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Merger of New Mexico Parkinson’s Coalition, PMDAlliance Expected to Improve Patient Services

PMDAlliance merger

The recent merger of the New Mexico Parkinson’s Coalition (NMPC) and national nonprofit Parkinson & Movement Disorder Alliance (PMDAlliance) is expected to significantly boost support services for Parkinson’s patients in the New Mexico area, according to the organizations.

“I’m a firm believer in mergers when the organizations share similar missions and are compatible in their purpose and goals,” Sarah Jones, CEO of PMDAlliance, said in a press release. “Bringing everything under one virtual roof creates exponential benefit. It saves money and allows us to serve more people in need.”

As a result, the organizations expect a fourfold increase in the programs offered to patients with Parkinson’s and other movement disorders in New Mexico.

The coalition website states that “the tough decision was made knowing that there would be new, innovative programs and support brought to New Mexico as well as funds to hire a community engagement manager,” adding that more patients will have access to education, exercise programs, and events.

These improvements in services will be expanded to include smaller areas in the state rather than being limited to larger cities such as Albuquerque, Santa Fe, and Las Cruces.

“Working collaboratively, we can expand our reach in New Mexico, including extending services to our Native American neighbors and rural communities,” said Karen St. Clair, a former coalition board member. “PMDAlliance is passionate about services, just as the coalition is. By merging we can allocate more resources to service delivery instead of administration.”

Next year, the PMDAlliance will bring to the state educational events such as a support group for leadership training, a retreat for caregivers and their partners, and a program that focuses on new medical treatments.

The NMPC will be folded into the PMDAlliance umbrella, although it will continue to co-brand — using both organizations’ logos — until the transition is complete in about eight months, St. Clair said in a phone interview with Parkinson’s News Today. After that, its website will discontinue. The coalition was formed the year after the American Parkinson’s Disease Association’s decision in 2013 to leave New Mexico.

Operating nationwide but with no brick-and-mortar base, PMDAlliance provides educational workshops for organization leaders and those affected by movement disorders. Its overall mission is to improve patients’ lives.

According to the Parkinson’s Foundation, about 60,000 U.S. residents are diagnosed with Parkinson’s annually.

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New Neurodegeneration Challenge Network Puts Focus on Causes of Parkinson’s, Other Disorders

Neurodegeneration Challenge Network

A new network launched by Facebook CEO Mark Zuckerberg and his wife, Priscilla Chan, will unite leading investigators from various biomedical fields, as well as biologists and physicians, in gaining insight into why neurodegenerative disorders such as Parkinson’s occur.

The Chan Zuckerberg Initiative’s (CZI) Neurodegeneration Challenge Network will focus on neurodegenerative diseases as a group of disorders that share common features — and possibly future cures.

”Neurodegenerative disorders, including Alzheimer’s, Parkinson’s, Huntington’s disease and ALS, are a class of diseases that affect millions of people worldwide,” CZI science program officer Katharine Brose said in a press release. “Meanwhile, the causes of most degenerative diseases are only partly understood, and there still are no effective therapies to cure, prevent or even treat most of these disorders.”

Research projects were selected in a competitive process. Grantees include 17 early-career investigators and nine collaborative teams. Each team — seven from the U.S, one from Sweden, and one from Belgium — will receive $1.05 million.

The Belgian team, led by Patrik Verstreken, PhD, plans to develop a new chip to study how Parkinson’s works. He will work alongside researchers Wim Vandenberghe, MD, PhD, and Dries Braeken, PhD.

”We will produce human neuronal microcircuits that are relevant to Parkinson’s disease on a multi-electrode array chip,” Braeken said. “This chip will be used to measure electrophysiological changes between neuronal circuits of cells obtained from healthy people and from an extensive collection of Parkinson’s patients.”

The 2D chip is needed to form a 3D human-relevant model for brain function and disorder.

Verstreken said he hopes to “print” small parts of the human brain on a unique chip, allowing scientists access to brain tissue from healthy individuals and patients. He explained that the technology can be used to monitor disease progression and to look for potential solutions.

”While we will develop this chip using tissue from Parkinson’s patients, the same technology can be used to create better models for Huntington’s disease or any other neurodegenerative disease, for that matter,” Vandenberghe said.

Years of research notwithstanding, there remains much about Parkinson’s and related diseases that scientists don’t yet understand.

“By supporting these nine interdisciplinary collaborations and generating shared tools, resources and platforms, we hope to inspire a new approach to tackling neurodegenerative disease — one that leverages the combined power of basic science and technology to accelerate progress toward clinical goals,” Brose said.

Zuckerberg is Facebook’s co-founder and CEO. Chan is a pediatrician and philanthropist. Founded by Zuckerberg and Chan in 2015, the CZI aims to use technology to solve some of the world’s toughest problems. Its focus areas are science, education, justice, and opportunity.

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Chinese Herbal Medicine Can Ease Brain Inflammation and Protect Neurons, Mice Study Reports

Chinese medicine and Parkinson's disease

A concoction made from several Chinese herbal medicines helped reduce brain inflammation and promoted nerve cell survival in a mouse model of Parkinson’s disease, a study finds.

The study, “Curative Anti-Inflammatory Properties of Chinese Optimized Yinxieling Formula in Models of Parkinson’s Disease,” was published in Evidence-Based Complementary and Alternative Medicine.

Parkinson’s disease is characterized by the gradual loss of dopaminergic neurons in the substantia nigra — a region of the brain responsible for movement control — together with brain inflammation caused by the over-activation of glial cells, which are cells that support and protect neuronal cells, and are more reactive and proliferative than neurons.

“In PD [Parkinson’s disease], neuroinflammation (…) mediated primarily by microglial activation can directly cause DAN [dopaminergic neurons] damage,” the researchers stated. Therefore, finding a way to reduce brain inflammation and prevent glial over-activation “could be an effective method for treating PD.”

The Optimized Yinxieling Formula (OYF), a Chinese concoction of eight different plants, has been used orally to treat patients with moderate and severe psoriasis, an autoimmune disease that affects the skin, characterized by itchy or sore thick patches with silvery scales. The effectiveness of OYF comes from its anti-inflammatory properties, scientists say.

A team of Chinese researchers investigated OYF to treat brain inflammation in a mouse model of Parkinson’s disease. The team found that the herbal medicine successfully blocked the production of pro-inflammatory cytokines (molecules that mediate immune responses) and reduced overall inflammation in mouse glial cells that were activated and cultured in a laboratory dish (in vitro).

As expected, animals treated with MPTP (a neurotoxin that induces Parkinson’s symptoms) showed glial over-activation and poor performance on different behavioral tests. However, when these animals were injected with OYF, glial over-activation was blocked and motor impairments greatly reduced.

To pinpoint the molecular mechanisms responsible for the positive effects of OYF, researchers compared the transcriptome of animals treated with OYF to those receiving a saline solution (control group). The transcriptome is the group of all RNA molecules produced from active genes in a cell or tissue.

Transcriptomic analysis identified 16 signaling pathways responsible for immune system regulation that were highly active in mice treated with OYF. In addition, OYF use lowered the activity of 15 other signaling cascades involved in inflammatory response, “suggesting that the physiological effects of OYF involve key roles of immune and inflammation regulations.”

“[O]ur data showed that OYF can inhibit microglial activation and suppress secretion of proinflammatory cytokines, which collectively protects DAN [dopaminergic neurons] from immune-mediate death,” the researchers said.

“This study suggests that OYF can be used as an effective anti-inflammatory treatment in PD mouse model, providing a novel perspective for the treatment and prevention of PD patients, although more studies of clinical trials in PD might be necessary,” they concluded.

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Key Parkinson’s Brain Area Implicated in Memory Loss, Study Suggests

substantia nigra, memory

Neurodegeneration in the substantia nigra, a critical area of the brain involved in Parkinson’s, leads to memory deficits, according to a study that explored the effects of levodopa on a rat model of the disease.

Findings of the study, titled “Implication of nigral dopaminergic lesion and repeated L-dopa exposure in neuropsychiatric symptoms of Parkinson’s disease,” also illustrated the key role dopamine plays in memory. It was published in the journal Behavioral Brain Research.

Similar to motor symptoms, loss of dopamine-producing neurons in the substantia nigra — a brain area implicated in motor function — has been proposed as the cause of neuropsychiatric manifestations in Parkinson’s disease. This has been shown in animal models, in which bilateral lesion of the substantia nigra (which selectively affects this region only) resulted in anxiety- and depression-like behaviors, as well as motivational, memory and social interaction deficits.  A study in rats also reported psychosis-like behavior in animals subjected to bilateral lesion.

Prior research has shown that chronic dopamine replacement therapy (DRT) — which compensates for the lack of dopamine and represents the standard treatment for different Parkinson’s motor symptoms — leads to impaired ability of neurons to fine-tune their responses in animals and is associated with Parkinson’s-related neuropsychiatric disorders in patients.

After lesion of the nigrostriatal pathway — including the substantia nigra and the dorsal striatum — DRT led to compulsive behavior in animals, which was associated with cellular alterations in brain regions involved in cognitive/affective information processing. Progressive degeneration of the brain’s nigrostriatal pathway — one of the four major dopamine pathways in the brain, involved in production of movement — is a characteristic event in Parkinson’s.

While chronic administration of levodopa worsened lesion-induced anxiety and depression in rats, lesioned primates showed psychotic-like behavior only after dopaminergic treatment.

Biotrial Pharmacology researchers have now evaluated the impact of substantia nigra neurodegeneration, repeated exposure to dopaminergic medication, and the combination of both on the development of neuropsychiatric symptoms of Parkinson’s. The team hypothesized that repeated exposure to levodopa could promote brain remodeling and avoid cognitive-like and affective-like deficits.

The team used a rat model based on bilateral substantia nigra injection of a toxin called 6-hydroxydopamine, which induces selective lesions of specific dopaminergic neurons that do not provoke motor deficits.

A subgroup of animals was repeatedly administered with levodopa (20 mg/kg per day) and benserazide (5 mg/kg daily) via under-the-skin injection over 10 consecutive days (chronic exposure), starting 10 days after partial substantia nigra lesion. Benserazide is an inhibitor of an enzyme called DOPA decarboxylase, which converts levodopa into dopamine.

Behavioral tests were started three weeks after the lesions. These included assessments of spontaneous locomotor activity; forelimb voluntary movement with the stepping test; anxiety-like behavior with the elevated plus maze, in which increased time spent on an open arm correlates with greater anxiety; social interaction, as indicated by the amount of time spent in active non-aggressive social behavior with another rat; memory through novel object recognition; and amphetamine-induced hyperlocomotion (AIH), used to assess responses to psychostimulants.

All animals (both with and without chronic levodopa exposure) received single acute injections of levodopa (12.5 mg/kg)/benserazide (15 mg/kg) before the elevated plus maze and novel object recognition tests.

Results revealed that, in contrast to preserved motor function, lesioned rats showed a significant memory deficit as well as anxiety-like behavior. Social interaction and AIH were unchanged. These animals also demonstrated a 48% decrease in the number of dopaminergic cells within the substantia nigra, whose extent did not correlate with the memory and anxiety results.

Researchers found that a single injection of levodopa/benserazide reversed the memory deficit, but not the anxiety-like behavior. According to the scientists, this suggests that dopaminergic pathways “were less directly involved in lesion-induced anxiety-like behavior.”

Chronic administration of levodopa did not change the results seen in lesioned rats (not chronically exposed), which was contrary to the team’s hypothesis. The investigators attributed this finding to having induced a partial lesion. Studies in more severely injured animals and with longer administrations of levodopa would be of interest, they believe.

The results in the memory test indicate “a not previously clearly identified critical role in cognition for the [substantia nigra],” and illustrate “the critical role of [dopamine] in this behavioural outcome,” the researchers wrote.

According to the team, the findings are in accordance “with clinical data suggesting that a panel of non-motor impairment including cognitive deficit and anxiety may be used as prodromal (early) markers of early stages of [Parkinson’s].”

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Defective Activity of GCase Enzyme Linked with Neurodegeneration in Parkinson’s, Mouse Study Finds

GCase study

Impaired activity of the enzyme glucocerebrosidase (GCase), which is responsible for breaking down and recycling cell waste, boosts neurodegeneration and accumulation of alpha-synuclein in Parkinson’s, according to a new mouse study.

The research, “Development and biochemical characterization of a mouse model of Parkinson’s disease bearing defective glucocerebrosidase activity,” was published in the journal Neurobiology of Disease.

Mutations in both copies (homozygous) of the GBA1 gene are responsible for the development of Gaucher disease, a disorder characterized by impaired activity of GCase — an enzyme responsible for the breakdown of a lipid, called glucosylceramide, inside cells.

If occurring in only one gene copy (heterozygous), mutations in GBA1 do not cause Gaucher, but are considered the most relevant risk factor for Parkinson’s after reaching advanced age. Nearly 10 percent of patients with sporadic Parkinson’s disease have heterozygous GBA1 mutations, showing more severe cognitive decline and a slightly younger age of onset compared to those without such mutations.

A link between the hallmark Parkinson’s protein alpha-synuclein and GCase has been suggested by the observation of a mutant form of this enzyme in Lewy bodies (protein clumps mainly formed by aggregates of alpha-synuclein). Also, prior studies have shown that inhibiting GCase activity boosts alpha-synuclein accumulation and activation of cells called microglia, a sign of neuroinflammation seen in patients with Parkinson’s disease.

Researchers at the IRCCS Mondino Foundation, in Italy, aimed to better understand the association between GCase deficiency and Parkinson’s. Specifically, they explored whether a partial defect in GCase comparable to that caused by heterozygous mutations in GBA1 (with approximately 50 percent of residual GCase activity) may increase the effects of MPTP, a widely used neurotoxin to cause Parkinson’s in animal models.

The team developed a model with partial deficiency of GCase activity caused by chronic (28 days) administration of low doses of CBE — a GCase inhibitor — in mice injected with MPTP for five days.

They then determined brain GCase activity, degeneration of dopamine-producing neurons in the nigrostriatal pathway, alpha-synuclein levels, and neuroinflammation. Of note, progressive degeneration of the brain’s nigrostriatal pathway — one of the four major dopamine pathways in the brain, involved in production of movement — is a characteristic event in Parkinson’s.

The results showed that a CBE dose of 50 mg/kg of body weight caused GCase activity reduction in the cerebral cortex similar to that seen in Parkinson’s patients with heterozygous GCase mutations.

The team then found that, although not statistically significant, pre-treatment with this CBE dose boosted MPTP-induced neurodegeneration in the striatum. This was assessed by the amount and signal of tyrosine hydroxylase — the enzyme that mediates the production of the dopamine precursor L-DOPA — as well as by the number of neurons containing this enzyme.

“Our results confirm the concept that GCase dysfunction renders nigrostriatal neurons more susceptible to neurodegeneration,” researchers wrote.

Also, using both CBE and MPTP was able to cause a significant increase in the number of dopamine-producing neurons expressing alpha-synuclein in the substantia nigra, leading to the initiation of the process of alpha-synuclein primary aggregation. Of note, the substantia nigra is a brain region that contains dopaminegic neurons, which are lost as a consequence of Parkinson’s disease.

In turn, microglia was markedly activated by either CBE or MPTP within the substantia nigra. Co-administration of these two compounds did not promote further activation, which the investigators attributed to all microglia cells already being activated by each compound separately.

“Overall, we believe this model may be used as an additional tool to study the biochemical processes underlying pathophysiology [changes of normal physiological functions associated with disease] characterizing [Parkinson’s] in the presence of GCase defects,” researchers wrote.

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Small Vessel Disease Linked to Severity of Motor Impairment in Parkinson’s Patients, Study Finds

small vessel disease

A disorder related to tiny blood vessels in the brain, known as cortical small vessel disease, is directly linked to worsening motor function in Parkinson’s disease, according to a recent study.

An additional association between modifiable vascular risk factors, in particular hypertension, and dementia highlights the need to manage these risk factors in Parkinson’s patients.

The study, “Impact of small vessel disease on severity of motor and cognitive impairment in Parkinson’s disease,” was published in the Journal of Clinical Neuroscience.

Symptoms of Parkinson’s disease can be affected by different risk factors — any attribute, characteristic, or exposure of an individual that increases the likelihood of developing a disorder or injury. Notably, issues with the heart and its blood vessels, or cardiovascular risk factors, have been shown to contribute to greater motor dysfunction in Parkinson’s disease.

In addition, disorders rooted in the brain’s blood vessels, or cerebrovascular pathologies, are linked with an increased prevalence of parkinsonian symptoms, such as motor dysfunction, and cognitive impairment in the elderly.

The relationship among cortical small vessel disease — an umbrella term covering a variety of abnormalities related to small blood vessels in the brain — cognitive decline, and dementia is well-established. Despite this, small vessel disease is not considered a significant cause underlying cognitive impairment in Parkinson’s, and it is not clear whether and to what extent its symptoms and progression contribute to Parkinson’s motor severity and cognitive impairment.

Some of the most concrete evidence for understanding the impact of comorbidities — the simultaneous presence of two chronic diseases or conditions in a patient — in Parkinson’s and other neurodegenerative diseases has been obtained through autopsies of patients’ brains.

By comparing the clinical information collected from patients, such as motor function and cognitive ability, during treatment with an autopsy report, doctors can better assess the link among risk factors, the course of Parkinson’s disease, and the severity of parkinsonian symptoms and dementia.

Cerebrovascular disease pathologies, such as small vessel disease, have only been assessed in a limited number of autopsy studies of Parkinson’s patients.

Now, researchers at the University of Sydney Medical School in Australia have studied the relationship among vascular risk factors and small vessel disease and the severity of motor impairment, cognitive dysfunction, and dementia in Parkinson’s patients. Vascular risk factors studied included stroke, heart disease, hypertension, diabetes, and cigarette smoking.

To do so, they examined clinical information from 77 autopsy-confirmed Parkinson’s patients who were similar in age, cause of death, and duration or severity of Parkinson’s disease.

The researchers then examined clinical information collected during patient visits to determine the severity of cognitive dysfunction and motor impairment. The severity of motor impairment and disease progression was determined using the Hoehn and Yahr scale, while the Clinical Dementia Rating was used to assess the severity of cognitive dysfunction and progression.

Of the 77 patients, 65 percent had advanced-stage dementia. The mean duration of Parkinson’s disease was 12 years for patients with and without dementia. Patients with dementia had more vascular risk factors than those without dementia, including stroke, heart disease, hypertension and diabetes, and a longer history of cigarette smoking.

Researchers observed that the severity of small vessel disease was related to the degree of motor impairment. They did not find a link between the severity of small vessel disease and the presence of dementia in these patients.

They also found a link between the severity of modifiable vascular risk factors and cognitive impairment in the autopsies of Parkinson’s patients. Among the vascular risk factors, only hypertension was linked with cognitive impairment and dementia.

“Modifiable vascular risk factors relate most to the severity of cognitive rather than motor impairment in Parkinson’s disease,” the researchers wrote. This emphasizes the importance “of a holistic approach to the treatment of PD  [Parkinson’s disease] including the potential for longterm cognitive benefits of early and aggressive management of vascular co-morbidities.”

“Our study suggests that neurologists treating patients with Parkinson’s disease should proactively manage their patient’s vascular risk factors, which may reduce gait and cognitive impairment, two of the main clinical features that undermine well-being and independence in patients with Parkinson’s disease,” lead study author Jillian Kril, PhD, said in a news article published in Neurology Today.

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First Patient Dosed with VY-AADC Gene Therapy in Parkinson’s Phase 2 Trial

RESTORE-1 Voyager VY-AADC

Voyager Therapeutics has begun patient dosing in a Phase 2 trial testing its investigational VY-AADC gene therapy in Parkinson’s patients whose motor symptoms are not responding adequately to oral medication.

The trial, called RESTORE-1 (NCT03562494), is recruiting participants across seven sites in the United States.

VY-AADC is a therapy that delivers the DDC gene, which provides instructions for making the AADC enzyme, directly to brain cells in the putamen region. The enzyme converts the standard-of-care Parkinson’s treatment levodopa into dopamine, the signaling molecule that is lacking in Parkinson’s disease.

The approach is expected to bypass the effects of degenerating dopamine neurons in the substantia nigra, a part of the midbrain, by increasing dopamine levels in the putamen.

In an ongoing Phase 1b trial (NCT01973543), a single administration of the therapy induced robust and durable improvements in patients’ motor function up to three years after treatment.

The treatment also effectively increased AADC enzyme activity, allowing patients to reduce their doses of oral levodopa. Also, patients reported significant improvement in quality of life.

The newly begun Phase 2 trial aims to determine whether VY-AADC is better than a placebo at reducing motor fluctuations in Parkinson’s patients whose symptoms are not effectively controlled with levodopa or related treatments.

The trial is expected to enroll approximately 42 patients who have been diagnosed with Parkinson’s disease for at least four years and are not responding adequately to oral medications. To be eligible, participants must be experiencing at least three hours of OFF time during the day, as measured by a validated, self-reported patient diary.

Participants will be randomized to receive either a single infusion of VY-AADC or a placebo into the brain via surgery. They will be followed for 12 months to determine their changes in motor fluctuations, changes in the ability to perform daily activities, and quality of life.

During the new Phase 2 trial, researchers will also determine the efficacy of treatment delivery by assessing AADC enzyme levels and activity in the putamen through positron emission tomography (PET). Changes in patients’ daily doses of oral levodopa and related medications will also be evaluated.

More information about RESTORE-1, including recruitment details, can be found here.

“Patients with Parkinson’s disease need new therapeutic options, especially as the disease progresses and there is less AADC enzyme in parts of the brain where it is needed to convert levodopa to dopamine,” Mark Richardson, MD, PhD, associate professor, director of Epilepsy and Movement Disorders Surgery at the University of Pittsburgh Medical Center and principal investigator in the RESTORE-1 trial, said in a press release.

The U.S. Food and Drug Administration granted regenerative medicine advanced therapy (RMAT) designation to VY-AADC for therapy-resistant motor fluctuations in Parkinson’s patients.

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Gut Bacteria Composition Linked to Parkinson’s Disease Severity, Study Shows

gut bacteria composition

The composition of intestinal bacteria in patients with Parkinson’s disease is correlated with disease severity and a worse prognosis, a study has found.

The study, “Gut microbiota are related to Parkinson’s disease and clinical phenotype,” was published in Movement Disorders.

Parkinson’s disease is a chronic and progressive neurodegenerative disorder, caused by the gradual loss of dopamine-producing neurons in the substantia nigra, a region of the brain responsible for movement control. Although the condition is mostly associated with motor symptoms, such as tremors, body rigidity, and balance instability, patients may also experience a series of non-motor symptoms.

Gastrointestinal problems, in particular constipation, are some of the most common non-motor symptoms of Parkinson’s. They are estimated to affect up to 80 percent of all patients and can occur years before the onset of the first motor symptoms.

Previous studies have shown that gut bacteria involved in the regulation of intestinal transit interact with the nervous system, “influencing brain activity, behavior, as well as levels of neurotransmitter receptors and neurotrophic factors,” according to the study. However, the impact of intestinal bacteria in neurological disorders, such as Parkinson’s disease, had never been investigated.

“Based on the early gastrointestinal involvement in PD [Parkinson’s disease] and the vast potential of microbiome-host interactions, we … hypothesized that the fecal microbiome of PD patients differs from that of matched control subjects in terms of bacterial diversity,” the researchers wrote.

To test this hypothesis, the University of Helsinki researchers compared the composition of intestinal bacteria found in stool samples from 72 patients with Parkinson’s disease and 72 healthy controls by genetic sequencing.

Data from the observational study (NCT01536769) revealed that patients with Parkinson’s had a 77.6% reduction in the amount of bacteria belonging to the Prevotellaceae family compared with controls. This family of bacteria, which includes the Prevotella genus, is a group of nonharmful bacteria that live in the colon and help break down complex foods.

“Our findings indicate that the Prevotella associated gut microbiome enterotype [bacteria that live in the intestine] could be underrepresented among PD patients. Investigating whether high abundance of Prevotellaceae has protective effects against PD or whether low abundance is rather an indicator of disturbed mucosal barrier function will be important,” the investigators wrote.

Interestingly, the amount of bacteria from the Enterobacteriaceae family was much higher in patients with postural instability and gait difficulty than in those with tremor-dominant (TD) symptoms. This family of bacteria includes several pathogens, such as Escherichia coli, and other species of harmless bacteria.

“In comparison with TD patients, patients with a non-TD phenotype progress faster [and] have a worse prognosis. Our results suggest that this may be associated with higher abundance of Enterobacteriaceae in the fecal microbiome of non-TD patients,” the researchers wrote.

“Further studies are warranted to elucidate the temporal and causal relationships between gut microbiota and PD and the suitability of the microbiome as a biomarker,” they added.

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IRL790 Is Safe, Reduces Levodopa-induced Dyskinesia in Parkinson’s, Phase 1b Trial Shows

IRL790 and Parkinson's

IRL790, Integrative Research Laboratories‘ investigational treatment for Parkinson’s disease patients, was safe and reduced levodopa-induced dyskinesia, a Phase 1b trial shows.

The results were published in the journal npj Parkinson’s Disease in the study, “Safety and tolerability of IRL790 in Parkinson’s disease with levodopa-induced dyskinesia—a phase 1b trial.”

Parkinson’s disease is a central nervous system disorder characterized by low levels of dopamine, causing tremors, stiffness, or slowing of movement.

Levodopa, a medication that helps counteract the shortage of dopamine in the brain, is the gold standard for treatment of Parkinson’s patients. But more than half the patients who use levodopa experience abnormal, involuntary movements — dyskinesia — within the first five years of treatment.

Studies have shown that long-term treatment with levopoda increases levels of a dopamine receptor, called dopamine D3 receptor, that seems to correlate with levodopa-induced dyskinesia.

IRL790 is a central nervous system medication that mainly targets the dopamine D3 receptor. In rat models of Parkinson’s disease, the treatment reduced involuntary movements caused by levodopa treatment without compromising the animals’ locomotion. Also, IRL790 showed anti-psychotic properties, suggesting its potential for treating both dyskinesia and psychosis in Parkinson’s patients.

In a prior Phase 1 trial, researchers tested ascending doses of IRL790 in healthy male volunteers. The treatment had a very good safety profile, with no serious adverse events reported, even at doses higher than those planned for patients.

Now, a team at the Karolinska Institutet in Sweden conducted a Phase 1b trial to determine the treatment’s safety and efficacy in Parkinson’s patients experiencing levodopa-induced dyskinesia.

The study (NCT03531060) included 15 Parkinson’s patients (nine men and six women) who randomly received oral capsules of IRL790 (11 patients) or an oral placebo (four patients) for four weeks. During the trial, all patients continued receiving their regular medication.

The study’s main objective was to assess the treatment’s safety — measured through the number of adverse events, physical examination, electrocardiogram, heart rate, blood pressure, and other laboratory measurements — after four weeks.

Secondary measures included changes from baseline in dyskinesia, measured with the Unified Dyskinesia Rating Scale (UDysRS), and Parkinson’s scores, measured with the Unified Parkinson’s Disease Rating Scale (UPDRS) and Parkinson’s Kinetigraph.

Thirteen patients completed the 4-week study, with IRL790 given at an average daily dose of 18 mg.

Overall, 14 patients (93.3%) reported 62 adverse effects. Most were reported during the first two weeks — when the dose of IRL790 was adjusted to each patient — and were mild to moderate, easily mitigated by dose adjustments. No serious adverse effects were reported in any of the groups.

Patients taking IRL790 had a mean reduction of 8.2 percent in dyskinesia scores compared to those taking a placebo.

“Among patients treated with IRL790, 55.5% were assessed as having an improved global clinical condition, as compared with baseline (much improved/minimally improved),” researchers stated.

There were no changes in symptoms relating to parkinsonism, either in the UPDRS or in measurements from the Parkinson’s Kinetigraph, a wrist-worn device that evaluates bradykinesia (slowness of movement) and dyskinesia during activities of daily living.

The results show that “IRL790 can be safely administered to patients with advanced PD,  which will now “be of guidance for the design of phase 2 studies,” researchers said.

IRL790 is already being tested in a Phase 2 trial (NCT03368170), which will assess whether the treatment can reduce dyskinesia in a larger population (74 patients). The trial will also help establish the optimal dose for further testing.

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Older IBD Patients Show Increased Risk for Parkinson’s Disease, Study Suggests

IBD risk factor

Older patients with inflammatory bowel disease (IBD) are more likely to develop Parkinson’s disease than those without the condition, a meta-analysis suggests.

Whether the same association exists for younger patients — ages 59 or younger — remains to be determined, according to the researchers.

The study, “Older patients with IBD might have higher risk of Parkinson’s disease,” was published in the journal Gut.

The chronic activation of pro-inflammatory mechanisms, which occurs in autoimmune conditions, has been increasingly recognized as a critical contributor of neurodegenerative disorders.

Studies suggest that this may happen due to the “gut-brain axis” — the two-way communication between the nervous system and the intestine that monitors gut function and links certain regions of the brain to intestinal functions, such as immune activation or intestinal permeability.

In line with the findings, some studies have already reported that patients with IBD — an autoimmune condition characterized by chronic inflammation of the gut — are 22-41% more likely to develop Parkinson’s than those without IBD.

However, a case-control study that examined Medicare data from 89,790 Parkinson’s cases and 118,095 population-based controls suggested that IBD actually reduced the risk for Parkinson’s by 15%.

To clarify this association, a team at Sichuan University in China reviewed all studies investigating the link between IBD and risk of Parkinson’s. Five studies met the inclusion criteria defined by the team, including a total of 9,174,766 participants.

Overall, IBD patients did not have a significantly higher risk of Parkinson’s than reference individuals, nor did patients with ulcerative colitis or Crohn’s disease — the two main forms of IBD — when examined individually.

However, patients 60 years or older were found to have a 32% higher risk of developing Parkinson’s. Patients 50 years or younger did not show this association, the researchers said.

“Our meta-analysis showed that patients with IBD did not have an increased risk of PD; however, subgroup analysis with cohort studies showed that they might be associated with increased risk of PD,” the researchers wrote.

“Age has been regarded as an important risk factor for Parkinson’s disease,” they added, but the findings suggest that “age at IBD diagnosis might be a risk factor of Parkinson’s disease.”

Interestingly, the team found that some studies reported medication-related side effects in the IBD population that resembled parkinsonism in the older population.

“It is necessary to take it into consideration whether older people will take more medications, and whether these medications lead to a higher risk of Parkinson’s also needs further studies to verify in the future,” they said.

Additional well-designed observational studies are still warranted to further explore the risk of Parkinson’s disease within the younger IBD population, the team noted.

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