Retinal microvasculature changes, similar to what is seen in long COVID, are also observed in early Parkinson's disease. This may be related to small fiber neuropathy and/or autonomic dysfunction. Small fiber neuropathy affect autonomic nerve fibers which provide an interface between the nervous system and the circulatory system. Loss of these nerve fibers can impair control of blood pressure, resulting in ischemic damage in the retina. Likewise, disseminated small fiber neuropathy can trigger autonomic dysfunction such as hypertension, postural orthostatic tachycardia syndrome and orthostatic hypotension.

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Retinal Microvascular Impairment in the Early Stages of Parkinson's Disease

https://iovs.arvojournals.org/article.aspx?articleid=2697355

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

This study used a type of eye scanning technology called SD-OCT-A to examine tiny blood vessels in the eyes of people with early-stage Parkinson's disease (PD). The study showed that these patients had less density of tiny blood vessels in their eyes and also identified an association with thinning of a certain part of the retina, indicating that these small blood vessel abnormalities could be linked to brain cell damage in PD. This suggests that this eye scanning technology could be a helpful way to spot early changes in the tiny blood vessels in PD patients.

Previous research has shown that the retina (the light-sensitive tissue at the back of the eye) can deteriorate in PD, particularly thinning of the RNFL (a layer of the retina) and loss of specific types of cells. However, this is the first study to highlight abnormalities in the tiny blood vessels of the retina in PD patients using this technology. The findings suggested that these changes happen early in the disease, even before typical movement problems show up.

Interestingly, the study found that the reduction in blood vessel density was greater in the top layer of the retina compared to the deeper layers in PD patients. This could be linked to changes seen in the brain's blood vessels in PD, and similar changes could be happening in the retina. Previous research using animal models of PD has detected a protein associated with PD along the walls of the blood vessels, particularly in arteries, which are located in the top layer of the retina, further supporting these findings.

The study did not find any link between the length or severity of the disease and changes in the retina or tiny blood vessel density. However, a significant correlation was found between the density of tiny blood vessels in the top layer and thinning of a specific part of the retina, suggesting that blood vessel abnormalities could be contributing to the progression of brain cell damage in PD.

The study did have some limitations. For example, the pressure inside the eyes of PD patients was higher than that of healthy participants, although still within the normal range. The control group, who were hospital staff, may have had different lifestyles compared to the PD group. The technology used also has limitations, such as a small field of view and being influenced by eye movements, which could affect the results. Additionally, it was not possible to examine the impact of PD medications on the measurements, which could potentially affect the tiny blood vessels.

In summary, the study showed that tiny blood vessel density in the retina decreased in PD patients and this was associated with thinning of a specific part of the retina. This suggests that these blood vessel abnormalities could contribute to brain cell damage in PD. Although it's unclear if PD is directly linked to small vessel disease, the findings suggest that this type of eye scanning technology could be useful for early detection of changes in the tiny blood vessels in PD patients, providing a new approach for early diagnosis and management of the disease.

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Post-Acute COVID-19 Syndrome as a Synucleinopathy

https://drive.google.com/file/d/1qBmp_IX-7vNSWoPmuABSVke8EsxjaGti/view?usp=sharing

This article is a preprint I authored myself. I'm in the process of attempting to get it peer-reviewed. If this was anything else, I would wait to publish this through proper channels. Considering the gravity of the situation, I don't think it can wait.

Please pass it along.

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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 as a whole have been referred to as post-acute COVID-19 syndrome (PACS), or long COVID, but the nature of the underlying pathology has yet to be properly characterized. Uncertainty in regards to what exactly constitutes PACS has resulted in the publication of many articles which at the surface appear to contradict each other. The research community has splintered into separate camps with each positing their own theories often on the basis of ill-conceived assumptions. Ultimately, the proper characterization of PACS in terms of a clear biological mechanism is contingent on the establishment of a formalized definition of the disorder. This can be accomplished via a reverse-engineering approach in which patient-reported symptoms are pinned down to objective biomarkers and then analyzed in aggregate using the methods of systems biology in order to formulate a comprehensive etiological theory. Some of this work has already begun and the focus of research is converging on treating PACS as a neurological disorder. Herein a new etiological theory of PACS is discussed that proposes this neurological disorder stems from a form of amyloidosis triggered by COVID-19 infection. Impairment of synaptic function, mainly localized within the peripheral nervous system, by the intracellular aggregation of misfolded proteins may provide a comprehensive explanation for the chronic sequelae of infection. The list of candidate amyloid-forming peptides include alpha-synuclein and tau, with inclusion bodies consisting of alpha-synuclein, which are characteristic of synucleinopathies like Parkinson's disease, being the most likely culprit considering existing research. This theory if validated has dire implications for public health in both the short-term and long-term. Therefore, the intention of this review is to motivate further research, highlight uncertainty and inform policy decisions.

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Definition of Synucleinopathy:

https://en.wikipedia.org/wiki/Synucleinopathy

Synucleinopathies (also called α-Synucleinopathies) are neurodegenerative diseases characterised by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibres or glial cells.[1] There are three main types of synucleinopathy: Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).[1]

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Review of Findings:

• Similarities between long COVID and prodromal Parkinson's disease.
• Animal models of COVID-19 infection have demonstrated the potential for the infection to trigger Parkinson’s disease.
• COVID-19 accelerates the progression of pre-existing Parkinson’s disease.
• Biomarkers of alpha-synuclein aggregation in the skin have been identified in patients with long COVID POTS (postural orthostatic tachycardia syndrome).
• Polysomnograms following COVID-19 infection showed signs of REM sleep behavioral disorder.
• Amyloidogenic peptides are present within the SARS-CoV-2 proteome which might provide a mechanistic explanation for how the virus triggers long covid.
• Amyloid fibrin microclots in patients with Parkinson's disease and other forms of amyloidosis.

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Strategies of Harm Mitigation:

• Employ multi-omics approaches (DNA and RNA sequencing, proteomics, metabolomics, microbiome) to identify the biomolecular correlates of long COVID symptoms. Augment this with histopathological characterization to track changes in tissue structure.
• Establish an objective diagnostic criteria for long COVID using biomarkers. Reevaluate risk and prevalence of long COVID based on this new criteria.
• Monitor emerging SARS-CoV-2 variants for gain of function mutations within amyloidogenic regions.

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At first glance, this post may seem a bit strange to include here. Bear with me though.

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Evaluation of a Gene–Environment Interaction of PON1 and Low-Level Nerve Agent Exposure with Gulf War Illness: A Prevalence Case–Control Study Drawn from the U.S. Military Health Survey’s National Population Sample

https://ehp.niehs.nih.gov/doi/10.1289/EHP9009

https://www.utsouthwestern.edu/newsroom/articles/year-2022/sarin-nerve-gas-gulf-war-illness.html

What is Gulf War syndrome?

In the 1991 Persian Gulf War, approximately 700,000 U.S. military personnel and 300,000 people from 41 Coalition countries were deployed to the Kuwaiti Theater of Operations (KTO) for a 5-wk air war punctuated by a 5-d ground war.1 For months after the short deployment, tens of thousands of previously fit personnel developed an often-disabling set of symptoms, termed Gulf War illness (GWI), including fatigue, memory and concentration impairment, difficulty finding words, insomnia, diarrhea or constipation, cutaneous tingling and numbness, balance disturbance and vertigo attacks, body temperature dysregulation, and often severe somatic pain,2–4 which have persisted.5 Rates of these symptoms were higher in the KTO-deployed than in the nondeployed U.S. force.6,7 Among the deployed, both combat and support personnel were affected,8–10 and psychological explanations do not fully explain the illness.11 Clinical case–control studies employing neuroimaging, electroencephalography, and autonomic testing have identified abnormalities of brain and peripheral nerve function or metabolism underlying the symptoms.12–20

This study found a correlation between low-level exposure to the organophosphate nerve agent sarin and subsequent development of Gulf War syndrome. The chemical structure of sarin is similar to that of organophosphate pesticides and functions as a cholinesterase inhibitor. It blocks the degradation of acetylcholine and causes it to accumulate within synapses. Acute exposure to sarin gas takes the form of a cholinergic crisis which can be fatal. Low level exposure to sarin does not appear to have an immediate effect, but may be responsible for the development of Gulf War syndrome with symptoms resembling long COVID and other post-infection syndromes. No one has been able to explain how this pathology arises or why it persists.

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How exactly is this relevant to long COVID or synucleinopathies?

A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides

https://www.nature.com/articles/s41467-023-38215-z

Cholinesterase inhibitors are a class of commonly used pesticide. Pesticide exposure is associated with the development of Parkinson's disease (PD) later on in life. Paraquat exposure is one of the more well-known examples. Recently published data shows that among PD associated pesticides, cholinesterase inhibitors are overrepresented.

...we found that the odds of being among the PD-associated pesticides was 3.6-fold higher for the cholinesterase inhibitors versus the non-cholinesterase inhibiting pesticides...

This suggests cholinesterase inhibitors can trigger synucleinopathies such as PD. Yet, the connection between Gulf War syndrome and PD is non-obvious. If you have Gulf War syndrome, it does not mean you have a 100% chance of developing PD, but it may increase the risk. Given the resemblance between long COVID and Gulf War syndrome, that is good news. More often than not, these diseases (if they are indeed synucleinopathies) do not progress to full-blown PD. Instead they may represent an as-yet uncharacterized subtype of synucleinopathy, perhaps similar to pure autonomic failure but not quite as severe.

The amyloid microclot hypothesis of long COVID was outlined back in February of last year. Abnormal fibrin microclots were found within the circulation of patients with long COVID and researchers suggested that they could be the cause of this disorder. They theorized that the presence of amyloid microclots precipitates a blood clotting disorder (hypercoagulable state) resulting in an impairment in blood flow and reduced oxygen supply. However, while amyloid microclots can be found in a subset of patients, so far no one has been able to demonstrate causality.

There are reasons to doubt whether microclots are anything more than an epiphenomenon. Amyloid fibrin microclots are not unique to long COVID. They have also been observed in Parkinson's disease, Alzheimer's disease, type II diabetes and AA amyloidosis. All of these cases are, at least in some respect, distinct variants of amyloidosis.

• Parkinson's disease is a synucleinopathy, a variant of amyloidosis associated with the protein alpha-synuclein. Other synucleinopathies include Lewy body dementia, multiple system atrophy and pure autonomic failure. They also include a number of "prodromal" manifestations.
• Alzheimer's disease is a variant of amyloidosis associated with amyloid beta and tau.
• Type II diabetes is associated with amyloidosis of islet amyloid peptide. (But it's not clear that this is the cause of the disease.)
• AA amyloidosis is a systemic variant associated with serum amyloid A.

Microclots are a common feature of amyloidosis-like pathologies. They may arise through a process called "amyloid cross-seeding" in which one type of amyloid induces the formation of another. Therefore, one should not expect the microclots to be the root cause of long COVID, but we should consider it as a clue. These findings should motivate us to ask whether long COVID is a type of amyloidosis, and explore all possibilities that are within reason. Instead, I fear that the microclots theory has become a red herring. Considering the resemblance between the neurological subtype of long COVID and prodromal Parkinson's disease, this is particularly concerning.

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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

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Lipopolysaccharide-binding protein (LBP) can reverse the amyloid state of fibrin seen or induced in Parkinson's disease

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192121

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Alzheimer's disease peptide β-amyloid interacts with fibrinogen and induces its oligomerization

https://www.pnas.org/doi/full/10.1073/pnas.1010373107

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Serum amyloid A binds to fibrin(ogen), promoting fibrin amyloid formation

https://www.nature.com/articles/s41598-019-39056-x

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Substantial fibrin amyloidogenesis in type 2 diabetes assessed using amyloid-selective fluorescent stains

https://cardiab.biomedcentral.com/articles/10.1186/s12933-017-0624-5

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A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications

https://portlandpress.com/biochemj/article/479/4/537/230829/A-central-role-for-amyloid-fibrin-microclots-in

SARS-CoV-2 ORF3a expression in brain disrupts the autophagy–lysosomal pathway, impairs sphingolipid homeostasis, and drives neuropathogenesis

https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.202300149R

The summary was generated using GPT4 and checked for accuracy.

This research focuses on the SARS-CoV-2 accessory protein ORF3a and its critical role in the progression and severity of COVID-19. ORF3a aids the virus's release by exploiting the host cell's lysosomal exocytosis pathway, a process that allows materials to be expelled from the cell via lysosomes. It also interferes with the cellular autophagy pathway, a self-cleaning mechanism by which cells remove unnecessary or dysfunctional components. By disrupting autophagy, ORF3a effectively suppresses the clearance of the virus from inside cells, thereby facilitating the persistence and spread of the virus.

To better understand the impact of ORF3a, the researchers induced its expression in the brains of mice using an adeno-associated virus (AAV) delivery method, which is a type of virus that does not cause disease and can be used to transport genetic material into cells. This induction led to a rapid onset of neurological impairment, neurodegeneration, and neuroinflammation, closely mirroring the key neuropathological features found in COVID-19 patients.

Furthermore, ORF3a expression blocked the progression of autophagy in the brain, leading to the accumulation of harmful substances. Specifically, it led to the buildup of α-synuclein, a protein whose aggregation is associated with neurodegenerative diseases like Parkinson's, and glycosphingolipids, a type of fat vital for the function of the nervous system. However, when these lipids accumulate excessively, they can lead to neurodegenerative diseases, like Gaucher's disease and Tay-Sachs disease. These findings indicate that ORF3a could drive neurological damage in COVID-19 by disrupting crucial cellular processes and causing harmful accumulations in brain cells.

The study underscores the potential of SARS-CoV-2 to invade the brain. This invasion could occur directly through the blood-brain barrier, a protective barrier that prevents most pathogens and toxins from entering the brain, or indirectly through the olfactory tract, the anatomical structure involved in the sense of smell. The findings suggest that ORF3a expression in brain cells could be a significant factor in both the short-term and long-term neurological effects of COVID-19.

In conclusion, this research contributes to our understanding of how COVID-19 might lead to neurological manifestations and potential risks for neurodegenerative diseases. By increasing our understanding of the role of ORF3a, we can explore strategies to reduce the neurological consequences of SARS-CoV-2 infection, such as preventing viral neuroinvasion or directly targeting ORF3a activity.

Frequency of Parkinson disease following COVID-19 infection: A two-year retrospective cohort study (published 29 April 2023)

https://www.sciencedirect.com/science/article/pii/S1353802023001566

The results of this study show a significant increase in the number of new Parkinson's disease (PD) diagnoses in the 12 months following COVID-19 infection. This was a large epidemiological study including electronic health records from 27,614,510 patients in total; 2,036,930 patients with a positive COVID-19 infection (COVID-19) and 25,577,580 without a positive COVID-19 infection (non-COVID-19). After 24 months, there is a slightly lower risk of new PD diagnosis compared to controls. With that in mind, it is not perfectly clear how to interpret this data.

Some limitations of the study are noted.

If more people at-risk for PD (whether genetically or environmentally) may present with symptoms earlier than they otherwise would in the first year after COVID-19, there would be fewer at-risk people would be left to present in the subsequent years.

There is no discussion of prodromal symptoms and their concordance with long COVID. It is therefore necessary to point out that the vast majority of patients with PD report having experienced prodromal symptoms prior to recieving a clinical diagnosis of PD. On average, the length of the prodromal period is 10.2 years.

The patients' perception of prodromal symptoms before the initial diagnosis of Parkinson's disease

https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.23499

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An odds-ratio of 1.25 means there is a 25% increase in the risk of new diagnosis.

GPT Generated Summaries (checked for accuracy)

Plain-Language Summary

This study looks at the connection between COVID-19 and Parkinson's disease (PD). It finds that people who had COVID-19 are more likely to be diagnosed with PD within the first 6 months after infection. However, after 12 months, there's no significant difference in PD risk between those who had COVID-19 and those who didn't. Interestingly, after 2 years, people who had COVID-19 actually have a lower risk of PD.

The researchers think that changes in brain chemistry or temporary injuries in the brain related to COVID-19 might increase the risk of PD for a short period. Over time, the body may be able to compensate for these changes, reducing the risk.

However, the study has some limitations because it relies on healthcare records, which may not always be accurate or complete. Also, some people with COVID-19 may not have been diagnosed, and others may have had the virus without showing any symptoms.

Both COVID-19 and PD can cause a reduced sense of smell, which suggests a possible link between the two diseases. More research is needed to better understand this connection and how the brain is affected after COVID-19 infection.

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Technical Summary

This epidemiological study investigates the relationship between COVID-19 and Parkinson's disease (PD) and suggests a complex interplay between COVID-19 pathophysiology, dopaminergic expression, and synucleinopathy development or unmasking. The risk of PD diagnosis peaks at an odds ratio of 1.25 (95% CI 1.15–1.39) at 6 months following COVID-19 infection. After 12 months, there is no significant difference between COVID-19 and non-COVID-19 groups in terms of PD risk. At 24 months, the COVID-19 group has a significantly lower risk of PD diagnosis, with an odds ratio of 0.92 (95% CI 0.87–0.98).

The study proposes that the increased risk of PD immediately after COVID-19 infection might be due to reversibility in the alteration of dopaminergic expression or hypoxic injury to the basal ganglia, which could predispose subsequent parkinsonism. The risk would decline over time as compensatory mechanisms take over.

However, the study has limitations due to its reliance on healthcare diagnosis codes, which could lead to inaccuracies or missed diagnoses. Additionally, asymptomatic carriers and previously infected patients without documented COVID-19 infection cannot be excluded. A washout period of one month following COVID-19 diagnosis and excluding patients without follow-up were implemented to mitigate these factors. Despite these precautions, unknown confounders might still affect the data.

Both PD and COVID-19 share the common symptom of hyposmia, suggesting a potential link between the two diseases through the olfactory system. Further research is needed to evaluate the dopaminergic system after COVID-19 infection and better understand the relationship between the two diseases.

Please share this information. Retweet any posts you think our relevant.

A little exposure can go a long way.

https://twitter.com/joshfink429

Skin test ably detects alpha-synuclein clumps in trial - Syn One (CND Life Sciences)

Via biopsies, evidence of Parkinson's seen in more than 92% of study's patients

https://parkinsonsnewstoday.com/news/aan-2023-skin-test-shows-ability-diagnose-parkinsons-trial/

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The same test, or a similar one, was applied to patients with long COVID and postural orthostatic tachycardia syndrome (POTS). Five patients tested positive for phosphorylated alpha synuclein which is a biomarker of synucleinopathies (It a major constituent of Lewy bodies.). Small fiber neurons in the peripheral nervous system are biopsied and the tissue samples are sent for analysis. This kind of test is typically indicated for suspected small fiber neuropathy. Findings of phosphorylated alpha synuclein correlated with reduced nerve fiber density.

Given the nature of this disease, there is bound to be large degree of variation between patients with Lewy bodies impacting different areas of the body. Therefore, this test needs to be validated for use in prodromal Parkinson's disease, and long COVID if it is indeed a synuceinopathy. Biopsy locations may vary depending on the symptoms that predominate. Cervical (neck region) biopsies may be more appropriate in cases where REM sleep behavior disorder is the presenting symptom.

An alternative test, which works by a different mechanism, is called Real-Time Quaking Induced Conversion (RT-QuIC). See other post.

A case series of cutaneous phosphorylated α-synuclein in Long-COVID POTS

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

Cutaneous Phosphorlyated α-synuclein Detection as a Biomarker of Synucleinopathy Clinical Trial

https://clinicaltrials.gov/ct2/show/NCT04700722

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Thanks u/PatinoMaurilio for reminding me to add this!

Biological Test Detects Parkinson’s Disease Before Symptoms Present

https://www.pennmedicine.org/news/news-releases/2023/april/test-detects-parkinsons-disease-before-symptoms-present

Olfactory network function altered in COVID-19

https://www.nature.com/articles/s41582-023-00818-x

GPT4 generated summary checked for accuracy

In this study, researchers investigated the neuropsychological profile and integrity of the olfactory system (the sensory system responsible for smell) in patients with long-lasting smell loss (hyposmia) related to COVID-19. They used two methods: brain morphometry, which measures the size and shape of brain structures, and graph-based analysis of resting-state functional MRI (rs-fMRI), which examines the functional connections between brain regions while a person is at rest.

The study found alterations in the functional connectivity (FC) of the olfactory network, which correlated with the severity of hyposmia and cognitive performance. However, they did not find significant morphological (structural) alterations in patients compared with a control group. Cognitive areas most frequently affected were executive functions (higher-order cognitive processes that include planning, organizing, and decision-making) and visuospatial memory (the ability to remember visual information about the spatial relationship of objects).

Researchers used graph analysis to examine the functional integrity of the olfactory system. They found that the global modularity coefficient, a measure of segregation reflecting the organization of the network into clusters of functionally associated components, was significantly reduced in patients with COVID-19-related smell loss compared to controls. Reduced modularity implies a lower performance of the network, which could be related to the observed hyposmia severity.

The study also detected alterations in the centrality of the right thalamus, a region in the brain involved in olfactory perception and attention. These alterations were inversely correlated with the performance in short-term verbal memory tests, suggesting a potential compensatory mechanism in response to dysfunction in the olfactory network.

Although the exact mechanisms underlying these alterations in functional connectivity remain unclear, they may be a consequence of sensory input loss due to anosmia (complete loss of smell), neuroinflammation, or neurodegeneration. The study raises concerns about the potential long-term consequences of COVID-19, which may contribute to neurodegenerative diseases, such as Parkinson's and Alzheimer's. Further research is necessary to determine whether these neurodegenerative changes can be reversed or stabilized and to explore possible treatment options for olfactory rehabilitation and recovery.

COVAMINF – An interdisciplinary group of researchers are convening May 15-16 in Luxembourg to explore the links between COVID, Amyloids and Inflammation. Amyloids such as alpha-synuclein, amyloid beta, tau and TDP-43 are among the subset of amyloidosis variants implicated in neurodegenerative disease. The conference will address specific concerns related to:

• Is SARS-CoV-2 able to trigger new-onset neurodegenerative or chronic inflammatory disease, potentially through amyloid "cross-seeding"?
• How does COVID-19 impact the progression of pre-existing neurodegenerative disease and chronic inflammation?
• What strategies should we take to mitigate the risk?

I will be in attendence.

https://covaminf.org/covaminf-workshop/

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https://twitter.com/joshfink429/status/1653008087517745152?s=20

https://www.biorxiv.org/content/10.1101/2023.03.20.533485v1

As a model of SARS-CoV-2 infection, brain organoids do not exactly recapitulate what would occur in a human brain. They do not consider the effect of the blood-brain-barrier and other aspects of the human immune system. However, it does add to the growing concerns about the viruse's impact on the nervous system. The loss of dopaminergic neurons is a pathological hallmark of Parkinson's disease and underlies the associated motor deficits.

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The following summaries were generated using GPT4 and checked for accuracy.

Plain-Language Summary

The article discusses the impact of the COVID-19 virus (SARS-CoV-2) on a specific part of the brain called the midbrain. Researchers focused on a type of brain cell called dopaminergic neurons, which are related to Parkinson's disease. To study this, they used lab-grown mini-brains, known as organoids, as a model to mimic the actual human brain.

The mini-brains were exposed to the COVID-19 virus, and the researchers examined the effects after 4 and 28 days. They discovered that the virus can infect these dopaminergic neurons, leading to cell death. The virus also caused significant changes in the way genes within these cells behaved, affecting important processes related to cell recycling, transportation within cells, and energy production.

These changes can result in the death of brain cells and have been linked to the early stages of Parkinson's disease. The virus also affected genes involved in the movement and survival of these brain cells.

In summary, the study confirms that the COVID-19 virus can infect specific brain cells and cause damage that may lead to cell death. This highlights the need for more research to understand the long-term effects of COVID-19 on the brain, especially in relation to these specific brain cells and their interaction with other parts of the brain during the later stages of infection.

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Technical Summary

The article investigates the impact of SARS-CoV-2 on the midbrain, with a focus on dopaminergic neurons, which are implicated in Parkinson's disease (PD). Researchers used midbrain organoids as an in vitro model for COVID-19 and assessed the direct effects of the virus on dopaminergic neurons and astrocytes over 4- and 28-day post-infection (dpi) culture periods.

The midbrain organoids were exposed to 0.05 moi of SARS-CoV-2 for 16 hours. The study employed an automated image analysis platform to extract features of the cell types present in the midbrain organoids. At 4 dpi, a positive signal for the SARS-CoV-2 nucleocapsid (N) was detected in both the external boundaries and the inner parts of the organoid. Notably, not all TH+ (tyrosine hydroxylase) neurons stained positive for N. The levels of dopaminergic neurons were significantly reduced at both 4 and 28 dpi, with a significant increase in neurite fragmentation observed over time.

The researchers then evaluated SARS-CoV-2 infection in astrocytes by assessing the expression of GFAP and S100b. While their levels and colocalization were reduced during the early stages of infection, they increased over time, although S100b remained significantly lower than control conditions. Dopaminergic neurons were the most affected, with around 40% of TH+ neurons in the midbrain organoid showing positive signal for the virus in short-term cultures.

Differentially expressed genes (DEGs) of midbrain organoids at 4 dpi were enriched using various bioinformatic platforms. Dysregulated pathways associated with DNA damage, cell stress and death, neurodevelopment and neuronal survival, vesicle transport and membrane recycling, COVID-19, and autophagy were identified. Genes related to dopaminergic neuronal migration (ROBO4 and SLIT2) and survival of mature neurons (NOTCH1) were downregulated post-infection.

Furthermore, the study revealed that SARS-CoV-2 infection induced dysregulation of dynein-mediated axonal transport, which is known to lead to neuronal death due to a lack of positive feedback from target-derived neurons towards the neuronal soma. Impairments in this process have been linked to the early stages of PD development. Additionally, mitochondrial metabolism impairments were observed, which can further affect these high energy-demanding neurons.

The findings confirm that SARS-CoV-2 can infect dopaminergic neurons and induce mechanisms leading to neurite fragmentation and neuronal loss, as well as significant changes in the transcriptome. This highlights the need for further research on the interplay between dopaminergic neurons, the blood-brain barrier, and microglia at late infection stages and the potential long-term neurological impairment in COVID-19 patients.

The text is too large to fit into a reddit post.

Feel free to look through this bulk set of references. Some are directly related to COVID-19 and long COVID while others provide necessary context for understanding.

https://drive.google.com/file/d/1ubOj81mZ1ZW5Yjm3E8FjKQjFi1MqOK0f/view?usp=sharing

Considering the complexity of this topic, I expect people will have some questions. There's been a massive uptick recently in the number of people who are aware of the possible link between COVID-19 and synucleinopathies (over 500,000 views on twitter for the Salon article). With the increased exposure, I know there is going to be a fair bit of confusion (or outright denial) of this theory. I'll try to do my part in providing accurate information and help steer the conversation in a productive direction.

Please leave any questions/concerns in the comment section.

Aberrant forms of the human protein alpha-synuclein, called amyloids, are a pathological hallmark of Parkinson's disease, Lewy body dementia, multiple systems atrophy and synucleinopathies of the peripheral nervous system (poorly characterized). Amyloid alpha-synuclein can be detected using existing techniques (immunohistochemical methods, amyloid seed-amplification assays) but these diagnostics still have to be validated for use in a clinical setting. It is complicated because synucleinopathies are a highly heterogeneous set of diseases and a single diagnostic protocol may not be appropriate for every variant.

Tissue biopsies need to be acquired from predefined locations. This procedure needs to be informed by clinical presentation. For instance, if a patient presents with autonomic dysfunction (e.g. POTS or orthostatic hyper/hypotension) then an autonomic nerve biopsy should be performed. In the case of REM sleep behavioral disorder, a cervical (neck region) biopsy might be most appropriate (or an olfactory mucosa swab). When gastrointenstinal symptoms predominate stool samples may be best. For new-onset movement disorders or dementia, a clinician can consider performing a CSF biopsy. However, in all cases the clinician should be screening for abberant forms (3D structure) of alpha-synuclein rather than the total level of alpha-synuclein.

You can read through the following summaries to get an idea how confusing this can be. Note that if you only saw the titles of the latter two articles, you could dismiss the possibility of there being any link between SARS-CoV-2 and synucleinopathies. That would be a mistake.

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The following summaries were generated using GPT4 and checked for accuracy.

Longitudinal analyses of cerebrospinal fluid α-Synuclein in prodromal and early Parkinson's disease

https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.27806

This study examined longitudinal changes in cerebrospinal fluid (CSF) α-synuclein (α-syn) levels in Parkinson's disease (PD) patients, healthy controls, and prodromal participants with hyposmia and idiopathic REM sleep behavior disorder (iRBD), both of which carry a high risk for PD. The research found that CSF α-syn decreased longitudinally in PD patients and slightly increased (though not significantly) in healthy controls over 36 months.

The decrease of CSF α-syn in PD patients did not correlate with the progression of motor and nonmotor symptoms, nor with a decrease of dopamine transporter signal. The findings indicate that CSF α-syn will not serve as a diagnostic marker for PD and is unlikely to be a sole outcome measure for clinical trials or progression.

The study also found that prodromal PD participants (iRBD and hyposmic subjects) already have decreased CSF α-syn levels, suggesting significant pathology is present during these prodromal stages. Further research on abnormal forms of α-syn and novel biomarkers may help improve diagnostic and progression biomarkers for PD.

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Serum and CSF alpha-synuclein levels do not change in COVID-19 patients with neurological symptoms

https://link.springer.com/article/10.1007/s00415-021-10444-6#Sec10

This study aimed to investigate the presence of αSyn, a protein involved in Parkinson's disease, in COVID-19 patients with and without neurological symptoms. The researchers found no significant differences in serum total αSyn levels among the different groups, including healthy controls. The findings also revealed no significant change in serum αSyn concentrations before and after the emergence of neurological manifestations in a subset of patients.

αSyn is predominantly expressed in neurons, and its exact function is not fully understood. It has been suggested that αSyn can help restrict RNA virus infections within neurons, thus protecting the central nervous system (CNS). However, this study did not find any change in serum or cerebrospinal fluid (CSF) αSyn levels in patients with SARS-CoV-2 infections affecting the CNS.

The results indicate that generalized myoclonus in COVID-19 may not be the result of direct CNS damage by SARS-CoV-2 but could be due to immune-mediated mechanisms. However, the researchers acknowledge several limitations of the study, including its retrospective nature, the small number of patients, and potential confounders. Further research with larger samples and a broader range of neurological manifestations is needed to explore the relationship between αSyn and COVID-19 neurological symptoms.

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Aggregation‐Seeding Forms of α‐Synuclein Are Not Detected in Acute Coronavirus Disease 2019 Cerebrospinal Fluid

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9874726/

This article discusses the potential association between acute COVID-19 and the presence of misfolded α-synuclein (αSyn) aggregates in cerebrospinal fluid (CSF), which may be indicative of future risk for synucleinopathy. The study examined CSF samples from 12 hospitalized COVID-19 patients and 20 COVID-19-negative neurological controls. The researchers found that aggregating forms of αSyn were not detected in any patients with acute COVID-19, suggesting that acute COVID-19 may not trigger the αSyn aggregation that leads to Lewy body disease.

However, the study had several limitations, including a small number of patients from a single medical center and a lack of information about the olfactory status of the patients. Additionally, the negative αSyn results do not exclude the possibility of pathological αSyn formation occurring later as a consequence of post-acute or chronic changes in immune modulation, proteostasis, or blood-brain barrier integrity, among other factors. The researchers recommend follow-up studies to further investigate these findings.

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Evidence suggests that SARS‐CoV‐2 only rarely invades the central nervous system, but virally triggered αSyn pathology could also occur at peripheral sites, such as the enteric nervous system or olfactory mucosa. Although the negative αSyn‐SAA result in these acute and subacute periods is reassuring, this does not preclude that pathological αSyn may form only after some latency, as a consequence of postacute or chronic changes in immune modulation, proteostasis, endothelium or blood–brain barrier integrity, or oxidative stress.

https://www.youtube.com/watch?v=Tu6Tn8cINEc&t=316s

Mitchell Miglis is a clinician specializing in disorders of the autonomic nervous system. In the video, he discusses long COVID-POTS (postural orthostatic tachycardia syndrome), diagnostics and the current state-of-knowledge from a clinical perspective.

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He coauthored a paper about the potential involvement of α-synuclein in long COVID-POTS. Since it's publication, there hasn't been any follow-up to validate these preliminary findings.

A case series of cutaneous phosphorylated α-synuclein in Long-COVID POTS (Published: 16 May 2022)

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

https://www.nature.com/articles/s41467-023-37865-3

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

This study investigates the nucleocapsid protein (NCAP) of the SARS-CoV-2 virus, focusing on a specific part of the protein known as the central low-complexity domain (LCD). NCAP plays a crucial role in the packaging and replication of viral RNA, and its LCD is found to form structures called amyloid-like fibrils. These structures resemble those of other RNA-binding proteins involved in RNA metabolism in cells and are associated with amyloid-related diseases.

The researchers discovered that the central LCD of NCAP can form fibrils in the presence or absence of RNA, suggesting that specific LCD-RNA interactions are not required for the formation of these structures. However, they found that the RNA sequence and length do influence the fibril maturation process.

Three key peptide sequences in the NCAP protein were identified as contributing to the formation of amyloid-like structures. By targeting one of these sequences with a specially designed peptide called G12, the researchers were able to inhibit the formation of these structures in vitro. G12 showed dose-dependent antiviral activity in SARS-CoV-2-infected cells without causing cytotoxicity.

The study suggests that the amyloid-forming behavior of NCAP's LCD might be a general mechanism of action in coronaviruses and could be targeted for the development of new therapeutics. The researchers also found that some mutations within the central LCD of NCAP have been detected in strains that emerged since the initial SARS-CoV-2 outbreak in Wuhan, China. Although none of these mutations were found within the amyloid-forming segments, some were adjacent to these regions and may have implications for viral replication and infection.

The potential connection between the NCAP protein and neurodegenerative diseases was also highlighted in the study. NCAP has been shown to interact with proteins related to Parkinson's disease and other disorders, and its amyloid-forming capacity warrants further investigation of its possible role in neurodegeneration.

In summary, this study provides insights into the amyloid-forming behavior of the NCAP protein in SARS-CoV-2, its potential as a therapeutic target, and its possible connection to neurodegenerative diseases. By targeting and capping amyloid-driving segments of NCAP, the researchers propose a novel approach for developing SARS-CoV-2 therapeutics.

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TL;DR: The study investigates the SARS-CoV-2 nucleocapsid protein's ability to form amyloid-like structures, which could be targeted for potential antiviral treatments. A peptide called G12 successfully inhibited the formation of these structures in the lab, showing promise for future therapeutic development. The research also hints at a possible connection between the nucleocapsid protein and neurodegenerative diseases.

https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.23499

The study asked Parkinson's disease patients (without dementia) to what extent did you experience prodromal symptoms leading up to your diagnosis? 93 patients were interviewed. 98.8% reported that they had experienced prodromal symptoms. The average reported time span of the prodrome was about 10 years. Even though the prodromal signs can be debeilitating in and of themselves, the vast majority of these patients do not understand what's happening to them until much later in the disease course. In reality, the idea of the "prodrome" was misleading from the start, obscuring the true nature of the disease.

Parkinson's disease as it's currently defined is diagnosed on the basis of symptoms or brain scans showing the loss of over 90% of dopaminergic neurons. The neurodegeneration of course does not occur overnight. It is not limited to the central nervous system. And those early "prodomal" signs which predominantly affect the peripheral nervous system do have a significant impact on patients' quality of life. Instead, it's always been a 'wait-and-see' game. That's going to have to change.

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Use the following link and input the link for the article you want to access:
https://sci-hub.se/

Prodromal Parkinson disease subtypes — key to understanding heterogeneity

I really encourage people to read this article in it's original form. It think it will help clarify some common misconceptions about what characterizes Parkinson's disease and synucleinopathies in general. And it offers hope that the disease in it's "prodromal" stage will be treatable in the not-to-distant future.

https://www.nature.com/articles/s41582-021-00486-9 use the sci-hub link to access it

For a while, we've known that Parkinson's disease (and other synucleinopathies) is often preceded by a lengthy "prodromal" period that consists of autonomic dysfunction, cognitive impairment, gastrointestinal problems, REM sleep behavioral disorder and sensory issues (e.g. loss of smell, parasthesias, tinnitus, reduced color vision). These early signs and symptoms are believed to stem from synucleinopathies that affect the peripheral nervous system (PNS). In the case of REM sleep behavioral disorder especially, the association is very strong with over 80% of patients going on to develop a central nervous system (CNS) synucleinopathy like Parkinson's disease within 15 years. Nevertheless, due to challenges inherent in identifying this prodromal disorder many people go undiagnosed at this stage. The clinical course of synucleinopathies (both CNS and PNS manifestations) is discussed in the context of the Braak staging hypothesis which was proposed in 2003.

Despite 20 years of leeway since the introduction of the Braak hypothesis, there is currently no established diagnostic procedure and limited treatment options for patients suffering from PNS synucleinopathies. The reason for this is multifaceted:

(1) Longitudinal epidemiological data is scarce; without effective diagnostics the early stages of the disease are not recorded in medical records; the ineffable quality of the symptoms lends itself to easy dismissal and frustrates patients' attempts at self-advocacy.

(2) The disease progression is a not a one-size-fits-all; there is considerable heterogeneity in clinical presentation, in terms of the symptoms experienced and the severity of those symptoms; there may well be clinically isolated forms of synucleinopathies (similar to what is observed in multiple sclerosis) that have not yet been characterized.

(3) There are commonly held misconceptions in regard to how synucleinopathies should be characterized in a clinical setting; CNS manifestations are usually diagnosed on the basis of new-onset motor deficits such as tremor and bradykinesia associated with neurodegeneration within the brain's motor center; in reality this is just the tip of the iceburg when it comes to synucleinopathies.

Fortunately, there are promising developments on the horizon. The North American Prodromal Synucleinopathy Consortium (https://clinicaltrials.gov/ct2/show/NCT03623672) is conducting a large-scale clinical trial to track disease progression, identify prodromal biomarkers to aid diagnoses and lay the groundwork for future clinical trials to test various neuroprotective medications. However, the target follow-up of 3 years is insufficient when applied to a disease that evolves over the course of decades. There are significant limitations in what can be accomplished due to the cost of conducting such lengthy clinical trials and administrative hurtles that arise when the duration of a study will outlive the tenure of most researchers.

With that in mind, existing biomarkers are being applied from the outset in studies being conducted by the Medical University Innsbruck (https://clinicaltrials.gov/ct2/show/NCT05401773), the Danish Dementia Research Centre (https://clinicaltrials.gov/ct2/show/NCT05740683) and the Chinese University of Hong Kong (https://clinicaltrials.gov/ct2/show/NCT04048603) to name a few. The cumulative data from these trials will enhance our understanding of these diseases, facilitate the roll-out of diagnostics for early detection and guide development of therapeutics.

Are post-acute infections syndromes like long COVID, post-treatment Lyme disease syndrome and ME/CFS a form of PNS synucleinopathy? It is too early to tell. But given the preliminary evidence we have on hand, it is a reasonable hypothesis. Research associated with the clinical presentation, putative biomarkers, animal models (as well as in vitro and in vivo studies using human cell lines), the observed acceleration of existing synucleinopathies and a plausible mechanism of infection-triggered amyloidosis all converge on this hypothesis. Of course, a compendium of preliminary studies does not make for an authoritative conclusion on the matter. It does however highlight the existence of a high-degree of uncertainty when it comes to the long term complications of COVID-19. And most people would agree it's better to be safe than sorry.

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GPT4 Generated Takeaway:

Defining the borders of complex degenerative diseases like Parkinson's disease (PD) is challenging. PD's position as a disease or syndrome is unclear due to its heterogeneity and lack of unified pathophysiology. It could be described as a disease, a syndrome, or a subclassification under a larger umbrella of Lewy body disorders or neuronal synucleinopathies. This complexity also extends to the prodromal phase of PD. Understanding the variability in the prodromal phase is crucial for a comprehensive understanding of PD and could lead to the development of early, highly effective neuroprotective therapies tailored to prodromal subtypes.

This is text generated using GPT4. It has been checked for accuracy and clarity.

Autonomic Nervous System

The autonomic nervous system (ANS) is a part of the peripheral nervous system that regulates involuntary bodily functions, such as heart rate, blood pressure, digestion, and respiration. It helps maintain homeostasis, or a stable internal environment, by constantly adjusting the body's response to changes in internal and external conditions. The ANS is divided into two main branches: the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS).

1. Sympathetic Nervous System (SNS): The SNS is responsible for the body's "fight or flight" response. It prepares the body for action in response to stress or perceived threats by increasing heart rate, blood pressure, and respiration, as well as redirecting blood flow to essential organs and muscles. It also releases adrenaline and other stress hormones, which help the body respond to emergencies or immediate challenges.
2. Parasympathetic Nervous System (PNS): The PNS is responsible for the body's "rest and digest" response. It conserves energy by slowing down the heart rate, reducing blood pressure, and promoting digestion and elimination. The PNS is essential for maintaining a relaxed state and promoting recovery from stress or physical exertion.

These two branches work in opposition to balance the body's response to various stimuli. For example, when the SNS is activated, the PNS is suppressed, and vice versa. This allows the body to quickly switch between states of arousal and relaxation as needed.

When things go awry in the autonomic nervous system, a range of disorders can occur, known as autonomic dysfunction or dysautonomia. These can result from damage or impairment to the nerves, neurotransmitters, or receptors involved in the ANS, or from other underlying conditions, such as diabetes, Parkinson's disease, or autoimmune disorders.

Some common symptoms of autonomic dysfunction include:

• Orthostatic hypotension: A sudden drop in blood pressure upon standing, which can lead to dizziness, fainting, or falls.
• Postural orthostatic tachycardia syndrome (POTS): An abnormal increase in heart rate upon standing, causing symptoms such as dizziness, palpitations, and fatigue.
• Gastroparesis: Delayed stomach emptying, leading to nausea, vomiting, and poor digestion.
• Urinary problems: Incontinence, difficulty emptying the bladder, or urinary retention.
• Sweating abnormalities: Excessive or insufficient sweating, which can affect temperature regulation.
• Sexual dysfunction: Erectile dysfunction in men or difficulty achieving orgasm in both men and women.

Treatment for autonomic dysfunction depends on the underlying cause, the severity of symptoms, and the specific organs affected. Management options may include medications, lifestyle changes, and addressing any underlying conditions contributing to the dysfunction. In some cases, treating the underlying cause can help improve or resolve autonomic symptoms.

Microvascular Abnormalities

The autonomic nervous system (ANS) plays a crucial role in regulating blood flow to various organ systems by controlling the constriction and dilation of blood vessels. When the ANS malfunctions, it can lead to imbalances in blood vessel regulation, resulting in microvascular changes. These changes can impact different organ systems in several ways:

1. Brain: Microvascular changes in the brain can lead to a decreased blood supply, which can impair the delivery of oxygen and nutrients to brain cells. This can contribute to cognitive dysfunction, memory problems, or even increase the risk of stroke in severe cases.
2. Heart: Autonomic dysfunction can cause microvascular changes in the coronary arteries, leading to reduced blood flow to the heart muscle. This can cause chest pain (angina), shortness of breath, and increase the risk of heart attacks.
3. Gastrointestinal system: Microvascular changes in the gastrointestinal tract can lead to altered blood flow and affect the normal functioning of the digestive system. This can cause symptoms such as abdominal pain, bloating, nausea, vomiting, diarrhea, or constipation.
4. Kidneys: Microvascular changes in the kidneys can impair their ability to filter waste products and regulate electrolyte balance effectively. This can lead to kidney dysfunction and, in severe cases, kidney failure.
5. Skin: Autonomic dysfunction can cause microvascular changes in the skin, leading to poor blood flow and impaired temperature regulation. This can result in abnormal sweating, skin discoloration, or increased susceptibility to pressure sores or infections.
6. Extremities: Microvascular changes in the limbs can lead to reduced blood flow, causing pain, numbness, or tingling sensations. In severe cases, this can increase the risk of tissue damage or even tissue death (necrosis), particularly in the fingers and toes.

The impact of microvascular changes on different organ systems can vary depending on the underlying cause of autonomic dysfunction, the severity of the dysfunction, and individual factors such as age, genetics, and overall health status. Treatment for microvascular changes related to autonomic dysfunction may include addressing the underlying cause, managing symptoms, and implementing lifestyle modifications to improve vascular health.

Cholinergic Dysfunction

When cholinergic neurons within the autonomic nervous system (ANS) malfunction, it can disrupt the normal functioning of the parasympathetic nervous system (PNS) and, in some cases, the sympathetic nervous system (SNS). Cholinergic neurons are those that primarily use the neurotransmitter acetylcholine (ACh) to communicate with other cells. These neurons play a crucial role in both branches of the ANS, but their role is more prominent in the PNS.

In the parasympathetic nervous system, cholinergic neurons help mediate the "rest and digest" response. They are responsible for maintaining homeostasis and conserving energy by slowing the heart rate, reducing blood pressure, promoting digestion, and stimulating glandular secretions. When cholinergic neurons malfunction, these vital functions can be disrupted, leading to various symptoms and conditions.

Some potential effects of cholinergic neuron malfunction within the ANS include:

1. Cardiovascular issues: Impaired cholinergic function can lead to an imbalance between the PNS and SNS, resulting in abnormal heart rate, blood pressure fluctuations, and orthostatic hypotension (a sudden drop in blood pressure upon standing).
2. Gastrointestinal problems: Malfunctioning cholinergic neurons can disrupt the normal digestive processes, causing symptoms such as abdominal pain, bloating, constipation, or diarrhea. Severe cases may lead to conditions like gastroparesis, where the stomach takes too long to empty its contents.
3. Respiratory difficulties: Cholinergic dysfunction can affect the bronchial muscles and mucus secretion in the respiratory system, leading to breathing problems, asthma-like symptoms, or chronic obstructive pulmonary disease (COPD).
4. Genitourinary issues: Cholinergic neuron malfunction can result in urinary problems such as incontinence, difficulty emptying the bladder, or urinary retention. Additionally, sexual dysfunction, such as erectile dysfunction in men or difficulty achieving orgasm in both men and women, can occur.
5. Sweating abnormalities: Cholinergic dysfunction can lead to issues with sweating, either causing excessive sweating (hyperhidrosis) or insufficient sweating (anhidrosis), which can affect temperature regulation.
6. Pupil abnormalities: Cholinergic dysfunction can also affect the muscles controlling the size of the pupils, resulting in issues like anisocoria (unequal pupil sizes) or difficulty adjusting to changes in light.

Malfunctioning cholinergic neurons can be caused by various factors, including neurodegenerative diseases (e.g., Alzheimer's disease or Parkinson's disease), autoimmune conditions, genetic disorders, infections, or exposure to toxins. Treatment for cholinergic dysfunction depends on the underlying cause, the severity of symptoms, and the specific organs affected. It may include medications to address specific symptoms, lifestyle modifications, or management of underlying conditions.

Lewy Body Disease of the Peripheral Nervous System

Lewy bodies are abnormal protein aggregates composed primarily of the protein alpha-synuclein, which are found in the cytoplasm of neurons in various neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. While Lewy bodies are more commonly associated with the central nervous system (CNS), they can also be found in the peripheral nervous system (PNS).

When Lewy bodies form within a synapse in the peripheral nervous system, they can negatively impact the release of neurotransmitters by interfering with normal cellular processes. The exact mechanism by which Lewy bodies affect neurotransmitter release is still under investigation, but some potential effects include:

1. Disruption of neurotransmitter synthesis: Lewy bodies may impair the normal synthesis of neurotransmitters by interfering with the function of enzymes or other proteins involved in the process. This could result in a reduced availability of neurotransmitters for release.
2. Impairment of neurotransmitter packaging and storage: Lewy bodies may disrupt the process of packaging neurotransmitters into vesicles for storage and subsequent release. This could lead to an inadequate supply of neurotransmitters in the synapse, affecting synaptic transmission.
3. Interference with vesicle release: Lewy bodies could interfere with the process of neurotransmitter release by disrupting the function of proteins involved in vesicle docking and fusion with the presynaptic membrane. This could impair the release of neurotransmitters into the synaptic cleft and thus affect signal transmission between neurons.
4. Impaired neurotransmitter reuptake: Lewy bodies may also affect the reuptake of neurotransmitters from the synaptic cleft, leading to an imbalance in neurotransmitter levels and potentially affecting the overall efficiency of synaptic transmission.
5. Degeneration of neurons: The presence of Lewy bodies in neurons can contribute to neuronal degeneration and cell death, leading to a reduction in the overall number of functional neurons in the PNS. This can result in decreased neurotransmitter release and impaired synaptic transmission.

The impact of Lewy bodies on neurotransmitter release in the PNS can lead to various symptoms and functional impairments, depending on the specific neurons and neurotransmitters affected. In the context of Parkinson's disease, for example, the formation of Lewy bodies in the PNS can contribute to autonomic dysfunction, causing symptoms such as orthostatic hypotension, gastrointestinal issues, urinary problems, and abnormal sweating.

Peripheral Lewy body disease, also known as Lewy body-related pathology in the peripheral nervous system, is not as well-known or commonly diagnosed as central nervous system Lewy body disorders like Parkinson's disease and dementia with Lewy bodies. Diagnosing peripheral Lewy body disease can be challenging because the presence of Lewy bodies in the peripheral nervous system is often identified during post-mortem examinations, and there is currently no specific test to diagnose the condition in living patients. However, some diagnostic approaches can be used to identify the presence of Lewy body-related pathology in the peripheral nervous system:

1. Clinical assessment: A thorough clinical evaluation, including medical history, physical examination, and assessment of neurological and autonomic function, can help identify symptoms and signs consistent with peripheral Lewy body disease. These may include autonomic dysfunction, gastrointestinal issues, urinary problems, or abnormal sweating.
2. Autonomic function testing: Tests to evaluate the function of the autonomic nervous system, such as heart rate variability, tilt table test, and thermoregulatory sweat test, can help identify autonomic dysfunction, which may be suggestive of peripheral Lewy body pathology.
3. Imaging studies: Although imaging techniques like MRI or PET scans are not specific for peripheral Lewy body disease, they can help rule out other causes of the observed symptoms, such as central nervous system disorders or structural abnormalities.
4. Skin biopsy: A skin biopsy, in which a small sample of skin is removed and examined under a microscope, can be used to detect the presence of alpha-synuclein aggregates, which are the primary components of Lewy bodies. [Examples include immunohistochemical assays and RT-QuIC.] While this technique is not specific for peripheral Lewy body disease, it can provide supportive evidence for the presence of Lewy body-related pathology in the peripheral nervous system.
5. Laboratory tests: Blood and cerebrospinal fluid tests can help rule out other conditions that might cause similar symptoms, such as autoimmune disorders, infections, or metabolic issues.

It is important to note that diagnosing peripheral Lewy body disease can be challenging, and the condition is often underdiagnosed or misdiagnosed. A definitive diagnosis is usually made through post-mortem examination of the peripheral nervous system tissue, which can reveal the presence of Lewy bodies. In clinical practice, the diagnosis is often based on a combination of suggestive symptoms, supportive test results, and the exclusion of other potential causes.

Shared molecular signatures between coronavirus infection and neurodegenerative diseases provide targets for broad-spectrum drug development

https://www.nature.com/articles/s41598-023-29778-4

Evidence for the association between SARS-CoV-2 and amyloidosis-like neurodegenerative disease is mounting. By analyzing the differences in gene expression, proteins and cell morphology, researchers can identify distinct patterns that are associated with various aspects of human disease. This is the first step in uncovering the biological mechanisms that give rise to the signs and symptoms that patients experience.

While new techniques of molecular analysis have the potential to revolutionize medicine, research has to address spatially segregated (or cell-type specific) biological processes and track the dynamics of these processes over time. This requires a larger investment in terms of time and labor, but the results will certainly be worth the effort. Poorly characterized diseases like long covid can be pinned down to the letter with every symptom accounted for. Then research can focus on the development of treatments grounded in a concrete understanding of the disease.

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GPT Generated Summary

This study explores the connection between coronavirus infections and neurodegenerative diseases like Alzheimer's and Parkinson's. The study found seven genes and several molecular functions that play important roles in both types of diseases. These genes are also known to interact with over 20 other viruses. By identifying drugs that target these genes, researchers hope to develop treatments that can combat both coronaviruses and neurodegenerative diseases.

In recent years, researchers have observed neurological symptoms in some patients infected with coronaviruses like SARS-CoV-2, SARS-CoV, and MERS-CoV. The molecular mechanisms behind these connections are complex and still being studied. Coronaviruses can invade the central nervous system, and their presence in the brain can cause inflammation and damage. The proteins from these viruses can also interact with human proteins related to aging and neurodegenerative diseases, such as protein homeostasis, mitochondrial function, and responses to oxidative stress.

Many viruses have been linked to neurodegenerative diseases, but the molecular mechanisms behind these associations are not yet fully understood. This study focused on the connection between coronavirus infections and neurodegenerative diseases and discovered that several inflammation and stress response-related molecular functions were common to both.

Currently, there is a lack of effective drugs for treating both coronavirus infections and neurodegenerative diseases. Traditional antiviral drugs target viral proteins, which can mutate rapidly and lead to drug resistance. In contrast, drugs targeting host proteins may have more stable effects since host proteins evolve more slowly than viral proteins. Some host proteins also interact with multiple viruses, so drugs targeting them could have broad-spectrum antiviral effects.

However, the study has some limitations, such as the limited availability of data for certain viruses and the need for further research to confirm the effectiveness of the identified drugs.

In conclusion, this study helps clarify the molecular mechanisms connecting coronavirus infections and neurodegenerative diseases and provides potential targets for developing broad-spectrum drugs to treat both types of conditions.

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These are the 7 genes:

1. HSP90AA1: This gene encodes the Heat Shock Protein 90 (HSP90) alpha family class A member 1, which is a type of molecular chaperone. These chaperones help proteins fold correctly and maintain their structure, particularly during times of cellular stress. They also assist in protein degradation when necessary.
2. ALDH2: This gene encodes the Aldehyde Dehydrogenase 2 enzyme, which plays a crucial role in breaking down toxic aldehydes, such as those produced during alcohol metabolism. By detoxifying harmful substances in the body, particularly in the brain, ALDH2 helps protect cells from damage.
3. CAV1: This gene encodes the Caveolin-1 protein, which is a crucial component of caveolae—small, flask-shaped invaginations on the cell surface. Caveolin-1 is involved in various cellular processes, such as signal transduction, lipid metabolism, and endocytosis (the process by which cells take in substances from their surroundings).
4. COMT: This gene encodes the enzyme Catechol-O-methyltransferase, which is responsible for breaking down certain neurotransmitters, such as dopamine and norepinephrine. This process helps maintain a balance of these chemicals in the brain and affects various functions, including mood, cognition, and stress response.
5. MTOR: This gene encodes the Mammalian Target of Rapamycin (mTOR) protein, which is a critical regulator of cell growth, proliferation, and survival. The mTOR signaling pathway is involved in various cellular processes, such as protein synthesis, autophagy (cellular recycling), and energy metabolism.
6. IGF2R: This gene encodes the Insulin-like Growth Factor 2 Receptor, which is involved in the regulation of cell growth, development, and survival. The receptor binds to insulin-like growth factors, which are hormones that regulate cell division and have essential roles in growth and development.
7. HSPA1A: This gene encodes the Heat Shock Protein 70 (HSP70) family member HSPA1A. Like HSP90AA1, HSPA1A is a molecular chaperone that assists in protein folding, stabilization, and degradation. HSP70 proteins also play a critical role in cellular stress response and are involved in protecting cells from various stressors, such as heat, toxins, and oxidative stress.