UAB Researchers Awarded $2.5M to Study Role of Gut Microbiome in Parkinson’s

gut microbiome study grant

The U.S. Army Medical Research and Materiel Command has awarded a four-year, $2.5 million grant to a team of scientists at the University of Alabama at Birmingham (UAB) to investigate the role of the gut microbiome — the trillions of microorganisms and their genetic material that live in the intestinal tract — in Parkinson’s disease.

A goal is to determine if changes made to bacteria in the intestinal tract might help to alter, and possibly interrupt, disease progression.

“Large patient studies have searched for genetic variations and environmental triggers shared by people who have Parkinson’s disease,” Haydeh Payami, PhD, professor in the UAB School of Medicine Department of Neurology, said in a university news release written by Matt Windsor.

“Dozens of genetic risk factors have been identified, but each only increases risk by a small amount,” Payami added. ” There is a significant link between exposure to pesticides and herbicides, as well as repeated head trauma … but again, not all people who have a genetic susceptibility and are exposed to these factors get the disease. There has to be something more than genes and environment.”

Researchers want to identify the specific microorganisms that contribute to disease development; pinpoint bacteria that interact with known genetic risk factors for Parkinson’s; evaluate the effects of two neuroprotective factors — cigarette smoking and caffeine consumption — on the microbiome; search for early microbial changes in patients with REM sleep behavior disorder — a disorder marked by people acting out vivid, often violent dreams, and one that appears to be linked to Parkinson’s; and to study the interaction between gut microbiome and illness progression in animal models of Parkinson’s disease.

Investigators plan to enroll 1,000 Parkinson’s patients and 600 healthy individuals from UAB and the other members of the NeuroGenetics Research Consortium — one of the largest datasets of Parkinson’s patient information — including Emory University, Oregon Health and Science University, the University of Washington in Seattle, and Albany Medical Center in New York.

Another 100 people be treated for REM sleep behavior disorder at UAB and in Montreal, Canada, will also be recruited.

“Eighty percent of people with REM sleep behavior disorder go on to be diagnosed with Parkinson’s or another neurodegenerative disease,” Payami said. “If we can see changes in the microbiomes of these patients decades before they develop Parkinson’s, we could take action. That’s what’s exciting.”

Studies have found that the gut microbiome is altered in Parkinson’s disease. In an experiment, CalTech scientists removed the community of microorganisms found in the intestines of a mouse model of Parkinson’s, and found motor symptoms eased.  When they next transplanted bacteria from Parkinson’s patients into these mice, the symptoms returned.

Payami and her team analyzed fecal samples from 197 Parkinson’s patients plus 130 controls from Seattle, New York and Atlanta, and found that the types of microorganisms in the guts of patients was significantly different from those of healthy individuals. Interestingly, they varied according to the person’s geographic site — which may reflect the contribution of environmental, lifestyle, and dietary factors in that person’s biological system. They also reported that Parkinson’s disease medications were associated with changes in the gut microbiome.

“The microbiome metabolizes drugs,” Payami said. “It can turn harmless drugs toxic, and vice versa. Exposure to pesticides and insecticides may be mediated by the microbiome as well. And because the microbiome is easily modifiable, it could offer a way to predict, prevent and even treat Parkinson’s disease.”

Studies have also shown that levodopa’s effectiveness was increased after eradicating a Helicobacter pylori infection in the gut of Parkinson’s patients. In addition, cutting the vagus nerve – the nerve that enables communication between the microbiota, the gut, and the brain – lowered the risk of developing Parkinson’s, adding to microbiome’s potential role in disease onset.

Whether the gut flora is altered because of the disease, if it contributes to the disease process itself, whether the composition of a patient’s intestinal bacteria influences his or her response to treatment, or even if medications change the microbiome in a specific way — all this remains to be understood.

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Investigational Herbal Therapy DA-9805 Shows Neuroprotective Effects in Parkinson’s Mouse Model

DA-9805 herbal treatment

An investigational herbal product called DA-9805 exerts its neuroprotective activity by preventing mitochondria damage in brain cells, a mouse study has found.

This compound is currently being evaluated in a Phase 2a clinical trial (NCT03189563) in early Parkinson’s disease patients.

The study, “Triple herbal extract DA-9805 exerts a neuroprotective effect via amelioration of mitochondrial damage in experimental models of Parkinson’s disease,” appeared in the journal Scientific Reports.

DA-9805 is an investigational compound being developed by the South Korean company Dong-A ST. It combines natural compounds extracted from three plants widely used in traditional Asian medicine: Moutan cortex, Angelica Dahurica root, and Bupleurum root.

Each of these plants is rich in compounds with broad therapeutic activities, including anti-inflammatory, antioxidant, anti-cancer, and analgesic proprieties.

Supported by their long history of use in traditional medicine for diseases caused by oxidative stress and inflammation, researchers hypothesized that they may also have the potential to treat Parkinson’s disease.

DA-9805 was obtained by extracting the main natural compounds of the three dried plants with 90% ethanol for 24 hours. A detailed analysis of the extracted compounds revealed the mixture was enriched for the active molecules paeonol, saikosaponin A, and imperatorin.

To evaluate the potential of the mixture, researchers exposed a cell line model often used to study Parkinson’s disease to increasing doses of DA-9805 or other reference compounds.

The treatment significantly prevented cell death induced by impaired activity of mitochondria — small cellular organelles that provide energy and are known as the “powerhouses” of cells — compared with the other tested compounds. The neuroprotective effect of DA-9805 was further confirmed when tested in cells collected from the superficial brain layer of rats.

Next, the team evaluated the effects of oral DA-9805 in a mouse model of Parkinson’s disease. This model was achieved by injecting animals with a neurotoxin called MPTP and its active metabolite MPP+, both of which exert neurotoxic effects on dopaminergic neurons — those that are mainly affected in Parkinson’s disease.

They found that treatment with DA-9805 effectively improved animals’ balance (bradykinesia) compared with placebo-treated mice. This positive effect on balance was similar to that observed in mice treated with approved Parkinson’s therapy Azilect (rasagiline).

Evaluation of dopamine levels in the striatum — the brain area most affected by the disease — showed that DA-9805, similar to Azilect, could also prevent dopamine reduction in the brain associated with Parkinson’s disease in these mice.

Importantly, although both compounds protected striatum dopaminergic neurons from death upon exposure to MPTP, DA-9805 showed a greater neuroprotective effect than Azilect.

These findings “suggest that DA-9805 has neuroprotective effects” in mice with Parkinson’s disease, according to the researchers.

Additional experiments revealed that DA-9805’s therapeutic effects were mediated by enhanced protection of mitochondria and their function, while reducing the levels of damaging oxidative molecules, also known as reactive oxygen species (ROS).

Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals, or ROS, are harmful to the cells and are associated with a number of diseases, including Parkinson’s.

“Given that mitochondria are involved in the pathogenesis of neurodegenerative diseases, we propose that DA-9805 may be a suitable candidate for disease-modifying therapeutics against Parkinson’s disease,” the researchers wrote.

DA-9805 is now being evaluated in a Phase 2a trial in patients with early Parkinson’s disease at the HealthPartners Institute in Minnesota.

Currently recruiting participants, the randomized, double-blind study is expected to enroll about 60 patients between the ages of 30 and 79 who have had mild to moderate Parkinson’s for two years or less.

Participants will be randomly assigned to receive a daily 45 or 90 mg dose of DA-9805, or a placebo for 12 weeks. Researchers will evaluate the safety and tolerability of the treatment, as well as its ability to improve patients’ motor function.

The study is expected to be completed by March 2019.

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Transient Cerebral Swelling a Common Side Effect of Deep Brain Stimulation, Study Suggests

brain edema DBS

Swelling of brain areas close to where the electrodes that deliver deep brain stimulation (DBS) are placed is a common and transient side effect of this treatment in Parkinson’s disease patients, a study suggests.

Long-term impact of this adverse reaction and potential related complications are still unknown and warrant further analysis, researchers say.

The study, “Peri-lead edema after DBS surgery for Parkinson’s disease: a prospective MRI study” was published in the European Journal of Neurology.

DBS is a surgical treatment in which thin wires are implanted in strategic brain areas (those that control complex movements) to deliver electrical impulses generated by a battery-operated device.

Studies have shown that DBS can be beneficial in treating a variety of neurological diseases, particularly Parkinson’s. DBS has been accepted as an effective therapy to reduce motor symptoms such as tremors, lower the necessary daily dose of medication and improve Parkinson’s patients’ quality of life.

The most common adverse events associated with DBS include hemorrhage, infection, and failure of the implant’s components. However, some studies have also reported rare events of cerebral swelling (edema) surrounding DBS electrodes a few days after the surgery.

To gain binsight on the prevalence of this complication, Italian researchers evaluated the progression of 19 Parkinson’s patients who had undergone DBS therapy.

Surgeries were uneventful in all patients, with no complications being reported. However, after surgery, two patients experienced small hemorrhages close to the placed electrodes without any other brain tissue alterations reported.

All patients were evaluated by magnetic resonance imaging (MRI) between days 7 and 20 after surgery.

Researchers found that all patients showed some degree of MRI signal alteration along the placed electrodes, which was consistent with edema. The analysis also revealed small symptomatic hemorrhage in four additional patients, raising the total number of hemorrhagic patients to six (31.57%).

Researchers failed to find any correlation between edema volume and patients’ age, gender, disease duration, or side of the brain in which DBS electrodes had been implanted.

Patients who had hemorrhages also showed tissue swelling on the side of the brain opposite the bleeding.

Most patients were asymptomatic, but six had transient confusional state — disorientation in space and time plus mild signs of frontal lobe dysfunction, which included disinhibition, inattentiveness, and slightly impaired speech with poor word retrieval. Patients did not show any new motor deficits after surgery.

Two symptomatic patients were treated with a short corticosteroid treatment, but no significant effect on symptoms was noted. Still, both patients recovered in two to four weeks.

At a mean time period of 40.64 days after surgery, MRI signs returned to normal values in eight  patients. Superficial edema was still detected in three patients. At follow-up, no patient had detectable bleeding around the DBS electrodes.

To further explore the prevalence of brain edema associated with DBS, the team retrospectively evaluated computed tomography (CT) imaging data of 77 patients who had undergone DBS surgery from January 2013 to February 2017.

Hemorrhage around DBS electrodes was detected in four (5.19%) patients and edema in six (7.78%) patients. In nine patients evaluated by CT scans on days 1, 2, and 3 after surgery, edema was present in two who also had hemorrhage, and another patient.

“Our prospective MRI study confirms that [transient] edema is a common finding in STN-DBS [subthalamic nucleus] implanted patients for Parkinson’s disease and that it is asymptomatic in most patients,” researchers said. “The reason of the extremely high incidence of our finding is likely due to the timing of imaging (average 10 days) from surgery.”

They stated their opinion that edema near the electrode sites “is a normal and constant finding in patients undergoing STN-DBS lead placement. Its recognition is biased mainly because it is mostly asymptomatic and also because of the lack of early routine MRI scans in DBS patients.”

The team suggested that to avoid overtreatment and complications, “no corticosteroid treatment should be administered to patients whose MRI shows … edema in the first 7 to 60 days from surgery.”

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Alpha-Synuclein Could Be Biomarker for Non-Motor Symptoms in Parkinson’s, Study Suggests

Alpha-synuclein biomarker

Reduced alpha-synuclein levels in the cerebrospinal fluid (CSF) — the liquid surrounding the brain and spinal cord — are associated with more severe non-motor symptoms in Parkinson’s patients, according to a study.

The study, “CSF α-synuclein inversely correlates with non-motor symptoms in a cohort of PD patients,” published in the journal Parkinsonism and Related Disorders, suggests that measurements of alpha-synuclein could be used as a biomarker for non-motor symptoms in Parkinson’s disease.

Unlike its characteristic motor symptoms, Parkinson’s non-motor symptoms — which include emotional and mood changes, cognitive changes or dementia, fatigue, or hallucinations — still lack reliable predictors.

While motor manifestations are due to degeneration of dopamine-producing neurons in a brain area called the substantia nigra, non-motor complications may be caused by more diverse and non-dopaminergic neurodegenerative processes.

Assessing CSF proteins enables the study of disease-related changes in the brain that occur in neurodegenerative diseases. Such an analysis, along with the identification of biomarkers, are key to developing effective treatments.

Italian researchers in this study hypothesized that widespread degeneration underlying non-motor symptoms may mirror the CSF protein profile, which could be used as a biomarker for these symptoms.

They evaluated the association between non-motor symptom severity and CSF levels of alpha-synuclein — the main component of clumps known as Lewy bodies in the brain of Parkinson’s patients; total tau and one of its altered (phosphorylated) versions that form tangles inside neurons in Parkinson’s disease; and a form of amyloid-beta called 42-amyloid-beta, which is also relevant in Alzheimer’s disease.

A total of 83 individuals were included, 46 with Parkinson’s (24 men, mean age 57.4 years) and 37 controls (22 men, mean age 60.9 years). The control group included participants with non-neurodegenerative conditions receiving a spinal tap for diagnostic purposes, but without signs of motor and cognitive impairment.

Standard clinical scores were used to assess Parkinson’s patients: Non-motor symptoms were measured using the Non Motor Symptoms Scale (NMSS) total and single-item scores, motor symptoms with the Unified Parkinson Disease Rating Scale part 2 and 3 (UPDRS 2-3), and cognition with the Mini Mental State Examination. Evaluations were conducted while patients were on standard antiparkinsonian medications.

The results showed that Parkinson’s patients had lower alpha-synuclein and total tau levels than controls. According to the authors, the reduced amount of alpha-synuclein in the CSF could be attributed to its accumulation in Lewy bodies.

Additionally, the phosphorylated/total tau ratio was significantly higher in Parkinson’s patients than in controls. However, the total tau/alpha-synuclein + 42-amyloid-beta ratio was lower in people with Parkinson’s. Alpha-synuclein at a cut-off value of 1,143 pg/ml showed the highest sensitivity (86%) and specificity (77%) for diagnostic accuracy.

Researchers also found that the lower the alpha-synuclein level, the higher (worse) the NMSS total score and single-item 3 scores, which refer to mood/cognition, and item 9 scores, referencing pain/smell/weight/sweating. This association was independent of age, disease duration, motor impairment severity and dopaminergic treatment, and indicates prominent dysfunction of brain networks controlling these functions, the scientists observed.

A similar inverse association was found between phosphorylated tau level and NMSS total score and item 3 score, though in this case it was not statistically significant. Alpha-synuclein level was not significantly associated with motor symptoms assessed with the UPDRS 2-3.

“We suggest that the decrease of CSF a-syn levels mirrors a widespread degenerative process involving non-dopaminergic networks,” the researchers wrote.

Although cautioning that the results are preliminary and need validation in longer studies, the team believes that “measurement of total CSF [alpha-synuclein] may represent a biomarker for NMS [non-motor symptoms], supporting the assessment of frailty in PD [Parkinson’s disease] patients.”

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The ABCs of Parkinson’s: ‘J’ Is for the Junk and Jewels of PD

jewels

Sherri Journeying Through

A continuation of the “ABCs of Parkinson’s” series.

You’ve likely heard that one’s man’s junk is another man’s treasure. Well, if not, you just did. One of my favorite things to do is to go to yard sales or thrift stores. I don’t look for anything in particular, but when I see something that catches my eye, I know that I have just stumbled upon a treasure that someone else threw in the “junk” pile.

Fifteen years have passed, come December, since my Parkinson’s disease (PD) diagnosis, though I’ve dealt with symptoms for over 20 or more. When I was told I had PD, I didn’t know much about it. I didn’t realize its implications, nor did I know what was (or could be) waiting for me down the road. I wondered how anything good could come from having a disease without a cure.

But then I met a stranger online through a PD chat room. Jewel 1 of having Parkinson’s disease was a stranger who became a close friend. Parkinson’s has come between some relationships in my life (junk) but it has also provided new, deep relationships in my life (jewel).

Jewel 2 is that my attitude regarding doctors was restored to a positive place when I met my movement disorder specialist. I had some pretty rotten experiences when it came to doctors, but his compassion, wisdom, humor, and availability gave me a renewed appreciation for doctors, especially those who have a great bedside manner.

Among the junk of PD, I have found other jewels. I learned to appreciate anew the time given to me right now; time to spend with my husband, my grown-up children, and my grandchildren. I have discovered just how important that jewel is, and it is perhaps my most treasured. Time is already short for each of us. Adding any sort of illness into the mix shortens that lifespan for so many reasons. Cherish the fleeting moments and live your best self through each one. 

Gratitude is just one more jewel I have experienced among the junk of PD. I was taking a walk with my grandson the other day and he kept looking up at the sky and smiling. I asked him what he was thinking. He looked up again, smiling, and replied, “The sky is just so blue.” A child sees through the eyes of wonder and often through unprompted thankfulness. It is a great joy to taste life through a child’s wonderment.

When experiencing discouragement or despair or if you’re just having a not-so-good day, try and find a jewel in your life. They are there. You may just have to uncover them.

***

Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

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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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Investigational Gene Therapy AXO-Lenti-PD Tested in Phase 1/2 Clinical Trial in Parkinson’s Patients

AXO-Lenti-PD

The first patient has been dosed in Axovant’s Phase 1/2 clinical trial testing the investigational gene therapy AXO-Lenti-PD for the treatment of Parkinson’s disease.

The patient reported no complications associated with surgery or administration of the therapy and was discharged as planned in the initial trial design. Preliminary data from the first group of patients treated in the trial are expected to be announced during the first half of 2019.

Currently recruiting participants, the trial (NCT03720418) is expected to enroll about 30 patients ages 48-70 who have had bilateral idiopathic (of unknown cause) Parkinson’s disease for at least 5 years.

The study, being conducted in the United Kingdom and France, consists of two parts. In part A, researchers will evaluate the safety and tolerability of increasing doses of the investigational gene therapy, and select the optimal dose to be used in further testing.

Part B is a randomized, double-blind phase in which patients will receive either the designated dose from Part A or an imitation surgical procedure (ISP). Patients will be followed for about 6 months to assess AXO-Lenti-PD’s safety and potential to enhance motor function and improve movement control.

AXO-Lenti-PD, also known as OXB-102, is a gene therapy that uses a harmless virus-based system to deliver three genes that encode critical enzymes involved the synthesis of dopamine — the signaling molecule, or neurotransmitter, produced at low levels in Parkinson’s patients.

This treatment is expected to provide significant and long-lasting clinical benefits to patients with Parkinson’s disease upon a single administration.

The gene therapy was initially designed by Oxford BioMedica, which in June 2018 granted the exclusive worldwide rights over AXO-Lenti-PD’s development and marketing to Axovant Sciences.

“We are very excited to bring AXO-Lenti-PD into clinical development and believe it will be an important new therapy for patients with Parkinson’s disease who suffer from motor fluctuations on the current standard of care,” Pavan Cheruvu, MD, the CEO of Axovant, said in a press release. “This marks the first of our gene therapy programs to enter the clinic, and our focus now is on rapid execution of the clinical study.”

A recently completed Phase 1/2 trial of ProSavin (NCT00627588), AXO-Lenti-PD’s predecessor, demonstrated favorable safety and tolerability and a significant improvement of motor function at 6 and 12 months in Parkinson’s patients. This benefit was sustained for up to six years.

Compared with ProSavin, preclinical studies of AXO-Lenti-PD showed increased production of the key enzymes, as well as at least a fivefold greater potency in improving behavior and movement in an animal model of the disease.

“Building upon the evidence of safety and durable improvements in motor symptoms seen up to six years in the prior clinical study of ProSavin, we feel a sense of urgent responsibility to accelerate the development of AXO-Lenti-PD,” Cheruvu said.

“Mid- to late-stage Parkinson’s disease remains a challenge to treat, with current therapies leading to debilitating adverse events and unpredictable therapeutic effects over time,” said Stéphane Palfi, MD, PhD, coordinating investigator of the AXO-Lenti-PD trial.

“We are pleased to advance AXO-Lenti-PD in the clinic and are eager to see the trial expand upon the long-term safety and efficacy results we observed in the Phase 1/2 clinical trial of ProSavin,” he said.

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Dopamine May Prevent Movement Impairment in Parkinson’s Patients, Study Suggests

dopamine, movement impairments

Levodopa treatment can prevent movement impairment in patients with Parkinson’s disease by increasing overall sensory attenuation, or the ability to fine-tune information received from the senses before a motor action is performed, a study suggests.

Based on these findings, researchers suggest that dopamine, which increases as a result of levodopa treatment, may be important for regulating brain activity to effectively integrate predictions of action with sensory information — a process required for the control of voluntary movements.

“This may provide a common framework for understanding the role of dopamine in perceptual, cognitive, and motor function,” they wrote.

The study, “Sensory attenuation in Parkinson’s disease is related to disease severity and dopamine dose,” was published at the journal Scientific Reports.

Parkinson’s disease is often characterized by slower movements, which are associated with the impaired ability of patients to plan, initiate, and execute voluntary movements. However, the underlying mechanisms that promote these deficits are still not very well understood.

Researchers evaluated the sensorial and motor response of 18 patients with idiopathic Parkinson’s disease and 175 age and gender-matched healthy volunteers used as controls. All Parkinson’s patients were receiving treatment with levodopa, one of the main therapies used to increase the levels of dopamine.

To quantify participants’ sensorimotor response, researchers used the force matching task, in which a torque motor applies one of four force levels through a lever to the left index finger. Participants are then asked to match the force they just sensed either by pressing the lever with their right index finger (direct condition), or by sliding a linear potentiometer that controls the torque motor (slider condition).

In response to this test, people often apply a stronger force when exposed to the direct condition, while they tend to use a more accurately matched force in the slider condition. The overcompensation of forces that occur in the direct condition has been associated with the integrity of the fronto-striatal network — an area of the brain strongly affected by dopamine deficits in Parkinson’s disease.

Task results revealed that Parkinson’s patients had less sensitivity than controls. Still, the overall force response to matching the applied motor force was similar between patients and controls.

Further analysis showed that overall sensory attenuation was negatively related to Parkinson’s motor severity, but positively linked to individual patient dopamine levels, as measured by levodopa dose equivalent.

In general, patients who were taking higher levodopa doses were also the ones showing greater overcompensation on the direct condition of the task.

“These results support the hypothesis that dopamine alleviates disorders of movement in Parkinson’s disease by restoring the precision and hence the typical reliance on sensorimotor predictions,” the researchers wrote.

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MJFF and Blackfynn Collaborate on Parkinson’s Study to Discover Biomarkers

MJFF and PPMI

The Michael J. Fox Foundation (MJFF) and Blackfynn are joining forces to make optimal use of an initiative that could uncover Parkinson’s disease biomarkers and bring about new therapies.

Called the Parkinson’s Progression Markers Initiative (PPMI), the MJFF-backed effort is an ongoing observational study of more than 1,300 volunteer participants both with and without Parkinson’s to validate biomarkers and, over time, identify disease risk factors. Participants undergo a battery of tests and assessments.

Biomarker discovery is critical in the quest for therapies that can slow or halt Parkinson’s progression. Specifically, it would allow for earlier diagnosis, better disease tracking, and more efficient therapy tests. Current treatments only temporarily ease symptoms.

To glean as much as possible from patient data, Blackfynn will lead the PPMI Advanced Analytics Core, established to analyze biomarker discovery. The firm has a data integration and analysis platform it uses to drive development of therapies, and advance translational research for neurological diseases.

“The goal of the Advanced Analytics Core is to accelerate our analysis of the comprehensive within-subject data collected through PPMI,” Kenneth Marek, PPMI principal investigator, said in a news release.

“By combining this rich, multimodal data with Blackfynn’s platform and data science expertise, we hope to uncover insights into the determinants of [Parkinson’s disease] progression that will lead to new therapies and improved quality of life for patients.”

The Blackfynn infrastructure incorporates a full complement of medical and scientific data to enable swift assessment of data correlations and complex data visualizations. PPMI scientists plan to use the platform to interpret data, develop verifiable hypotheses, and better collaborate with the goal of more targeted translational research.

“Our work with MJFF and the PPMI investigators will maximize the value of this important patient dataset and help drive novel discovery with the potential to lead to the development of effective therapies for patients with PD,” said Amanda Christini, president of Blackfynn.

“Blackfynn will enable a new lens through which discoveries can be made, by looking at all raw and metadata together, in context, to find new patterns that are otherwise obscured when data are in isolation.”

Citing an unwieldiness caused by an abundance of Parkinson’s-related biomarker information, an editorial in the journal The Lancet Neurology heralded the efficiencies of collaborative research. Particularly, it applauded the Accelerating Medicines Partnership for its efforts to find a Parkinson’s cure.

As for the PPMI, five-year results have already shown that clinical trials in patients with early-stage Parkinson’s may benefit from assessing markers of disease progression — namely, changes in the Movement Disorder Society (MDS)-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and dopamine transporter imaging.

Launched in 2010, PPMI is underway in the United States, Europe, Israel and Australia.

The MJFF is dedicated to finding a cure for Parkinson’s by funding research and ensuring the development of improved therapies for those living with the disease. It has funded more than $800 million in research to date.

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Facial Expressions in Parkinson’s Patients Mirror Asymmetry Seen in Motor Symptoms, Study Says

facial expressions

Although no marked differences in the asymmetry of facial expressions distinguished Parkinson’s disease patients and healthy individuals in a study, patients most clearly expressed an emotional reaction on the side of the face corresponding to the side of the body less affected by Parkinson’s motor symptoms, a study found.

Its researchers concluded patients’ facial asymmetry when displaying emotions is a consequence of general motor symptom asymmetry, rather than difficulties or problems in processing emotions.

The study, “Emotional facedness in Parkinson’s disease,” was published in the Journal of Neurotransmission.

Parkinson’s is characterized by the gradual loss of muscle control and lack of facial expression, sometimes accompanied by cognitive deficits.

Previous studies have suggested that hemispheric dominance — a phenomenon in which one side of the brain is more important than the other for a given function — in emotional processing can lead to an asymmetric facial expression.

Although Parkinson’s motor symptoms tend to be rather asymmetric (i.e., more pronounced on one side of the body), studies had not addressed facial and emotional asymmetry in Parkinson’s patients.

A research team in London and Italy explored the relationship between motor symptom asymmetry and facial expressiveness in Parkinson’s disease.

The study enrolled 20 patients and 20 healthy people serving as controls, who were video-recorded while displaying facial expressions: one that was neutral, and six basic emotions (anger, disgust, fear, happiness, sadness, and surprise).

The most expressive pictures obtained from the video-recordings were then cut down the middle and put through a program to generate ‘chimeric’ faces that showed only the right side of the face (right side manipulated to make full face) and the left side (a left-left combination). Investigators then asked nine healthy people with no prior connection to the study to rate which one of the two chimeric faces looked more expressive. Raters’ choices, reaction times, and confidence levels were recorded.

To evaluate a possible link between facial expressiveness and motor symptom asymmetry, researchers performed correlation analysis between the global facial laterality index (pooling all emotions together) as well as for the indexes of each emotion separately, and the body laterality index (defined by the side of the body most affected by Parkinson’s symptoms).

No substantial differences were found in how the nine raters judged emotional expressiveness on the two chimeric faces (right-right and left-left), whether within the Parkinson’s and the control group, or between the two groups.

In Parkinson’s patients, however, investigators found a correlation between the global facial laterality index and the body laterality index, suggesting that each patient’s most expressive side of the face corresponded to the body side less affected by Parkinson’s symptom’s.

“Despite the lack of significant facial asymmetry in PD [Parkinson’s disease] and healthy subjects, the relationship we found between the intensity of facial expression and motor symptom lateralization supports the hypothesis that there is some facial asymmetry of emotional expression in PD which relates to the general lateralisation of the motor features of the disorder rather than a specific abnormality in emotional processing,” the researchers wrote.

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