PD and Hypoxemia

[K.Ibsen]

I've been working on a time-line for the development and progression of my symptoms. In looking at the time-line, I realized that the onset of the stiffness and rigidity (my first symptoms) seem to coincide with the onset of sleep apnea. Well, sleep apnea causes hypoxemia (inadequate oxygenation of the blood). I started wondering if the lack of oxygen in the blood could have somehow played a role in the degeneration of the cells that produce dopamine. I know that sleep apnea causes some seriously painful headaches.

Does anyone know of any studies that suggest or support that hypoxia, especially chronic hypoxia, may contribute to PD?

Karl

[Ronhutton]

Hi Karl,
I was interested in your post since I have sleep apnea, so bad my wife says I stop breathing for minutes. I think I have got her worried I am not going to restart!!!!
I was curious since I had not realized that sleep apnea causes hypoxemia, so I did a search. When you Google "hypoxemea Parkinson's", I got over half a million references. It seems there is a definite link between PD and hypoxemia.
Best wishes
Ron

[reverett123]

I read somewhere that older folk in general often have hypoxia due to shallow breathing. Given our diaphraghm rigidity and lack of exercise, it is bound to be a factor.

[vlhperry]

Dear gang;

The research in China and the UK is much more advanced than America. They have clearly recognized that the person who has Parkin mutations symptoms are clearly recognized as different than Young onset juvenile Parkinson's disease from ideopathic Parkinson's disease.

America, who has been focusing on fighting about embryonic stem cells, suddenly is discovering the UK is on the right path. Now suddenly American reseachers have stopped batteling for money for embryonic stem cell research to genetic research. What I question is why America has to redo the Europeon nations research instead of helping to work with the other countries to find a cure? Why spend so much money and time remaking the research?

Vicky

[reverett123]

....could explain a lot.

[Heidi L]

The symptoms of PD are noticable when there is already loss of 60-80% of the dopamine cells.

If your apnea coincided with the other symptoms, it argues for it being a symptom rather than the cause. Hypoxia may accelerate the process however.

Sleep breathing disorders in patients with idiopathic Parkinson's disease (http://cat.inist.fr/?aModele=afficheN&cpsidt=15117271)
Our results suggest that sleep breathing disorders, predominantly obstructive, seem to be common in PD and those events correlate with the severity of the disease.

Ronhutton, isn't hypoxia associated with BBB damage?

[Heidi L]

By the way-

Ronhutton- get to a sleep center ASAP!!! Apnea like that is extremely serious. You truly may not restart. It happens. And you're doing major damage to your heart pumping deoxygenated blood around like that.

All your PD research will be for nothing if you drop dead from a heart attack next week!

[Heidi L]

And Vicky-
It's all about the patents. Nothing else. I worked for a pharma co, believe me- treating sick people is only a side effect of the business.

[Ibken]

whose driving conviction was that reduced blood flow to the brain resulted in - or at least was a major causitive factor in developing PD symptoms. His experience with EECP prooved this to him -as he would say - "beyond the shadow of a doubt." His symptoms were instantly alleviated by the pumping action of the machine.

for those who may not know, EECP is a cardiac therapy - termed the natural by-pass - that increases blood flow (oxygen) to the heart - and brain. That this was helpful with PD symptoms was discovered by chance by a patient - who told his cardiologist - who then did a study to see if it worked for other PD'ers.

It does...however it must be repeated periodically as effects typically wane.
There is more but I haven't enough Oxygen myself to continue tonight. zzzzzzzzzzzz

Ibby

[StevePocetaMD]

Hello. There is no evidence of which I am aware that sleep apnea can in anyway contribute to or cause Parkinson's disease. I wrote a little blog on the topic at my own site in response to this discussion. Here is the link:

http://www.revolutionhealth.com/blogs/stevepocetamd/sleep-disorders-and-p-8215

Thank you for a nice forum. -Steve Poceta

[K.Ibsen]

Ron Hutton: If you're stopping breathing at all, you need to get a sleep study. Don't put it off. Do it now. I've been on a machine that assists my breathing for almost two years. It really does make a difference--both for you and your sleeping partner. My wife said she could never get a good night's sleep because she was always worrying about me stopping breathing. You are welcome to PM me about this. There's also a sleep apnea forum on this site that I also visit occasionally.

StevePocetaMD: I don't know if there's a direct link between sleep apnea and PD. I was referring to reduced oxygenation of the blood that can be caused by sleep apnea. Every cell in the body needs oxygen so it seems reasonable that some may suffer if subjected to reduced oxygen. Then there's genetics. Both my father and my paternal grandfather had neural disorders that started in their fifties. So, do you think that a genetic predisposition and hypoxia together could have led to problems with my dopamine-producing cells?

Heidi: Thanks for the link. Your posts are always interesting.

[K.Ibsen]

If your apnea coincided with the other symptoms, it argues for it being a symptom rather than the cause.

That's a possibility, because I'm not the typical obstructive sleep apnea patient. I'm not overweight, for example. I also have some episodes of central sleep apnea. That is, I sometimes stop breathing while I'm awake. This hasn't bothered me much since I've been on sinemet full-time. Interesting.

I still use a continuous positive air pressure (CPAP) machine to keep me breathing during sleep. It's actually a wonderful device--simple and effective, once one gets used to it. I sometimes use it during the day when I have a headache because it actually helps.

Karl

[reverett123]

HO is what they use when a diver gets the bends. Only eight studies on medline.


1: Zh Nevropatol Psikhiatr Im S S Korsakova. 1989;89(10):38-40.

[Hyperbaric oxygenation in the complex treatment of Parkinson disease]

[Article in Russian]

Neretin VIa, Lobov MA, Kotov SV, Cheskidova GF, Molchanova GS.

Hyperbaric oxygenation (HBO) was used for the treatment of 64 patients suffering
from parkinsonism of different etiology. HBO sessions were provided daily, 8-12
per course, the treatment pressure amounted to 1.3-2 atm exposure to 40-60
minutes. The beneficial effect was marked in 55 patients. The results of the
treatment turned out better in vascular parkinsonism, in patients under 65 years,
with a disease standing of 1-5 years. The akineticorigid syndrome regressed to a
greater degree, whereas in trembling hyperkinesis, HBO turned out to be less
potent.

PMID: 2618228 [PubMed - indexed for MEDLINE]

[Heidi L]

Hyperbaric oxygen reduces blood-brain barrier damage and edema after transient focal cerebral ischemia. (http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=pubmed&dopt=AbstractPlus&list_uids=16020761&query_hl=2)

[Ronhutton]

Hi Heidi L and Karl,
Thanks for your concern over my sleep apnea, I am sure you are right, and I will see my Doc. I have hesitated since I seem to be always seeing him over one problem or another. I have problems raising my left arm after a fall a year ago, I had the falling into the greenhouse episode a few months ago, now my right knee seems to be cracked or chipped, and I am in agony when I put weight on it. Sleep apnea seemed low in the priorities!!!
Heidi L,
Yes, you are right also when you say isn't hypoxia associated with BBB damage. See
http://davislab.med.arizona.edu/currenthypoxia.htm

Effects of Hypoxia/Reoxygenation on the Blood Brain Barrier
Stroke is the leading cause of death and long-term disability in the United States, yet little is understood regarding how an ischemic event induces a breakdown and increased permeability of the blood brain barrier (BBB). Although hypoxia associated with stroke has been reported to cause increased BBB permeability, effects of re-oxygenation on brain endothelial cells following a hypoxic insult remain unclear. We are currently investigating the effect of hypoxia and reoxygenation on junctional and cytoskeletal proteins.
Ron

[indigogo]

I agree that shallow breathing / apnea / etc. is a symptom rather than cause of PD.

I don't have apnea, but I am aware that I frequently hold my breath. I am told this is not only PD related but also anxiety related.

My attempt to deal with this starts on Tuesday when I begin Kripalu yoga classes that emphasize meditation, breathing, and relaxation in connection with yoga poses. I am doing this at the urging of my doctor, a noted movement disorder specialist.

Swimming is also helping me with regulating my breathing.

Seems dealing with PD keeps coming back always and all ways with restoring balance in your mind, body, and life.

[K.Ibsen]

Seems dealing with PD keeps coming back always and all ways with restoring balance in your mind, body, and life.

Yep. I've pretty much reached that conclusion as well. Perhaps part of the challenge is that it is a different "balance" than we knew in the days before PD became a big part of our lives. I sometimes feel that the more I fight it, the worse I feel.

Karl

[indigogo]

Karl - I agree. I'm learning that less is more with PD; managing stress and coming to terms with my desire to remain as "normal" as possible in the face of abnormality have been my greatest challenges. The more that I accept the new reality, the more comfortable I feel.

I don't think acceptance is the opposite of fighting back - I think it is one way to fight back effectively and efficiently. One neuropsychologist I saw described a PET scan of a man who had been brain damaged in an accident that had destroyed the tiny part of his brain that controlled tying his shoes. He was determined to learn to tie them again, and finally accomplished the task. A new PET scan revealed that now it took practically the whole brain working to do something that only required a small portion before.

I say, why not just wear slip-ons?

We need to put our limited energy into doing what is important for each of us to retain our dignity and good quality of life; that can differ widely. Improving your breathing might be one fairly simple thing that many of us can do to give us an additional boost of good health.

[ZucchiniFlower]

{Hypoxia / hypoxemia is a condition in which there is an inadequate supply of oxygen in the blood.}

"It is suggested that hypoxia may
be a potential clinical tool to treat Parkinson's disease."!!

Hypoxia promotes the differentiation of neural stem cells into dopaminergic neurons

T Zhao, CP Zhang, LL Zhu, B Jin, X Huang, M Fan - Sheng Li Xue Bao, 2007 - ncbi.nlm.nih.gov
Sheng Li Xue Bao. 2007 Jun 25;59(3):273-7

"DA content in the supernatant of culture medium in hypoxia group increased significantly, about twice of that in normoxia group (P<0.05, n=8). The results demonstrate that hypoxia (3% O2) promotes the differentiation of NSCs into neurons, especially dopaminergic neurons. It is suggested that hypoxia may be a potential clinical tool to treat"

ABSTRACT:

Neural stem cells (NSCs) are multipotent and widely used in many research fields such as transplantation. Hypoxia not only improves the proliferation of various stem cells in vitro but also plays an important role in the differentiation of stem cells. The aim of the present study was to investigate the effect of hypoxia on the differentiation of NSCs. NSCs were isolated from the midbrain of embryonic Wistar rats (E13.5d), and cultured in serum-free DMEM/F12 medium (containing 20 ng/mL EGF, 20 ng/mL bFGF, 1% N2 and B27). The neurospheres were passaged every 3-5 d, and the third generation of NSCs was used for the following experiments. NSCs were induced under normoxia (20% O2) and hypoxia (3% O2), respectively, for 3 d, and then differentiated under normoxia for 5-7 d (DMEM/F12 medium containing 1% FBS, N2 and B27). Immunohistochemistry of nestin, NeuN and TH was used for NSC identification and differentiation assay. The number of TH-positive cells was evaluated by flow cytometry. Dopamine (DA) content in the supernatant of culture medium was detected by HPLC. The results showed that NSCs could self-renew and were all nestin-positive. NSCs under hypoxic condition differentiated more neurons than those under normoxic condition. The percentage of TH-positive cells differentiated from NSCs under normoxia and hypoxia was (10.25+/-1.03) % and (19.88+/-1.44) %, respectively.

In addition, DA content in the supernatant of culture medium in hypoxia group increased significantly, about twice of that in normoxia group (P<0.05, n=8). The results demonstrate that hypoxia (3% O2) promotes the differentiation of NSCs into neurons, especially dopaminergic neurons. It is suggested that hypoxia may be a potential clinical tool to treat Parkinson's disease.

[K.Ibsen]

"It is suggested that hypoxia may be a potential clinical tool to treat Parkinson's disease."!!

Does this mean that the answer is simply to stop breathing? :wink:

If this were true, then the many years when my sleep apnea was untreated should have prevented PD or limited it's progression. Excuse me while I think for a minute...

My PD symptoms have been with me for many years. As I noted when I started this thread, some of the symptoms have bothered me for more than fifteen years--it had been a very slow progression. However, in the last year or so, and especially in the last six months, the progression of the disease seems to have increased. This increase in the rate of progression overlaps the period of time that I have been using my CPAP machine, which prevents hypoxia.

PD is indeed a very strange thing. Even though I think this is very strange, I'll take a risk and click "Submit Reply" anyway. Please excuse my rambling thoughts.

Karl

[ZucchiniFlower]

Karl, I don't know if there's a connection to your use of that machine or not. But other studies say the same thing:

"Parallel results indicating that reduced oxygen levels can also promote the survival, proliferation, and catecholaminergic differentiation of CNS stem cells (Studer et al., 2000) suggests that neural stem cells may exhibit a conserved response to reduced oxygen levels."

From:

Culture in Reduced Levels of Oxygen Promotes Clonogenic Sympathoadrenal Differentiation by Isolated Neural Crest Stem Cells

http://www.jneurosci.org/cgi/content/abstract/20/19/7370

http://www.jneurosci.org/cgi/content/abstract/20/19/7377

*****************

"These results suggest that although hypoxia induces an increase in the extracellular dopamine levels (hence, an apparent increase in the activity of the dopaminergic neurons), this increase is not the result of an increase in dopamine release itself, but rather the result of inhibition of the dopamine reuptake mechanism."
http://www.blackwell-synergy.com/doi/abs/10.1111/j.1471-4159.1991.tb08249.x

[K.Ibsen]

Well, this sort of sounds like the often referenced rock and hard place. I need the machine to breathe but it may be facilitating the progression of PD.

It sounds from the discussion that the onset of PD symptoms and the onset of sleep apnea are probably unrelated. That was my original question. I certainly wasn't expecting to learn about a possible beneficial role of hypoxemia. I had anticipated that it would make PD worse.

I'm not sure where to go from this point. At 6'3" and 210 lbs, I'm not what most would call over-weight. I am trying to get my weight down to about 190, which is what it was when I was in my 30's. It's also what I weighed when the apnea started, however. Also, Heidi has recommended a gluten-free diet. I'm looking into that as well.

Perhaps, with the right changes, I may be able to get off the CPAP machine. It has helped so much that it's difficult to accept that there may be a down side to its use.

I have to say that I'm a bit taken aback by this turn of events. Perhaps I should visit the sleep apnea forum to see what I can learn there.

Karl

[ZucchiniFlower]

Karl, I wouldn't worry about the machine making your PD worse. Possibly, the dopamine reuptake mechanism is temporarily affected, but this doesn't mean your PD is getting worse because of it. Also:

"Effects of the Obstructive Sleep Apnea Syndrome (OSAS): Patients with obstructive sleep apnea syndrome (OSAS) ( which includes difficulty sleeping, sleep fragmentation and nocturnal hypoxemia) have sown short-term memory and cognitive impairment."

That sounds pretty bad, too, so OSAS should be addressed.

Also, PWPD respond subnormally to hypoxia which can be dangerous, so it should be avoided:

Parkinson's disease and impaired chemosensitivity to hypoxia

Correspondence

Parkinson's disease and impaired chemosensitivity to hypoxia

Hiroshi Onoderaa, Corresponding Author Contact Information, Shinichi Okabeb, Yoshihiro Kikuchib, Takehide Tsudab and Yasuto Itoyamab
aDepartment of Neurology, Tohoku University School of Medicine, Sendai 980-8574, Japan
bFirst Department of Internal Medicine, Sendai, Japan

Available online 1 April 2005.

Refers to: Parkinson's disease and impaired chemosensitivity to hypoxia
The Lancet, Volume 356, Issue 9247, 16 December 2000, Page 2099
Georg Röggla, Wim Weber and Martin Röggla



Authors' reply

Sir—We reported that patients with Parkinson's disease had an impaired hypoxic ventilatory response (HVR) accompanied by blunted perception of dyspnoea, even at an early stage of disease. Since dopamine decreases HVR and dopamine receptor antagonists increase HVR,1 Georg Röggla and colleagues raise an important issue; whether the disease itself or the therapy is causal for impaired HVR. We believe that Parkinson's disease itself impairs the chemosensitivity to hypoxia, as evidenced by the fact that parkinsonian patients taking no drugs that affect dopaminergic functions (levodopa, dopamine-receptor agonists, or both) had a significant reduction of HVR compared with controls.

We compared HVR in patients who had no history of taking dopaminergic drugs (mean age 54·2 years [SD 9·7]) with that in patients taking levodopa, dopamine-receptor agonists, or both (mean age 60·2 years [SD 7·6]). Patients with Parkinson's disease (Hoehn and Yahr stage 2–3) and controls (mean age 53·8 years [9·5]) did not smoke and had no history of respiratory disorders during the previous 6 months. In the hypoxic test, end-tidal carbon dioxide tension (PETCO2) was maintained at the value of each participant's resting PETCO2 during the procedure. The chemosensitivities to hypoxia were expressed as the slope of the regression line relating ventilation to changes in oxygen saturation in arterial blood calculated by least-squares linear regression analysis and measured in L/min, divided by the percentage change in saturation. All patients and controls had normal basic pulmonary functions, such as vital capacity, forced expiratory volume in 1 s, arterial oxygen tension, and arterial carbon dioxide tension.

Chemosensitivity to hypoxia was significantly lower in parkinsonian patients taking dopaminergic medications than in controls. Patients who received no dopaminergic medication had significantly lower HVR than controls. Interestingly, the degree of impairment in HVR of patients without dopaminergic medication was similar to that of patients taking these drugs. These results clearly show that Parkinson's disease itself impairs the chemosensitivity to hypoxia. Dopaminergic drugs at the doses commonly used to treat patients with Parkinson's disease might not, therefore, impair further the HVR in patients with Parkinson's disease. Investigation would be useful of whether dopamine receptor antagonists that do not cross the blood-brain barrier could have a beneficial effect on HVR in patients with Parkinson's disease.2 As Röggla and colleagues mention a study is needed of whether patients with Parkinson's disease have a higher risk of respiratory disorders or sudden death in conditions than non-parkinsonian patients when hypoxia is induced, for example, while flying or at high altitude.

The impaired HVR in Parkinson patients cannot be explained solely by a dysfunction of the dopaminergic system. If only dopaminergic systems in the carotid body were damaged in Parkinson's disease, patients would have higher HVR than controls.1 and 2 We must take into account the possibility that other neurotransmitter systems commonly affected in Parkinson's disease, such as serotonergic or noradrenergic systems, play a critical part in the impaired HVR.3

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1B-4FVCHYK-291&_user=501045&_coverDate=12%2F16%2F2000&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000022659&_version=1&_urlVersion=0&_userid=501045&md5=b803ffc0355ddc0fb7f66f6aac8aa8d6

[ZucchiniFlower]

Annals of the New York Academy of Sciences 939:33-44 (2001)
© 2001 New York Academy of Sciences

Lack of Protective Effect by Intermittent Hypoxia on MPTP-Induced Neurotoxicity in Mice

GIN-HEUY LAIa, CHAU-FONG CHENb, YU SUc, LOW-TONE HOa AND ANYA MAAN-YUH LINa,c

In contrast to acute ischemia and subsequent reperfusion that produce excess free radicals, intermittent hypoxia (IH) is reported to play an important role in upregulation of antioxidative defensive mechanisms. In the study we report here, the neuroprotective effect of IH was evaluated using intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in ICR mice. Adult male ICR mice were subjected to 380 mmHg in an altitude chamber for 15 hours/day for 14 or 28 days. MPTP decreased striatal dopamine content in normoxic mice.

However, IH did not significantly alter the MPTP-induced depletion of striatal dopamine content. Furthermore, MPTP had no effect on GSH content but reduced GSH/GSSG ratio in mouse striatum. IH altered neither GSH content nor MPTP-induced reduction in GSH/GSSG ratio. Although MPTP had no effect on striatal SOD activity in normoxic mouse, IH increased SOD activity in the saline and MPTP groups. Neither MPTP nor IH affected GPx in mouse striatum.

Furthermore, in our ex vivo study, both the autooxidation and iron induced lipid peroxidation of cortical homogenates were lower in the IH-treated group than those of the normoxic group, indicating a reduced oxidative status after IH treatment.

In conclusion, exposure to IH has been suggested to be beneficial in preventing iron-induced oxidative injuries in biological organisms, and our data support this notion in that IH not only decreased iron-induced lipid peroxidation but also increased antioxidative defense enzyme activity in mouse brain.

Furthermore, the lack of neuroprotective effect by IH of MPTP-induced depletion of striatal dopamine content suggests that oxidative stress may not be the only mechanism for the MPTP-induced neurotoxicity.

[ZucchiniFlower]

Intermittent hypoxia (IH) improves hypoxic ventilatory sensitivity and blood dopamine (DA) in patients with parkinson's disease (PD)


Abstract:

DA takes part in respiratory control system as a neurotransmitter in carotid bodies and central structures. Adaptation to IH produces enhanced hypoxic ventilatory responses (HVR) in healthy humans.

This study tested the hypothesis that decreased HVR in PD patients is associated with disturbances in DA metabolism which could be improved by IH training. 18 healthy young (23+/-2 yr: G1), 17 healthy old (60+/-1.4 yr: G2) males, and 18 PD patients (59+/-2.1 yr: G3) were studied before and after 15 days of IH.

Before training, HVR in G3, when compared to G2 and G1, was 24% and 42% lower, venous blood DA content was 26% and 73% higher, and precursor DOPA content was 98% and 460% higher, respectively.

IH training provoked a doubling in HVR in both G1 and G2, and increase by 250% in G3. This increased HVR was accompanied by augmentation of DA/DOPA in G1 (24% and 190%, respectively), and monoamines reduction in G2 (by 29% and 40%, respectively) and G3 (by 66% and 34%, respectively).

Thus, IH training normalized the hypoxic ventilatory sensitivity in PD patients and approached blood DA/DOPA level to healthy subjects. We suggest that the relationships between HVR and reciprocal DA/DOPA values in associated with age decrease of DA receptor sensitivity and an enhance DA reuptake during IH traning.

http://www.ingentaconnect.com/content/els/09284680/1998/00000005/90000001/art81209

*****************

Fiziol Zh. 2003;49(3):95-103.

[Respiratory regulation during adaptation to intermittent hypoxia in patients with Parkinson disease]

[Article in Ukrainian]

Serebrovs'ka TV, Kolesnikova IeE, Karaban' IM.

Bogomoletz Institute of Physiology, Institute of Gerontology, Kiev, Ukraine.

Ventilatory responses to hypoxic (HVR) and hypercapnic (HCVR) stimuli in relation with dopamine (DA) and DAs precursor dihydroxy phenylalanine (DOPA) venous blood content were studied in healthy people aged 55-65 years (Gr. 1) and Parkinson's disease (PD) patients without (Gr. 2) and with (Gr. 3) L-DOPA treatment under intermittent hypoxic training (IHT, three identical daily isocapnic, progressive, hypoxic rebreathing sessions separated by 5-minute breaks for 14 consecutive days). HVR in Gr. 2, when compared to Gr. 1, was 48% lower showing almost linear dependence and was accompanied by lower levels of blood DOPA and DA content (26% and 20%, respectively). HVR in Gr. 3 was only 17% lower compared to Gr. 1 and was accompanied by higher levels of blood DOPA and DA content (40% and 147%, respectively). No differences in HCVR between groups were registered. IHT produced a 75% increase in HVR in Gr. 1 (p < 0.05), 52% augmentation of HVR in Gr. 2 (p < 0.05, at that the curves became hyperbolic in shape), and 2.2-fold increase in Gr. 3 (p < 0.01). The augmentation of hypoxic sensitivity under IHT was accompanied by significant decrease in DOPA blood concentration in Gr. 1 and Gr. 3, although no changes in Gr. 2 were observed. It was no changes in DA blood content in all groups. IHT produced no significant changes in HCVR.

This investigation confirms the conception that PD is accompanied by DA deficit not only in basal ganglia but also in peripheral chemoreceptors provoking a decrease in hypoxic ventilatory sensitivity. PD does not influence on hypercapnic sensitivity. L-DOPA-treatment as well as IHT improve the functioning of respiratory system, increase HVR and do not influence on HCVR. The method of IHT can be involved in complex therapy of PD.