Diabetes Medication Exenatide Shows Promise In Treating Parkinson’s Disease

MedicalResearch.com Interview with:
Dr Dilan Athauda MRCP
Sobell Department of Motor Neuroscience and Movement Disorders
UCL Institute of Neurology & The National Hospital for Neurology and Neurosurgery
London

MedicalResearch.com: What is the background for this study?

Response: Exenatide is a synthetic version of a naturally occurring protein – exendin-4 – that was originally discovered by Dr John Eng in the early 1990’s in the saliva of the Gila Monster, a venomous lizard native to the Southwestern United states. He and his team were looking for bio-active peptides in insect and lizard venom that could be useful for people with Type 2 diabetes. They discovered that exendin-4 was extremely similar to a human hormone called Glucagon-like peptide-1 (GLP-1).  In humans, GLP-1 is secreted after you eat a meal to stimulate insulin secretion (and inhibit glucagon production) of which the end result is a lowering of blood sugar. Unfortunately human GLP-1 is rapidly broken down by a circulating enzyme called dipeptidyl peptidase IV (DPP-IV) and its effects only last minutes.

Importantly, it was discovered that exendin-4 is naturally resistant to the actions of this enzyme, meaning it’s effects on blood sugar control lasts much longer in the body.  These properties made it very attractive to people trying to treat people with Type 2 diabetes and following many successful randomised controlled trials of patients with Type 2 diabetes in 2005, exenatide was approved for use as a treatment.  During this time, work led by Nigel Greig’s group at the NIA showed that first evidence that exendin-4 had neuroprotective properties, and could protect neurons from a variety of stresses and could also improve growth and rescue degenerating cells. Over the next few years, various groups used exendin-4 in a variety of animal toxin models of Parkinson’s disease and showed that exendin-4 could halt the progression of Parkinsonism and prevent cell death in these models through beneficial effects on inflammation, mitochondrial function and cell survival.

Based on this encouraging pre-clinical data, Professor Foltynie supervised the first small, “open-label”, human trial of exenatide in patients with Parkinson’s disease.  The team found that patients treated with exenatide for 1 year (in addition to their usual medication) had less decline in their motor symptoms when assessed without their medication compared to the control group (just on their usual medication) and this advantage over the control group was still present 1 year after stopping the exenatide injections.  However, this trial was open-label – patients knew they were getting a (potentially beneficial) experimental therapy and so we couldn’t exclude the fact that placebo effects were explaining some of the results we saw.

As a result of the potentially beneficial results seen in this small open label trial we carried out a double-blind, placebo controlled trial.

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Extended-Release Amantadine Reduces Dyskinesia in Parkinson’s Disease

MedicalResearch.com Interview with:
Rajesh Pahwa MD
Department of Neurology
University of Kansas Medical Center, Kansas City, KS,

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Dyskinesia are one of the major unmet needs in Parkinson Disease patients. At the present time there are no approved medication for dyskinesia, however immediate release amantadine is used in PD patients with dyskinesia. ADS-5102 is a long acting, extended release capsule formulation of amantadine HCl administered once daily at bedtime. This study investigated the safety, efficacy and tolerability of ADS-5102 in Parkinson’s disease (PD) patients with levodopa-induced dyskinesia.

This was a randomized, double-blind, placebo-controlled study of Parkinson’s disease patients with levodopa-induced dyskinesia. In total, 126 patients were randomized to placebo or 274 mg ADS-5102 administered orally at bedtime. ADS-5102 was associated with a significant reduction in dyskinesia at 12 weeks compared with placebo, as measured by the mean change in Unified Dyskinesia Rating Scale (treatment difference, –7.9; P =.0009). OFF time was significantly reduced in ADS-5102 patients compared to placebo (treatment difference -0.9 hours, p=.017).

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Vagotomy May Point To Gut Origin of Parkinson’s Disease

MedicalResearch.com Interview with:

Karin Wirdefeldt, MD, PhD</strong> Associate professor Karolinska Institutet Stockholm, Sweden

Dr. Wirdefeldt

Karin Wirdefeldt, MD, PhD
Associate professor
Karolinska Institutet
Stockholm, Sweden

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: It has been hypothesized that Parkinson’s disease may start in the gut and spread to the brain via the vagal nerve. We found that people who had a truncal vagotomy (ie, the nerve trunk fully resected) at least 5 years earlier were less likely to develop Parkinson’s disease compared to people without vagotomy or people who had a selective vagotomy (ie, only branches of the nerve resected).

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Parkinson’s Disease Linked To Increase in Number of Inflammatory Markers

MedicalResearch.com Interview with:

Yong Cheng, PhD, post-doc fellow Section on Cellular Neurobiology Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda, Maryland

Dr. Yong Cheng

Yong Cheng, PhD, post-doc fellow
Section on Cellular Neurobiology
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institutes of Health
Bethesda, Maryland

MedicalResearch.com: What is the background for this study?

Response: Parkinson’s disease is the second most neurodegenerative disease after Alzheimer’s disease. The symptoms of the disease are typically movement related. However, the nonmotor features in PD are increasingly recognized. Evidence suggests that inflammation may play a role in the development of AD, and a substantial number of studies have demonstrated altered levels of peripheral blood inflammatory cytokines in patients with  Parkinson’s disease, but findings have been inconsistent for individual cytokines and between studies. Therefore, we undertook a systematic review of the scientific literature, using a meta-analysis to quantitatively summarize clinical data on blood cytokine levels in patients with PD, compared with healthy controls.

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Promising Study Evaluates Chemotherapy for Parkinson’s and Lewy Body Dementia

MedicalResearch.com Interview with:

Charbel Moussa MD. PhD Assistant Professor of Neurology Director- Laboratory for Dementia and Parkinsonism Clinical Research Director- National Parkinson's Foundation Center for Excellence Translational Neurotherapeutics Program Department of Neurology Georgetown University Medical Center Washington DC.

Dr. Charbel Moussa

Charbel Moussa MD. PhD
Assistant Professor of Neurology
Director- Laboratory for Dementia and Parkinsonism
Clinical Research Director- National Parkinson’s Foundation Center for Excellence
Translational Neurotherapeutics Program
Department of Neurology
Georgetown University Medical Center
Washington DC.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We conducted a pilot open label proof-of-concept study to evaluate the safety and tolerability of Nilotinib in participants with advanced Parkinson’s disease (PD) with dementia (PDD) or dementia with Lewy bodies (DLB). Our primary objective is to demonstrate that low oral daily doses of 150mg or 300mg Nilotinib (compared to 600-800mg in cancer) are safe and tolerated.

Our secondary objectives are that Nilotinib will cross the blood brain barier and may inhibit cerebral spinal fluid Abl. Based on preclinical data we also hypothesized that Nilotinib will increase DA levels. Motor and cognitive functions were also measured as exploratory clinical outcomes. Other exploratory outcomes are that Nilotinib may alter PD-related CSF biomarkers DJ-1 and α-synuclein. As most participants in this study had dementia we also explored the effects of Nilotinib on Alzheimer’s Disease-related CSF biomarkers, including Aβ40 and Aβ42, total tau and phosphorylated tau (p-tau).

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No Increased Risk of Parkinson’s From MRI Gadolinium Exposure

MedicalResearch.com Interview with:

Blayne Welk, MD, MSc,FRCSC Assistant Professor of Surgery Western University London, Canada

Dr. Blayne Welk

Blayne Welk, MD, MSc,FRCSC
Assistant Professor of Surgery
Western University
London, Canada

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Prior research has demonstrated that gadolinium, which may be used during MRI scans to help visualise the body organs, can be deposited in the body, and remain there for years. The US FDA released a notice last year stating that further research was needed to evaluate the clinical implications of these brain deposits. One of the areas that gadolinium is deposited is the brain, specifically in two regions which control voluntary movement (the globus pallidus and dentate nucleus). Damage to these areas could cause symptoms of Parkinsonism. We used administrative data from Ontario, Canada to evaluate whether people who underwent MRI scans with gadolinium had a higher risk of developing Parkinsonism in the future. In this study, we did not demonstrate an increased risk of Parkinsonism in patients exposed to gadolinium.

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Hip Fractures and Falls Increase Years Before Parkinson’s disease Diagnosed

MedicalResearch.com Interview with:

Helena Nyström MD, PhD Candidate Department of Community Medicine and Rehabilitation Umeå University Umeå, Sweden

Helena Nyström

Helena Nyström MD, PhD Candidate
Department of Community Medicine and Rehabilitation
Umeå University
Umeå, Sweden

Medical Research: What is the background for this study?

Response: Parkinson’s disease (PD) has an insidious onset and the prodromal phase, preceding the onset of the characteristic PD symptoms, may last for decades. Most prodromal signs previously reported are of non-motor type, such as sleep and mood disorders. However, recent studies have reported balance problems and an increased risk of accidental injuries in the last 3-5 years before diagnosis of Parkinson’s disease , and in a previous study we found a lower muscle strength at military conscription in men who were diagnosed with  Parkinson’s disease three decades later. In this study, we aimed to investigate if such subtle strength deficits may translate into an increased risk of fall-related injuries.

Medical Research: What are the main findings?

Response: The median study time was 20 years before the diagnosis of  Parkinson’s disease , and during this time more individuals with PD (18%) than controls (11.5%) had at least one fall-related injury. The risk was most increased in the last few years before the diagnosis of  Parkinson’s disease , but a difference between the groups appeared already a decade before the PD diagnosis. The risk of hip fracture was increased during the entire study time of 26 years before the diagnosis of Parkinson’s disease .

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Parkinson’s Disease: No Benefit from Physical Therapy in Mild to Moderate Disease

Professor Carl E Clarke Professor of Clinical Neurology and Honorary Consultant Neurologist Department of Neurology City Hospital Sandwell and West Birmingham Hospitals NHS Trust Birmingham UK

Prof. Carl Clarke

More Interviews on Neurological Disorders on MedicalResearch.com
MedicalResearch.com Interview with:
Professor Carl E Clarke
Professor of Clinical Neurology and Honorary Consultant Neurologist Department of Neurology City Hospital
Sandwell and West Birmingham Hospitals NHS Trust
Birmingham UK 

Medical Research: What is the background for this study?  

Dr. ClarkeParkinson’s disease causes problems with activities of daily living that are only partially treated by medication and occasionally surgery. Physiotherapy and occupational therapy are traditionally used later in the disease, but it is unclear whether they are clinically and cost-effective in Parkinson’s disease.

Medical Research:   What are the main findings?

Dr. ClarkeWe performed a large pragmatic randomised trial to evaluate the clinical and cost-effectiveness of individualized physiotherapy and occupational therapy in Parkinson’s disease. The PD REHAB trial was a multicenter, open label, parallel group, controlled efficacy trial. 762 patients with mild-moderate Parkinson’s disease were recruited from 38 sites across the United Kingdom. For patients with mild to moderate Parkinson disease, there were no clinically meaningful benefits in activities of daily living or quality of life associated with physiotherapy and occupational therapy.

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Parkinson’s Drug L-DOPA May Protect Against Macular Degeneration

Brian S. McKay, Ph.D Associate Professor Department of Ophthalmology and Vision Science University of Arizona Medical Research Building, Room 212 Tucson, AZ 85724

Dr. McKay

MedicalResearch.com Interview with:
Brian S. McKay, Ph.D

Associate Professor
Department of Ophthalmology and Vision Science
University of Arizona
Medical Research Building, Room 212
Tucson, AZ 85724 

Medical Research: What is the background for this study?

Dr. McKay: AMD (age-related macular degeneration) is a disease that is race-related. White people get the disease and lose vision to AMD at much higher rate than Blacks or Hispanics.

Thus, while race is complex, pigmentation may protect from the disease. With this starting point, my laboratory went after the pigmentation pathway to determine how pigment may affect photoreceptor (the retinal cells that actually catch the light) survival. The  pigmented cells in the back of the eye are the retinal pigment epithelial cells (RPE), the rest of the retina does not pigment, it is clear not brown. We discovered that when the RPE make pigment they turn on molecular pathways to foster photoreceptor survival. Next we discovered the ligand for a receptor on the RPE that was tied to governing photoreceptor survival and pigmentation. That ligand was L-DOPA.

Knowing that L-DOPA is given to many aging individuals (those at risk of AMD), we developed a team to ask whether those taking L-DOPA for movement disorders are protected from AMD.

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Parkinson’s Disease Can Be Stratified Into Three Distinct Groups

Ron Postuma, MD, MSc Associate Professor Department of Neurology Montreal General Hospital Montreal, QuebecMedicalResearch.com Interview with:
Ron Postuma, MD, MSc
Associate Professor
Department of Neurology
Montreal General Hospital
Montreal, Quebec

Medical Research: What is the background for this study? What are the main findings?

Dr. Postuma: The background is that we often think about Parkinson’s Disease as a single disease.  However, every clinician knows that there is a great deal of variability from patient to patient.  If we can understand the main aspects that separate patients into groups, we can target therapy better.

The analysis used a semi-automated means to divide Parkinson’s patients into groups, using extensive information about motor and non-motor aspects of disease.  We found that the non-motor symptoms, especially cognition, sleep disorders, and blood pressure changes were the most powerful predictors of which group a patient would be in.  Based on these non-motor (and some motor aspects), the most accurate way to divide patients was into three groups – diffuse (many non-motor symptoms), pure motor, and intermediate (halfway between the other).  We then followed patients over time.  The diffuse group had, by far, the worse prognosis.  This was not only for the non-motor aspects, but the motor as well. Continue reading

Study Finds No Link Between Head Injuries and Parkinson’s Disease

MedicalResearch.com Interview with:
Line Kenborg, MSc, PhD

Survivorship Unit
Danish Cancer Society Research Center
Copenhagen

Medical Research: What is the background for this study? What are the main findings?

Response: The hypothesis that head injuries increase the risk for Parkinson disease has been examined in many studies during the past decades, but the findings have been highly inconsistent. We have previously examined the hypothesis in a study based on information on head injuries and Parkinson disease from the Danish National Hospital Registry. In this study, we found a positive association between a hospital contact for a head injury in middle or late adulthood and a diagnosis of Parkinson disease. The reported association, however, was almost entirely due to injuries that occurred during the months preceding the first hospital contact for Parkinson disease. Because we used information from registries, we lacked detailed diagnostic information to distinguish Parkinson disease from other types of parkinsonism, and we had no information on milder head injuries and head injuries in early life. So we wanted to study whether head injuries throughout life increased the risk for Parkinson disease in the largest interview-based case-control study to date including patients with a verified diagnosis of Parkinson disease. The main finding of our study is that we do not find any association between head injuries and Parkinson disease.

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Parkinson’s Disease Associated With Altered Intestinal Bacteria

Filip Scheperjans MD Department of Neurology Helsinki University Central Hospital Department of Neurological Sciences University of Helsinki, Helsinki, FinlandMedicalResearch.com Interview with:
Filip Scheperjans MD

Department of Neurology
Helsinki University Central Hospital
Department of Neurological Sciences
University of Helsinki, Helsinki, Finland

Medical Research: What is the background for this study? What are the main findings?

Dr. Scheperjans: In Parkinson’s disease (PD), the first neurodegenerative changes are seen in the olfactory bulb and enteric nervous system. Correspondingly, most Parkinson’s disease patients suffer from hyposmia and gastrointestinal symptoms, frequently years before motor symptoms evolve. Therefore, it has been suggested that an environmental factor acting through the nose or gut, could be involved in Parkinson’s disease. Interestingly, those two habitats are where our body gets mostly exposed to environmental agents, including microbes. Previous attempts to identify microbes related to Parkinson’s disease pointed to Helicobacter pylori and small intestinal bacterial overgrowth, but in the end had been somewhat inconclusive. But there possibly was a signal. We saw next generation sequencing approaches as a new opportunity to revisit the microbe theory in PD. Studies of gut microbiome composition in neurodegenerative disease have not been published before, although alterations in gut microbiota have been demonstrated in many other diseases and gut microbiota are in close interaction with the central nervous system.

The fecal microbiome of Parkinson’s disease subjects clearly differed from that of matched controls and this difference was independent of the potential confounders that we assessed. The most significant finding was that the abundance of bacteria from the Prevotellaceae family was reduced by 78% in Parkinson’s disease patients. A low abundance of Prevotellaceae was 86% sensitive for PD, but rather unspecific. However, a combination of 4 bacterial families increased specificity for PD to 90%. So microbiome analysis performed quite well in distinguishing Parkinson’s disease patients from control subjects. Another interesting finding was that, within the Parkinson’s disease group, abundance of Enterobacteriaceae bacteria was related to the motor symptoms of patients. They were positively associated with the severity of postural instability and gait difficulty.
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Parkinson Disease: Naltrexone May Be Useful For Impulse Control

Associate Professor of Psychiatry and Neurology Perelman School of Medicine at the University of Pennsylvania Philadelphia, PA 19104-2676 Parkinson's Disease Research, Education and Clinical Center (PADRECC) Mental Illness Research, Education and Clinical Center (MIRECC) Philadelphia Veterans Affairs Medical CenterMedicalResearch.com Interview with:
Daniel Weintraub, M.D.
Associate Professor of Psychiatry and Neurology
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA 19104-2676
Parkinson’s Disease Research, Education and Clinical Center (PADRECC)
Mental Illness Research, Education and Clinical Center (MIRECC)
Philadelphia Veterans Affairs Medical Center

Medical Research: What are the main findings of the study?

Dr. Weintraub: That there is mixed evidence for the efficacy of naltrexone in the treatment of impulse control disorders in Parkinson’s disease, and the evidence is sufficient to support further study of this compound class for this indication.  In addition, the study demonstrates that it is possible to conduct a clinical trial in this area.
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Parkinson’s Disease: Cognitive Impairment and Plasma Ceramides

Michelle M. Mielke, Ph.D. Associate Professor Department of Health Sciences Research Division of Epidemiology Mayo Clinic 200 First Street SW Rochester, MN 55905MedicalResearch.com: Interview with:

Michelle M. Mielke, Ph.D.
Associate Professor
Department of Health Sciences Research
Division of Epidemiology
Mayo Clinic 200 First Street SW
Rochester, MN 55905

MedicalResearch.com: What are the main findings of the study?

Dr. Mielke: Among Parkinson’s disease (PD) patients, plasma levels of ceramides and monohexylceramides were higher in patients with cognitive impairment or dementia compared to patients who were cognitively normal.  Levels of these lipids were also higher in the combined group of PD patients compared to non-PD controls but the number of controls were small.

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