Parkinsons Disease / Covid 19 & Parkinsons

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trader32176
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Parkinsons Disease / Covid 19 & Parkinsons

Post by trader32176 »

Parkinson's disease is an independent risk factor for dying from COVID-19, study suggests

10/1/20

https://www.news-medical.net/news/20201 ... gests.aspx

A new study of approximately 80,000 patients shows that people with Parkinson's disease (PD) have a 30% higher risk of dying from COVID-19 than people without the neurodegenerative condition.

The new analysis conducted by researchers with University of Iowa Health Care based on patient data in the TriNetX COVID-19 research network suggests that Parkinson's disease is an independent risk factor for dying from COVID-19.

The UI research team led by neurologists Qiang Zhang, MD, and Nandakumar Narayanan, MD, PhD, identified the COVID-19 patient cohort as of July 15 and analyzed the mortality data eight weeks later. They found that 5.5% (4,290 out of 78,355) of COVID-19 patients without PD died compared to 21.3% (148 of 694) COVID-19 patients who also had PD.

However, the patients with PD were generally older, more likely to be male, and less likely to be African American than the patients without PD. All of these factors also increase the risk of death from COVID-19.

So, the UI team used two approaches to account for these differences: logistic regression with age, sex, and race as covariates, and matching each PD patient with five non-PD patients with the exact age, sex, and race, and performing a conditional logistic regression. In both cases, the researchers found that the risk of dying from COVID-19 was 30% higher for patients with PD. The findings are published in the journal Movement Disorders.


" We recognize the limitations of this study; it is retrospective data from a single database, but we are confident that these data show that Parkinson's disease is independent risk factor for death in COVID-19. We believe this observation will be of interest to clinicians treating patients with Parkinson's disease, and public health officials."

- Nandakumar Narayanan, UI associate professor of neurology and a member of the Iowa Neuroscience Institute

The researchers say the findings should also inform patients with PD, and their physicians, of the increased importance of preventing COVID-19 infection in these patients.

"For our own patients, we can give advice that it's important that you wear a mask. It's important that you socially distance," says Zhang, an associate in the UI Department of Neurology.

Zhang adds that physicians should also weigh the increased risk of death from COVID-19 when considering how to care for PD patients in person during the pandemic.

A potential reason why PD patients have an increased risk of death from COVID-19 may be related to the fact that COVID can cause pneumonia and pneumonia is a leading cause of death in patients with PD. This is partly because Parkinson's patients can have trouble swallowing or choking that can cause aspiration.

"We are all focused on COVID right now, but this is a clear example of a respiratory illness that leads to increased mortality [in PD patients]. These findings may also have implications for understanding risks for PD patients from other diseases, including influenza," Narayanan says. "I would recommend a flu vaccine and pneumonia vaccine to try to prevent these problems in patients with PD."
trader32176
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Re: Parkinsons Disease / Covid 19 & Parkinsons

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COVID-19 and possible links with Parkinson’s disease and parkinsonism: from bench to bedside

August 20, 2020

https://www.nature.com/articles/s41531-020-00123-0

Abstract

This Viewpoint discusses insights from basic science and clinical perspectives on coronavirus disease 2019 (COVID-19)/severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection in the brain, with a particular focus on Parkinson’s disease. Major points include that neuropathology studies have not answered the central issue of whether the virus enters central nervous system neurons, astrocytes or microglia, and the brain vascular cell types that express virus have not yet been identified. Currently, there is no clear evidence for human neuronal or astrocyte expression of angiotensin-converting enzyme 2 (ACE2), the major receptor for viral entry, but ACE2 expression may be activated by inflammation, and a comparison of healthy and infected brains is important. In contrast to the 1918 influenza pandemic and avian flu, reports of encephalopathy in COVID-19 have been slow to emerge, and there are so far no documented reports of parkinsonism apart from a single case report. We recommend consensus guidelines for the clinical treatment of Parkinson’s patients with COVID-19. While a role for the virus in causing or exacerbating Parkinson’s disease appears unlikely at this time, aggravation of specific motor and non-motor symptoms has been reported, and it will be important to monitor subjects after recovery, particularly for those with persisting hyposmia.

Introduction

Over the past twenty years, novel viral epidemics, including influenza, severe acute respiratory syndrome (SARS) and Middle Eastern respiratory syndrome (MERS), have appeared, likely through zoonosis1,2,3,4,5,6. There are few, if any, therapeutic options for treating these disorders and they can induce significant mortality7,8. In 2019, a novel coronavirus outbreak, known as COVID-19, was reported in China, and as of May 2020, it had spread to 229 countries9.

This coronavirus, known as SARS-CoV-2, is a large enveloped non‐segmented positive‐sense RNA virus10. When the SARS-CoV-2 virus, and in particular its Spike (S) protein, makes contact with cells, it binds to a number of host proteins (known as virus receptors) that assist in its entry10.

Symptoms

Like its related family members SARS-CoV and MERS-CoV, SARS-CoV-2 initially presents as a respiratory illness, characterized by cough, dyspnea, fever, and other upper and lower respiratory systems manifestations11. However, COVID-19 is associated with a variety of other symptoms and clinical manifestations due to its spread to many other organs and systems11.

At this time, it appears that all subjects who have recovered from COVID-19 have developed T cells that recognize specific viral epitopes, including the S protein12. The extraordinarily wide range of symptoms and severity, including many infected subjects showing mild or no effects, may be due to cross-reactivity of T cells previously developed in response to prior coronavirus infections that cross-react with SARS-CoV-2, and it is remarkable that nearly half of individuals tested from blood samples prior to 2019 have such cells12. It is also possible that different routes of infection, including via the gastrointestinal tract, may result in different symptoms13.

Epidemiological and public health studies indicate that infection with the SARS-CoV-2 affects all demographics, but has grave implications for older frail subjects14, particularly those with comorbidities as well as Black, Asian, and minority ethnic (BAME) subjects in a disproportionate manner (https://www.england.nhs.uk/coronavirus/ ... n-the-nhs/). This is not always the case for viral disorders, as some, like polio, are typically more dangerous for the young15. The impression that SARS-CoV-2 infection was particularly pathogenic in older frail subjects has been confirmed by high mortality rates, particularly in residential home patients across the United Kingdom, Italy, the United States, and many other countries16,17. Moreover, other comorbidities and factors have been associated with more severe infection, such as diabetes, obesity, pre-existing end organ disease, hypertension, and male sex18,19. It has been suggested that the cytokine storm is more easily triggered in patients with chronic inflammation, such as those with diabetes, obesity, and cardiac disease20. The cause of high mortality in older BAME subjects reported in the UK and USA remains unclear, although role of comorbidities such as diabetes, hypertension, and obesity as well as social deprivation are implicated (https://www.england.nhs.uk/coronavirus/ ... n-the-nhs/).

While the majority of infected people exhibit mild or moderate symptoms and do not require hospitalization, more severe patients need to be hospitalized and sometimes intubated due to severe respiratory distress21. Other serious consequences of COVID-19 include acute kidney injury, a coagulopathy similar to disseminated intravascular coagulation22, thrombosis23, and a newly recognized post-infection syndrome in children, known as multi-system inflammatory syndrome in children potentially associated with COVID-1924. The sequelae of each of these syndromes can result in multi-organ failure11,25.

A significant number of those diagnosed with COVID-19 have reported a broad spectrum of neurological consequences26,27,28,29,30,31,32. Neurological symptoms include those associated with dysfunction of the central (fatigue, headache, confusion, stroke33, dizziness, syncope34, seizure, anorexia, and insomnia)35,36,37,38, peripheral (anosmia, ageusia, myoclonus39, neuropathic pain, and myalgias)26,35,40, combined central-peripheral (Guillain Barre syndrome41) and enteric nervous systems (diarrhea13). Some gastrointestinal manifestations, including diarrhea, may be related to the expression of the viral receptor ACE2 and a serine protease, transmembrane serine protease 2 (TMPRSS2), involved in S protein priming, in the small intestinal epithelia and colon42.

As many as 65% of COVID-19 affected individuals reported hyposmia and ageusia43, features that suggest the possibility of trans-synaptic spread via the olfactory, lingual, and glossopharyngeal nerves (Fig. 1), secondary to a respiratory route of infection. Hyposmia is now officially recognized as a symptom of COVID-19 by the UK government and may be a sign in “asymptomatic” carriers who may not have upper respiratory tract symptoms.

A recent review of 43 confirmed COVID-19 cases in a London, UK hospital suggested emergence of specific neurological presentations, including encephalopathies, inflammatory central nervous system syndromes, ischemic strokes, and peripheral neurological disorders, although parkinsonism and rates of hyposmia or ageusia were not reported44.

We and others have previously flagged concerns regarding COVID-19 in people with Parkinson’s disease (PD), especially for older and frail subjects with advanced PD who may be particularly vulnerable45,46.

Historical aspects of viruses and parkinsonism


It is remarkable that a relationship between the presence of antibodies to coronaviruses that cause the common cold, coronavirus OC43 and 229E, in the cerebrospinal fluid (CSF) and Parkinson’s disease was reported nearly twenty years prior to the current pandemic by Stanley Fahn and colleagues47. Prior coronaviruses have been occasionally reported to exhibit neurological manifestations and CSF invasion48, including in children49,50.

Medical history provides observations supporting links between viral infections and parkinsonism51. The best known example is the post-encephalitic parkinsonism observed during the encephalitic lethargica outbreak that overlapped with the Spanish Flu (influenza A virus H1N1) pandemic in 191852. However, after 100 years, the cause of encephalitis lethargica still remains a mystery53. While a causal role of influenza A H1N1 virus in the development of post-encephalitic parkinsonism is not confirmed52, an association between influenza A virus infection and development of transient parkinsonism is reported54. Notably, the avian flu resulted in parkinsonism in many survivors55. Other viral infections have been associated with the development of transient or, more rarely, permanent parkinsonism, including Epstein-Barr, Japanese encephalitis, Coxsackie, West Nile, Western equine encephalomyelitis, and human immunodeficiency virus, mostly due to induction of neuroinflammation and/or hypoxic brain injury with structural/functional damage within the basal ganglia51,54 (Table 1). In addition, debated evidence suggests that previous infection with herpes simplex 1, Epstein-Barr, varicella zoster, hepatitis C, and influenza A virus can increase the risk of developing PD in the long-term54. Although the “viral hypothesis“ was generally ignored after the discovery of genetic mutations involved in PD pathogenesis, the role of “environmental” factors acting as peripheral triggers of the neurodegenerative process in susceptible individuals has been increasingly acknowledged56.

SARS-CoV-2 receptors and cellular uptake

There is a wide diversity of proteins, particularly glycoproteins, that act as cellular receptors for coronavirus spike proteins57.

SARS-CoV-2 shares 70–80% of its genome with SARS-CoV and a smaller but significant homology with MERS-CoV58. This homology extends to the S protein58 that is the point of attachment to plasma membrane proteins which act as viral receptors for cellular infection. The S protein is thought to require a priming step in which it is cleaved by a cellular protease, which for SARS-CoV and SARS-CoV-2 is reported to be the cellular serine protease, TMPRSS259.

The extensive research devoted to determining how the binding of the virus leads to cellular endocytosis of the virus, leading ultimately to RNA translation, transcription, and viral replication, will not be reviewed here.

At this time it appears that the main protein responsible for cellular accumulation of SARS-CoV-2 is angiotensin-converting enzyme 2 (ACE2)27,60,61, an enzyme that converts angiotensin II to angiotensin. ACE2 also acts as a receptor for several other coronavirus, including SARS-CoV62,63. The distribution of ACE2 throughout the body and brain is discussed below.

Recent in-silico studies64,65 propose that, in addition to ACE2, a second mechanism may enable cellular endocytosis of SARS-CoV-2. Similar to MERS-CoV, and in contrast to SARS-CoV, SARS-CoV-2 appears to display high binding affinity to sialic acid residues, providing an additional candidate for binding. Sialic acid residues are found on plasma membrane proteins of many cell types, including neurons, and are very highly expressed in the upper respiratory tract.

Additional observations that may test the predictions from in-silico reports implicating a role for sialic acid residues as SARS-CoV-2 receptors include (1) efficacy of the therapeutic use of lactoferrin66, an antiviral agent that interacts with sialic acid residues; (2) an ongoing clinical trial of DAS181 (https://clinicaltrials.gov/ct2/show/NCT04324489), a drug designed to block viral access by cleaving sialic acid; (3) that the shedding pattern of SARS-CoV-2 infection is different from that of SARS-CoV and more similar to that of “standard” influenza66, where sialic acid receptors play a major role; (4) a bioinformatic study reports binding of S-protein to sialic acid glycans in a region close to that identified by the in silico studies65,67. To our knowledge, while links between sialic acid and neurotropism for mouse hepatitis virus68 and adenoviruses69 have been suggested, there are no published investigations on this alternative pathway for SARS-CoV-2 interaction in the nervous system.

There are additional strong candidates for receptors for the virus, including the lectin CD209L (also known as L-SIGN), which acts as a receptor for the SARS virus62,70. This should be analyzed both in the nervous system and additional tissues, as well as other suggested candidate coronavirus receptors, most of which are highly charged and glycosylated57.

Potential neurotropism of COVID-19 virus


At this time, we know very little about SARS-CoV-2 in the brain. Post-mortem studies on patients with SARS, however to have suggested the presence of viral particles in central nervous system (CNS) tissue71,72.

A recent publication examining the localization of SARS-CoV-2 in 27 people who died from COVID-19 demonstrated that 36% had apparently low levels of SARS-CoV-2 RNA and proteins in the brain, although they did not report the cellular localization or regions examined, and the signals may not have been present within the brain parenchyma73. A second study similarly reports detectable SARS-CoV-2 RNA in four of 12 brain samples, although again the signal may not have been from brain parenchymal cells74.

While there is, at this time, little evidence that SARS-CoV-2 enters the brain parenchyma, there are multiple means by which the virus might be able to do so75. Preclinical animal studies (reviewed by Natoli et al.76) report that after intranasal inoculation of SARS‐CoV in transgenic mice that overexpress human ACE277, or MERS-CoV in mice overexpressing human dipeptidyl peptidase 478, SARS‐CoV and MERS-CoV can invade the brain, possibly via transit through the olfactory nerves, to reach CNS nuclei, including thalamus and brainstem; we note, however, that these mice over-express the viral receptors, and these reports do not model normal infection routes.

Trans-synaptic transfer has been documented in rat and pig for other types of coronavirus, including hemagglutinating encephalomyelitis virus (HEV)79,80,81 and avian infectious bronchitis virus (IBV, also known as avian coronavirus)82, in both in vitro and in vivo studies.

Coronavirus might also reach the CNS via the hematogenous or lymphatic route, although this seems unlikely in early phases of the disease, as particles of SARS-CoV were not detected in non-neuronal cells in human post-mortem brain tissue71,72.

One potential mechanism for SARS-CoV-2 RNA presence within the CNS is blood-brain barrier (BBB) breakdown due to the cytokine storm associated with peripheral viral infection. It is well established that pro-inflammatory cytokines associated with inflammation and/or SARS-CoV-2 viral infection, such as tumor necrosis factor (TNF) and interleukin 1 beta (IL-1beta), mediate BBB breakdown83. This breakdown could either be long-term, similar to the one observed in neurodegenerative diseases allowing for infiltration of immune cells and viral particles, or transient, resulting in encephalitis84,85.

We note that while there are at this time several millions of SARS-CoV-2 infected individuals, there are only a few reports suggesting possible encephalitis, and only two that show evidence of COVID-19 virus in the CSF as assessed by reverse transcription polymerase chain reaction (RT-PCR). This suggests that even with the presence of high viral load in the blood stream and severe inflammation, COVID-19 virus is unlikely to exhibit direct neurotropism, but rather appears to cause inflammatory-mediated brain responses86.

Presence of SARS-CoV-2 receptors in the brain

ACE2 was identified in 2000 as a novel carboxypeptidase that cleaves the vasoconstrictor angiotensin II to the vasodilator angiotensin (1–7), in addition to cleaving several other peptides87. ACE2 is a transmembrane protein, and can itself be cleaved near the transmembrane region and thereby be “shed” into a soluble form with anti-viral activity88,89, in part as the soluble form likely binds virus. Plasma membrane ACE2 is, confusingly, often referred to as the “ACE2 receptor”, but this is intended to convey that the protein, in addition to its normal function, can act as a receptor for virus—and not that it is a receptor for ACE2.

ACE2 is widely expressed in human tissue90 and appears to be increased by inflammatory signals including in macrophages91. Evidence supporting ACE2 expression in human brain parenchyma, however, remains poor, in contrast to clear expression in the brain vessels92. There is an extensive literature indicating that ACE2 may serve as a protective stress-induced response pathway93,94,95 and that its expression might be harnessed clinically for cardiac and neurological disorders, which will not be reviewed here.

In particular, while ACE2 expression has been demonstrated in CNS neurons in some animal models96,97, the presence of ACE2 in human CNS neurons is not well established, nor are specific brain regions or neuronal, astrocyte, microglial, immune or vascular cell types well characterized.

The ACE2 promoter harbors five hypoxia-responsive elements, and hypoxia may upregulate ACE2 via HIF1A-independent mechanisms98, but it has not yet been determined if hypoxia upregulates ACE2 in brain cells.

It is very important to compare the presence of brain ACE2, and perhaps of CD209L and molecules with sialic acid residues, in both control individuals and those with high inflammation. The expression of some of these “receptors”, including ACE2, can be enhanced by cytokines, such as interferon99, or other inflammatory responses90, and may be regulated by excitotoxicity100.

The Human Protein Atlas reports that ACE2 is not detected in normal human brain, but indicates low amounts in mouse brain (https://www.proteinatlas.org/ENSG000001 ... CE2/tissue). As mentioned, an immunocytochemistry study of human brain tissue indicated that ACE2 is present in non-neuronal cells of vasculature in human brain tissue92, although that study did not define the precise cell types that express the receptor. A preprint of a single cell transcriptomic analysis suggests differential levels of ACE2 mRNA in different mouse brain regions101. Another preprint features a meta-analysis of single-cell and single-nucleus RNA sequencing datasets indicating co-expression of ACE2 and TMPRSS2 in oligodendrocytes102. However, additional studies are required to validate and localize protein co-expression in the CNS.

Because SARS-CoV-2 proteins can interact with host proteins involved in pathways that are altered during aging, including potential mitochondrial dysfunction, loss of proteostasis, autophagy dysfunction, inflammation, and endoplasmic reticulum stress, it is possible that SARS-CoV-2 infection may prompt protein misfolding and aggregation (Fig. 1)103,104,105. Of particular relevance for PD, recent studies have suggested that the aggregation-prone protein, alpha-synuclein, plays a role in the innate immune response to viral infections106,107.

It will be important to follow up and clinically monitor patients infected by COVID-19 virus, particularly those who developed specific neurological disturbances, such as sustained hyposmia108, syncope, and persistent confusion, given the relevance of these conditions to PD and PD dementia. Hyposmia is a well-recognized prodromal feature of PD109 as well as Alzheimer’s disease110 and may be due in part to dysfunction of inhibitory dopaminergic neurons in the olfactory bulb111. Although we do not yet know the precise mechanisms underlying hyposmia in COVID-19, it may be that patients who develop hyposmia become more susceptible to a neurodegenerative process or, alternatively, hyposmia may be a sign of peripheral inflammatory involvement of the olfactory mucosa. It is, therefore, reasonable to suggest specifically following up those COVID-19-linked cases where recovery is associated with sustained hyposmia after the acute illness of COVID-19 has subsided.

COVID-19 and the possibility of a post-viral parkinsonism: clinical and molecular rationales


Some literature has already highlighted potential links between COVID-19 virus and neurodegenerative conditions, including suggestions regarding PD104,112. These are based on multiple observations:

1.

The ability of coronaviruses to enter the CNS through the nasal cavity with subsequent neuronal death77,78, as shown in animal studies.
2.

Hyposmia is well documented in COVID-19 patients without nasal obstruction and rhinorrhea108,113,114 and is also a common prodromal feature of PD115.
3.

Basal ganglia lesions may occur in the context of a thromboembolic encephalopathy in COVID-19116.

4.

The presence of higher levels of antibodies against other coronaviruses that cause the common cold in the CSF of PD patients compared to healthy controls suggests a possible involvement of viral infection in the pathogenesis of PD47.
5.

There are reports that ACE2 may be expressed in various regions of the nervous system93,117, although as detailed above, further neuropathological investigation is required. Given the interferon activation of this protein, it will be important to examine subjects with CNS inflammation or encephalitis.
6.

The recent reports of syncope with no abnormal rhythms on cardiac device interrogation hint at a potential role for neurally-mediated syncope34 vs. orthostasis, suggesting the importance of these investigations for PD patients who often suffer from dysautonomia118.

7.

A single case report of a patient who developed myoclonus and an acute but spontaneously reversible hypokinetic rigid syndrome, with DaTscan showing reduction of dopamine transporter uptake in the putamen as well as hyposmia119.
8.

The angiotensin system, which is implicated in COVID-19 pathogenesis, may be important in neuroinflammatory and neurodegenerative mechanisms observed in PD120,121.
9.

SARS-CoV-2 proteins can interact with human proteins involved in biological mechanisms that drive dysfunction of protein homeostasis that may lead to protein misfolding and aggregation (Fig. 1)103,104.

10.

The release of cytokines may activate resident immune cells in the CNS and/or lead to their infiltration from the periphery that result in brain cell damage. Such cells may include activated T cells and microglia that may kill neurons122,123,124, astrocytes, and vascular cell types. This may occur through the selection of cells that specifically recognize presented antigens from the infection or previous infections, or via a general activation of cytotoxic cells that recognize other antigens, including autoantigens, such as those derived from alpha-synuclein which are implicated in PD, Lewy Body dementias, multiple system atrophy, and multiple sclerosis125,126. High levels of pro-inflammatory cytokines, such as TNF and IL-1beta, are associated with increased risk of PD, while use of non-steroidal anti-inflammatory drugs (NSAIDs) and anti-TNF biologics reduce the risk127. Anti-TNF biologics are currently under investigation for COVID-19.

Beyond the significant observational literature discussed above that suggests a relationship between viral infection and PD51, a number of preclinical studies have directly addressed this issue. Jang et al. examined the potential for a neurotropic Type A influenza virus (A/Vietnam, 1203/04, H5N1, a.k.a. bird flu) to induce parkinsonian pathology in mice. They found that this strain of influenza virus directly infected neurons, with particular affinity for circuits involved in PD. Subsequent to recovery from this infection, the mice exhibited ataxia, tremor, and bradykinesia128 as well as a transient but significant loss of dopaminergic neuron phenotype, an early neuroinflammatory program, long-lasting microgliosis and an increase in alpha-synuclein expression129.

Another neurotropic virus, the mosquito-borne alphavirus, Western equine encephalitic virus (WEEV) also induces post-encephalitic parkinsonism. Like the influenza virus, WEEV induced activation of microglia and astrocytes, selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and behavioral abnormalities consistent with PD in mouse models130. Importantly, the common denominator of these viruses is that they enter the CNS and directly infect cells.

As we do not yet know if the SARS-CoV-2 virus directly infects CNS neurons, it is important to determine if non-neurotropic viruses also have the potential to contribute to development of PD. The idea that a peripheral cytokine storm from non-neurotropic viruses can induce encephalitis has been suggested for many other viral infections, including the 1918 Spanish influenza (Type A H1N1)131,132 as well as respiratory syncytial virus133.

Notably, the pandemic 2009 H1N1 (CA/09) influenza virus does not infect neurons in the central, peripheral or enteric nervous systems, but can nevertheless induce a significant inflammatory response in the CNS, including within the SNpc. Evidence that an indirect neuroinflammatory mechanism of this sort might increase the risk of parkinsonism is that mice infected with the 2009 H1N1 virus, after complete resolution of peripheral infection, displayed a higher level of SNpc DA neuron death after injection with the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Administration of an influenza vaccine or the neuraminidase inhibitor oseltamivir (Tamiflu) protected against the synergistic response to the neurotoxin134. In these preclinical studies, microgliosis and increase in inflammatory cytokines and chemokines in the brain were not due to invasion of CD4+/CD8+ T-cells from the periphery, suggesting that inflammatory cytokines released during peripheral infection passed through the blood-brain barrier135 and indirectly activated microglia, leading to a parkinsonian cascade.

Interestingly, influenza vaccination in humans enhanced levels of the anti-inflammatory cytokine interleukin 10 (IL-10)136, while prophylactic treatment with oseltamivir (Tamiflu) decreased disease severity of influenza in both human and mouse models, and did not appear to interfere with appropriate T cell responses to new influenza infection137. It may be that vaccination is protective for nervous system inflammatory responses even from viruses that do not infect neurons and astrocytes.

The need for detailed autopsy studies

As deaths from SARS-CoV-2 infection continue, autopsy studies will play a key role in defining CNS pathology, including in patients with PD. However, due to increased precautions taken at the time of autopsy, relatively few brain autopsies are being performed. The U.S. Centers for Disease Control has issued guidance on autopsies for confirmed SARS-CoV-2 decedents and advises against performing procedures that generate aerosols, such as those used to remove the brain (https://www.cdc.gov/coronavirus/2019-nc ... #biosafety). Most studies thus far lack neuropathologic characterization altogether138,139,140,141,142, and an autopsy case series did not provide detailed neuropathologic descriptions74. Moreover, deaths occurring in nursing home and long-term care facilities, where a large subset of patients suffering from dementia reside, are less likely to result in autopsies. We thus expect a delay in understanding whether and how SARS-CoV-2 infection specifically alters neuropathology, including in PD.

Of the available studies with some neuropathologic data, one case series of ten autopsies documented no signs of encephalitis or CNS vasculitis, although the extent of neuroanatomic sampling was not provided31. A second study of COVID-19 autopsy findings included four brains that exhibited no encephalitis or neuronal necrosis, but mild hypoxemic changes in three of the four brains examined143. Although these studies have not identified specific neuropathologic alterations, the extent of involvement of the CNS in SARS-CoV-2 infection cannot be inferred from only 14 brains.

To establish how SARS-CoV-2 infection affects the CNS, the field will require detailed neuropathologic studies with thorough sampling of specific brain regions. At the Columbia University Medical Center, a current approach involves sampling of multiple neuroanatomic regions, including the cerebral cortex, watershed areas, white matter, olfactory system, hippocampus, amygdala, thalamus, hypothalamus, corpus striatum, pallidum, cerebellum, midbrain, pons, medulla oblongata, and cervical cord. We recommend that special attention be directed at documenting the presence and neuroanatomic distribution of hypoxia-related as well as inflammation-related pathologies, including leptomeningitis, encephalitis, and vasculitis.

The clinical perspective


Clinical implications of SARS-CoV-2 infection on PD are largely speculative apart from two case series and case reports45,46. A community-based case control study in Italy of 12 PD COVID-19 cases suggested substantial worsening of motor and non-motor symptoms during mild to moderate COVID-19 illness, independent of age and disease duration144, in line with an original case report series by Antonini et al. In another survey across the Lombardy region of Italy, 105 probable COVID-19 cases were identified and the authors concluded that the risk, morbidity, and mortality in patients with mild-to moderate PD with COVID-19 did not differ from the general population145. Several viewpoints and editorials have been published on the topic in addition to extensive coverage in social media and journal viewpoint papers146,147,148,149,150,151.

Currently there is no robust evidence that having PD imparts an increased risk for susceptibility to COVID-19 or that COVID-19 confers a greater risk of PD, although, as noted above, there are reported cases of worsening of PD symptoms in infected patients, particularly in older frail patients on advanced therapies and one case report of development of an acute hypokinetic syndrome with hyposmia post COVID-19.

Broadly, the clinical impact of COVID-19 on PD could occur through multiple avenues:

1.

Development of COVID-19-related symptoms, particularly high fever, severe respiratory distress, coagulopathy-related syndrome, fatigue, myalgias, and related impaired stress mechanisms.
2.

Worsening of pre-existing dyspnea due to respiratory distress; dyspnea may exist in up to 39% of PD patients152.
3.

In acutely ill patients admitted to hospital, confusion and delirium could occur (reported in over 25% of COVID-19 hospitalized subjects out of a survey of 3500 patients)38.
4.

Worsening of specific symptoms, including motor symptoms as well as non-motor issues, such as pain, anxiety, sleep disturbances and fatigue, especially with reduced access to physical therapy and counseling45,144.

5.

Social isolation and aggravation of underlying cognitive and behavioral symptoms, specifically anxiety153.
6.

Possibility of post-traumatic stress disorder (PTSD) as observed in previous SARS and MERS pandemics38.
7.

Increased levodopa requirement during acute admissions and need for non-oral dopaminergic therapies in some subjects with severe COVID-19 related symptoms45.
8.

Potential for drug interaction of over the counter cough remedies with anti-parkinsonian drugs such as monoamine oxidase inhibitors.
9.

Complexity in therapeutic management related to limitations of in-person consultations and admissions to hospital147.

The impact of severe infection (by default, implying a high viral load or a pro-inflammatory state) may lead to hospitalization and the need for supported breathing or mechanical ventilation, particularly in older PD patients with multimorbidity and a high frailty index154. The issue is further compounded because such patients may be on non-oral therapies (subcutaneous apomorphine, intrajejunal levodopa infusion, and deep brain stimulation (DBS)) for advanced PD151. Limited observations from admission of such cases around the world (personal communication) and the published case series suggest that such patients are particularly vulnerable, with high mortality rates and may have an increased levodopa requirement during the acute illness45,46. Pre-existing dyspnea of PD152,155, respiratory muscle bradykinesia155 in addition to a possible direct SARS-CoV-2-related brainstem-generated suppression of cough reflex and perhaps of autoregulation of blood flow may play additional negative roles77,78,156,157.

Fatigue has been commonly reported after many viral infections, most notably with Epstein-Barr virus158, and is evident in many non-PD cases with COVID-19159. Fatigue was also common in the series of PD cases reported45 and is an important contributor of quality of life160. Myalgia is also common after viral illnesses including COVID-1940,161, and in some cases of COVID-19 with PD, myalgia can be severe and involve muscles of the back. If these observations are confirmed in larger cohorts of PD patients with COVID-19, specific anti-fatigue/myalgia measures may need to be implemented160. Consideration for the use of amantadine-like drugs may be particularly relevant given their putative antiviral effects162,163; however specific clinical trials are lacking.

Social isolation and its impact on PD are a concern and has been called a “hidden sorrow” of the pandemic164. Social isolation may cause heightened anxiety, aggravation of pre-existing depression, the negative effects of stress on PD165, as well as lack of exercise. In the previous SARS and MERS epidemics, one in three hospitalized cases went on to develop a PTSD with 15% developing depression and anxiety at 1 year, and fatigue in more than 15%38. Anxiety in PD during COVID-19-related lockdown and consequent stress is widely reported during telephone consultations in many countries, and specific strategies for home care using telemedicine or remote counselling may need to be implemented.

An overall consensus-led guideline for management of PD with varying grades of COVID-19 needs to be developed and circulated for implementation. A suggested template is provided in Fig. 2. These observations can be applied to the elderly as well as subjects with other neurodegenerative disorders, such as Alzheimer’s disease or amyotrophic lateral sclerosis.

Conclusions

There has been a large number of papers on COVID-19 and PD speculating on etiology, risks and consequences, in addition to two documented case series of PD with COVID-19. We attempt to prove a critical approach to these observations from currently available clinical and molecular insights.


The COVID-19 pandemic has led to an unprecedented crisis for older people globally. There is a broad range of COVID-19 symptoms, perhaps related to pre-existing conditions and in part to different modes of viral entry and the presence of T cells that are reactive to prior coronavirus infections. The neurological manifestations may be related to inflammation involving capillaries and the blood-brain barrier, hypoxemia, and thrombosis acting as triggers for seizures or leading to ischemic or hemorrhagic strokes.

Neuropathology studies have not yet clearly answered the central issue of whether the virus enters central nervous system neurons, astrocytes or microglia.

In brain vasculature, the cell types that express virus have not yet been identified.

There is no clear evidence in human neurons or astrocytes for expression of the protein ACE2, which is thought to act as the major viral receptor that enables viral entry. Such expression may, however, be activated by inflammation, and thus comparison of healthy and infected brains will be important.

There is a variety of alternative viral receptors for coronavirus, including sialic acid residues, that are insufficiently characterized and may provide entry into neurons and astrocytes.

In contrast to the 1918 influenza pandemic and avian flu, reports of encephalopathy in COVID-19 have been slow to emerge, and there are so far no documented reports of an induction of parkinsonism apart from a single report. While a role for the virus in causing or exacerbating Parkinson’s disease appears unlikely at this time, the aggravation of specific motor and non-motor symptoms is reported.

As the prevalence of PD rises sharply in the older age group, particularly in those over the age of 80 years, a personalized approach in the management of PD patients affected by COVID-19 based on clinical and basic science evidence is required. In addition, it will be important to monitor subjects after recovery, particularly for those with persisting hyposmia.
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Re: Parkinsons Disease / Covid 19 & Parkinsons

Post by trader32176 »

COVID-19 Slams Parkinson's Disease Patients

— Even those who avoided infection still suffered from the pandemic's disruptions

July 23, 2020


https://www.medpagetoday.com/neurology/ ... ease/87719

Most Parkinson's disease patients who had COVID-19 reported new or worsening motor and non-motor symptoms, survey data from the Michael J. Fox Foundation for Parkinson's Research showed.

And among Parkinson's patients not infected with the virus, nearly two-thirds also reported adverse effects from the pandemic: canceled healthcare appointments, reductions in home care, or difficulty obtaining medications, according to Caroline Tanner, MD, PhD, of the University of California San Francisco, and co-authors in a manuscript published on the medRxiv preprint server.

The findings represent the first and largest self-reported data set to date about Parkinson's disease symptoms and care disruptions during the COVID-19 pandemic. "This is quite useful because it gives us insight into the patient's own experience," Tanner said in an interview with MedPage Today. "Pretty much everyone had a worsening of Parkinson's symptoms if they were also infected with COVID-19."

"That isn't exactly surprising because we know when people get other infections, their Parkinsonism worsens," she noted."But it's relevant for us to have this in mind, so it's part of what we're thinking when we hear patients talk about sudden worsening."

The survey was part of the Fox Insight online clinical study, which first was launched in 2017 to give neurologists and researchers a window into the experience of people with Parkinson's. To date, Fox Insight has enrolled nearly 50,000 participants and has the largest cohort of patient-reported outcomes in Parkinson's research.

From April 23 to May 23, 2020, Fox Insight participants were invited to complete an online survey; a total of 5,429 Parkinson's patients and 1,452 people without Parkinson's responded. Of these, 77 people reported a COVID-19 diagnosis, including 51 Parkinson's patients.

During SARS-CoV-2 infection, the majority of Parkinson's patients experienced new or worsening motor symptoms (63%) and non-motor (75%) symptoms, including stiffness, tremor, difficulty walking, mood symptoms, cognition, and fatigue.

Among all respondents with COVID-19, outcomes were largely similar between people with and without Parkinson's. Longer Parkinson's disease duration was associated with a higher risk of pneumonia, the need for supplemental oxygen, or hospitalization (44% for disease duration greater than 9 years vs 14% for disease duration of 9 years or less).

"What was really remarkable was the number of people who didn't have COVID, but who did suffer from the experience of the pandemic," Tanner noted. Medical care (64%), exercise (21%), and social activities (57%) were disrupted for these patients, and many reported worse Parkinson's motor (43%) and non-motor (52%) symptoms.

New-onset motor symptoms in particular were more likely in Parkinson's patients who had disrupted medical care (8.2% vs 5.1%; adjusted OR 1.63, 95% CI 1.31-2.04; P<0.001). Patients who experienced interruptions to exercise, social activities, or who were asked to self-isolate also were more likely to report worsening of Parkinson's symptoms.

Disruptions in healthcare were more common for Parkinson's patients who lived alone and for those with lower income and non-white race. Non-white race and lower household income also were independently associated with difficulty obtaining medications. People with lower income were less likely to find alternative ways to exercise and engage in social activities and were less likely to use telemedicine.

While the survey showed the resilience of the Parkinson's community, it also highlighted disparities, Tanner pointed out. "People with lower incomes or people who are nonwhite have less opportunity to use alternative means of health care and connection," she said. "That's something we continue to need to work on."

The study had several limitations, the researchers acknowledged. It relied on self-reported data and was limited to people healthy enough to complete an online survey. Certain populations may be under-represented; in particular, findings among low-income and non-white populations may vary.
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Re: Parkinsons Disease / Covid 19 & Parkinsons

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Potential impact and challenges associated with Parkinson’s disease patient care amidst the COVID-19 global pandemic

Published: 08 August 2020

https://clinicalmovementdisorders.biome ... 20-00089-4

Abstract

Background

COVID-19 has made itself known to health care providers and families across the world in a matter of months. While primarily a respiratory disorder, it has also been shown to cause neurological symptoms, which can be a concern for Parkinson’s disease (PD) patients. Although PD is not as common as other conditions such as cardiovascular diseases, it affects millions of patients around the world whose care has been affected by the global pandemic.

Objectives

The aim of this review is to provide insight into the direct and indirect associations between COVID-19 and PD patient care.


Results

Potential direct effects of COVID-19 include possible neurodegeneration, concerns of symptom self-management with over-the-counter (OTC) products and ICU challenges that can arise in PD patients. In addition, a subset of PD patients may be at higher risk of severe COVID-19 infection. The indirect effects of the pandemic are associated with the social distancing measures and disruptions in health care systems and PD clinical trials, which may negatively affect PD patients’ mental wellbeing and create barriers in controlling their PD symptoms. On a more positive note, telemedical care is quickly emerging as a primary communication tool for virtual patient care. However, further research should be conducted to examine the applicability of telemedicine across the entire PD population, such as those with more severe symptoms living in less developed areas. With all the uncertainty during this time, it is hopeful to hear many promising COVID-19 treatments being researched, one of them being a PD drug therapy, amantadine.

Conclusion

Hopefully, we can consider this pandemic an opportunity to strengthen the PD community and learn more about the impact of the SARS-COV-2 virus. This review provides an overview of the interaction between COVID-19 and PD patients and future investigational retrospective studies are suggested to validate the observations.

Background

The world is facing an unprecedented time where new patients are being infected by the novel coronavirus called severe acute respiratory syndrome coronavirus (SARS CoV-2). Starting as an epidemic in Wuhan, China at the beginning of December 2019, SARS-CoV-2 has spread so quickly that the World Health Organization officially called it ‘coronavirus disease 2019’ (COVID-19) and declared it a pandemic on March 11, 2020. COVID-19 has now spread to 216 countries and has over 6.9 million confirmed cases worldwide as of June 7, 2020 [1]. COVID-19 is mainly a respiratory disorder that causes most patients to be asymptomatic or present with mild upper respiratory symptoms such as fever, dry cough, sputum production, shortness of breath and sore throat. However, severe manifestations may also occur causing acute respiratory distress which may lead to death. Additionally, there have been reports of neurologic complications associated with COVID-19 as well. Undoubtedly, the COVID-19 pandemic has caused drastic changes to health care systems as well as new challenges to social life brought by social distancing and lockdown measures across the world.

There are concerns that patients with health conditions are more vulnerable to the impact of COVID-19, including neurological conditions like Parkinson’s Disease (PD). PD is a chronic progressive neurodegenerative disease that manifests with key features including tremor, bradykinesia, and rigidity. Nonmotor symptoms including dementia, psychosis and autonomic dysfunction may present as the disease progresses. PD patients could be at higher risk of diseases as well as many PD patients are elderly and have multiple comorbidities. With PD affecting many individuals around the world, it is important to understand how they are impacted by the current pandemic. We conducted a literature search using the keywords “covid”, “coronavirus”, and “parkinson” and summarized key findings in this review. We also discuss the key direct and indirect interaction between COVID-19 and PD patients, as well as explore a promising COVID-19 treatment drug within the PD field (Fig. 1).

Discussion

Direct impact of COVID-19 on PD patients

Possible neurodegeneration among COVID-19 infected PD patients


The SARS-CoV-2 virus is of RNA origin and has a higher infectivity rate than the influenza virus [2]. Once infected, the virus glycoprotein can bind to angiotensin-converting enzyme 2 receptors (ACE2) which are highly expressed in the lungs [3]. This can result in acute alveolar damage, pulmonary edema and inflammation and evolve into acute respiratory distress syndrome (ARDS). Although COVID-19 mainly affects the respiratory system, there is evidence that SARS-CoV-2 infects the brain including the brainstem [4]. As PD is a neurological disorder, there is a concern that SARS-CoV-2 brain penetration could worsen symptomology of PD patients. For many years, antibodies against coronavirus have been found in the cerebrospinal fluid of PD patients, suggesting a role of viral infection in neurodegeneration [5]. Neurological manifestations associated with COVID-19 have also been well documented including dizziness, headache, hyposmia, hypogeusia, dysphagia and nerve pain [6]. Additionally, there is evidence that fever is associated with motor deterioration with PD patients and can even predispose them to parkinsonism-hyperpyrexia syndrome, a movement disorder emergency [6]. With fever being the most common symptom of COVID-19, as seen in 87.9% of affected patients, there is a strong possibility that COVID-19 can cause worsening of parkinsonian symptoms [6]. While there is no causal evidence that COVID-19 causes neurodegeneration, clinical case reports of worsening PD features have been documented in PD patients infected with COVID-19 [5]. In a case report of 8 PD patients, all showed worsened motor functions that lead to additional levodopa dosing [5]. Additionally, an observational case-control study found that motor symptoms significantly worsened in COVID-19 infected PD patients compared to noninfected PD controls [7].

Although, it was speculated that clinical changes may be caused by systemic inflammatory response rather than viral invasion of the central nervous system [7]. Nonmotor symptoms also appeared to be affected, however was not consistently described among different cases. Cilia et al. reported increased urinary urge/incontinence in infected patients [7], while Antonini et al. described worsened orthostatic hypotension, cognitive impairment and psychosis [5]. Both studies commonly observed increased fatigue in infected patients as well [5, 7]. Grabli and Hainque also highlighted the difficulty of detecting COVID-19 as some symptoms such as fatigue, asnomia, hot flush and painful limbs can also present as non-motor PD signs [8]. Current findings are suggestive of worsening motor and nonmotor PD symptoms following infection with COVID-19, however longitudinal studies would be beneficial to confirm this observation.

Concerns of mild COVID-19 symptom management with OTC medications in PD patients

Patients have been advised to manage their symptoms at home in most cases where COVID-19 infection appear to be mild of nature. Patients may present with symptoms of fever, dry cough, and sore throat with mild infection and many may choose to self-medicate with OTC products. For PD patients, it is especially important to discuss with a doctor or pharmacist about self-medicating since some OTC products can interfere with their Parkinson’s symptoms and medications. In addition to motor symptoms, PD patients may present with dementia as well as autonomic dysfunction such as bladder problems, constipation, sexual dysfunction, dry mouth, sweating and orthostatic hypotension [9]. Caution should be noted if PD patients take OTC medications containing antihistamines like diphenhydramine and dimenhydrinate, since they have anticholinergic properties and can worsen constipation, confusion as well as urinary symptoms. An additional concern is if PD patients are taking anticholinergic agents like benztropine or trihexyphenidyl for Parkinson’s symptoms. If these agents are taken together with OTC antihistamines, anticholinergic side effects like dry mouth, blurred vision, constipation, and urinary retention could be enhanced and therefore close monitoring is advised [10]. For PD patients taking monoamine oxidase B inhibitors (MAOI) like rasagiline, safinamide and selegiline, more serious drug-drug interactions can occur if taken together with cough syrups containing dextromethorphan or nasal decongestants containing pseudoephedrine, phenylephrine or phenylpropanolamine [11]. The combination of MAOIs and dextromethorphan is not recommended since MAOIs can enhance the serotonergic effects of dextromethorphan which can lead to serotonin syndrome [12]. If MAOIs and decongestants are taken together, it could enhance the alpha agonist effects of decongestants and lead to severe hypertensive outcomes as well [13]. As many OTC cough and cold medications are available as combination products, it is important to consult a pharmacist if deciding to self-medicate to avoid dangerous drug combinations and to safely treat mild COVID-19 symptoms.

Are PD patients at risk of COVID-19 infection?

The question of whether patients with PD are at greater risk of COVID-19 infection is of interest in the PD community. A case-control survey conducted in Italy aimed to investigate this matter. Fasano et al. found that the risk of COVID-19 infection did not differ between PD patients and the general population [14]. While the patients in the study were community-dwelling PD patients, the risk profile of severe patients living in nursing homes or long-term care facilities remains unclear. Regarding the risk of developing severe COVID-19 infections, reports have found that elderly patients and those with comorbidities, such as cardiovascular disease, are especially vulnerable to progression to severe COVID-19 infections [15]. To date, there is no evidence showing PD itself puts patients at higher risk of severe COVID-19 infections [16]. However, PD patients have been shown to have more comorbidities than patients without PD. In a large population study, patients with PD had more physical and nonphysical comorbidities than those without PD, namely coronary artery disease, cerebrovascular disease, and heart failure [17].PD prevalence also primarily affects the elderly, as the onset is usually around 65 to 70 years [18]. These comorbidities along with the older age of PD patients can increase their risk for more severe forms of COVID-19. There may also be a possible direct association with severe COVID-19 in a certain subset of PD patients. Older advanced PD patients with respiratory dysfunction may present with dyspnea, respiratory muscle rigidity and impaired cough reflex. These respiratory restrictions in PD patients put them at increased risk of pulmonary decompensation and pneumonia, which are features of severe COVID-19 infection [6].

Challenges faced by COVID-19 infected PD patients in the ICU

In the case that PD patients develop severe COVID-19 infection and require admission into the ICU, there are many issues that need to be considered. Severe respiratory issues such as acute respiratory distress syndrome and pneumonia secondary to COVID-19 may require patients to undergo ventilation. As noted earlier, PD patients may already have respiratory restrictions characterized by respiratory muscle bradykinesia, rigidity, and dystonia, which may make intubation more challenging [19]. Swallowing may also be negatively affected in these patients, where saliva can pool in the mouth and lead to aspiration [6, 19]. When coupled with weak coughs due to chest wall rigidity, there may be a higher risk of aspiration pneumonia as well, which can complicate COVID-19 management [6]. Although there is no published evidence supporting this association, it is worthwhile investigating in future retrospective studies. With respect to the care strategy for PD patients admitted to the ICU, there are no current guidelines [16]. However, efforts should be made to ensure PD patients continue to receive anti-PD therapy. In cases of pneumonia, maintenance of previous PD medications or an equivalent levodopa dose is crucial to avoid rigidity and further respiratory impairment from dopaminergic withdrawal [16]. Patients on apomorphine pump therapy and levodopa/carbidopa intestinal gel (LCIG) continuous infusion may be continued if already implemented. In some cases, PD therapy must be adapted in the ICU, such as in severely akinetic patients with dysphagia where oral administration of drugs is no longer possible. The easiest, most cost-effective and efficient way is to convert to levodopa solution which is given via a nasogastric tube [16]. Starting an apomorphine pump in the ICU is generally not advised, however can be considered only if akinesia poses a real risk to the patient [16]. Another option is to use transdermal rotigotine, however it is considerably less efficacious than levodopa or apomorphine [16]. Since there are no guidelines dictating the therapeutic alternative of choice to use in PD patients in the ICU, it may be determined using the medical team’s best judgement on a case-by-case basis.

Indirect impact of COVID-19 on PD patients

Disruptions to global health care systems

The COVID-19 pandemic has certainly caused disruptions in health care systems which can have indirect effects on PD patients. Neurologists are essential in the circle of care for PD patients and it is important to think about how their impact from COVID-19 can have subsequent effects on patients. Like many health care providers, neurologists are at risk of exposure to COVID-19 patients and if infected, they will be restricted in their ability to provide care for PD patients. In some regions where there is a shortage of medical staff, some neurologists may also be forced to provide care for COVID-19 patients, which ultimately leads to less time spent caring for PD patients as well [16]. In many medical communities, nonurgent surgical procedures have been postponed to prevent patients from being infected. Regarding PD patients, elective surgical procedures like deep brain stimulation (DBS) have been delayed, as well as the initiation of LCIG and apomorphine pump [16]. These delays create barriers for PD patients from accessing vital medications that can control their condition, which can possibly lead to worsened symptoms. Fortunately, there has been no report so far on the impact of the pandemic on global medication transport and supply chain issues for PD patients [3].

The transition to virtual PD patient care


Another consequence of COVID-19 is the rapid implementation of telemedicine across many health care systems, whereby communication technology is used to provide virtual patient care. Many PD patients and neurologists have transitioned to telemedicine visits, particularly with synchronous videoconferencing. To assist movement disorders neurologists, the Movement Disorders Society (MDS) Telemedicine Study Group has created a step-by-step guide to implementing telemedicine [20]. The use of telemedicine and telerehabilitation to assess PD patients has been well documented and validated [21]. However, with virtual assessments, the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) can not be recommended since muscle rigidity and retropulsion pull testing can not be properly assessed via videoconferencing [16, 22]. Instead, a modified version of the MDS-UPDRS without rigidity and retropulsion pull testing is reliable and valid to use [23]. Advantages of telemedicine include access to specialists, convenience, time savings and cost reductions [24]. Nevertheless, there are still limitations to telemedicine. In a recent online survey with 781 PD patients who participated in telemedicine, the main concerns were lack of hands-on care, lack of intimacy and technical difficulties [25] A consistent barrier in providing virtual care is poor internet connectivity and video quality issues, which is especially limiting in less developed countries [24, 26]. To bypass this problem, asynchronous videos can be used to capture PD symptoms and sent to neurologists via email, which is more widely accessible [26].

In a review by Adams et al., several studies demonstrated that remote care of PD patients is feasible, effective, and valuable [24]. However, it is important to note the major limitations to these studies. The PD population may be underrepresented since participants had generally mild disease severity with UPDRS part III scores ranging from 24.2–44.1 (max score 128) and live in more developed countries like USA, Canada, Italy and Japan [24]. More severe patients with persistent tremor, rigidity and speech impairments may have a range of difficulties navigating telemedicine who were not represented in the studies. Future research involving more severe PD patients and those living in less developed countries is suggested to gain a more holistic understanding of the applicability of telemedicine in PD patient care.

There are also additional challenges with respect to virtual management of device aided therapies in PD, such as DBS and infusion pump devices, as telemedicine has not been universally established for these therapies [27]. Patients need to be educated on how to adjust device settings, monitor battery life, as well as troubleshoot device issues. With these new challenges in place, there is an emerging interest in the development of remote access to device programing, which could ease the technical burden on PD patients. Some pilot studies have been performed with remote control of apomorphine infusion where the results are promising [28]. In addition, 2 dB manufacturers, PINS Medical (Beijing, China) and SceneRay Corporation Ltd. (Suzhou, China) developed a remote, wireless DBS programming system where the settings may be adjusted remotely by clinicians [29,30,31]. Although this technology is currently only available in China, it is hopeful that it will become globally accessible soon.

Social distancing effects on PD patients’ mental health

The COVID-19 pandemic has also caused drastic changes to PD patients’ normal routine with social distancing and lockdowns in place across the world. Understandably, many PD patients will experience a negative impact on their mental health. In a case report from a movement disorder clinic in Cairo, PD patients reported worse stress, depression, anxiety and quality of life compared to matched controls during the pandemic [32]. A possible explanation is that the pathophysiology of PD naturally increases their risk of chronic stress since reduced dopamine levels impair coping mechanisms for stress [33]. This is concerning since stress can cause short term and long-term consequences for patients with PD. It has been shown that psychological stress can worsen motor symptoms such as tremor, gait and dyskinesia [34]. Stress can also reduce the effect of dopaminergic medications, such as levodopa’s effect on Parkinson’s tremor [35]. Increased stress may also unmask a latent hypokinetic rigid syndrome, perhaps leading to new PD diagnoses during the pandemic [6]. Preventative measures during the pandemic also significantly reduce mobility and physical exercise leading to a sedentary lifestyle. This is important to consider since physical exercise can attenuate clinical PD symptom progression and associated stress [33]. Thus, promoting home-based exercises, such as online exercise or dancing classes for PD patients, are crucial in maintaining their overall health during the pandemic.

Delays to novel PD drug therapies due to COVID-19

Another consequence that may be overlooked with respect to the COVID-19 pandemic is its impact on PD research and clinical trials. Many biopharmaceutical companies have delayed timelines for pipeline PD drugs due to COVID-19, which may result in additional burden on those whose parkinsonism is not adequately controlled by current medications on the market. We will discuss five pipeline medications in particular. First, Neurocrine Bioscience Inc’s novel drug ONGENTYS (opicapone) was recently approved by the FDA for add-on treatment to levodopa/carvidopa in PD patients experiencing “off” episodes, but will delay its launch in the US until later in 2020 due to COVID-19 [36]. ONGENTYS is an oral selective catechol-O-methyltransferase (COMT) inhibitor that blocks COMT from breaking down levodopa, resulting in more levodopa available to reach the brain and provide clinical effects [37]. Second, Addex Therapeutics has postponed the initiation of a Phase IIb/III clinical trial of dipraglurant, a novel orally available metabotropic glutamate receptor 5 (mGluR5) inhibitor, for PD patients with levodopa-induced dyskinesias [38]. Third, the enrollment for Phase 1 and Phase 1b trials have been paused for Denali Therapeutics’ backup pipeline drug DNL151 [39]. This small molecule inhibits LRRK2, which is an enzyme involved in lysosomal dysfunction and neurodegeneration, a key pathology seen in PD [39]. Fourth, a new investigational gene therapy drug, NBIb-1817 by Neurocine, has temporarily paused enrollment of patients into the Phase II RESTORE-1 Trial [40]. This novel therapy is aimed at delivering the aromatic l-amino acid decarboxylase (AADC) gene directly into neurons of the putamen, where AADC enzyme will be produced to convert levodopa into dopamine [40]. Fifth, resTORbio has also announced delays in enrollment of its fifth cohort in the ongoing Phase 1b/2a trial of RTB101 in PD patients [41]. RTB101 is a small molecule candidate that inhibits rapamycin complex 1 (TORC1), which contributes to the decline of neurologic function [42]. Unfortunately, these delays may negatively affect patients who are urgently waiting for new PD therapies to control their condition.

Potential PD therapy repurposed to treat COVID-19

The race to find a new vaccine or potential cure to COVID-19 has been on ever since the start of the pandemic. One investigational drug that is used to treat PD could be a possible prevention or treatment therapy for COVID-19 infection. Amantadine is an adamantine derivative that blocks NDMA activity. Its exact mechanism of action in PD is unknown, however it has a role in decreasing excess neuronal activity and neuroprotection [15]. Currently it is used as an add-on therapy to PD patients with persistent dyskinesia that is not controlled by existing therapy. Interestingly, amantadine also has antiviral activity, as it was initially marketed as treatment against influenza A [15]. Amantadine can block the matrix-2 (M2) protein ion channel, thereby inhibiting viral uncoating inside the infected cell [15]. In addition, there is a new model suggesting amantadine can disrupt lysosomal gene expression which could decrease the capacity of viral replication in COVID-19 [43]. Although it has yet to reach early clinical trials, its potential protective antiviral effects may be seen in various case reports. Rejdak et al. describes 15 neurological patients, 5 of whom have PD, who were receiving treatment with amantadine and were confirmed to have COVID-19 infection. All of them spent 2 weeks in quarantine and none had developed clinical manifestations of the virus [44]. These promising observations as well as its safe side effect profile warrants further studies for its use as a potential COVID-19 treatment.

Conclusion

The COVID-19 pandemic has changed the lives of many around the world, causing respiratory distress and even death. PD patients, especially those that are elderly and have CVD comorbidities are likely at a higher risk of severe COVID-19 infection. Once infected, there may be concerns of neurodegeneration, issues with self-medication with OTC products as well as ICU challenges specific to PD patients. With social distancing and preventative measures in place, health care systems and clinical research have been disrupted, patient care has been transitioned to virtual means, and many patients’ mental health have been negatively affected. Amid all the uncertainty, it is encouraging to discover that a PD drug, amantadine, could be a potential protective and treatment for COVID-19. As the number of COVID-19 infected patients increases, it is imperative to learn more about the SARS-CoV-2 virus and its impact on different patient populations. With telemedicine emerging as a primary communication tool for PD patient visits, it is also important to realize its advantages and limitations. Further research should be considered in order to generalize its validity across the entire PD population. As noted in this review, patterns have been emerging with respect to PD patients, and future investigation should be performed to confirm the observations.
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Importance of exercise intensity in Parkinson's patients | Giselle Petzinger

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Importance of exercise intensity in Parkinson's patients | Giselle Petzinger

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Re: Parkinsons Disease / Covid 19 & Parkinsons

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COVID-19 Infection May Raise Risk of Parkinson’s, Scientists Say

October 28, 2020


https://parkinsonsnewstoday.com/2020/10 ... tists-say/


People who are infected with SARS-CoV2 — the virus that causes COVID-19 — may be at greater risk of later developing Parkinson’s disease, researchers suggest in a commentary.

In their commentary, “Is COVID-19 a perfect storm for Parkinson’s disease?” published in Trends in Neurosciences, the researchers reviewed three cases of Parkinson’s-like symptoms appearing in people within weeks of contracting COVID-19.

While these cases, and similar reports, do not prove a connection between COVID-19 and Parkinson’s, they highlight the need for detailed record-keeping to better understand whether a relationship exists and how it might form.

“As we continue to grapple with the COVID-19 pandemic today, we also must consider its implications for the future,” Patrik Brundin, MD, PhD, a commentary author and Parkinson’s specialist with the Van Andel Institute in Michigan, said in a press release.

“COVID-19 is clearly a major and ongoing public health threat, but the consequences of infection may end up being with us for years and decades to come,” Brundin added.

SARS-CoV2 was characterized less than a year ago, and researchers are still working to understand how this virus can affect the body, both in the short and long term.

Since the start of the pandemic, there have been three published cases of people — in Brazil, Israel, and Spain — who developed Parkinson’s-like symptoms shortly after becoming infected with SARS-CoV2. These patients, ages 35, 45 and 58, all had respiratory infection severe enough to require hospitalization.


None had a family history of Parkinson’s, or any early signs of the disease. Genetic testing performed on one patient identified no Parkinson’s-associated mutations.

In all three cases, brain imaging tests found evidence of reduced activity in a brain region where the dopamine, a chemical messenger that helps control movement, is produced — one of the hallmarks of Parkinson’s.

Two people were treated with medications that increase dopamine activity (e.g., levodopa), and responded to treatment. The remaining patient recovered without treatment.

The researchers emphasized that these individual cases cannot establish a cause-and-effect relationship between COVID-19 and Parkinson’s.

“Possibly, the reported patients were destined to develop PD [Parkinson’s disease] and were on the cusp of losing the number of [dopamine-producing] neurons required for the emergence of motor symptoms, and the viral infection only accelerated an ongoing neurodegenerative process around a critical timepoint,” the researchers wrote.

“However, the rapid onset of severe motor symptoms in close temporal proximity to the viral infection is still suggestive of a causal link,” they added.

They also proposed three mechanisms by which COVID-19 might set the stage for Parkinson’s.

First, COVID-19 has been linked with blood clots and other problems with the circulatory system. It is possible that such problems may cause brain damage, possibly by affecting blood flow to certain parts of the brain. If this happens in brain regions where dopamine is produced, patients could develop symptoms similar to those of Parkinson’s.

Second, Parkinson’s has been associated with increased brain inflammation. Conceivably, the acute inflammation that results from viral infection could lead to brain inflammation similar to what occurs in the context of Parkinson’s.

“Evidence is mounting that the side effects of COVID-19 infection, such as inflammation and damage to the vascular system, could lay the foundation for development of Parkinson’s disease,” Brundin said.

Third
, SARS-CoV2 may infect brain cells, and be a neurotropic virus. This hypothesis is backed up by studies reporting the virus has been detected in the brains of some people who died from COVID-19; other studies show dopamine-producing neurons contain high levels of the protein receptor that SARS-CoV2 uses to infect cells.

“SARS-CoV-2 is considered a respiratory virus, however, its virulence and pathogenic [disease-causing] potential particularly for neurological complications continues to surprise us. Some patients can develop severe neurological manifestations despite mild respiratory symptoms,” said Avindra Nath, MD, a co-author and infections specialist with the National Institute of Neurological Disorders and Stroke.

It is possible that a brain infection could raise levels of the Parkinson’s-related protein alpha-synuclein, as has been observed in other viral brain infections, such as those caused by the West Nile virus.

“While acute parkinsonism in conjunction with COVID-19 appears to be rare, spread of SARS-CoV-2 widely in society might lead to a high proportion of people being predisposed to developing PD later in life,” the researchers concluded. “Therefore, it is important to carefully follow large cohorts of people affected by COVID-19, and monitor them for manifestations of PD.”
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Re: Parkinsons Disease / Covid 19 & Parkinsons

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Loneliness in Parkinson's disease may increase risk for symptom severity

11/18/20


https://www.news-medical.net/news/20201 ... erity.aspx


Research from UCLA scientists and colleagues from other institutions finds that people with Parkinson's disease who lack meaningful social interactions may be at an increased risk for severe symptoms related to the disease.

The study, which was published in the journal NPJ Parkinson's Disease, evaluated not only the social and emotional life of patients, but also their nutrition and exercise habits.

Over a 5-year period, from 2014-2019, researchers at UCLA, the University of Washington and Bastyr University collected information from 1,500 people with Parkinson's disease. Study participants were surveyed most recently in December. Participants who reported being most lonely, also reported exercising less, were less likely to follow healthier diets and experienced a lower quality of life.

"That surprised us," says study author Dr. Indu Subramanian, a neurologist at the David Geffen School of Medicine at UCLA and director of the Southwest Veteran Affairs Parkinson's Disease Research, Education and Clinical Centers.

"One of the most detrimental things is actually being lonely," Subramanian says. The negative impact of loneliness on symptom severity, she says, was as large as the positive effect from exercise.

Millions of people have curtailed their social interactions to stay safe during the COVID-19 pandemic. While this is good practice for avoiding a virus, the resulting isolation and loneliness can create a health hazard that could be particularly hard on people with Parkinson's disease who sometimes limit interactions due to adverse disease symptoms such as tremor.

Subramanian and the rest of the team recently sent out a new survey to the study participants to collect data about how the pandemic has affected their symptoms.

Even patients who have happy family lives can suffer from loneliness, she adds, though that may seem counterintuitive.

People thrive in three spheres of social interaction: One is the intimate connection of a marriage or partnership; the next wider sphere is a circle of friends; and the third is belonging to a group with a shared sense of identity.

" For people with Parkinson's disease, they may be in a support group. It could even be something like a book club."

- Dr. Indu Subramanian, Neurologist, David Geffen School of Medicine at UCLA

To support that shared sense of identity during the pandemic, Subramanian started a virtual support group, which meets two to three times a week, for people with Parkinson's disease.

"It's called social prescribing, because you literally prescribe to your patients to be more socially connected," Subramanian says. "It's actually grown into an international group of patients. People have grown to enjoy and connect through it. Some people have told me it's the only social thing they do at all."
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Re: Parkinsons Disease / Covid 19 & Parkinsons

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Researchers use AI technology to evaluate speech disorders related to Parkinson's disease

11/24/20


https://www.news-medical.net/news/20201 ... sease.aspx


The COVID-19 pandemic is leading a Purdue University innovator to make changes as she works to provide new options for people with Parkinson's disease.

Jessica Huber, a professor of Speech, Language, and Hearing Sciences and associate dean for research in Purdue's College of Health and Human Sciences, leads Purdue's Motor Speech Lab. Huber and her team are now doing virtual studies to evaluate speech disorders related to Parkinson's using artificial intelligence technology platforms.

Huber and her team have been working to develop telepractice tools for the assessment and treatment of speech impairments like Parkinson's disease.

They received a National Institutes of Health small business innovation and research grant to develop a telehealth platform to facilitate the provision of speech treatment with the SpeechVive device, which has received attention at the Annual Convention of the American Speech-Language-Hearing Association.

In the current study, Huber and her team are collaborating with a startup company, Modality AI, which developed the AI platform that will be used in the study.


" The application of the technology we are evaluating may lead to far-reaching insights into more standardization in assessments, earlier diagnoses and possibly an easier way to track discrete changes over time to guide interventions. My personal research passion, and the mission of our lab, is to find ways to improve the quality of life for people with Parkinson's and other related diseases."

- Andrew Exner, Graduate Research Assistant in Motor Speech Lab. Purdue University

Exner is leading the virtual study for participants across the country to evaluate an AI platform that can collect and automatically measure the speech skills of people with Parkinson's disease. The need for AI platforms is increasing as the use of telepractice explodes as a result of the COVID-19 pandemic.

"My interest in speech-language pathology actually started during my training as an actor and opera singer," Exner said. "I saw the effects of pathology on the voice and wanted to extend that interest into speech disorders."

SpeechVive Inc. is an Indiana startup company based on Huber's research. The company has developed a wearable medical device to improve the speech clarity of people with Parkinson's.
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Re: Parkinsons Disease / Covid 19 & Parkinsons

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AI-assisted video analysis can help doctors to diagnose Parkinson’s disease at an early stage

2/12/21


https://www.news-medical.net/news/20210 ... stage.aspx


Scientists from Skoltech and A.I. Burnazyan Federal Medical and Biophysical Center have designed and developed a second opinion system, based on AI-assisted video analysis, which can help medical professionals to objectively assess patients with Parkinson’s disease (PD) even at an early stage. This approach can help avoid misdiagnosing this disease, distinguishing between its stages, adjusting therapy and recommending diagnosed patients for deep brain stimulation surgery. The paper was published in IEEE Sensors Journal.

A growing number of people with neurodegenerative diseases, due to population aging, will mean that in the coming decades, humanity might face a bona fide ‘Parkinson’s disease pandemic’. PD, currently the fastest growing neurodegenerative disease, affects the patients’ quality of life quite severely and needs to be diagnosed as accurately and as early as possible. The challenge there is to distinguish between Parkinson’s and other diseases with similar motor symptoms, for instance, essential tremor. So far, PD has no single biomarker that could be used to diagnose it consistently, and doctors have to rely on their observations, which often lead to wrong diagnoses revealed in pathological examinations.

Assistant Professor Andrey Somov and his colleagues built a so-called second opinion system that uses machine-learning algorithms to analyze video recordings of patients performing specific motor tasks. In a small pilot study, this system showed a very high level of performance in detecting potential cases of PD and distinguishing it from essential tremor.

The system uses video recordings, making the diagnostic process fast, unobtrusive and comfortable for the patients. The team designed a set of 15 common exercises such as walking, sitting down on chair, standing up, folding a towel, filling a glass with water, and touching one’s nose with one’s index finger. These were general and finer movements, no movement at all (to assess tremor at rest) and some activities that clinicians use to evaluate the tremor.

" The exercises were designed under the supervision of neurologists and came from several different sources, including scales that are used for monitoring Parkinson’s disease and previous research done in this area. Each exercise had a target symptom that it could reveal.”

- Ekaterina Kovalenko, Skoltech PhD student and coauthor of the paper

In the pilot study, 83 patients with or without neurodegenerative diseases were recorded performing these tasks. The videos were then processed using a piece of software that places keypoints onto the human body corresponding to joints and other parts of the body, creating simplified models of moving subjects. Those were analyzed using machine learning techniques.

The team says that the use of video and machine learning introduces a certain degree of objectiveness into the diagnostic process, allowing researchers and doctors to detect very specific features of the disease and its stages which are not visible to the naked eye.

“Our preliminary results show potential in improving diagnosis with the help of video analysis. Our goal is to provide a second opinion for doctors and clinicians, not to replace them. A video-based method perhaps is the most convenient for patients, as it is the most versatile and noninvasive when compared to various sensors and testing,” the authors write in their paper.

" Machine learning and computer vision methods we used in this research are already well established in a number of medical applications; they can be trusted, and the diagnostic exercises for Parkinson’s disease have been in development by neurologists for some time. What is truly new about this study is our quantitative ranking of these exercises according to their contribution to a precise and specific final diagnosis. This could only be achieved in collaboration between doctors, mathematicians and engineers.”

- Dmitry Dylov, Skoltech Associate Professor and coauthor of the study

In earlier studies, Somov’s team also used wearable sensors in a similar feasibility study that helped them detect the most informative exercises for machine learning-assisted diagnosis of Parkinson’s.

“As part of the research process, we had the opportunity to closely interact with doctors and medical personnel, who shared their ideas and experience. It was fascinating observing how two seemingly different disciplines came together to help people. We also had the opportunity to monitor all parts of the research, from designing the methodology to data analysis and machine learning,” Kovalenko said.

“This collaboration between doctors and scientists in data analysis allows for many important clinical nuances and details that help achieve the best results. We as doctors see great potential in this; apart from differential diagnosis, we need objective tools to assess motor fluctuation in patients with PD. These tools can provide a more personalized approach to therapy and help make decisions on neurosurgical interventions as well as assess the outcomes of surgery later,” neurologist Ekaterina Bril, a coauthor of the paper, noted.

Andrey Somov said the team’s next goal is to combine video analysis and sensor data in the task of detecting PD and diagnosing its stages – they expect that this will improve accuracy. “We also keep in mind the innovation aspects of our work – our team agrees that it does make sense to consider converting our research results into an intuitive software product. We believe our joint research efforts will have a positive effect for the patients with PD,” he added.

Source:

Skolkovo Institute of Science and Technology

Journal reference:


Kovalenko, E., et al. (2021) Distinguishing Between Parkinson’s Disease and Essential Tremor Through Video Analytics Using Machine Learning: a Pilot Study. IEEE Sensors. doi.org/10.1109/JSEN.2020.3035240.
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Re: Parkinsons Disease / Covid 19 & Parkinsons

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Bacteria in Patients’ Guts Show Changes That May Weigh on Disease

3/15/21


https://parkinsonsnewstoday.com/2021/03 ... t-disease/


People with Parkinson’s disease have substantial changes in the bacteria living in their gut relative to people without this neurodegenerative disorder, an analysis underscores.

“This dysbiosis [microbial imbalance] might result in a pro-inflammatory status which could be linked to the recurrent gastrointestinal symptoms affecting PD [Parkinson’s disease] patients,” its researchers wrote.

These findings were in the study “Meta-analysis of the Parkinson’s disease gut microbiome suggests alterations linked to intestinal inflammation,” published in npj Parkinson’s Disease.

The human gut is home to billions of bacteria, called the gut microbiome. These bacteria have profound effects on, and are affected by, the health of the person in which they live.

Emerging research has indicated that the gut microbiome may be altered in Parkinson’s patients. However, individual studies often find inconsistent — or even contradictory — results, which has made it difficult for researchers to get a holistic understanding of the relationship between Parkinson’s and the gut microbiome.

A team of researchers with the Quadram Institute Bioscience, in the UK, conducted a meta-analysis to better understand this relationship. A meta-analysis is a type of study in which scientists synthesize data from multiple, previously published studies. Because they assess data from multiple works, meta-analyses generally have more statistical power than individual studies.

Researchers analyzed data from 10 previously studies, which reported data on nine groups of people (two studies covered the same group at different points in time). All were case-control studies, meaning they analyzed and compared the gut microbiomes of cases (people with Parkinson’s) compared with controls (people without Parkinson’s). Collectively, the studies included data on 1,269 people with and without Parkinson’s.

All of the studies used 16S rRNA-gene amplicon sequencing to assess the gut microbiome. Simply put, this technique determines what types of bacteria are in a given sample by sequencing a specific part of the bacteria’s genetic code.

A major finding from this meta-analysis was that, even though all these studies used the same overall technique, there were many methodological details that differed study-to-study.

“Various sampling protocols were used across studies, with considerable variation in the methods adopted to preserve the samples before processing,” the researchers wrote. “In some cases, samples were kept at room temperature for up to 48 hours before analysis, in others, samples were stored either in DNA preservative or on ice. DNA extractions and sequencing strategies also varied across studies.”

Statistical analyses on the pooled data found a greater effect on the variance of the gut microbiome than disease status. In other words, study-to-study differences in the gut microbiome were more profound, in a statistical sense, than differences between Parkinson’s cases and control individuals.

Methodological differences, the researchers wrote, “might be the main reasons for the heterogeneity [variability] across the datasets we considered.” They noted a need for further research in this area, and for efforts to better standardize data collecting methodologies.

The researchers then performed additional statistical analyses, which attempted to account for intra-study variability, in order to look for differences in the gut microbiome of people with or without Parkinson’s.

They found a few noteworthy results. For example, people with Parkinson’s generally had more diverse gut microbiomes. Specifically, Parkinson’s patients tended to have lower levels of bacteria that are usually abundant in the guts of healthy people, and higher levels of bacteria that are typically rare in the healthy gut.

Parkinson’s patients also tended to have lower levels of bacteria that produce butyrate, a compound important for the activity of the cells that line the gut and for mediating cross-talk between the gut and the nervous system, the team reported. Increased levels of bacteria that produce methane were also evident, which the researchers speculated could, together with bacteria that deplete mucus, be tied to constipation in Parkinson’s patients.

Such alteration in the diversity and abundance of different types of bacteria “points towards an important role of the gut microbiota in modulating the immune function in this disease,” the researchers wrote.

While the “variability across studies is very big… we can still detect differences between the gut microbiome of patients and controls. This means that microbiome alterations in Parkinson’s disease are consistent across sampling cohorts [groups],” Stefano Romano, PhD, a researcher at Quadram and study co-author, said in a press release.

“The restoration of a balanced microbiome in patients might alleviate some of the symptoms of Parkinson’s, and this is a really exciting route of research we are exploring,” Romano added.

A noteworthy limitation of this study is that the analyses were not designed to find cause-and-effect relationships. That is, it is not clear whether Parkinson’s causes alterations to the gut microbiome, or whether changes in the gut microbiome predispose a person to Parkinson’s and affect its course.

Additionally, most patients in these studies were actively receiving treatment, making it difficult to tease out whether effects seen are due to Parkinson’s itself or to its medications.
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