatedcontent.com/art...sm.html?cat=70

"The activation of these proteins leads to altered cell behaviour. Increased calcium within cells results in increased damaging oxygen free radical production by mitochondria. Abnormal mitochondrial function is associated with autism. Palmieri et al confirmed the importance of these associations in a study of several patients with autism.

L-type calcium channels (LTCC) are voltage-gated calcium channels that are found in

1. The central nervous system - LTCC are important in the regulation of nerve cell development.

2. The immune system - LTCC are important in the function of white cells including regulatory T-cells TREGS which control immune system activity

3. Gastro-intestinal tract - LTCC are related to activity and inflammation of the stomach, intestines and pancreas."

And, finally, the NYT article Laura mentioned
http://health.nytimes.com/health/gui.../overview.html

This is what I suspect that I have had for a minimum of five years. And for a number of reasons, I think that it may be something that PWP may tend to develop as they "progress." As such, it would behoove us to be aware of the possibility.

It results from an overly active thyroid. This sort of thyroid condition can exist in a sub-clinical state for decades and then "bloom" in response to extreme emotional stress. You may recall my recent posts about the stress of the tree removal around my home. That was the culmination of a six-month period of high stress and drug on for six weeks or more. I developed some new symptoms and had old ones amplified. Among the most obvious were three times that I collapsed in the floor and could not move for two to three hours. Another was a near panic attack when I thought the machinery was starting up early and I was trapped. I also developed a marginal increase in body temperature, hot flashes, increased sweating, headache, and blood pressure fluctuations. All this pointed toward thyroid problems tied to the stress onslaught. Of the symptoms listed in the NYT piece for both the hyperthyroid and the thyrotoxic periodic paralysis, I had 80% of them. While you may not have them today, a year from now you might. So keep it in mind.

My problem turned out to be a blessing, however. Unlike PD, this particular periodic paralysis can be treated by means of treating the underlying thyroid problem. According to the sparse research available, when both PD and hyperthyroid are present, treating the latter produces big improvement in the former.

Before I rushed off to another doc, however. I decided to do some research to see if there was something I might try on my own. As it turned out, there was, and I was already taking it in a smaller dose.

Acetyl-L-Carnitine does many things, including damping down an over-active thyroid and it seems to be working. A week ago today I was nearly helpless the entire day. Today I am doing well.

I'm not sure what to make of this. If PWP do tend to develop this sort of problem as time goes on, then it may be a sub-clinical factor from Day One. If so, there should be value in taking ALC now.

Even if my hunch is wrong, however, there is still reason to look at ALC. In addition to having an excellent safety profile, it also has other benefits:

"L-Carnitine is an essential co-factor in the metabolism of lipids and consequently in the production of cellular energy. This molecule has important physiological roles, including its involvement in the beta-oxidation of fatty acids by facilitating the transport of long-chain fatty acids across the mitochondrial inner membrane as acylcarnitine esters. In the brain, L-carnitine and acetyl-L-carnitine have important roles in cerebral bioenergetics and in neuroprotection through a variety of mechanisms including their antioxidant properties and in the modulation and promotion of synaptic neurotransmission, most notably cholinergic neurotransmission. "

Rick, bingo! This is huge as it essentially links major things we know thay are going on from researchers' perspective but that is fragmented by very nature of the reductive approach used in science and medicine. I find the link to the gut especially interesting; I am seeing how PD seems most definitely part channelopathy, and I see how we might apply this info in light of Braak's staging. I remember reading that in parathyroidism, people may experience anosmia? Well, I just looked up vagus nerve and sure enough- neurotransmitters in the olfactory area rely on L type Calcium Channels.

My next question is when do our dopa neurons change from ion to calcium channels and is this change a pivotal point or the stress point from exogenous triggers that result in PD? Or can this change take place at any time? Hmmm…where are our scientist members?

Will read the excellent channelopathy info you shared when I can (little one must be sleeping)- just had time to skim so far

Laura

I think this gets really complicated.

Those calcium channels are everywhere and also involved in pain transmission!

http://en.wikipedia.org/wiki/Astrocyte

There are other players in the cascade as well.
This one especially puzzles me-- when used with morphine better pain control can be had, but when used alone, nothing!
http://www.ijaweb.org/article.asp?is...1;aulast=Kumar