Friday, June 19, 2015

parkinson's notes

 Proven protectors:

Brocolli, raw
Coconut oil
Beer.  Alcohol in 50% of studies had an effect, may be related to non-sensation seeking personality.
For the following
Tangerine extract in men (flavones: tangeretin, nobiletin: good theory, weak epidemiological)
Bitter orange extract in men (0.80, flavanones: naringin, hesperidin)
Apple extract (0.54 in men, ursolic acid, polymers)
strawberries, blueberries, red wine, oranges (0.80 each) (blueberry extract is as expensive as blueberries in content, 0.7% anthocyanidins in dry weight, $200 for 1 kg of 25% concentrate)
flavan-3-ols (0.75 men only, catechins, epicatechins, gallocatechins, epigallocatechin, epicatechin 3 gallate, epigallocatechin 3 gallate)
polymers (in apples, 0.62 men only, proanthocyanidins, theaflavins, thearubigins)
flavanones (0.75 men only)
anthocyanins (tea, berries) (0.75)
flavonols (0.75 men only)

flavones (weak evidence for common ones, 0.85 p=0.4, but nobiletin, HMF, and tangeretin may have strong effect on ghrelin (stomach neuronal compound) and these all individually work on PD models.

2014, n=6,700, PD n=101 cases. Moderate alcohol and higher BMI associated with PD, and heavy leisure time activity as protective as nicotine

2007 n=6,700 10 cups of coffee as protective as nicotine if overweight and low cholesterol

MAO-B inhibitors can be iron chelating and cross BBB
green tea (EGCG and Catechins) and black tea, coffee much less so. One study said coffee advanced the age of onset by 5 years. Black tea operates independently from smoking and coffee. It increases estrogen. High doses seem to cause jitteriness.

fish oil decreases depression (2008). The omega-3 PUFA are protective (2008)

Selenium ... here and here and here

highest dietary cholesterol for men 0.53 risk but omega 3 and 6 had no effect after adjustment for risk factors. n=216 men from N=63,000 (Singapore). But a 2014 review of such studies showed weak inverse correlation (reduced risk) with higher dietary cholesterol and strong effect with lower food energy intake, but both were cancelled when smoking and caffeine were adjusted for. Fats did not seem to effect it after adjustments, but n-6 PUFAs seemed to increase it. Cholesterol may protect from lipid peroxidation caused by a-Syn. Lack of ferritin immunoreactivty decreases ability to utilize dietary cholesterol

Mucuna pruriens 3 to 8% L-DOPA without the side effects (chelates iron) Ethanol extract included additional benefits

Sardines (herring, sprats, brewer's yeast 4x, or anchovies), exercise, and alcohol at same time.
magnesium (need more research) (fava beans, 200 mg/100 g)
Creatine, vitamin E, fish oil, b-complex. Too much niacin may be very bad and destroy complex 1 via manganese exposure
No milk (100 ml/day can cancel coffee, at least in men)
No Manganese

Good sleep, enjoying life, exercise, no social stressors

number is pubmed abstracts

6 Bacopa monnieri. worked better than Gotu Kola and M. pruriens in one study of flies
12 Broad beans, aka fava beans, aka vicia faba 0.3% L-DOPA
12 Ashwagandha (Withania somnifera) Works on mouse model
9 Gotu Kola (Centella asiatica) A few positive articles in pubmed

(alcohol and lactic acid increase uric acid production from diet sardines...exercise gives 3x the increase) Sauna increases uric acid. >6 cups coffee per day appear to reduce hyperuricemia OR= 0.57. (coffee lowers by 0.43 mg/dL) but the effect does not seem to be caffeine. Korean study disagreed about the reduction. Not seen in teas. Oxalic acid, lactic acid (weight training and alcohol) and ketone bodies compete with uric acid for excretion.

fish oil

nicotinamide (the amide of niacin) showed protection and motor function in flies.   Two case reports here and here showed it helped a lot. The first link's authors also has a full paper here.  L-dopa depletes niacin and a forum patient said it relieved hallucinations from the L-Dopa. Hoffer noted schizophrenics also were not able to convert tryptophan to niacin and excreted more kynurenine in the urine, who's metaboliets are implicated in PD. Then the amide form of niacin was shown to help in MPTP mice. higher doses may increase NNMT-mediated Mn-MNT damage. A by product of nicotinamide via NNMT-Mn is toxic methylnicotinamide (MNA). Niacin as a cause of PD has been mentioned here and here and here. Niacin (nicotinic acid) gets to mouse brain easier than nicotinamide and niacin is largely converted to nicotinamide.

PQQ may not cross blood-brain barrier. May help process ethanol. Highest source is green tea.

Vitamin E and Isothiocyanates (from chewing raw broccoli that lets myrosinase increase the amount of isothiocyanates glucosinolates.

ginkgo bilboa?

NNMT expression is associated with neurons that degenerate in PD.

2011 japan n=249 When adjusted for smoking, years of education, BMI, and dietary factors including cholesterol, dietary glycemic index, vitamin E, β-carotene, vitamin B(6), caffeine, iron, and alcohol, no association was found for vit D and milk (how many in Japan drink milk?).

marijuana, Cannabidiol (CBD, not psychoactive)
alcohol for temporary relief, in moderation. Niacin seems to sometimes help.
curcmin might reach the brain:

Broad beans, aka fava beans: Vicia faba (Vf) is a ubiquitous plant rich in easily absorbable L-DOPA. Following ingestion of 40 g freshly chopped Vf containing 120-130 mg of L-DOPA, plasma L-DOPA and urinary sodium and DA excretion increased significantly. The DA/Cre ratio reached a maximum level (280 ± 58 µg/g) 60 minutes after Vf ingestion. This was significantly higher than the DA/Cre ratio after a control meal (1.8 ± 0.2 µ/g; P < 0.0005). .. A study looking at memory used 100 mg. A single bean like I cook weighs 5 g after cooking. A cup is about 40 beans, 200 g, if "fresh" it would have been 600 mg L-DOPA. It does not seem I have tried Mucuna pruriens, which has 3 to 6% L-DOPA instead of this 0.3%. 1 pill of mucuna supplement is 60 mg.

black tea, catechins, vitamin E, zinc are iron chelating

6x higher risk of dementia

vit C helps generate DA cells in embryonic development

Higher pigment density, lower presence of cholesterol, oxidation vulnerability, and iron loading preclude a-Syn pathology that results in cell death and pigment loss (2005).

nicotine may stimulate dopamine release, inhibit free-radical damage to nigral cells, and alter activity of monoamine oxidase B

Dr Michael Murray says Ginkgo biloba extract , NADH (raises dopamine), CoQ10 (he did not cite the latest, failed study), and low protein to reduce tremors. Phosphatidylserine for mood and mental functioning, but not muscle control.

Dietary iron surprise in Japan: 0.24 95% (CI: 0.10-0.57, P for trend=0.0003)

Iron effect complicated, but genes predisposed to iron accumulation 0.97 per 10 ug/dl increase in blood. Highest acceptable iron levels in men result in 0.60. Epidemiological meta-analysis on iron was insignificant, but was complicated by "heterogeneity" between studies.

Iron chelator deferiprone (FERRIPROX) at 30 mg/kg/day (possibly $5,000 a year) helped PD patients in phase 2, possibly reverting status by 3 years. Motor UPDRS score improved 3 points in 6 to 18 months instead of getting worse. Good chelator because it does not reduce iron from blood but may harm liver. Concern: it was said on it's datasheet that this compound removes ferritin from blood, contrary to theory that ferritin/free iron ratio needs to increase

1993:The cytoprotective effect of three flavonoids, catechin, quercetin and diosmetin, was investigated on iron-loaded hepatocyte cultures....catechin > quercetin > diosmetin. These IC50 values have been related to structural characteristics of the flavonoids tested. Moreover, the investigation of the capacity of these flavonoids to remove iron from iron-loaded hepatocytes revealed a good relationship between this iron-chelating ability and the cytoprotective effect. The cytoprotective activity of catechin, quercetin and diosmetin could thus be ascribed to their widely known antiradical property but also to their iron-chelating effectiveness

curcumin is a great iron chelator, but its bioavailability is very questionable, especially in the brain.

carnitine, omega3 fatty acids

IP6 is possibly useful for iron chelation PD (the only other he mentioned was EGCG) and it at least gets into the blood very effectively: 2013: Very promising in both AD and PD animal models.

"Iron (and in some cases copper) is also strongly implicated in a variety of neurodegenerative diseases .... iron can catalyse the oxidation of dopamine to a quinine form that can bind covalently to and then aggregate proteins" 

1988: nicotine blocks transfer of iron into cells

ferritin (protein-bound iron) probably protects against free iron in the brain, but lack of iron in diet and blood can lead to low ferritin.

free iron excess and less bound iron known since 1991 to be implicated in PD: only in PD was there an increased total iron level, decreased ferritin content, decreased copper content, and an increased zinc concentration in substantia nigra.

uric acid delays and slows progression.Uric acid chelates iron and is higher when iron in PD is lower. Higher serum urate predicts slower progression of PD. Iron chelator, antioxidant. One study found no correlation between UA and Fe in the SN, but they adjusted for age, gender, UPDRS score, and progression, which I do not understand if UA is a direct causative factor independent of these things. Beer has 20 mg/L. Sardines, herring, mackerel have 350 mg/100 g. Progression is 2/5 as fast in men highest vs lowest quintiles. > 7 mg/dL should delay progression 30% in men. Historically intelligent men had gout. Dairy decreases uric acid levels. Highest quintile of coffee can lower it by 0.3 mg/dL. Highest quintile of alcohol > 2 drinks/day appears to be raise it 1 mg/dL. Normal for men is 3.4 to 7 mg/dL.Beer twice as good as liquor and wine for raising uric acid levels. Beer has purines and the alcohol might stop urinary excretion but definitely helps production. So eat sardines and alcohol at same time.

Magnesium: 0.33, Zinc: 0.50
Copper and manganese: no effect
Greatest outdoor activity, OR: 0.44
Greatest vitamin D intake: OR: 0.54
Caffiene-containing beverages in Japan: OR 0.55
Caffiene: 0.76 per 300 mg/day (2.5 cups), especially in men
2002: Former smokers: 0.6, current smokers: 0.4, tea: 0.4, cola: 0.6
3 packs/day cigarettes for 10 years: 0.38
2009: 3 cups coffee/day caused age of onset to be 5 yrs EARLIER, 3 cups tea/day delayed it 8 yrs

known since 1992 magnesium levels are low in PD:
Milk risk: OR 1.66 in men
Vitamin E, 1200 IU becoming an accepted standard.
Green tea, black tea, and grape seed extract.
In rat model, fish oil worked better than Melatonin and Vit E, which also help

Epidemiological findings suggest that the consumption of berries rich in anthocyanins and proanthocyanidins may reduce PD risk.

Lack of CoQ10 has a 5x risk factor but 16 months of 2400 mg/day did not help in phase 3 and other tests.
Ibuprofen takers were about 17% less likely.

proprioception deficiency is part of the balance problem in PD:

Need to investigate:
Ferulic acid (a by-product of rosmarinic acid)
Rosmarinic acid (not hardly bioavailable?)

"Weak evidence suggests that lower risk of PD is associated with increased vitamin E intake, alcohol, tea, NSAIDs, and vigorous physical exercise"

gamma and delta tocotrienols activated same cellular mechanisms as caffeine:

"cytoprotective effect due to the activation of the PI3K/Akt pathways in SH-SY5Y cells"

review in Spanish in 2014: (in my opinion, does not appear to be a good article, but I can't see full text. For example, lack of green tea and no mention of outdoor work)

Evidence consistently suggests that a lower risk of PD is associated with hyperuricaemia, tobacco and coffee use...weak evidence suggesting that higher risk of PD is associated with high milk consumption in men, high iron intake, chronic anaemia and traumatic brain injury....Weak evidence suggests that lower risk of PD is associated with increased vitamin E intake, alcohol, tea, NSAIDs, and vigorous physical exercise.


post to Parkinson's web site

I could not find that dentists are more likely to get it, but I might could trace some of my Parkinson's symptoms to mercury at age 12, which profoundly affected my emotional/social/anxiety/hay fever life. I From fillings and other elemental mercury exposure, it is the vapor, not the swallowing.

For 10 years I took 10 to 15 grams/day of vitamin C which converts protein-bound copper to free copper and the protein-bound form is needed to protect the SN from iron toxicity. It may also raise free iron levels in the brain, but this is probably unknown. The 4 the people I have the information on who took more than 10 g/day for more than two weeks experienced a sudden dramatic drop in libido. Lack of libido could be caused by decreased dopamine. Lack of dopamine also helps inform us we are thirsty, and I became aware of my body not doing this about the time of my high doses of vitamin C began. For 20 years, since my vitamin C exposure began, a headache is how I realize that I forgot to drink something today. Linus Pauling started showing signs of Parkinson's (weak voice, trembling fingers, nodding head) in a 1981 video, maybe 5 to 10 years after he started the > 10 g/day high doses.

I helped my father garden a lot in the 1970's when there were some particularly PD-bad pesticides still in use. The military now admits agent orange is associated with PD. My other risk factors are male, non-smoker, non-coffee drinker, non-tea drinker, computer worker, generally stressed, college educated, lots of colds and flu from a history of low vitamin D, and probably low magnesium too. Absolutely no family history of neurodegeneration. Speaking of programmers: post-secondary teachers, in-door, religious workers, welders, and pesticide-related occupations are also more likely to get it.

My tremors are in the early stages and my decreased balance is beginning to be a little annoying, but not measurably worse than others. Nicotine gum is the best thing I've found so far for lifting my mood if not decreasing the very consistent finger trembling. Mucuna Pruriens (500 mg L-Dopa at a time in 1 test, 10 pills, no effect) and a myriad of other things have not shown an effect, or at least do not work as fast and obvious as nicotine. Broccoli in large quantity (1/3 a 2 pound bundle per day, but eating only on the very tips) seems to have really helped recently, maybe even improving sleep quite nicely, as well as libido in the first few days of eating it, but I could not find that it has dopamine-like effects. It does have selenium which might be great in reducing SN oxidation. 1 cup of broad beans, 200 gram is supposed to be about 400 mg L-Dopa and it seemed to have an effect on the thumb tremor, but not in the 2nd and 3rd test. I take magnesium, black tea extract, green tea extract, and coffee in large doses each day. Niacin a 1 gram levels seems to help thinking for the day, but they suspect that at least in manganese-related cases this might be very dangerous. After a great deal of research in pubmed looking for compounds that work in at least prevention I am going to also take selenocysteine, pyruvate, vit E, fish oil, vit D, creatine, b-complex, and coconut oil. And also see about raising my uric acid levels. Also, 10 minutes exercise bike before and after sleep to get oxygen to the brain, and coconut oil, pyruvate, and decaffeinated green tea extract before bed. And blueberries and pomegranates whenever possible. Also beer and egg yolks nearly daily. And absolutely no milk. The amount in coffee could offset the coffee benefits. Coffee is the weakest protector of everything I've mentioned, but it's well-proven due to lots of people taking it and make it statistically significant. I'm also looking into the Ayudervic medicine's Bacopa Monnieri and Gotu Kola.

I also used to get a lot of viral infections from not getting outside (no vit D) and that turned around completely with 2000 IU vit D these days. PD could result from viruses travelling up the sinuses, but it is just as likely that it is a protein-folding problem that is being transmitted as in other neuro diseases. a-Syn transfers to implanted cells in animals. Then again, you can't ignore the benefits of vit D and outside work (vit D from sunlight, not to mention exercise and lower mental stress) as possibly being due to reduced viral attacks.

So in order of importance based on research, thinking, and experience so far:

no social stressors
green tea and black tea extracts

All the others, or one of the others that I will not be able to identify, might work as good as 2 of the above.


Things that help me:

1) no social-interaction stressors...causes a flare up in tremors of my lips and whole body if not classic finger twitch
2) nicotine gum

3) broccoli tips (must be raw to double or triple the dose, certainly not more than lightly steamed)

4) aerobic exercise at least twice daily to oxygenate neurons

5) black tea and green tea extracts, operating from different mechanisms than simply the caffeine, are the 2nd best proven preventors, and therefore possibly are the best "delayer's".

The lowest risk factors that have stronger effect than tea extracts and coffee are smoking, outdoor work (12 year delay in 1 study), no history of pesticide exposure, and (strangely) in 1 study ( ) highest dietary iron and magnesium. But I do not take iron because it's level in the brain correlate with the disease, and the recent phase 2 study on the iron chelator (deferiprone) actually reversed motor symptoms.

Then I have a sizeable list of other nutritional supplements that have been shown to help and are easy to take without danger. These are:

fish oil (to increase omega3 / omega6 ratio, so olive oil is not as good)

coconut oil (to get ketone energy path activated since the glucose path is compromised, but I have not tested it enough personally, except that it was a very strong energy and mood effect before I got PD, and that's why it's popular in exercise circles: people notice the benefits fro 2 hours afterwards)

pyruvate (a different energy path than straight glucose have not yet finished researching it)
vitamins E, A, D, C (200 mg 3x/day to prevent free copper toxicity in a-Syn), and B-complex
vit B6
zinc, magnesium
copper? (it has been said to help, but if it increases the free form in the brain, a-Syn will use it to make the free iron toxic. If I understand the articles, vit C may regenerate the toxic iron to a dangerous form, but vit C has also been said to help)

selenium and selenocysteine? (have not finished researching it)

iron (huge benefit in prevention in the study linked to above, but I have not researched it yet, and this is not what people are expecting. The theory is that sufficient iron helps the body generate the protien-bound form better and that somehow helps reduce the free form in the SN. RR=0.24 which is even better than smoking's RR=0.26 at 3 packs of cigarettes a day for 10 years...nicotine is another free iron chelator)

sardines with beer after strength training to raise uric acid level. Uric acid is an iron chelator that crosses blood brain barrier and proven in multiple epidemiological studies, not to mention the fish oil that can help the vit E, A, and E absorption.

Those I have not yet researched with strong proponents: alpha-lipoic acid, acetyl-L-carnitine

IP6 (unproven to cross BBB, but a good article suggested only it and green tea as possible iron chelators)

Co-Q10 (now in doubt...assists complex 3 but not complex 1)

Curcumin (probably no benefit, does not cross human blood brain barrier, could not find epidemiological study to support it)

Ginseng? (hurts sleep)

Blueberries, pomegranate, cranberry juice....basically any dark color plant in the most intense form with the least amount of carb-based calories. High fructose corn syrup may not be completely bad since it raises uric acid, but I don't do that for fear that flooding the brain with sugar is harmful (no data on that specifically).

2 eggs per day for higher cholesterol?

Others that work in animals but unproven in humans, often due to blood brain barrier

Mucuna pruriens
Ginkgo Bilboa
Bacopa monnieri
Gotu Kola
resveratrol (huge benefits in animals, with researchers trying to find a way for it to absorb and cross BBB)

As you can see from this list and my comments, there has been a huge amount of research in the past 15 years, and there is opportunity for supplements to help. There appear to be many paths to getting PD, with pesticides being the strongest single causative factor. Outdoor work (less thinking stress) and smoking are the biggest protectors, with dietary iron and magnesium needing investigation. About half of the protectors happen to be free-iron chelators, and iron chelation in the brain seems to be the only blunt-force single chemical solution at the core of activity. Alternate (non-glucose) energy paths for the neurons (aerobic exercise 2 or 3 times a day, coconut oil, pyruvate, hyperbaric oxygen chambers) seems very important, with exercise being the only one proven. Then there are the anti-oxidant oil and oil-based antioxidants omega 3, vit E, A, and D, and sufficient cholesterol in the brain being needed, which makes me wonder about the statins being said here as a causative factor, not to mention the Co-Q10 decrease they cause. Then there are the plant-based non-vitamin antioxidants and stimulants.

So to categorize these opportunities: iron chelation, mineral supplements, different energy paths including non-methamphetamine natural stimulants and exercise, oil-based anti-oxidants, and complex plant-based antioxidants.

For each supplement I've listed, I've spent an average of 1 hour searching pubmed.
So far my treatment priority based on research and experience goes like this:
canola oil ? (still testing, and then will compare to olive oil)
fish oil (general brain health if not PD)
black tea better than green tea extract
magnesium, zinc
apple and strawberry 10:1 extract powders 12 g/day
broccoli (Isothiocyanates)
black tea extract
grape seed extract
I'm trying to experiement, think about, research, observe, and tolerate a whole host of other things. fisetin (blueberry), now inosine, naringin- nobiletin-tangeretin (citrus peel chemicals tested in PD models in about 7 different papers amount other indications, specficially ghrelin), niacin, citicoline, citrulline, calcium pyruvate, alpha-lipoic/carnitine, and ginseng that keeps me up at not, but maybe I should reconsider if there's that "nicotine like" effect.
The rasagiline discoverer is very interested in "multi-modal, multi-disease" pharmaceuticals. Likewise, it is very interesting to see certain things frequently common in most PD nutrients: weak iron chelators, iron anti-oxidant, stimulants, and urate increase. About 5 of those I've listed above have all these qualities. Then there is another class: those that utilize fat burning instead of glucose burning in the brain, or otherwise assist oxygen-based fuel. PD a-syn is affecting the cells like cancer: messing up mitochondria function, allowing fermentation (non-oxygen burning) of the fuel in the brain, and spreading. There's a theory DNA affects are only secondary to cancer spreading via a spreadable mitochondrial-fermentation defect, not clunks of virus-like DNA moving from cell to cell. CPAP, HBOT, and exercise all increase oxygen to brain and help PD patients. I wonder if breathing response is suppressed in PD, helping it to spread itself, and forcing people to wake up early in the morning and get moving from lack of air. So if my condition progresses, I'm going to want an oxygen tank next to the bed. At least I'm trying to exercise as soon as I wake up, the hardest thing and therefore maybe the best. I'm plagued with ideas like this all day in all things.
The brand does not matter. Inexpensive ones are "doctor's best", "spring valley", and "now". The best supplements in terms of order of evidence for humans are, generally 300% to 400% less likely to get PD:

black tea extract (most expensive one, but very reliable)
vitamin D

Other compounds with 50% to 100% less likely to get PD in humans:

Isothiocyanates (possibly sulfur is enough)

alcohol here and here , but not here and here, and non-drinking may only be because of parkinson's personality  here and here.  Possibly beer is more protective. Or combining with smoking is best
vitamin E
green tea extract
omega-3 (fish oil, canola oil)
Monounsaturated fat (canola oil, olive oil)
ellagic acid (olive oil)

DHA in fish oil may not be good, so canola oil and olive oil may be better.

People have a strong bias against supplements. As you can see the science does not support this position. They will argue that these are only for prevention, but my response is that since so many PD patients report noticing symptoms 10 years before diagnosis, obviously a lot of people have beginning stages of PD and never come to realize it because they have the highest nutritional status in these compounds.

In men only:
strawberries, apples.
Men general seem to be much better protected from flavonoids.

I do not know how coconut oil got a good reputation because there isn't any research. Magnesium data is excellent but sparse, 4 times more likely to get PD if you're in the lowest levels.

No comments:

Post a Comment