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Number of Dopaminergic Neurons at Birth Could Affect Lifetime Parkinson’s Risk, Report Suggests

Dopaminergic neurons at birth

The number of dopamine-producing (dopaminergic) neurons at birth could influence a person’s lifetime risk of developing Parkinson’s disease, according to a group of experts.

Because these nerve cells die over the course of the disease, having fewer of them to begin with could translate to a higher risk, the scientists said.

Their report, “Does Developmental Variability in the Number of Midbrain Dopamine Neurons Affect Individual Risk for Sporadic Parkinson’s Disease?” is a review of scientific literature on the topic. It was published in the Journal of Parkinson’s Disease.

Parkinson’s is a progressive neurodegenerative disease, meaning that it steadily worsens as neurons die over time. The hallmark of Parkinson’s is the loss of dopamine — a neurotransmitter crucial for coordinating movement and regulating mood — that occurs when dopaminergic neurons in a brain structure called the substantia nigra malfunction and die.

The substantia nigra communicates with a neighboring brain structure called the striatum and it is believed that the loss of dopamine and dopaminergic neurons in these structures must cross a certain threshold before the symptoms of Parkinson’s become noticeable. The number of dopaminergic neurons an individual is born with, therefore, might influence how soon this threshold is reached.

Precisely how many of these neurons must die before symptoms appear remains an open question. No datasets of nigral (belonging to the substantia nigra) dopaminergic neuron counts are available for individuals with recent onset of Parkinson’s symptoms.

Nor is there a strong scientific consensus regarding the number of dopaminergic neurons in normal substantia nigra. Different methods for marking both dopaminergic neurons and age-related changes that can limit the number of functional neurons within the brain hinder precise counts.

To estimate the variation in dopaminergic neuron numbers across people, a team of scientists now examined the data in four previous studies. Each study followed strict exclusion criteria, such as not admitting patients with histories of neuropsychiatric disease and/or other neurological damage.

The studies are: Ageing of substantia nigra in humans: cell loss may be compensated by hypertrophy, published in 2002; The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson’s disease estimated with an unbiased stereological method, published in 1991; Unbiased morphometrical measurements show loss of pigmented nigral neurones with ageing, published in 2002; and Morphometry of the human substantia nigra in ageing and Parkinson’s disease, published in 2008.

In the review, the researchers focused on individuals who died before their 51st birthday, to minimize the risk that any observed variation was due to age-related effects, or to undiagnosed progressive disorders.

The studies showed a wide variation between individuals — ranging from 147% to 433% — in terms of the difference between those with the most and the fewest dopaminergic neurons. Such variation must be better understood to properly understand its significance, the researchers said.

Many of the genes implicated in rare developmental abnormalities in humans also are involved in determining the location, formation, and size of the dopaminergic neuron population. Based on past studies, the researchers suggest that subtle changes in how active these genes are throughout development likely determine the variation witnessed between individuals.

Although clearly defining these changes poses a significant challenge, some clues are emerging.

One recent study, for example, linked Parkinson’s risk to single nucleotide polymorphisms (SNPs) — changes of one single letter of the genetic code — that affected gene regulatory elements involved in early nervous system development. This, in turn, affects the number of neurons an organism has.

Other studies have shown that Parkinson’s-related mutations also can reduce the number of dopaminergic neurons capable of being grown in the lab.

The alpha-synuclein protein plays a well-documented role in Parkinson’s progression. Its role in early development is less understood. One mouse study showed that the expression of the alpha-synuclein gene could affect the number of dopaminergic neurons in the substantia nigra. This suggests that, beyond the pathogenic role it plays in Parkinson’s, alpha-synuclein may help determine the early development and survival of dopaminergic neurons.

Non-genetic factors also appear to impact dopaminergic neurons by affecting critical periods of brain development. These factors include viral infection, exposure to environmental toxins, and hypoxia (low oxygen) at birth.

Based on the information collected throughout their review, the researchers propose that the number of nigral dopaminergic neurons individuals are born with and that survive immediately following birth affects their lifetime risk of developing Parkinson’s disease.

However, the researchers note that current knowledge of the factors influencing the development and survival of dopaminergic neurons is incomplete.

Therefore, “we need to explore the changes that occur both during development and during adulthood and aging when we seek to understand the full landscape of [Parkinson’s] risk,” they said.

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Falls and Poor Bone Health Top Reasons for High Fracture Risk in Parkinson’s, Study Says

fractures and risk

People with Parkinson’s disease are at elevated risk of hip and non-vertebral fractures mostly because of the balance problems inherent to the disease and poorer bone health, a review study reports.

These findings support making fracture risk assessment part of standard care for Parkinson’s patients.

The study, “The risk of hip and non-vertebral fractures in patients with Parkinson’s disease and parkinsonism: A systematic review and meta-analysis,” was published in the journal Bone.

Several studies have shown that people with Parkinson’s are at a higher risk of falls and osteoporosis, and have lower bone mineral density (BMD) that others their age without this disease.

These factors are thought to contribute to the previously reported increased risk of fractures — with hip fractures being the most common — in these patients compared with the general population: A risk of falling is three times higher in Parkinson’s patients compared to age- and gender-matched healthy individuals.

A previous study using Medicare data showed that a hip fracture also more than doubled the risk of death in Parkinson’s patients (and particularly in men), compared again to people without the disease. The occurrence of non-vertebral fractures — those that do not occur in the spine or skull — is also thought relevant by researchers and doctors.

While vertebral fractures can also be quite disabling, the large proportion of asymptomatic fractures, as well as their challenging identification (requiring serial radiographs), puts them among the least well-reported.

“Despite the numerous individual studies published on the risk of fractures, the relationship between PD [Parkinson’s disease] and the risk of hip and non-vertebral fractures has not been systematically assessed,” the team wrote.

Researchers at the University of Sheffield, in the U.K., along with American colleagues systematically reviewed published studies on the occurrence of hip and non-vertebral fractures in Parkinson’s patients and people without the disease.

From a total of 261 studies initially considered, 18 met the intended criteria and were included in the review, covering a total of 2.33 million participants. The selected studies also involved people diagnosed with parkinsonism — a general term for neurological disorders that cause movement problems similar to those of Parkinson’s.

Seventeen of these studies were included in the hip fracture analysis, while nine studies were included in the non-vertebral fracture analysis.

Results showed that people with Parkinson’s had a more than two-fold increased risk of hip fractures and a nearly two-fold increased risk of non-vertebral fractures than did the other group.

Researchers noted significant differences between studies in the hip fracture analysis, which could affect their results. Further evaluation suggested that gender and location were responsible for 74.1% of this variation.

Nevertheless, they emphasized that their results were consistent with those reported in previous, smaller studies.

Subgroup analysis of potential factors fracture risk influencing showed that the relative risk of hip fractures was higher in men than in women with Parkinson’s disease.

The team hypothesized that this difference may be partly due to a lower rate of fractures in men than in women without Parkinson’s, since hip fractures in the general population are more common in women.

“[W]e recommend a re-evaluation of the clinical guidelines on bone health in patients with PD to address this,” the researchers wrote.

“Fracture risk assessment and evidence-based treatment for osteoporosis should be part of the care in patients with PD,” they added.

The team noted, however, that these findings may not be applicable to Parkinson’s patients worldwide, since their work was based only on English-written studies in mostly Caucasian patients, and there was a significant heterogeneity between the studies.

Researchers suggested that future studies could also assess the effect of BMD, falls, Parkinson’s medication, as well as anti-osteoporotic treatment on the occurrence of fractures in Parkinson’s patients.

A U.S.-based Phase 4 clinical trial (NCT03924414), set to recruit up to 3,500 patients 65 years or older, will assess one-time use of an approved treatment for osteoporosis against a placebo in lowering the fracture risk of Parkinson’s. After an intravenous infusion, participants will be followed for at least two years.

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Using ENT-01 to Target Alpha-Synuclein Found in Gut May Help Slow Parkinson’s Progression, Review Finds

Parkinson's, ENT-01

Enterin’s ENT-01, a compound that targets and reduces the accumulation of alpha-synuclein in nerve cells found in the gut, may slow the progression of Parkinson’s disease, according to a review study.

The review, “Gastrointestinal Immunity and Alpha-Synuclein,” was published in the Journal of Parkinson’s Disease.

A hallmark feature of Parkinson’s is the progressive degeneration of brain cells due to the accumulation of toxic clumps of the protein alpha-synuclein, called Lewy bodies.

Some scientists believe Lewy bodies form in the enteric nervous system — the network of nerves that innervate the gastrointestinal (GI) tract — then spread to the brain, where they gradually damage and destroy brain cells.

For that reason, many researchers are now investigating the possibility of using compounds that specifically target and reduce the build-up of alpha-synuclein in nerve cells found in the gut to restore the function of the GI tract in people with Parkinson’s, and eventually slow down the progression of the disease in the central nervous system (composed of the brain and spinal cord).

“There is growing evidence that [Parkinson’s disease] may start off in the gut,” Michael Zasloff, MD, PhD, founder of Enterin, scientific director of the MedStar Georgetown Transplant Institute and senior author of the study, said in a press release.

“The concept is that aggregates of the protein alpha-synuclein, thought to play a key role in the disease, arise within the enteric nervous system (ENS) and travel up the peripheral nerves to the central nervous system (CNS) where they ultimately cause inflammation and destruction of parts of the brain. Targeting the formation of alpha-synuclein aggregates in the ENS may therefore slow the progression of the disease,” Zasloff said.

In normal conditions, alpha-synuclein helps protect the nerve cells found in the GI tract from viral or bacterial infections by calling immune cells into action.

However, when a person develops chronic GI infections or their gut cells are no longer able to control which substances should be absorbed and which should be discarded as waste, alpha-synuclein may start to accumulate inside nerve cells from the gut, becoming highly toxic and possibly contributing to the onset of Parkinson’s.

“Based on this perspective, we are testing the hypothesis that by targeting the ENS with ENT-01, a compound that can inhibit the intracellular aggregation of [alpha-synuclein], we can restore ENS functioning in the short term, and possibly slow the progressive deterioration of the CNS in the long term,” the researchers wrote.

ENT-01 is an artificial compound derived from squalamine, a substance originally discovered in the liver and gall bladder of the dogfish shark. Preclinical studies have shown that ENT-01 is able to displace alpha-synuclein from the membranes of nerve cells found in the gut, restoring their normal electric activity and reducing the formation of toxic aggregates.

An open-label, Phase 2a clinical trial called RASMET (NCT03047629) in 2018 demonstrated that treatment with ENT-01 lessened constipation, a common GI symptom of Parkinson’s, in 80% of the 50 patients participating in the study.

“Surprisingly, we also observed benefits in both motor and non-motor symptoms. The RASMET study demonstrated that it is possible to correct long standing dysfunction of the ENS which might have been assumed to be irreversibly damaged,” the researchers wrote.

The team is currently leading a double-blind, placebo-controlled, Phase 2b trial called KARMET (NCT03781791) to investigate the effects of ENT-01 tablets on constipation and other neurologic symptoms of Parkinson’s in a group of 110 participants.

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Lack of Standardized Vitamin D Data Hampers Efforts to Determine Its Role in Parkinson’s, Review Study Says

Vitamin D, Parkinson's risk

Low vitamin D serum levels have been associated with Parkinson’s disease, but the lack of standardized data makes it difficult to determine vitamin D’s exact role in Parkinson’s pathology, according to a recent review article.

The study, “Standardized measurement of circulating vitamin D [25(OH)D] and its putative role as a serum biomarker in Alzheimer’s disease and Parkinson’s disease,” was published in Clinica Chimica Acta.

Vitamin D is essential to maintain homeostasis of the musculoskeletal system, and exists in two forms: 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D. The major form found in the blood is 25-hydroxyvitamin D, and as such, testing usually quantifies these levels to monitor vitamin D status in individuals.

Low serum vitamin D levels have been associated with Parkinson’s disease, suggesting that elevated vitamin D levels could protect against this neurodegenerative disorder.

In 2010, researchers analyzed the blood concentrations of vitamin D in 3,173 men and women, 50–79 years old, and found that those with higher levels were less likely to develop Parkinson’s. Standardized techniques were used to measure these levels, which revealed that 50 out of the 3,173 people developed Parkinson’s, which is a relatively small number for scientists to draw conclusions on the “protective power” of vitamin D.

In another study, 25-hydroxyvitamin D blood concentration was found to be significantly associated with motor severity in 145 Parkinson’s patients who were followed for three years. These findings were further supported by two recent meta-analyses evaluating a total of 4,199 patients. Results revealed that serum vitamin D levels were inversely associated with Parkinson’s risk and severity, and that vitamin D supplementation did not improve subjects’ motor function. However, the methods used to quantify vitamin D levels varied between the studies included in the combined statistical analyses.

In an attempt to standardize vitamin D measurements, researchers in the current study reviewed the performance of 25-hydroxyvitamin D assays over the last three decades. So far, “only a few studies evaluating relatively small samples reported standardized data,” the researchers wrote.

“Literature studies in the field of vitamin D mainly report unstandardized results, which hampers the development of consensus guidelines defining optimal vitamin D status,” they said, adding that current data do not support the usefulness of vitamin D as a biomarker for Parkinson’s disease and that further studies “using internationally recognized measurement procedures and materials are required.”

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Acupuncture May Help Alleviate Parkinson’s Motor Symptoms, Preclinical Data Suggest

Acupuncture mice studies

Acupuncture may be beneficial to alleviate motor symptoms associated with Parkinson’s disease, according to data collected from mouse studies.

The findings were published in the study, “Does Acupuncture Protect Dopamine Neurons in Parkinson’s Disease Rodent Model?: A Systematic Review and Meta-Analysis,” in the journal Frontiers in Aging Neuroscience.

Acupuncture has long been used in East Asian countries to treat motor dysfunctions and neurological disorders such as Parkinson’s.

Evidence suggests that acupuncture may enhance motor function-associated neural responses in patients with Parkinson’s, and its effect has been shown in clinical studies: Parkinson’s patients who underwent bee venom acupuncture treatment saw their motor function improved; and “motor function-associated neural responses” with acupuncture have been shown in Parkinson’s patients using magnetic resonance imaging.

To understand the extent to which acupuncture affects the recovery of dopaminergic neurons — those affected in Parkinson’s disease — different rodent models have been used. However, results have been controversial: while some studies report that acupuncture recovered dopaminergic neurons, others failed to demonstrate the therapy’s neuroprotective potential in a different mouse model of the disease.

In this study, Korean researchers reviewed data from 42 published studies that focused on the preclinical assessment of acupuncture’s therapeutic potential for Parkinson’s disease.

Because these studies used different mouse models of Parkinson’s disease, they allowed researchers to have a broad view of the therapy’s impact without biological bias of the type of model used.

Of the 42 studies, 23 tested the effects of electroacupuncture and 19 used manual acupuncture.

All of the studies, with the exception of two, showed that acupuncture increased the levels of an enzyme called tyrosine hydroxylase (TH) in the substantia nigra — the main brain region affected in Parkinson’s disease — which suggests healthier dopamine-producing brain cells.

Tyrosine hydroxylase is involved in the processing of dopamine, and as such, low levels of this enzyme are associated with disease progression.

TH-positive neurons were increased after acupuncture in nearly all studies. “Overall, integrated changes of TH+ neurons in PD [Parkinson’s disease] models demonstrated 35.94% of normal brain and, interestingly, those of acupuncture treated improved these neuronal deficits by 70.43%,” the researchers wrote.

“[This] analysis indicated that dopaminergic neurons in Parkinson’s disease model rodents were recovered by acupuncture,” they added.

Despite this positive effect, acupuncture failed to induce changes in dopamine levels. Still, some studies provided evidence that Parkinson’s motor dysfunctions in mice were alleviated upon treatment.

This suggests that acupuncture may not directly reverse brain nerve cell damage and help increase the production of dopamine, but it can probably enhance communication networks between brain cells.

Based on these findings, the team believes that “acupuncture treatment potentially protected [dopamine] neurons through various beneficial mechanisms.”

“Nevertheless, resolving the low quality of studies and further research investigating the efficacy of different acupuncture treatment methods in PD [Parkinson’s disease] rodent models will be needed,” they added.

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Gut Alpha-Synuclein May Be Used as Biomarker of Parkinson’s, Study Suggests

Gut alpha-synuclein

Alpha-synuclein levels in the gut are linked to Parkinson’s disease, indicating that gut alpha-synuclein may be used in combination with other disease biomarkers to facilitate patients’ diagnosis, a review study found.

The study, “Diagnostic utility of gut α-synuclein in Parkinson’s disease: A systematic review and meta-analysis,” was published in Behavioural Brain Research.

Parkinson’s disease is associated with the overproduction of the protein alpha-synuclein in nerve cells of the brain. When this protein clumps together, it gives rise to small toxic deposits inside brain cells, called Lewy bodies.

Alpha-synuclein phosphorylation — a chemical modification in which a phosphate group is added to the protein — is known to occur in Parkinson’s disease, and is thought to be a critical step in disease progression as it enhances alpha-synuclein’s toxicity, possibly by increasing the formation of alpha-synuclein aggregates.

Some scientists think Lewy bodies form in the enteric nervous system (ENS) — the network of nerves that innervate the gastrointestinal tract — then spread to the brain, where they will gradually damage and destroy brain cells.

Although alpha-synuclein has already been detected in tissue samples collected from the stomachs and colons of Parkinson’s patients, its usefulness as a disease biomarker is still controversial.

Chinese researchers conducted a systematic review focused on assessing the relationship between gut alpha-synuclein and Parkinson’s, as well as its diagnostic power in distinguishing patients with the disease from those without it (controls). They reviewed 21 previously published studies reporting findings on gut alpha-synuclein, or phosphorylated alpha-synuclein.

Pooled data from the studies revealed that patients with Parkinson’s were approximately 10 times more likely to have deposits of alpha-synuclein in the gut compared to control subjects. This suggests a direct relationship between gut alpha-synuclein and Parkinson’s disease.

Further analysis showed that gut alpha-synuclein and phosphorylated alpha-synuclein could correctly identify 81.9% and 82.2% of individuals who did not have Parkinson’s disease. However, both had poor sensitivity and failed to distinguish patients with the disease from control subjects in approximately half the cases — a sensitivity of 56.8% for gut alpha-synuclein and 57.9% for phosphorylated alpha-synuclein.

“These results showed that a single measurement of gut [alpha]-synuclein could lead to the underdiagnosis of Parkinson’s disease,” researchers said. “This systematic review and meta-analysis confirmed a high degree of association between gut α-synuclein and Parkinson’s, which suggested that gut [alpha]-synuclein is a potential therapeutic intervention.”

Additional studies are still warranted to further explore the diagnostic potential of gut alpha-synuclein when combined with other biochemical markers of the disease, and “more efforts should be made to improve the standardization of current assays,” they said.

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Next 20 Years Expected to Bring ‘Message of Hope’ to Parkinson’s Patients, Review Study Finds

hope and Parkinson's

Discoveries into molecular mechanisms, risk factors — especially genetic — and advances in potential and repurposed therapies for Parkinson’s disease over the last 20 years are reason to believe that major breakthroughs await the next two decades, a review article by two researchers states.

The review article, “Therapies to Slow, Stop, or Reverse Parkinson’s Disease” was published in a supplement of the Journal of Parkinson’s Disease.

The development of better laboratory models, especially animal models that capture the slowly progressive nature of Parkinson’s, together with data resulting from scientific research and early clinical trials “strongly justifies sending this message of hope,” the authors write, explaining that the mechanisms underlying this neurodegenerative disease are gradually being deciphered.

The researchers, Tom Foltynie at University College London and J. William Langston at Stanford University, highlighted possible therapies that are most likely to emerge as disease-modifying treatments for Parkinson’s, despite the considerable challenges that remain in bringing a treatment successfully through a clinical study.

Based on the knowledge that mutations in the LRRK2 gene are one of the most common genetic causes of Parkinson’s disease, researchers have focused on therapies that can inhibit (block) LRRK2. But these efforts have been hindered by lung complications (lung toxicity) in primates exposed to inhibitor candidates, and scientists are exploring more selective ways of delivering such medications to avoid toxicity.

Questions also remain as to whether the brain is the prime target for LRRK2 activity, with some evidence pointing to the gut as well.

Treatments targeting the GBA gene, which encodes an enzyme called beta-glucocerebrosidase, may be relevant for people with sporadic forms of the disease in whom low levels of beta-glucocerebrosidase have been observed. This enzyme plays an important role in the mobilization and processing of alpha synuclein, which is low in GBA mutation carriers.

Ambroxol, an approved treatment for respiratory diseases associated with sticky or excessive mucus, is known to boost beta-glucocerebrosidase activity. However, it remains to be determined if Parkinson’s patients can tolerate the dose required for this therapy to reach the central nervous system. Other molecules that work in the body in ways similar to Ambroxol have been identified.

Since most available Parkinson’s therapies aim to ease motor symptoms, targeting non-motor features like cognition, speech, gait, balance difficulties and autonomic failure (or problems with regulating blood pressure and other process controlled by the autonomic nervous system) is important, given that many of these may precede motor onset. This could allow treatments to be started earlier, possibly delaying or preventing the onset of motor symptoms.

One approach to slowing disease progression gaining interest is that of “repurposing” medications already approved for diseases other than Parkinson’s. Preclinical studies found that type 2 diabetes medications — scientifically known as glucagon-like peptide 1 (GLP-1) receptor agonists — protect against alpha-synuclein-induced neurodegeneration. Various ongoing Phase 2 trials are assessing the effect of various GLP-1 receptor agonists (liraglutide, lixisenatide and semaglutide ) in Parkinson’s disease patients — NCT03659682NCT03439943NCT02953665). Plans for a Phase 3 trial of exenatide, another GLP-1 agonist, are underway.

Medicines used to treat primary biliary cirrhosis (an autoimmune disease of the liver; ursodeoxycholic acid), chronic myelocytic leukemia (nilotinib) and asthma (salbutamol and clenbuterol) also hold promise for Parkinson’s as they seem to contribute to nerve cell survival, eliminate toxic alpha-synuclein buildup, and modulate alpha-synuclein production, respectively.

Various studies have linked alpha-synuclein-induced neuroinflammation to Parkinson’s disease. As such, immunomodulatory therapies can be a treatment option. Evidence suggests a person’s immune system can react to toxic forms of alpha-synuclein and trigger an inflammatory reaction, which can speed disease progression. Azathioprine and sargramostim, both immunomodulatory medications, are being considered as potential candidates for slowing Parkinson’s progression.

A link between metabolism products generated by gut bacteria and brain inflammation has also been identified, and scientists might look to manipulate the gut microbiome — the trillions of microorganisms and their genetic material that live in the intestinal tract — in Parkinson’s patients, study the effects of such manipulation on the neurodegeneration process.

Lastly, the authors highlighted the possible use of nanoparticles in the disease context, as these molecules have been shown to block the formation of toxic alpha-synuclein clusters and actively work against their aggregation. In theory, nanotechnology might hold the potential to accurately target Parkinson’s-related neuropathology.

“We now have better understanding of the processes involved in PD [Parkinson’s disease] degeneration and can therefore have greater confidence that laboratory data and positive results from early clinical trials will ultimately translate to therapies that slow down PD progression,” Foltynie and Langston said in a news release.

“There are currently no drugs that have been proven to slow down PD progression. Demonstrating that one or several of the candidate approaches is successful will lead to a frameshift in patient care,” they added. “Useful cooperation and coordination between investigators around the globe are significantly accelerating the path towards discovering agents that may slow, stop, or even reverse the progression of PD.”

Their review concluded by stressing the possible importance of combination treatments in future clinical trials.

“It is tempting to speculate that the future patient may be recruited into research reminiscent of the current state of play in HIV/cancer fields, e.g., where following genotyping/ microbiome testing, they are either given the curative enzyme corrective therapy or randomised to receive combination therapies rather than any/each of these alone,” they wrote.

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Data Lacking on Link Between Genetic Mutations and Parkinson’s Symptoms, Review Finds

genetic mutations, symptoms

There is a substantial lack of data describing the link between the genetic mutations identified as inheritable causes of Parkinson’s — those that affect the SNCA, LRRK2, and VPS35 genes — and patient symptoms, a review study has found.

Despite this missing information, the researchers conducting the review were still able to make some determinations, including findings indicating that SNCA mutation carriers are younger in age at disease onset and have additional psychiatric symptoms, while VPS35 mutation carriers have a good response to levodopa therapy.

The study, “Genotype‐phenotype relations for the Parkinson’s disease genes SNCA, LRRK2, VPS35: MDSGene systematic review,” was published in Movement Disorders.

Parkinson’s disease, the second most prevalent neurodegenerative disease in the elderly after Alzheimer’s disease, is a complex, multifactorial disorder characterized by the gradual loss of muscle control, sometimes accompanied by cognitive deficits.

Previous studies have estimated that genetic factors may account for up to 34 percent of all Parkinson’s cases. More specifically, genetic mutations in the SNCA, LRRK2, and VPS35 autosomal genes (genes located on any chromosome other than sex chromosomes) are considered a cause of disease in up to 30 percent of all patients with Parkinson’s, depending on family history, age at onset, and population background.

“The International Parkinson and Movement Disorder Society Genetic mutation database (MDSGene) aims to systematically collect clinical and genetic information for movement disorder patients who have pathogenic mutations. In this study, we present a systematic MDSGene review and devote it to autosomal-dominant PD [Parkinson’s disease] across the three disorders, PARK-SNCA, PARK-LRRK2, and PARK-VPS35,” the researchers wrote.

The comprehensive, systematic review gathered information from 199 studies (54 on SNCA, 133 on LRRK2, and 12 on VPS35) involving a total of 937 patients (146 SNCA, 724 LRRK2, and 67 VPS35 mutation carriers) with inherited Parkinson’s disease attributed to 44 different mutations in these three genes.

“A major challenge for this systematic review was the degree of missingness of phenotypic [disease symptoms] data. Missing data not only affected non-motor signs and symptoms (NMS) of all patients, but specific information was even often unavailable for basic demographic information such as age at onset or sex or cardinal motor signs,” the authors said.

Despite the lack of data, the review managed to validate findings from previous studies showing that patients carrying mutations in the SNCA gene were more likely to develop Parkinson’s disease at an earlier age than those carrying mutations in LRRK2 and VPS35.

Pooled data also revealed that SNCA mutation carriers more frequently experienced psychiatric symptoms, while LRRK2 mutation carriers rarely had atypical symptoms of Parkinson’s disease. The researchers also found that VPS35 mutation carriers responded rather well to levodopa therapy.

“The most significant finding is the proportion of missing phenotypic data. … We propose to utilize MDSGene as the basis for the systematic collection of curated clinical and genetic information on inherited movement disorders as a solution to increase reporting of phenotypes for better genetic counseling and future gene-specific therapies,” the researchers wrote.

“To this end, the MDS Task Force on Genetic Nomenclature in Movement Disorders is drafting checklists that we propose should become the standard for clinical data reporting of individuals with movement disorders. Standard reporting of core features could improve the situation considerably,” they concluded.

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Inflammatory Bowel Disease Linked to Risk of Parkinson’s in Large Review Study

People with inflammatory bowel disease (IBD), an umbrella name for disorders marked by prolonged inflammation of the digestive tract, are at a higher-than-usual risk for Parkinson’s disease, a review study involving 8.9 million IBD patients suggests.
The study, “The risk of Parkinson’s disease in inflammatory bowel disease: A systematic review and meta-analysis,” was published in the journal Digestive and Liver Disease.
Inflammatory bowel disease (IBD) is a term that includes two main disorders — ulcerative colitis and Crohn’s disease — and is characterized by an imbalanced immune response that triggers prolonged inflammation of the digestive tract.
Inflammation in ulcerative colitis is confined to the colon (large intestine), while in Crohn’s disease it can involve any part of the digestive system. But inflammation in Crohn’s is most common at the end of the ileum (the last section of the small intestine) or the colon.
Several studies have reported that some of the inflammatory pathways impaired in Parkinson’s are also found in IBD. Certain population-based studies have also reported an increased prevalence of Parkinson’s among IBD patients, but the link between both disorders remains controversial. Another follow-up study failed to confirm those initial findings.
Researchers in China conducted a meta-analysis of published literature focusing on Parkinson’s risk in IBD using two databases, PubMed and Embase, and including in their search the keywords “ulcerative colitis” and “Crohn’s disease.” For the meta-analysis, they included cohort or case-control studies with patients diagnosed with IBD, either ulcerative colitis and Crohn’s disease, and whose main outcome was Parkinson’s.
Out of an initial pool of 172 studies, four studies accounting for a total of more than 8.9 million patients were included in the meta-analysis. (A meta-analysis is a statistical technique used to summarize in a quantitative manner the findings of multiple studies.)
Performed in the United States, Denmark, Sweden and Taiwan, these four studies assessed the incidence rate of Parkinson’s in IBD patients, specifically those with Crohn’s and ulcerative colitis. Three had been conducted in 2018, and one in 2016.
“To our knowledge, this is the first MA [meta-analysis] to focus on the risk of PD [Parkinson’s] in IBD patients,” the research team wrote. “Despite the small number of studies included, the patient numbers were large due to the population-based nature of the included studies.”
Pooled results of all studies suggested that an IBD diagnosis was associated with a 41% increased risk of developing Parkinson’s.
Assessing the risk of ulcerative colitis and Crohn’s disease separately, researchers found that both disease subtypes were linked to a higher Parkinson’s risk compared with age- and sex-matched controls — Crohn’s patients had a 28% higher risk of Parkinson’s, and those with ulcerative colitis a 30% increased risk, the study reported.
Among the IBD patients, the risk for Parkinson’s was not affected by gender, with similar rates seen in male and female patients, or by age.
Overall, this meta-analysis “identified an increased risk of PD in IBD patients,” the reseachers wrote, which “remained significant when separately analysing CD [Crohn’s disease] and UC [ulcerative colitis] subgroups.”
“More comprehensive and detailed MA using a larger number of studies are required to validate our

Source: Parkinson's News Today

Use More Human Cells and Tissues Rather Than Animal Models, Parkinson’s Study Urges

Parkinson’s researchers need to focus on human cells and tissues, implement modern computer modeling approaches, and shift away from animal models, according to a recent study.
Earlier transition from preclinical studies to clinical trials also could be beneficial, the study authors suggest.
The study, “Parkinson’s disease research: adopting a more human perspective to accelerate advances,” was published in the journal Drug Discovery Today.
Lindsay Marshall, PhD, and Catherine Willett, PhD,  from Humane Society International and The Humane Society of the United States, reviewed progress and limitations of the several existing animal models of Parkinson’s disease and suggested methods to better understand pathological processes, improve clinical outcome, and reduce dependence on animal research.
Despite a vast number of studies on Parkinson’s, the current gold standard for treatment — levodopa — is still based on findings from the 1950s and, similar to deep brain stimulation, does not target the disease’s underlying mechanisms. Also, dopaminergic therapy is associated with the development of adverse side effects on motor function, cognition, and mental health.
Research conducted to date, although providing valuable information on Parkinson’s disease processes, has not led to approaches effectively targeting the disorder’s hallmark neurodegeneration. Besides the fact that degeneration is already advanced by the time symptoms emerge — thereby shifting efforts to symptomatic treatment — researchers considered that another major cause for this lack of therapeutic success is the difficult translation of findings in animals to the complex pathology of clinical signs and symptoms in humans.
“Animal disease models will never fully replicate the healthy or diseased human brain,” researchers wrote. Rather than replicating Parkinson’s complete biology, these models — which have included rodents, monkeys, cats, dogs, worms, fruit flies, fish, frogs and toads — focus on specific pathological components. “Animal models therefore have limited capacity to reveal the true causes of, or identify real cures for, human Parkinson’s,” Willett said in a press release.
This had led to high failure rates, such as with gene therapy and glial cell line-derived neurotrophic factor, a type of approach delivering peptides (small proteins) rather than genes.
In the widely used transgenic mice, which mimic mutations found in familial Parkinson’s, reasons for failure have included variability related to the mouse strain, and not presenting the charateristic degeneration of dopamine-producing neurons in the brain or accumulation of the alpha-synuclein protein, the main component of Lewy bodies.
In turn, clinical trials of human tissue transplants have used lessons learned from prior studies regarding patient selection, tissue processing, transplant dose and immunosuppression strategy, which could be obtained only from human clinical trials, not from animal experiments.
“This suggests that transitioning from preclinical to human studies earlier during the development pipeline would accelerate the translational pathway,” the scientists wrote.
The limitations presented by animal models indicate that rather than developing new or modifying existent animal models, “new approaches need to focus directly on human systems per se,” the investigators said. This would include human cell and 3D cultures, patient-derived stem cells, as well as computer modeling and non-invasive imaging methods.
In particular, induced pluripotent stem cells (iPSCs), generated from adult cells by

Source: Parkinson's News Today