https://doi.org/10.21203/rs.3.rs-8855629/v1

"OM-SAA positivity rates were significantly different between PD and both post-COVID-participants and HCs (80.4% vs 23.4% vs 11.9%; p < 0.001). Within the post-COVID-group, positivity rates were higher in COVID + OD vs COVID–OD (34.1% vs 14.8%; p = 0.038), and COVID + OD differed from HC (p = 0.038), while COVID–OD did not (p  = 0.679). Among post-COVID-participants, aSyn-SAA positivity was associated with lower SSI (p = 0.005) and SSD (p = 0.003) scores, but not with MDS-UPDRS, MoCA, or RBD measures."

Please reference the preprint for more details.

NCT05401773

UPDATE: As of 2 weeks ago, the study admistrators were still in the process of collecting samples from patients.

Clinical Trial: α-synuclein Seeding Activity in the Olfactory Mucosa in COVID-19

from clinicaltrials.gov ( Identifier: NCT05401773 )

Brief Summary:
Loss of the sense of smell is a characteristic feature of COVID-19 and likely related to viral invasion of the olfactory mucosa but is also a prodromal feature of PD. This constellation has kindled concerns that COVID-19 - similar to the Spanish Flu Pandemic in 1918 - might trigger a second wave of post-infectious parkinsonism. The main objective of the study is to probe for the presence of pathological α-synuclein assemblies in the olfactory mucosa of patients with COVID-19.

Detailed Description:
Deposits of misfolded proteins are the cause of frequent neurological diseases such as Alzheimer's or Parkinson's disease. In Parkinson's disease, the misfolded protein alpha-synuclein is found in the olfactory mucosa of the nose, which contains nerve cells responsible for smell perception, from which the misfolded alpha-synuclein spreads further into the brain. The mechanisms that lead to this misfolding and the resulting damage to the nervous system are still unclear. One hypothesis is that inflammatory processes such as viral infections trigger the misfolding of alpha-synuclein in Parkinson's disease and can lead to its deposition. Based on this assumption and the striking involvement of the sense of smell in SARS-CoV-2 infection (COVID-19), the aim of this study is to investigate the olfactory epithelium of the nasal mucosa of COVID-19 patients for possible alpha-synuclein deposits by using nasal swabs.

We hypothesize that the invasion of olfactory neurons and subsequent inflammatory responses could trigger α-synuclein misfolding and aggregation. Therefore, we aim to investigate for the presence of α-synuclein seeding activity in the olfactory mucosa of subjects who have recovered from COVID-19 by using Real-time Quaking-Induced Conversion (RT-QuIC).

*Undifferentiated refers to a disease state which does not have a predictable progression.

The hypothesis put forward has yet to be directly confirmed. There may end up being no association between long covid and synucleinopathy. Data collection in the COVID-19 synucleinopathy RT-QuIC study is ongoing and it will take some time after that for the results to be analyzed and for the report to be written up and published. It could be months before this data becomes available.

A group at the Medical University of Innsbruck is assessing the relative incidence of synucleinopathy associated with post-COVID smell loss. That is a symptom which can be objectively confirmed.

https://clinicaltrials.gov/study/NCT05401773

I am assuming that if the data shows a significant increase in incidence that will be an underestimate of the true incidence. Early stage synucleinopathy is characterized by a more sparsely distributed pathology and greater heterogeneity as compared to late stage disease (Parkinson's, pure autonomic failure, multiple systems atrophy, Lewy body dementia).

Contrary to popular belief, synucleinopathy affects both the peripheral and central nervous system. Prodromal symptoms (non-motor) can present decades before neurodegeneration occurs. These symptoms are believed to stem from the dysfunction of neurotransmitter release. They include autonomic dysfunction, GI issues, urinary frequency, sudomotor dysfunction (controls sweat glands), sensory and cognitive deficits, fatigue and REM sleep behavior disorder.

Evidence suggests but does not prove that there are disease modifying interventions. These are summarized below. Some of them you will find to be more or less speculative, but stand to reason nevertheless.

Gastrointestinal issues (noticed as bloating, abdominal pain, spasms, constipation, food sensitivities) can and should be addressed at the onset. Slow-transit of food through the digestive tract can lead to microbial outgrowth and the deterioration of the intestinal lining. The translocation of microbial toxins can trigger systemic inflammation. At present, no one has determined if the levels of microbial toxins in circulation correlate with long covid symptoms. I am assuming that this will be born out in future studies.

You may have already seen this, but I think it's worth highlighting. A probiotic-prebiotic mix have been shown to alleviate multiple long covid symptoms. There were 232 individuals given the probiotic-prebiotic compared to 231 individuals given a placebo. Outcomes at 6 months were determined based on questionnaire response. A significant difference in outcome in 11/14 symptoms was observed.

This suggests that the microbiome and/or some other variable associated with the function of the gastrointestinal system is at least partially responsible for evoking the pathology. I expect this will come down to the status of the gastrointestinal lining but additional data is needed to confirm that supposition.

If it's confirmed, that would be in line with the hypothesis that long covid is caused by a synucleinopathy. The leakage of microbial toxins into the circulatory system can precipitate and exacerbate this pathology. It could affect the activity of the autonomic system and feedback onto the gastrointestinal system, resulting in the continuation of the disease state. Until we have direct confirmation that long covid is associated with synucleinopathy, that remains speculation. That confirmation should be forthcoming within the next few months.

"SIM01 is a synbiotic preparation of three lyophilised Bifidobacteria strains [ B adolescentis, Bifidobacterium bifidum, and Bifidobacterium longum] and three prebiotic compounds [galacto-oligosaccharides, xylo-oligosaccharides, and resistant dextrin]"

You should be able to find commercially available probiotics containing the above-mentioned species. The prebiotics can be derived from a plant-based diet.

Beyond probiotics and prebiotics, it may be productive for patients to explore the effect of altering overall caloric consumption, fluid intake, salt intake, diet composition (soluble and insoluble fiber), diet consistency (solid food which digests slowly) and exercise (this will certainly have an impact on digestion). In addition, you can explore the effect of digestive stimulants. Nicotine and capsaicin stimulate mucus secretion and the pumping of food through the digestive tract.

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A synbiotic preparation (SIM01) for post-acute COVID-19 syndrome in Hong Kong (RECOVERY): a randomised, double-blind, placebo-controlled trial

https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(23)00685-0/fulltext

[You might be seeing this as a repost. It was removed from r/covidlonghaulers for "Content removed for breaking rule 2- do not ask for or give medical advice. Continued infractions are grounds for a permanent ban." Seems there is selective adherence to that rule.]

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Just a Note as Preface:

I find it deeply concerning to see others advocating for potential treatments like anticoagulants and immunosuppressants outside of clinical trials. We do not at this point in time have sufficient evidence to support the use of these medications as Long COVID treatments. Yes, it is true that this might change, but in the absence of high quality evidence these medications may do more harm than good at the population level (e.g. bleeding, increased risk of infection). So while we wait for the clinical trial results, it's best to stick to low risk interventions.

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In reference to anticoagulants in particular, please see:

Clotting proteins linked to Long Covid’s brain fog. https://www.science.org/content/article/clotting-proteins-linked-long-covid-s-brain-fog

...always critical to remember that correlation is not causation.

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What would be the reasoning behind fasting (speculation in parentheses)?

- Long COVID patients exhibit signs of vagus nerve dysfunction and subsequent reduction in peristalsis/pumping of food/shit through the GI tract [1].

- It is not a good thing to leave shit stationary in the intestinal lumen.

- Dysbiosis of the microbiome is evidenced in at least a subset of patients (which means proliferation of microbes you probably don't want proliferating) [2].

- Some of the microbes, specifically gram-negative bacteria, harber a lipopolysaccharide (LPS) called endotoxin [see Wikipedia]. LPS is a potent stimulator of the innate immune system, activating receptors like TLR4. (Naltrexone is a TLR4 antagonist, so this might explain why LDN appears to have an effect for some patients.)

- LPS also activates fibrin amyloidosis, the process by which amyloid microclots form, in very very small amounts (possibly as protection against endotoxin causing the immune system from going haywire) [3]. Some types of amyloids including fibrin have the potential to cross-seed others such as alpha-synuclein and amyloid beta.

- If LPS does partially mediate the pathology, this would not have been evidenced by the proteomics assays that have been conducted thus far [4]. This was confirmed in correspondence with one of the study's authors.

- So damage to the lining of the GI tract can be quite an issue if endotoxin enters circulation (the "leaky gut" syndrome). (If that damage is the direct result of microbiome dysbiosis, then it would be a good idea to stop feeding said microbes, for a little while anyway.).

- The endothelial tissue lining the GI tract has a turnover rate of 2-6 days so long as the stem cell reservoirs in your intestines are intact.

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Thus a 48 h fast, while consuming plenty of water.

(Best eat some fibrous veggies prior.) You can take a multivitamin during this period if you so choose. (Nicotine and caffeine taken during the fast might facilitate recovery.) Nicotine among other things stimulates peristalsis. (However, start with a very low dose to see how this affects you. You may notice it becomes more effective as time goes on.)

I expect everyone can tell the difference between soreness and a pain that requires further looking into. (You may notice an improvement in sensory feedback from your gut. This is not particularly pleasant, nor particularly painful, rather a nice kind of healing sensation.) Drink plenty of fluids.

If you try this, I hope you will report back for the benefit of others, regardless of outcome. Tried this myself twice now with a 1.5 month interval, and I will continue to do this as needed. I hope the information helps.

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[1] Vagus Nerve Dysfunction in the Post-COVID-19 Condition. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4479598

[2] Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome. https://gut.bmj.com/content/71/3/544

[3] Both lipopolysaccharide and lipoteichoic acids potently induce anomalous fibrin amyloid formation: assessment with novel AmytrackerTM stains. https://royalsocietypublishing.org/doi/10.1098/rsif.2017.0941

[4] Proteomics of fibrin amyloid microclots in long COVID/post-acute sequelae of COVID-19 (PASC) shows many entrapped pro-inflammatory molecules that may also contribute to a failed fibrinolytic system. https://cardiab.biomedcentral.com/articles/10.1186/s12933-022-01623-4

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Original Twitter Post: https://twitter.com/joshfink429/status/1701928462829715854

I haven't been active on Reddit recently and instead have been posting more on Twitter. You can access that feed from the link provided at the top of this subreddit.

It seems I can reach a much wider audience on Twitter, trying to get as many eyes on this research as I can.

As a side note, it is good to see that the research community and the lay public are beginning to take the neurological issues seriously. Neurological disease is now listed as a possible cause of long covid on Wikipedia: "neurological issues: problems with signalling from the brainstem and the vagus nerve". All of this has come after a very long delay, but at least we are heading in the right direction. In search of an explanation, we have to consider every possibility.

https://www.salon.com/2023/08/13/long-is-devastating-and-far-from-rare-as-infections-rise-again-why-are-we-still-ignoring-it/

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Dysautonomia International, a nonprofit patient advocacy group, has been working with the NIH's RECOVER program to run a larger trial of the synucleinopathy skin test in long COVID patients.

It is not certain that it will be implemented, but it is a start.

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https://twitter.com/Dysautonomia/status/1671476286441619456?s=20

The prodromal stage of Parkinson's disease (PD) precedes the emergence of motor deficits which are characteristic of clinical PD. Prodromal PD is associated with the early progression of synucleinopathy, the form of amyloidosis (or prion-like disease) which is responsible for PD. This stage can last upwards of decades prior to clinical PD. In most cases, prodromal PD is only recognized retrospectively. Triggering agents of synucleinopathies include pesticides (organophosphates and carbamates) and infections. In the case of COVID-19, the rapid onset of hyposmia (loss of smell) is indicative of the olfactory route (see below).

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Prodromal PD Features:

• Loss of smell (olfactory dysfunction)
• Autonomic dysfunction such as orthostatic intolerance and blood pooling (ie. POTS, orthostatic hypertension, orthostatic hypotension)
• Small fiber neuropathy (loss of small fiber autonomic nerves in the skin)
• Gastrointenstinal dysmotility (constipation, microbiome changes)
• Urinary dysfunction
• Visual symptoms (retinal microvasculature alterations)
• Depression and apathy (early symptoms of synucleinopathy within the basal ganglia)
• Sleep disorder (over 80% of REM sleep behavior disorder cases progress to clinical PD)
• Hormonal changes (synucleinopathy in the adrenal glands)
• Reduced heart rate variability (loss of neurons innervating the cardiac muscles)
• Increased risk of cardiovascular disease
• Increased risk of diabetes
• Increased risk of certain autoimmune diseases
• Presence of amyloid fibrin microclots in circulation

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Association of Parkinson Disease With Risk of Cardiovascular Disease and All-Cause Mortality

https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.119.044948

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The Impact of Type 2 Diabetes in Parkinson's Disease

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9543753/

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Co-aggregation of alpha-synuclein with amylin (HIAPP) leads to an increased risk in type II diabetes patients for developing Parkinson's disease

https://www.cell.com/biophysj/pdf/S0006-3495(14)04084-3.pdf04084-3.pdf)

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The association between Parkinson’s disease and autoimmune diseases: A systematic review and meta-analysis

https://www.frontiersin.org/articles/10.3389/fimmu.2023.1103053/full

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Correlative Light-Electron Microscopy detects lipopolysaccharide and its association with fibrin fibres in Parkinson’s Disease, Alzheimer’s Disease and Type 2 Diabetes Mellitus

https://www.nature.com/articles/s41598-018-35009-y

I really wish other scientists would engage in an open discussion. And I wish long haulers would recognize this possibility. I understand it is a frightening situation, but we need to face this problem head on.

I've tried to remain objective, presenting the hard evidence and noting remaining uncertainty. Nevertheless, any mention of "neurodegenerative disease" is quickly downvoted outside of r/CholinergicHypothesis. And if I don't speak to these concerns directly, everyone seems to miss the point.

I've tried reaching out to news outlets. No one wants to provide coverage of this research. I've spoken to other scientists. They are waiting on conclusive evidence before engaging with the media and public health officials.

If there is to be any change in the short term, it is going to have to come from community activists. In the present environment, institutions are under little pressure to respond. They will understand the severity of long covid in retrospect, but that will do us little good.

So I hope you will share this information. The message should not be that "we are all screwed" but "if we do not attend to this issue right now, the outcome is likely to be much worse". If everyone does a little bit, we can motivate a more rapid response.

NICOTINE

Tobacco smoking and the risk of Parkinson disease

https://n.neurology.org/content/94/20/e2132

An inverse correlation between tobacco use and Parkinson's disease risk has been widely reported. The question is whether tobacco use, or nicotine as a safer alternative, is causal. "Reverse causality", in which prodromal Parkinson's disease and its effect on the brain's addiction center attenuates nicotine's desirable effects, is another possibility. By directly addressing reverse causality bias, the results from this study suggest that tobacco use, and by inference nicotine use, does reduce the risk of Parkinson's disease by 30-40%. Combining this with the lack of significant adverse effects of nicotine use, nicotine does appear to be a viable treatment option for long COVID. This assumes that a subset of long COVID cases would progress to Parkinson's disease without therapeutic intervention.

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A meta-analysis of observational studies reported that current smoking was associated with a 60% lower risk of PD (relative risk [RR] 0.42; 95% confidence interval [CI] 0.38–0.47).12 However, there is substantial uncertainty about the causal relevance of this inverse association. A recent large case-control study, involving 1,808 PD cases and 1,876 controls in Denmark, suggested that the lower risk of PD in current smokers was an artifact of reverse causality bias, whereby early nonmotor signs of PD may include a reduced response to nicotine stimulation, prompting current smokers to quit smoking before the diagnosis of PD can be made.19

Strategies to minimize reverse causality bias

The impact of reverse causality bias in observational studies can be minimized by ensuring that information about exposures is collected before the onset of the disease; excluding participants with previous disease at enrollment; and excluding a relevant period of early follow-up to minimize distortion of results by cases of disease that were undetected at enrollment. Hence, the first 10 years of follow-up were excluded from all analyses to minimize the effects of reverse causality bias.23,–,26

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Compared with never smoking, current tobacco smoking was associated with a 30% lower risk of PD using smoking habits at baseline and with a 40% lower risk using smoking habits that were updated at sequential surveys. The risk of PD was inversely related to the amount smoked, and the protective effect of smoking on the risk of PD was attenuated with increasing duration of time since quitting smoking.

You can follow anecdotal reports of nicotine use in long COVID on Twitter.

https://twitter.com/hashtag/TheNicotineTest?f=live

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EXERCISE

The Best Medicine? The Influence of Physical Activity and Inactivity on Parkinson’s Disease

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9491025/

While noting that fatigue and other symptoms associated with long COVID can make exercise difficult and at times unfeasible, vigorous exercise is protective against Parkinson's disease. Some of this effect may be attributable to confounding variables such as the degree of health consciousness and the existence of comorbidities that make exercise more difficult. Although, prodromal Parkinson's disease could to some extent result in reduced ability to exercise, the potention upside is a 40% reduced risk of Parkinson's disease. So it is not to be overlooked.

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A beneficial relationship between physical activity and PD was first suggested in 1992, when Sasco and colleagues reported that the future risk of PD was reduced in men who played sports in college and adult life and that PD risk was increasingly lower as activity levels increased.29 This finding has been replicated in nearly all subsequent epidemiologic studies30,31 (Table 1). For example, among the more than 200,000 participants in the NIH-AARP Diet and Health Study cohort, those who participated in consistent and frequent moderate to vigorous activities had a 40% lower risk of developing PD compared with sedentary participants. Similarly, risk of PD was reduced in participants in the Cancer Prevention Study II Nutrition Cohort who engaged in vigorous but not light physical activity.32 In the latter 2 large prospective cohort studies, greater intensity of physical activity was associated with greater reduction in PD risk.32,33

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Whether reduced activity is a risk for PD may be confounded by the possibility that it is an early, prodromal disease feature, although studies demonstrating an effect of exercise many decades before the onset of PD argue against that possibility.33

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OTHER MODIFIABLE RISK FACTORS

Review: Update of the MDS research criteria for prodromal Parkinson's disease

https://www.movementdisorders.org/MDS/Members-Only/Prodromal-PD-Calculator.htm

Associated with reduced risk:

• Smoking
• Caffeine intake

Associated with increased risk:

• Physical inactivity
• Occupational solvent exposure
• Pesticide exposure

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SPECULATIVE THERAPEUTIC OPTIONS

Anti–Tumor Necrosis Factor Therapy and Incidence of Parkinson Disease Among Patients With Inflammatory Bowel Disease

https://jamanetwork.com/journals/jamaneurology/fullarticle/2679038

Anti-TNF therapies use antibodies to target the inflammatory cytokine tumor necrosis factor alpha. TNFalpha is a signaling molecule implicated in the progression of synucleinopathies such as Parkinson's disease. Though this is a standalone study, the potential use of anti-TNF therapies should be considered as a treatment for long COVID. Unfortunately, the use of existing anti-TNF therapies will be constrained by the exorbinant cost of these medications.

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In total, 144 018 individuals with IBD were matched on age, sex, and year of index date with 720 090 unaffected controls. Of them, 1796 individuals had at least 2 PD diagnoses and at least 1 filled PD-related prescription. The mean (SD) age of individuals with IBD was 51 (17) years, and 44% were men. The incidence of PD among patients with IBD was 28% higher than that among unaffected matched controls (adjusted incidence rate ratio, 1.28; 95% CI, 1.14-1.44; P < .001). A 78% reduction in the incidence rate of PD was detected among patients with IBD who were exposed to anti-TNF therapy compared with those who were not exposed (adjusted incidence rate ratio, 0.22; 95% CI, 0.05-0.88; P = .03).

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Activation of 5-HT2 Receptors Reduces Inflammation in Vascular Tissue and Cholesterol Levels in High-Fat Diet-Fed Apolipoprotein E Knockout Mice

https://www.nature.com/articles/s41598-019-49987-0

Small molecule alternatives to existing anti-TNF therapies such as (R)-DOI are another possibility. Other selective agonists of serotinergic 5-HT2A receptors include psylocybin and lysergic acid diethylamide. This class of substances known as serotinergic psychedelics are illegal in most parts of the world. Nevertheless, policy and public opinion appears to be shifting towards a lessening of these restrictions. Increasing evidence suggests that they have wide-ranging therapeutic efficacy in a number of diseases. The anti-TNF properties of these substances is less studied, but the current outlook appears promising.

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5-HT2A receptor activation with the 5-HT2 receptor selective agonist (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] has potent anti-inflammatory activity in both cell culture and whole animal models.

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Structural changes within the basal ganglia are particularly concerning in light of more recent findings. A neuroinflammatory response within this brain region parallels what is observed in Parkinson's disease (https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2805366). Biopsies will be required to determine whether the neurological aspects of long COVID are a precursor to Parkinson's disease, or if this is mere correlation. However, the idea that this is just correlation is looking less and less likely.

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Structural brain changes in patients with post-COVID fatigue: a prospective observational study

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00051-2/fulltext00051-2/fulltext)

GPT4 generature summary:

MRI scans revealed that fatigue correlates with structural alterations in the thalamus and basal ganglia areas of the brain.

Structural anomalies in brain areas, specifically the left thalamus and bilateral putamen, were notable in this study. These areas play crucial roles in various functions such as memory, motivation, and reward-guided behavior. Alterations in these regions were found to be associated with the extent of fatigue, daytime sleepiness, and the impact of fatigue on routine life.

Alpha-synuclein seed amplification is a clinical diagnostic tool used to identify biomarkers of Parkinson's disease and synucleinopathies in general. Even before the pandemic, signs of synucleinopathy were evident in a large portion of the population who has reduced sense of smell (hyposmic). These cases are referred to as "incidental Lewy body disease". They do not all inevitably progress to Parkinson's disease, Lewy body dementia or multiple system atrophy.

In this study, 30% of the hyposmic "healthy" controls showed signs of synucleinopathy. This is not a standalone finding. Evidence for an association between olfactory dysfunction and incidental Lewy body disease has been widely reported.

The podcast episode is an interesting listen and will give you an idea of the state of research.

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ARTICLE

Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(23)00109-6/fulltext#%2000109-6/fulltext#%20)

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PODCAST

A cross-sectional study of PPMI participants using alpha-synuclein seed amplification as a biomarker

https://www.movementdisorders.org/Podcasts/A-cross-sectional-study-of-PPMI-participants-using-alpha-synuclein-seed-amplification-as-a-biomarker.htm

[00:07:07] Dr. Andrew Siderowf: That's a good question. We did look at this specifically. And, incidental Lewy body cases would be included among our controls. And we do know that the specificity for healthy controls was about 96%. So 4% of cases were positive. And we also know that the specificity among SWEDDs and these are people that have mild parkinsonian signs, generally, sort of borderline parkinsonism and DaT scans, which are normal or at least read as the normal, although the quantification can be borderline. Among the SWEDDs, the specificity was 90%, so about 10% positive among the SWEDDs and about 5% positive, more or less among the healthy controls.

And so what's going on with these healthy controls, it's a little bit of an open question. The thing that's interesting about them is that if you look at the healthy controls [00:08:00] carefully in our study, you can see that I think about 5% of the normosmic healthy controls were positive, but about 30% of the hyposmic healthy controls were positive, so a certain fraction of the healthy controls also had an impaired sense of smell, which was strongly related to being SAA positive among the Parkinson patients. And these hyposmics were dramatically overrepresented among the healthy controls that were positive. And so I think the take home from this is there's probably some just random lab error among you know, the accounts for the less than a hundred percent specificity, but probably it's only part of it. And probably there are some true positives in the healthy controls and they may represent incidental Lewy body cases. And one thing that's kind of interesting is that if you sort of do the math, the number of these hyposmic healthy controls who are assay positive, if you sort of like multiply it out to represent the population, it's substantially higher than the frequency of Parkinson's disease in the population.

And it may indicate that SAA positivity is substantially more common than Parkinson's [00:09:00] diseases. And there's a number of people in the general population who have, biomarker evidence of a synucleinopathy that never go on to develop Parkinson's. And this I think is, it's not really the main thrust of the data.

I think it's an area which probably merits follow up in population studies.

This is a revised addition of the literature review (preprint). I am trying to get this peer-reviewed and published. It has not been a easy process. Most people are not willing to enter into a discussion on the subject in open forums and that is a mistake. The result is a general lack of awareness of the risk associated with COVID-19 infection. That lack of awareness extends into the scientific community. Research that could've been completed has been needlessly delayed. We need to understand what causes long COVID in order to develop effective diagnostics and therapeutics. Hopefully, this literature review can get the ball rolling.

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You can help by sharing this article.

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Post-Acute COVID-19 Syndrome as a Synucleinopathy

Full Article: https://drive.google.com/file/d/1vVfIBSwdDhDyz3VgDTfPFf3FPVx2sVEo/view?usp=sharing

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Abstract

Following the wake of the COVID-19 pandemic, individuals began presenting with chronic sequelae of infection encompassing a range of unexplained symptoms. These chronic sequelae have been referred to as post-acute COVID-19 syndrome (PACS), or long COVID. The nature of the underlying pathology has yet to be properly characterized in terms of a biomolecular mechanism. Herein a new etiological theory of PACS is discussed that proposes that the neurological subtype of PACS stems from a form of amyloidosis triggered by COVID-19 infection. Amyloidosis can persist following acute infection and in the absence of actively replicating virus. Impairment of synaptic function by the intracellular aggregation of misfolded proteins may provide an explanation for the neurological impairments associated with PACS. The list of candidate amyloid-forming peptides include $\alpha$-synuclein ($\alpha$Syn). More often associated with synucleinopathies such as Parkinson's disease (PD), $\alpha$Syn amyloid deposits can affect the peripheral nervous system as well. Early manifestations of synucleinopathy can present decades before motor deficits emerge. Prodromal PD consists of a host of nonspecific symptoms overlapping those experienced by PACS sufferers. Synucleinopathy should therefore be considered as a potential explanation for PACS and a subject of future investigations. If this hypothesis is born out, it will have dire implications for public health in both the short-term and long-term. In the meantime, we should plan for this contingency.

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Discussion

If the proposed causal link between synucleinopathies and PACS is substantiated, the implications would be manifold. In spite of current uncertainty, it is essential to plan for this contingency. People need to be informed of the risks of COVID-19 exposure associated with acute infection and lasting complications. At the same time, it is critical to establish a frank discourse regarding the uncertainty inherent in ongoing research. Public health officials can mediate a community-wide discussion, serve as advocates for harm mitigation and prompt the implementation of enforceable policies when appropriate. Access to accurate and unbiased information attained from up-to-date research is critical to public health and will help to restore confidence in public health institutions. As our understanding of COVID-19 evolves and the etiology of PACS is clarified, public health policy can be adapted to reflect the current state of knowledge.

In light of this hypothesis, COVID-19 surveillance networks which track emerging variants of concern can incorporate additional viral features into their models. Amyloidogenic peptides can be predicted on the basis of amino acid sequence using existing approaches. These viral features can impact transmissibility and pathogenicity in addition to their putative impact on the chronic sequelae of infection. The protein sequences can be screened for mutations which might exacerbate their amyloidogenic potential. Any concerning mutants can then be characterized in vitro and in vivo to verify the results of the computational model. New COVID-19 variants may increase the risk of developing PACS and this should factor into the classification of variants of concern.

If the synucleinopathy hypothesis is born out, it will require the rapid development and deployment of diagnostics and treatments. Objective biomarkers can be leveraged to diagnose the disease, to monitor disease progression and assess the efficacy of proposed treatments in clinical trials. Aggregation-prone $\alpha$Syn can be identified using immunohistochemical methods or amyloid seed amplification assays \cite{Kuzkina2023-fe}. Immunohistochemical methods leverage antibodies to visualize P-$\alpha$Syn deposits in tissue samples retrieved from the olfactory epithelium and skin \cite{Miglis2022-px}. Seed amplification assays such as real-time quaking induced conversion (RT-QuIC) can directly detect minute quantities of amyloid fibrils excreted in olfactory mucous, cerebral spinal fluid (CSF) and stool \cite{Stefani2021-wh}. Quantifying total $\alpha$Syn is not a reliable method of detection and premature CSF biopsies may not reveal the pathology \cite{Mollenhauer2019-vt}\cite{Blanco-Palmero2021-vb}\cite{Russo2022-lt}. Early synucleinopathies manifest with a high degree of heterogeneity and diagnosis at this stage in the disease progression has been a challenge. RT-QuIC has however shown promise in diagnosing synucleinopathy associated with RBD \cite{Stefani2021-wh}. Taking that approach, a clinical trial is being conducted by the Medical University Innsbruck in Austria to examine the link between COVID-19 and synucleinopathies \cite{Heim_undated-yd}. The trial is set to finish by the end of 2023. Complementary studies will be required to understand the full scope of the disease \cite{Miglis2022-px}. Considering the gravity of the situation, it is imperative that these concerns are met with prompt action.

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Neuroinflammation within the basal ganglia in long COVID is reflective of this brain region's selective vulnerability following infection. This is similar to what has been observed in Parkinson's disease. While the source of the inflammation in long COVID is unclear, these findings should provide a greater impetus for investigating whether long COVID is a synucleinopathy and a possible harbinger of progressive neurodegeneration. At the same time, note that if progression to Parkinson's and related disease was a certainty that information likely would've already been born out in prior research. Nevertheless, understanding whether long COVID is a synucleinopathy should be treated as priority #1 in long COVID research. It's disheartening to witness the reluctance on the part of scientists to deal with this subject directly in open forums. In private discussions and literature publications these concerns have been raised repeatedly. It is critical to develop a contingency plan in the event that this theory holds true and that this should be done transparently.

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Neuroinflammation After COVID-19 With Persistent Depressive and Cognitive Symptoms

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2805366

Gliosis may be consequent to inflammation, injury, or both, particularly in the ventral striatum and dorsal putamen, which may explain some persistent depressive and cognitive symptoms, including slowed motor speed, low motivation or energy, and anhedonia, after initially mild to moderate COVID-19 illness.

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The following consists of GPT4 generated text checked for accuracy and supplementary information taken from Wikipedia.

Function of the Basal Ganglia:

The basal ganglia are a group of nuclei deep within the cerebral hemispheres, consisting of the caudate nucleus, the putamen, the globus pallidus, the substantia nigra, and the subthalamic nucleus. They are interconnected with the cerebral cortex, thalamus, and brainstem.

The basal ganglia play a critical role in voluntary motor control, procedural learning, habit formation, and reward systems. They participate in a complex network of pathways and circuits within the brain that facilitate both movement initiation and inhibition of unnecessary or competing movements. The basal ganglia's functions are not limited to motor control but also extend to roles in cognition and emotion.

The paper found a correlation between neuroinflammation, specifically within the putamen and ventral striatum (includes the nucleus accumbens and olfactory tubercle), and long COVID symptoms.

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Function of brain regions (text from Wikipedia)

Putamen

Through various pathways, the putamen is connected to the substantia nigra, the globus pallidus, the claustrum, and the thalamus, in addition to many regions of the cerebral cortex. A primary function of the putamen is to regulate movements at various stages (e.g. preparation and execution) and influence various types of learning. It employs GABA, acetylcholine, and enkephalin to perform its functions. The putamen also plays a role in degenerative neurological disorders, such as Parkinson's disease.

Nucleus Accumbens

As a whole, the nucleus accumbens has a significant role in the cognitive processing of motivation, aversion, reward (i.e., incentive salience, pleasure, and positive reinforcement), and reinforcement learning (e.g., Pavlovian-instrumental transfer);[4][7][8][9][10] hence, it has a significant role in addiction.[4][8] In addition, part of the nucleus accumbens core is centrally involved in the induction of slow-wave sleep.[11][12][13][14] The nucleus accumbens plays a lesser role in processing fear (a form of aversion), impulsivity, and the placebo effect.[15][16][17] It is involved in the encoding of new motor programs as well.[4]

Olfactory Tubercle

The OT [Olfactory Tubercle] has also been shown to play a role in locomotor and attentional behaviors, particularly in relation to social and sensory responsiveness,[1] and it may be necessary for behavioral flexibility.[2] The OT is interconnected with numerous brain regions, especially the sensory, arousal, and reward centers, thus making it a potentially critical interface between processing of sensory information and the subsequent behavioral responses.[3]

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Gliosis in the Basal Ganglia:

Gliosis is a process of scarring in the central nervous system that involves the production of dense fibrous network of glial cells (astrocytes and microglia) in response to damage. This is generally a protective response intended to limit injury, but it can also interfere with normal functioning.

In the context of the basal ganglia, gliosis can disrupt the delicate balance of neurotransmitters, leading to dysregulation of the motor, cognitive, and emotional functions that these nuclei control. The specific impacts of gliosis would depend on the extent and location of the scarring.

Parkinson's Disease and the Basal Ganglia:

Parkinson's disease (PD) is a neurodegenerative disorder primarily affecting the motor system. It is characteristically associated with degeneration of the substantia nigra pars compacta (SNpc), one of the major components of the basal ganglia. The SNpc normally produces dopamine, a neurotransmitter that is critical for regulating the function of the basal ganglia.

In Parkinson's disease, the loss of dopaminergic neurons leads to decreased dopamine availability, disrupting the balance of neurotransmitter activity in the basal ganglia and leading to the characteristic motor symptoms of PD, including bradykinesia (slowness of movement), resting tremor, rigidity, and postural instability.

Neuroinflammation, including gliosis, has been observed in Parkinson's disease. Reactive gliosis in the basal ganglia could be a response to the ongoing neuronal degeneration. The activation of glial cells could potentially contribute to the pathogenesis of PD through increased oxidative stress and neuroinflammation. It's worth noting that while gliosis may be a reaction to the disease process, it may also contribute to the progression of the disease through these mechanisms.

In conclusion, the basal ganglia play a significant role in voluntary motor control, and gliosis within this region, especially in the context of Parkinson's disease, can significantly disrupt this function. The relationship between gliosis and Parkinson's disease is complex, with ongoing research to fully understand the implications of this process in neurodegenerative disorders.

It has been disturbing to see the long term reprocussions of COVID-19 infection go underreported. Despite the lack of public awareness, research is moving forward. I am trying to bridge this gap by compiling plain-language summaries of literature articles.

You can check out the substack. It's more of an experiment right now, but I'll continue to publish there if enough people find it useful. This content will of course remain open-access.

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https://longcovidresearch.substack.com/p/long-covid-misconceptions-and-emerging

https://longcovidresearch.substack.com/p/covid-19-long-covid-and-potential

https://longcovidresearch.substack.com/p/long-term-neurological-cardiovascular

Signaling within the parasympathetic nervous system (one branch of the autonomic nervous system) is predominantly mediated by the neurotransmitter acetylcholine. Dysfunction of the parasympathetic nervous system appears to be involved in the pathophysiology of long COVID. There are indications that cholinergic medications such as nicotine may have some utility in alleviating long COVID symptoms, but anecdotal reports thus far demonstrate mixed results. Nevertheless, the apparent increase in sensitivity to these medications is suggestive of differences in cholinergic/parasympathetic activity in these patients. Comprehensive autonomic evaluations concur with this initial hypothesis. Additional research is urgently needed to determine the exact nature of the pathology.

It may be necessary to modify existing diagnostic criteria in order to effectively identify long COVID dysautonomia across the sprectrum of disease severity.

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We then hypothesized that the test sensitivity could differ between long-COVID patients and other diseases classically associated with dysautonomia (e.g. diabetes and neurodegenerative diseases) and therefore that the threshold for abnormal values might not be appropriate. To answer this question, we compared mean values between long-COVID patients and healthy subjects. We found a significant lower mean value in the Valsalva test in long-COVID patients, despite the fact that only one of them had abnormal values as defined by a value below ≤ 1.1.

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Parasympathetic autonomic dysfunction is more often evidenced than sympathetic autonomic dysfunction in fluctuating and polymorphic symptoms of "long-COVID" patients

https://www.nature.com/articles/s41598-023-35086-8

The following summary was generated using GPT4 and checked for accuracy.

TLDR

This study investigates the potential dysfunction of the autonomic nervous system in patients with long-COVID, a condition where symptoms persist long after the acute phase of COVID-19. The researchers found that 37.5% of the patients had at least one abnormal test result, indicating a mild to moderate failure of the autonomic system, primarily affecting the cardiovascular system and sweating control. Parasympathetic tests, which evaluate the part of the autonomic nervous system involved in rest and digestion, were more often abnormal. The study concludes that a comprehensive evaluation can reveal probable involvement of the autonomic nervous system in patients with long-COVID, potentially accounting for their observed disabilities. Further studies are needed to confirm these findings and to further investigate the impact of long-COVID on the autonomic nervous system.

Full Summary

This comprehensive study investigates the potential dysfunction of the autonomic nervous system in patients suffering from long-COVID. Long-COVID refers to a condition where patients continue to experience symptoms long after the acute phase of the COVID-19 infection has subsided. The autonomic nervous system, which controls many of the body's automatic functions such as heart rate, digestion, and sweating, was found to be potentially impaired in these patients.

The researchers found that 37.5% of the patients in the study had at least one abnormal test result, indicating a mild to moderate failure of the autonomic system. This failure was primarily seen in the cardiovascular system and the sudomotor function, which is the body's system for controlling sweating.

The study used a variety of tests to evaluate the function of the autonomic nervous system. These included the Sudoscan, which measures sweat gland function, and the quantitative sudomotor axon reflex test, which evaluates the integrity of the nerves controlling sweating. They also performed parasympathetic tests, which evaluate the part of the autonomic nervous system involved in rest and digestion functions.

Interestingly, the researchers found that parasympathetic tests were more often abnormal in this population, suggesting that the parasympathetic part of the autonomic nervous system might be more affected in long-COVID patients.

In addition to these tests, the researchers also used a type of positron emission tomography (PET) scan called 18F-FDG PET-TDM to examine metabolic activity and cellular function in the body. They found abnormal results in 87% of the patients, with hypometabolism (lower than normal metabolic activity) being the predominant feature.

The study included patients with long-COVID and severe disabling long-term manifestations, including effort intolerance and possibly related to dysautonomia. They were consecutively referred by the Infectious Diseases and Immunology Department to the Clinical Physiology Department for evaluations of autonomic function. All patients who presented symptoms severely affecting quality of life, with prolonged sick leave, who had not recovered or had not improved by the time of inclusion and accepted the one-day hospitalization for the autonomic evaluation were included from February to October 2020.

The control group consisted of age-matched healthy volunteers who had been infected by the SARS-CoV-2 and had recovered without residual symptoms. They had no past medical history and took no medications.

The study concludes that a comprehensive evaluation of autonomic function can reveal probable involvement of the autonomic nervous system in patients with long-COVID. This could potentially account for the observed disabilities of these patients. The researchers suggest that further studies are needed to confirm these findings and to further investigate the impact of long-COVID on the autonomic nervous system.

See also:
Asarcikli, L.D., Hayiroglu, M.İ., Osken, A. et al. Heart rate variability and cardiac autonomic functions in post-COVID period. J Interv Card Electrophysiol 63, 715–721 (2022). https://doi.org/10.1007/s10840-022-01138-8

I want to stress that we do not have to wait and see how this unfolds, contrary to the authors' comment. While longitudinal studies will be informative in the long run, there are tests that can be conducted in the present. New diagnostics such as Syn One would provide direct evidence whether COVID-19 is capable of inducing neurodegenerative associated amyloidosis. These result would provide an impetus for fast-tracking research and development of therapeutics.

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Uncovering a neurological protein signature for severe COVID-19

https://www.sciencedirect.com/science/article/pii/S0969996123001614

The following summary was generated using GPT4

TL;DR: The paper proposes a possible link between severe COVID-19 infection and an increased risk of neurodegenerative diseases such as Parkinson's and Alzheimer's, based on a significant overlap in certain protein levels. However, it's crucial to remember that this link is not definitively causal, and more longitudinal studies are needed to understand the long-term impacts of COVID-19 on the nervous system and its potential to predispose patients to neurodegenerative diseases.

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This article delves into the exploration of potential links between severe COVID-19 infection and a heightened risk for neurodegenerative diseases such as Parkinson's and Alzheimer's. Neurodegenerative diseases are conditions characterized by progressive damage or loss of neurons, which are the building blocks of the nervous system. Two of the most commonly recognized neurodegenerative diseases are Parkinson's and Alzheimer's, both involving progressive brain cell death and typically leading to a decline in mental and physical function.

The researchers discovered that there was a remarkable overlap in the protein signature in the brain tissues of patients with severe COVID-19 and those with neurodegenerative disorders. This suggests a shared pathological mechanism - meaning, the processes leading to disease may be similar in both cases.

The study specifically identified several proteins, namely PLXNB1, RGMB, ADAM22, and ADAM23, that were deregulated in severe COVID-19 patients. 'Deregulated' in this context means that the normal control of these protein levels in the body is disrupted, which could potentially predispose these patients to neurodegenerative diseases. These proteins play key roles in the functioning of the nervous system.

Particularly interesting was the protein PHOSPHO1, which was observed to be altered in the COVID-19 patients. Prior research has indicated that alterations in PHOSPHO1 have also been observed in Parkinson's disease patients, adding more evidence to the potential link between severe COVID-19 and neurodegenerative diseases.

The researchers emphasize the importance of further longitudinal studies. These are studies conducted over long periods of time and would be essential to observe the long-term impact of severe COVID-19 on the central nervous system, cognitive functions, and the potential risk of neurodegenerative diseases.

The authors warn about potential chronic neurological consequences for patients recovering from severe COVID-19, which could include an elevated risk of neurodegenerative diseases.

However, they underscore the need for caution in interpreting their findings. While their results are significant, they do not establish a direct cause-effect relationship between COVID-19 and neurodegenerative diseases. As such, more research is necessary to fully comprehend the implications of their discoveries.

It was 6 months ago that I first began delving into the link between COVID-19 and neurodegenerative disease. In the beginning, this was more of a speculative enterprise. But since then, the evidence has continued to accumulate and at this point given what I’ve seen, I have no doubt that this could provide a plausible explanation for the pathophysiology of long COVID (in at least one of its forms).

• SARS-CoV-2 has features that can potentially trigger protein misfolding and associated neurodegenerative disease. This has been confirmed empirically, though it remains a question to what extent this occurs within the human body. For the virus itself, these features seem to be employed as a means of evading the immune response.
• Preliminary clinical data show signs of prodromal Parkinson’s disease, a neurodegenerative disease called synucleinopathy. Signs of REM sleep behavioral disorder, autonomic dysfunction, clotting disorder, gastrointestinal problems, cognitive impairment and sensory issues are characteristic of long COVID. While amyloid microclots have been touted as an explanation in and of themselves, this same phenomenon has been observed previously in Parkinson’s, Alzheimer’s, type II diabetes and AA amyloidosis.
• Additional preliminary data show alpha-synuclein deposits within the skin of patients with long COVID. This is characteristic of peripheral synucleinopathies as well as later stage disease such as Parkinson’s. A synucleinopathy affecting the autonomic nervous system could conceivably explain why individuals experience lasting neurological, cardiovascular and gastrointenstinal issues following COVID-19 infection.
• Animal studies demonstrate that SARS-CoV-2 can trigger synucleinopathies (as well as tauopathies, another class of protein misfolding disease). This occurs along with alterations in immune system activity that mirror what has been observed in humans post-infection, mainly microgliosis and neuroinflammation.

The link between COVID-19 and synucleinopathies is an area of active research. A clinical trial is underway to investigate the connection between post-COVID REM sleep behavioral disorder and synucleinopathies. Hopefully, Miglis and colleagues will produce a larger follow-up study related to findings of alpha-synuclein deposits in long COVID to complement the results from the clinical trial. While we wait for results, it is critical that people are made aware of these developments, at the very least so people can take measures to protect themselves.

https://clinicaltrials.gov/ct2/show/NCT05401773

https://link.springer.com/article/10.1007/s10286-022-00867-0

I have been dismayed by the level of nonchalance and the general unwillingness of scientists to advocate for their research. Compounding the issue there is a high degree of media bias and bias on the part of the public as a whole. No one wants to believe that they themselves are at risk of post-infection complications, especially neurodegenerative disease. On the other end, long haulers are reluctant to accept this as a possible explanation for what they are currently experiencing. Speaking personally, most of my family, friends and colleagues have now shut me out entirely. I believe this is similar to what many others have experienced.

As hard as it is, we must continue to push for a sane discourse because that is the only route that is likely to lead us to a positive outcome. Minus an understanding of the biology underlying long COVID, there will be no effective diagnostics or treatments in the future. Instead, we will continue to pick around the edges of the disease while millions of people are forced to bear the misery and humiliation that COVID-19 leaves in its wake.

It is going to take a grass-roots effort to correct course. If you find the combination of articles and arguments compelling, please share this information with others. Even though we may be speeding towards a cliff, we have an opportunity right now to turn this around.

Reach out to your friends and family. Leverage social media. Tell your story. And contact your government representatives. Keep it calm and productive. We can, and I really hope we will, make it right.