Author Topic: Parkinson's in the setting of PawPaw consumption (and other Annonaceaes) article  (Read 5449 times)

Pouteria_fan

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Hi all,

I recently read this journal article:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156197/
Kaas B, Hillis AE, Pantelyat A. Progressive supranuclear palsy and pawpaw. Neurol Clin Pract. 2020 Apr;10(2):e17-e18. doi: 10.1212/CPJ.0000000000000704. PMID: 32309040; PMCID: PMC7156197.

Quote
"The patient died due to aspiration 5 years after symptom onset. Subsequently, his wife disclosed that he had habitually consumed pawpaw fruit from their family-owned nursery, starting 5 years prior to symptom onset and continuing until his death (10 years total). She estimated that he had consumed up to 13.6 kg of raw fruit annually over the five-year period prior to death."

That's about 30 lbs of fruit, which I imagine is not that much when spread out over 5 years, especially if you have a fruit forest.


Quote
"Annonacin is present in the fruit, leaves, and bark of plants belonging to the Annonaceae family, which includes Annona muricata (soursop) and Asimina triloba (pawpaw).4 Pawpaw is native to the eastern United States and southern Canada and is the only fruit-bearing annonaceous plant widely distributed in North America. A recent regional increase in pawpaw's popularity is concerning in light of studies demonstrating the neurotoxicity of annonacin as well as possible associations with the development of neurodegenerative disease. A 1999 case–control study in Guadeloupe described an association between regular consumption (at least monthly, for at least 2 years) of fruit and tea from annonaceous plants and diagnosis of an akinetic-rigid parkinsonian disorder resembling PSP, with the PSP-like patients more likely to have reported routine consumption of these plant products compared to patients with Parkinson's disease (odds ratio 5.98, 95% CI 1.05–34.22).5 This study also reported an unusual prevalence of atypical parkinsonism in this population: of 87 consecutive patients presenting with parkinsonism, only 25% presented as idiopathic Parkinson disease. A smaller 2004 study also described a high proportion of atypical parkinsonism in New Caledonia and noted a higher percentage of habitual Annonaceae consumers in the atypical parkinsonism group.6 This association has therefore been noted in 2 genetically distinct populations, making the possibility of a common environmental exposure more compelling. The authors report that the plant products consumed in these regions are derived from A. muricata, Annona squamosa, and Annona reticulata. Notably, annonacin represents 0.007% of pawpaw fruit pulp by weight, which is higher than other analyzed sources (soursop pulp contains only 0.002% annonacin).4"
This has probably been discussed in the past, but this is a relatively new publication, and is in regards to a disease (PSP, https://www.ninds.nih.gov/progressive-supranuclear-palsy-fact-sheet) which shares similarities to Parkinsons.

For those growing and/or consuming frequent amounts of annonaceous plants, are you concerned about the above, and other reports linking this particular group to various forms of degenerative neurological conditions?

I ask this as someone who finds Rollinia and Cherimoya delicious, and could easily eats pounds and pounds of the stuff.

elouicious

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This is very well documented science- you should never consume the seeds of annonacae and the fruit should be consumed in limited quantities.

Jaboticaba45

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There was a controversial thread about this a year or so ago.
To be honest I am fine with me just avoiding the seeds and leaves.
Annonas are decent fruits that are good enough for me to not stop eating them but bad enough that I would rather eat mangoes or others over them.

roblack

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The fruit consumed was listed as annually, for 5 years prior to symptom onset and ongoing 5 more years until death (10 years total, approx 30lbs fruit per year, 300 lbs of pawpaw).

slopat

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Most items should be consumed in moderation. 

Even drinking too much plain water can be hazardous( lookup radio station water contest Sacramento,  ca). FWIW, I know of at least 5 people who have Parkinson's, tremors,  or ALS who have never knowlingly eaten pawpaws or cherimoyas.

30 lbs is a lot, how would one not suffer from IBS symptoms?

But still,  good to know the repercussions of.

K-Rimes

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Life is short. You may not make it to the ripe old age where Parkinson's may naturally onset anyways. The sample size in most of these studies is small so it is difficult to say the study will have accurate enough results to draw a direct conclusion. I do certainly see enough evidence to say that overconsumption of annonacae may be problematic, but that any reasonable consumption should be fine and thus I will continue to do so when opportunity presents itself.

I hope to be so inundated with annona from my yard one day to have to actively decide to put down the spoon for my health.

Pouteria_fan

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The fruit consumed was listed as annually, for 5 years prior to symptom onset and ongoing 5 more years until death (10 years total, approx 30lbs fruit per year, 300 lbs of pawpaw).

Good catch, important distinction!

Yes, life is short for some - but with the average life expectancy in the USA of ~78 years, certainly good chance of making it to the "golden years."

pagnr

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Subsequently, his wife disclosed that he had habitually consumed pawpaw fruit from their family-owned nursery


The Journal article doesn't seem to cover any other Family Risk Factors, ie Family History of Parkinsons
or for that matter other risk factors from work /lifestyle including chemical use in the plant nursery which could easily parallel the fruit consumption.

elouicious

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It is worth noting most of these studies have their root in epidemiological observations from the Island of Guadaloupe, https://pubmed.ncbi.nlm.nih.gov/17303592/

Abstract-
    In Guadeloupe, there is an abnormally high frequency of atypical parkinsonism. Only one-third of the patients that develop parkinsonian symptoms were reported to present the classical features of idiopathic Parkinson disease and one-third a syndrome resembling progressive supranuclear palsy (PSP). The others were unclassifiable, according to established criteria. We carried out a cross-sectional study of 160 parkinsonian patients to: (i) define more precisely the clinical phenotypes of the PSP-like syndrome and the parkinsonism that was considered unclassifiable in comparison with previously known disorders; (ii) define the neuropsychological and brain imaging features of these patients; (iii) evaluate to what extent a candidate aetiological factor, the mitochondrial complex I inhibitor annonacin contained in the fruit and leaves of the tropical plant Annona muricata (soursop) plays a role in the neurological syndrome. Neuropsychological tests and MRI were used to classify the patients into those with Parkinson's disease (31%), Guadeloupean PSP-like syndrome (32%), Guadeloupean parkinsonism-dementia complex (PDC, 31%) and other parkinsonism-related disorders (6%). Patients with a PSP-like syndrome developed levodopa-resistant parkinsonism, associated with early postural instability and supranuclear oculomotor dysfunction. They differed, however, from classical PSP patients by the frequency of tremor (>50%), dysautonomia (50%) and the occurrence of hallucinations (59%). PDC patients had levodopa-resistant parkinsonism associated with frontosubcortical dementia, 52% of these patients had hallucinations, but, importantly, none had oculomotor dysfunction. The pattern of neuropsychological deficits was similar in both subgroups. Cerebral atrophy was seen in the majority of the PSP-like and PDC patients, with enlargement of the third ventricle and marked T2-hypointensity in the basal ganglia, particularly the substantia nigra. Consumption of soursop was significantly greater in both PSP-like and PDC patients than in controls and Parkinson's disease patients. In conclusion, atypical Guadeloupean parkinsonism comprises two forms of parkinsonism and dementia that differ clinically by the presence of oculomotor signs, but have similar cognitive profiles and neuroimaging features, suggesting that they may constitute a single disease entity, and both were similarly exposed to annonaceous neurotoxins, notably annonacin.

Annonacin is certainly a neurotoxin, demonstrated many times in rodents and primates, I do not think sample size is an issue in this topic

K-Rimes

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No doubt that annonacin is a well documented neurotoxin and any consumption of those is problematic, no arguments there - just saying a larger sample size, including other risk factors of participants along with some data on general rate of Parkinson's in the population studied would add more value.

30lb of PawPaw doesn't seem difficult in a year. A couple a day for a month or two.




pagnr

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There is a similar Parkinsons type syndrome in Guam and other Islands.
It was first linked to Cycad seed consumption, then Fruit Bat Consumption, then consumption of Fruit Bats that eat Cycad seeds.

Guadeloupe has a unique population, founded on imported slaves. There could be inherited factors in the Parkinsons syndrome, but as I remember from when this topic came up on another fruit forum, the studies didn't show family member inheritance.
They did seem to have low samples of patient numbers.

It would be interesting to note if the same type of Parkinsons syndrome appears in other Annona fruit eating countries.
They must also be heavily consumed elsewhere in South America, Caribbean etc.
Soursop drinks are pretty popular in SE Asia, Phillipines, etc. Canned versions are available at my local supermarket and Asian grocery.



Gone tropo

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This is a real concern I have Annona's planted everywhere.

W.

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A case study like this seems so specific to this particular individual that, while it is good to know about, I am not sure whether it is applicable to the general (Annona-eating) population. This individual could have been predisposed to developing Parkinson's, a disease whose cause is still a mystery to the medical community. It could be that this gentleman was punched in the head too much as a young man (à la Muhammad Ali); it could be that he simply developed it due to advanced age; it could be that he developed it due to long-term exposure to pesticides at his nursery; or it could be because he ate too many pawpaws. The populations the authors of this study cited for correlation between higher than average parkinsonism and higher than average Annonaceae consumption were those of Guadeloupe and New Caledonia, both small, somewhat isolated populations that could also suffer from founder effect. There are no such studies (at least none cited by Drs. Kaas, Hillis, and Pantelyat) from the large, intermingled, heavily Annonaceae consuming countries of Central America.

I do not want to criticize this study too much, but I think the last sentence is the key thought we should take away from it:

Quote
"Further study is necessary to better understand the relationship between consumption of fruits such as the increasingly popular pawpaw and neurodegenerative presentations."

I could not agree more with that sentence, and I hope more research on the subject is undertaken in the future.

greg_D

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Life is short. You may not make it to the ripe old age where Parkinson's may naturally onset anyways. The sample size in most of these studies is small so it is difficult to say the study will have accurate enough results to draw a direct conclusion. I do certainly see enough evidence to say that overconsumption of annonacae may be problematic, but that any reasonable consumption should be fine and thus I will continue to do so when opportunity presents itself.

I hope to be so inundated with annona from my yard one day to have to actively decide to put down the spoon for my health.

To the horror of every teacher I had growing up, I do generally trust Wikipedia. The Annonacin article cites more than one case study, but paints a picture of lifetime daily consumption (not just of fruit, but of nectar and tea as well) being linked to these issues, without mention of incidental consumption being linked to negative outcomes. Most people already consume things that would cause issues if eaten every day. You could have a heart attack if you ate a ribeye steak every day. You could get Type 2 Diabetes if you drank a can of coca cola with every meal. I'll view plants from this family as a 'sometimes food' going forward.

Acetogenin

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Between Russia and N Korea threatening to irradiate planet, it won’t matter anyway once nuclear winter sets in.  For now enjoy the pawpaw

CeeJey

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"You might get hit by a bus/ there might be a nuclear holocaust at some point in the future, so you should feel free to go hog-wild without concern on a known neurotoxin" seems like questionable logic to me, of the same kind that landed a bunch of my smoker friends in the lung cancer ward over time, but to each their own. Anybody who's been around someone with Parkinson's should know it probably isn't worth eating a ton of fruit if that's potentially a risk. And I'm saying this as somebody who loves annona fruit, I have skin in the game here.

Also in regards to the "it could be something else" line of thinking: Sure, but it isn't in question that annonacin is a neurotoxin, as Elocious said: it causes brain lesions in dopaminagenic structures when administered to rats or applied to cultured human dopaminagenic brain cells. The dosage required and susceptibility to do the same in live humans may be in debate, but it's just true that annonacin CAN do this at large enough doses. That would suggest caution as the issue being discussed is caused by the loss/damage of dopaminagenic neurons. To use the smoking analogy again, if you saw a cluster of people with lung cancer, and they all smoked a pack a day for years, saying "well they COULD have been exposed to some other carcinogen as children or have a genetic susceptibility" doesn't then lead to "and so smoking slightly fewer than a pack a day is probably fine for the rest of us". You know?
 
All THAT said, it seems to not come up very often in these discussions that the populations in Guadeloupe drink the leaves in tea form, daily in some cases:

"The unusually high number of parkinsonian patients with atypical clinical
features in Guadeloupe and the cross-ethnic representation of the patients
suggested that an environmental toxin might be responsible for the cluster of
cases. This hypothesis was supported by case–control studies [3, 18] showing
that patients with atypical parkinsonism consumed significantly more fruit and
infusions or decoctions of leaves from plants of the Annonaceae family, parti-
cularly Annona muricata L. (soursop, guanabana, graviola, corossol) than
patients with I-PD or control subjects. The leaves of these plants are used in
traditional Creole medicine from early childhood to old age, sometimes daily,
for heart and digestive problems, for sedative purposes or to maintain general
health. Comforting the idea that this family of plants played a key role in the
development of the atypical parkinsonian syndrome in Guadeloupe, a similar
clinical entity has also been associated to annonaceae consumption in patients
of Caribbean origin living in London [7] and in PD patients from new Caledonia,
a French Western Pacific island [1][/i]

-from study/analysis here: https://link.springer.com/chapter/10.1007/978-1-60327-252-0_18

So those people are getting a regular dose over a long period of time beyond just eating the fruit, which could explain why those populations in particular seem to be having this issue as compared to annona-eaters outside the Caribbean. Although, one soursop a day (which is probably more than most of us have access to without, say, an orchard) contained enough annonacin to hit the equivalent human threshold to amounts that cause brain damage in rats: https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.20632 . Which, by the way, is very possibly causing negative effects of some kind well before the pseudo-Parkinson's sets in due to what is being damaged.

Personally I just try to keep my consumption low and seasonal.

EDIT: TLDR of the above is "we know that annonacin causes the kind of brain damage that leads to this exact set of symptoms, but don't know in what dosages how often or what the lowest safe dose is for the average person consuming the fruit but not leaves, or even how much of the toxin is in annonas outside the Muricata family specifically (some other amounts have been studied in paw paw, atemoya and biriba, linked in a comment down below)."
« Last Edit: October 27, 2022, 01:16:46 AM by CeeJey »

Pouteria_fan

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CeeJay, well said.
I was also thinking about comments people would make to me in the past where they would say well, I'm not going to live forever, when it came to smoking, as a way of an excuse for current behavior. Parkinson's and related neurodegenerative conditions are no joke and a crummy way to go..

Jaboticaba45

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It's interesting that soursop leaves are said to be anti cancerous. I wonder where they are getting that information from and the results of annonacins from the leaves. Should be some articles out somewhere?

CeeJey

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I did some more digging into the research for some additional numbers:

- According to that last research link I posted (https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.20632), the annonacin content of the fruit pulp is much higher than the leaf decoction content by a factor of about 100 and the highest dose to people in Guadeloupe would have been from the fruit and not the leaves. Or canned with nectar, canned had an even higher concentration for some reason. The researchers used multiple methods to attempt to determine the content of annonacin (this is important since different methods can give different results)

-A 70kg human (about in the rough global average) would get about 1 mg/kg yearly from eating one Guadeloupe soursop per day, orally administered. This is versus 3.8mg/kg/year (administered in a large dose over a much shorter period) administered intravenously to rats that guaranteed (not "might have" but "definitely had") extreme neurological damage.

-That said, the authors admit that the bio-availability of orally administered annonacin isn't known (i.e. not sure how much makes it to your brain from your gut), so comparing it to intravaneously administration (as with the rats in that other study) isn't likely to be an exact match. A person eating a can of the stuff a day would be reaching about what the rats were getting but that's a lot of freaking fruit.

-Some troubling research on paw paws specificially: I found two studies ( https://pubmed.ncbi.nlm.nih.gov/22130466/ ) and ( https://pubs.acs.org/doi/10.1021/jf504500g ) looking at the annonacin content of asmina triloba. The second study was done to address methodological issues in the first study and found a much higher content under optimal extraction conditions, about 7724mg/kg in the paw paw fruit pulp compared to 525mg/kg in the Guadeloupe soursop. That's, ah, a lot. This needs replication but IF the second study is correct then paw paw (at least the ones they tested) potentially has quite a bit more annonacin than the muricatas.

-The first study in the point above is still relevant since it determined that crude pulp extract (not just purified annonacin) was capable of causing neuro-degenerative damage. this also means there might be some kind of synnergistic effects one way or another. Likewise the second study determined that there are multiple isomers (chemical arrangements) of annonacin in paw paw, but it was beyond the scope of the study to determine if that matters in regards to neurodegenerative potential or anything else.

I'm still in the "in moderation seasonally" camp after reading all this, but actually looking at the available data is definitely concerning.

EDIT: Napkin math says that if that second study on paw paw annonacin content is accurate, that guy eating 13.6 kilos per year was getting about 1500mg/kg of annonacin per year, or 4mg/kg/day average which is slightly higher than the equivalent intravenous dose that was definitely giving a bunch of rats pseudo-Parkinson's. I'd imagine the oral availability is lower than intravenous by some significant amount (needs research) but that's higher than the folks in Guadeloupe were getting.

CeeJay, well said.
I was also thinking about comments people would make to me in the past where they would say well, I'm not going to live forever, when it came to smoking, as a way of an excuse for current behavior. Parkinson's and related neurodegenerative conditions are no joke and a crummy way to go..

Yeah, I wouldn't wish something like Parkinson's (or smoking related diseases for that matter) on my worst enemy.

It's interesting that soursop leaves are said to be anti cancerous. I wonder where they are getting that information from and the results of annonacins from the leaves. Should be some articles out somewhere?

If you go to Pubmed and search for "annonacin cancer", you can find most of them I think. there's a number of research studies, in cell cultures or rats (no in-human trials, likely because of the whole known neurotoxin thing).

The first link I posted in this post has the annonacin content of soursop leaves a couple of pages in. Not as high content as I would have thought.
« Last Edit: October 26, 2022, 10:32:46 PM by CeeJey »

Gone tropo

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So were mostly talking about "paw paw" We call papaya "paw paw" in australia not the same thing and soursops.  How about Sugar apples and Atemoya and illama? Are these fruits in the same class as paw paw and soursops in terms of toxicity ?

Jaboticaba45

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So were mostly talking about "paw paw" We call papaya "paw paw" in australia not the same thing and soursops.  How about Sugar apples and Atemoya and illama? Are these fruits in the same class as paw paw and soursops in terms of toxicity ?
Paw paw here is asimina triloba.
Trees in the annona family
So this makes me wonder about other related fruits also. Junglesop, kepel, and uvarias all come to mind. Of course no one has access to much fruit of any of these trees if at all. So I'd doubt there are studies published. At least soursop and sugar apple are very common in central America and the surrounding regions.

CeeJey

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Back in an older thread on the forums (https://tropicalfruitforum.com/index.php?topic=20267.0), NullZero linked to an FDA review that had different known amounts:




I'd take some of these with a grain of salt since they used different extraction methods for some of those, and that paw paw study indicated that you could undershoot by quite a lot depending on the extraction method and temperature. That said, another meta-study I came across couldn't find any acetogenins (the compounds that annonacin is one of) in atemoya flesh samples at all (as opposed to plenty in the seeds), so this chart might be accurate that they're very low in the flesh (as opposed to the seeds). The huge range of soursop values (all done with the same extraction method) depending on location sure suggests that cultivar or environment might have a very large effect on the values even in-species.

I can't find anything about cherimoya or sugar apple, which is surprising since those are getting pretty common (hell, I think there's cherimoya at the corner market near me in Phoenix right now). Not sure anyone has looked at those, but I'd be interested to hear about it if anyone else finds any research on those. Seems like the potential range might be huge from species to species, and I feel a little safer about eating the atemoya parents now, I guess.
« Last Edit: October 27, 2022, 01:12:03 AM by CeeJey »

elouicious

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ooof those Asiminia triloba numbers are off the charts- wonder if it was true fruit pulp or a concoction of the seeds and pulp

Also FTR- I still eat annona- and before I was more knowledgeable about the seeds ate a lot of pawpaw seeds from difficult to clean fruit- wicked stomach ache after that lasted a few days that was enough to have me never eating a seed again-

Also worth noting in Guadeloupe they blend the fruit (seeds and all) into the beverage that is most often consumed, on top of the tea leaf consumption.
« Last Edit: October 27, 2022, 12:41:25 PM by elouicious »

nullzero

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ooof those Asiminia triloba numbers are off the charts- wonder if it was true fruit pulp or a concoction of the seeds and pulp

Also FTR- I still eat annona- and before I was more knowledgeable about the seeds ate a lot of pawpaw seeds from difficult to clean fruit- wicked stomach ache after that lasted a few days that was enough to have me never eating a seed again-

Also worth noting in Guadeloupe they blend the fruit (seeds and all) into the beverage that is most often consumed, on top of the tea leaf consumption.

I think you may be onto something with Soursop numbers, it may be skewed because the typical preparation is juice.
Grow mainly fruits, vegetables, and herbs.

CeeJey

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ooof those Asiminia triloba numbers are off the charts- wonder if it was true fruit pulp or a concoction of the seeds and pulp

All of those numbers in the chart are from just the fruit pulp unless otherwise indicated that it was a seed tested. The Asminia Triloba numbers were from this study specifically: https://pubs.acs.org/doi/10.1021/jf504500g . I read the full study yesterday and it was just the pulp. The thing is, the authors of that study worked hard to find a really good way to determine the actual annonacin content, and they did, with the implication being that other studies (including some of the tests of other annonas) may be detecting way less than there actually is if they aren't using the right method or extraction solvent temperature (this has come up in a couple of other papers that I read as well, apparently the method used to extract the acetogenins matters a lot for accuracy).

Ideally it'd be good to see more studies on paw paws of different varieties/ different areas to see if those numbers are reflective of the species in general or if they're an outlier, especially given that other species (soursop) seems to have a large swing in values depending on the origin location. It would also be great if somebody would cross-reference soursop consumption/ annonacin content in places in Brazil to look for any other correlative hotspots that couldn't be explained by age of the population.

Also, there's very little comparative research on the other acetogenins unique to annonas, but they're all toxic to cells to some degree and there are like ten of them. Squamocin, that other chemical in the chart up there (named because it's found in high amounts in a. squamosa seeds, apparently) , may not be disrupting neuron proteins but definitely has cytotoxic effects which is why they've been investigated for potential anti-cancer applications. Also apparently there's a completely different neurotoxin in some annonas (like soursop) that they thought was causing the Parkinsons-like disease at first. Some of those chemicals might actually be good for some things in smaller doses. There's just not enough research it seems like.

Also worth noting in Guadeloupe they blend the fruit (seeds and all) into the beverage that is most often consumed, on top of the tea leaf consumption.

That is interesting. Could definitely go some way to explaining why some places are affected and not others.

One of the most damning things I found when I was poking around in the research that pointed to "yeah it was probably food related" was that cases of Parkinson's and Parkinson's-like diseases cratered in Guam (which was also super-high) and New Caledonia with a switch to the Western diet and changes in cultivated local food but no demographics changes that would have indicated a genetic shift. That was from an old Toxicology Journal back in the 90's.

This whole thing needs a ton more research.
« Last Edit: October 27, 2022, 03:29:33 PM by CeeJey »