Parkinson’s disease and Ghana’s untold medical feat

By George Sydney Abugri
June 24, 2016

The perplexing medical condition known as Parkinson’s disease, has come to fairly wide public attention in Ghana in recent weeks for three reasons: First, Africawatch magazine alleged that former President Jerry John Rawlings had been diagnoses with the disease. The rumour died in its infancy when the former president staunchly denied the report and threatened to sue the magazine over the publication.

Next, came the revelation around the same time, that boxing legend Mohammed Ali who has been an idol of most Ghanaians for decades, had suffered from Parkinson’s disease for 30 agonizing years. 

Then this week, an organization called the “Parkinson’s Disease Support Group”, which draws its membership from people suffering from the disease, doctors, pharmacists, physiotherapists, speech therapists, nutritionists and other health professionals, was launched in Ghana.

At the launch in Accra, the group explained that it intends to create public awareness of Parkinson’s disease and educate people suffering from the condition and their caregivers on the nature, progression and management of the disease.

What many outside medical circles in Ghana may not know, is that Ghana made medical history and recorded a major breakthrough in brain surgery in November 2007, when a team of brain surgeons at the Tema International Neuro-Center successfully performed a seven-hour operation to treat a patient suffering from Parkinson's disease.

For the first time in sub-Saharan Africa, a patient with Parkinson's disease had a brain pacemaker placed within the sensitive structure of his brain, in order to stop the disabling, abnormal movements associated with the disease. The procedure is called Deep Brain Stimulation (DBS).

The head of the surgical team, Ghanaian neurosurgeon, Dr. Nii Bonney Andrews led colleague surgeons, Dr. Van den Mencken and Dr. Rick Shuurman, both of the Academic Medical Centre in Amsterdam and Dr Philip Batiade of Germany to successfully perform a marathon surgical operation to treat the patient. 

They were assisted by neurosurgical theatre technologist, Grace Fiagbe, radiology technologists, Theodore Ntiri and Thomas Kweku Aperko, Dr L. John, a specialist in deep brain surgery anaesthesia and Steve Bati a nurse anaesthetist of the Narh-Bita Hospital.

The 63-year old patient had been suffering from Parkinson's disease for 20 years and had not been able to walk steadily. He fell frequently and had multiple shoulder dislocations as a result. He also shook uncontrollably and had great difficulty rising from a chair. The epoch-making medical drama began that memorable morning in the Scan Suite of the Medlab Building located at Roman Ridge in Accra at 8 o’clock in the morning: 

The surgeons first placed a specialized metal frame called a “Leksell frame” round the patient's head. A special scan of the patient's head was next performed in order to obtain a detailed map of his brain, to pin point the exact location of the brain abnormality, where an electrode/wire was to be placed. With the metal frame still attached to the patient's head, the patient was transported by ambulance to the Narh-Bita Hospital in Tema. The main surgical operation began at 9 am and lasted seven hours.

Parkinson's disease is a disorder of the nervous system characterised by violent trembling of the hands, arms, legs, jaw, and face as well as stiffness of the limbs and trunk. Victims of Parkinson's disease have great difficulty walking and only manage to shuffle along.

Other symptoms of the disease include difficulty in swallowing, chewing, speaking; urinary problems, constipation, skin problems, and sleep disruptions.?

Dr Andrews said, Parkinson's disease patients also had great difficulty getting up, after sitting for a while. “They literally get stuck in chairs after sitting for some time”, he said.

The list of world famous sportsmen, politicians, clergymen, actors, musicians and heads of state who have suffered from Parkinson’s disease is a very long one.

The 63-year old Parkinson’s disease patient who underwent deep brain surgery made significant progress within hours of the operation.

The patient was able to walk better, his tremors decreased considerably and 48 hours after the surgery, he was able to sit for more than an hour, playing an exciting game of chess which is his favourite pastime.

There are currently no blood or laboratory tests that have been proven to help in diagnosing the Parkinson's disease, which tends to afflict people in their 50s and older.

Dr Andrews said a diagnosis of the disease is mainly based on the medical history and a neurological examination of persons suspected to be suffering from early stages of the disease.?

He said Deep Brain Stimulation (DBS) was performed for the first time ever in 1994, in Grenoble, France. 'Since then, numerous clinical reports from all over the world have confirmed major improvements for all Parkinson's disease symptoms in patients who have undergone DBS surgery”, the Ghanaian surgeon said.

He described DBS as “a very complex and delicate operation requiring highly specialised skills and technology” and said its successful performance in Ghana “is a fine example of Ghanaian expertise linking up with international know-how, to improve medical outcomes in patients and expand medical knowledge.”

“There was an air of great excitement among the surgeons, as the first electrode was passed deep into the brain of the patient.” Dr Andrews reported. He said this was because for the first time in surgical intervention in Ghana, “the electrical charge from living and functioning cells deep within the human brain, could be heard by surgeons as specific rhythmic sounds!”

The work of Tema International NeuroCenter at the Narh-Bita Hospital is funded by the medical NGO NeuroGHANA. Dr Andrews revealed that since its inception in 1996, the medical NGO has promoted and pioneered the use of modern techniques in brain surgery, key-hole video surgery, as well as Gamma Knife (GK) or “incisionless” surgery in Ghana.

NeuroGHANA which is an indigenous NGO, dependent on its own resources for its activities, is willing to link up with medical professionals and institutions dedicated to helping people fight serious diseases such as brain tumours, strokes, neck pain, back pain and paralysis.

Following the successful DBS surgical operation Dr Andrews said, a special center was being set up to manage Parkinson's disease in Ghana. 

The brain surgeon told me that many patients suffering from Parkinson's disease confuse their condition with stroke: “When we administer drugs to Parkinson's disease patients at the Neuro-Centre and their condition improves, they spread the news that there is a doctor at the Narh-Bita Hospital who cures stroke.” 

The brain surgeon attributed the success of the Neuro-Centre to the support it received from the Narh-Bita Hospital administration. He said Dr Edward Narh, the Medical Director of the hospital, had been outlining productive medical service concepts and inviting suitable partners to develop them for an expansion in the range of specialised medical services at one of Ghana’s leading private medical facilities.

“Dr Narh does not interfere in the work of specialists working at the hospital. He allows them to employ their creativity and skills to achieve results. That accounts for the numerous medical service innovations and successes chalked by the hospital”, the brain surgeon told me at the time.

Website: www.sydneyabugri.com/Web

http://www.ghanaweb.com/GhanaHomePage/NewsArchive/Parkinson-s-disease-and-Ghana-s-untold-medical-feat-450163

Blue Ribbon Highlights Session Recognizes Best Posters From 20th International Congress of Parkinson’s Disease and Movement Disorders

June 24, 2016

BERLIN – The annual Blue Ribbon Highlights Session took place on Thursday, June 23rd, during the 20th International Congress of Parkinson’s Disease and Movement Disorders. This special session provides a critical review of the best poster presentations by a panel of experts, highlighting the relevance, nov¬elty, and quality of both clinical and basic research presented by delegates.

Of the 2,204 abstracts accepted for presentation at this year’s International Congress, only 17 were given this special recognition. The Blue Ribbon Highlights Session was chaired by C. Warren Olanow, New York, NY, USA and Louis Tan, Singapore, and the panel was led by Marie-Francoise Chesselet, Los Angeles, CA, USA, and Caroline Tanner, San Francisco, CA, USA.

The poster numbers chosen for the 2016 Blue Ribbon Highlights include:

Basic Science:

1046: A missense mutation in RAB39B causes X-linked dominant Parkinson's disease

LBA 33: PINK1 selectively accumulates at mitochondria-associated membranes during mitophagy and promotes ER-mitochondria tethering and autophagosome formation

743: A pathological link between Parkinson’s disease and amyotrophic lateral sclerosis?

593: Exome sequencing in Dementia with Lewy bodies

1337: Heart rate variability in LRRK2-associated Parkinson’s disease

LBA 24: Drug re-positioning for Parkinson's disease dementia

Clinical Science:

1183: Evaluating the natural history of prodromal PD in the PARS cohort

654: Epigenome-wide association study of Parkinson’s disease

621: Inflammatory profile discriminates clinical subtypes in LRRK2-associated PD

1138: Enroll-HD: A global clinical research platform for Huntington’s disease

1530: A study on the movement disorder associated with N-methyl-d-aspartate receptor antibody encephalitis 2095: KINECT 3: A randomized , double blind, placebo controlled trial of valbenazine (NBI-98854) for tardive dyskinesia 916: A randomized, double-blind, placebo-controlled trial of deutetrabenazine for the treatment of tardive dyskinesia (ARM-TD)

2012: ADS-5102 (amantadine HCl) extended-release capsules reduced levodopa-induced dyskinesia in the phase 3 EASE LID study

133: An international, randomized, controlled trial of focused ultrasound thalamotomy for essential tremor  

1467: EARLYSTIM: STN-DBS alleviates behavioural side effects of dopamine replacement therapy when compared to best medical treatment

708: Clinical and neuroimaging outcomes up to 18 years after fetal tissue transplant in Parkinson’s disease  

For complete abstracts, Late Breaking Abstracts and author information, visit: 

http://www.mdscongress2016.org/Congress-2016/Abstracts.htm

About the 20th International Congress of Parkinson's Disease and Movement Disorders: Meeting attendees gather to learn the latest research findings and state-of-the-art treatment options in Movement Disorders, including Parkinson's disease. Over 5,000 physicians and medical professionals from more than 86 countries will be able to view over 2,200 scientific abstracts submitted by clinicians from around the world.

About the International Parkinson and Movement Disorder Society: The International Parkinson and Movement Disorder Society (MDS), an international society of over 5,000 clinicians, scientists, and other healthcare professionals, is dedicated to improving patient care through education and research. For more information about MDS, visit www.movementdisorders.org.

http://www.biospace.com/News/blue-ribbon-highlights-session-recognizes-best/424450

Scientists offer new view on origins of Parkinson's disease

Catharine Paddock PhD
June 24, 2016

The researchers suggest a general breakdown of mitochondria is not the complete picture of what goes on inside brain cells in Parkinson's disease.

The death of brain cells in Parkinson's disease is likely a result of stress in their endoplasmic reticulum or protein-folding machinery rather than just a general failure of their mitochondria or powerhouses.

So conclude researchers from the University of Leicester in the United Kingdom, who report their findings, based on research conducted in fruit flies, in the journal Cell Death and Disease.

Dr. Miguel Martins, who heads a group in the MRC Toxicology Unit at Leicester, says:

"This research challenges the current held belief the Parkinson's disease is a result of malfunctioning mitochondria."

He and his colleagues used fruit flies because they provide a good genetic model for studying humans - the insects carry about 75 percent of the genes that cause human disease. Due to obvious ethical and technical constraints, it is not possible to experiment with signaling pathways and cellular processes underlying brain-wasting diseases in humans.

The chief hallmark of Parkinson's disease is the death of dopamine-producing cells in a part of the brain that controls a number of functions, including movement. As the devastating disease progresses, more and more brain cells die and patients gradually lose their ability to walk, talk, and take care of themselves.

Two genes - pink1 and parkin - are known to be mutated in humans with hereditary versions of Parkinson's disease. Fruit flies with either of these mutations also show classic features of Parkinson's disease - they have weak muscles, move slowly, struggle to fly, and show loss of dopamine cells in their brains.

Blocking ER stress prevented brain cell death

Previous studies have suggested that some inherited forms of Parkinson's disease are the result of faulty mitochondria - the powerhouses inside cells that provide the energy they need to function. If their mitochondria stop working, brain cells wither and die.

However, in the new study, the researchers suggest a general breakdown of mitochondria is not the complete picture of what goes on inside cells in Parkinson's disease. Instead, they suggest stress on the endoplasmic reticulum (ER) - and its knock-on effect on mitochondria - is the key event.

Using fruit flies, they showed that chemicals that block the effects of stress on the ER prevented the death of brain cells associated with Parkinson's disease.

The ER is a maze-like compartment inside cells that has the important job of folding proteins into the correct shapes for carrying out the essential work of cells. If the ER starts producing misfolded proteins, the cell shuts it down. While this protects the cell up to a point, eventually it causes the cell to die.

The team found that fruit flies with mutations in pink1 and parkin experienced large amounts of ER stress. They did not make proteins as well or as fast as normal flies, and they had higher levels of a protein-folding molecule called BiP - a known marker of ER stress.

ER stress linked to extra tethering of mitochondria

The ER is tethered to mitochondria via a protein called mitofusion. The breakdown of the protein is controlled by pink1 and parkin. An important aspect of this is letting go of mitochondria that have stopped working so they can be removed and disposed of.

However, the researchers found that the flies with mutated versions of pink1 and parkin had more of their mitochondria attached to the ER than normal flies. This led them to conclude that the ER stress is linked to extra tethering of mitochondria, thus blocking the release of faulty ones.

The team also found that flies with mutated versions of pink1 and parkin, which have more of these tethers, also have fewer dopamine-producing brain cells, the classic hallmark of Parkinson's disease.

In a further experiment, the researchers lowered the levels of mitofusion in the mutant flies and showed this led to reduction in numbers of mitochondria tethered to the ER, and prevented death of brain cells. Also, the flies' muscles remained strong, even though they had defective mitochondria.

The researchers suggest these findings show the death of brain cells seen in Parkinson's disease stems from ER stressrather than a general failure of mitochondria.

"By identifying and preventing ER stress in a model of the disease it was possible for us to prevent neurodegeneration. Lab experiments, like this, allow us to see what effect ER stress has on Parkinson's disease."

Dr. Miguel Martins

So far, the results only apply to fruit flies, but the team believes further investigations will show that something similar could work in humans to treat certain forms of Parkinson's disease.

The following video summarizes the findings and their implications:

http://www.medicalnewstoday.com/articles/311203.php

Data from Studies on PKAN and ‘Off’ Episodes in Parkinson’s Presented at 2016 Congress

Teresa F. Pais PHD 
June 24, 2016

Retrophin presented new data from a physician-initiated study of RE-024, the company’s investigational replacement therapy for pantothenate kinase-associated neurodegeneration (PKAN), a rare movement disorder. The findings, from treatment in two adults with PKAN, suggest the treatment is both safe and effective, with patients showing clinical improvement and stable disease progression.

These results, as well as complementary data from two Phase 3 studies (on APL-130277, a treatment being developed by Cynapsus, and CVT-301, from Acorda) in Parkinson’s patients, were presented at the recent  20th International Congress of Parkinson’s Disease and Movement Disorders in Berlin.

RE-024 was tested by physicians treating two brothers, who were diagnosed with PKAN as children (the disease is genetic) and developed parkinsonism, a condition similar to Parkinson’s disease and whose symptoms can include tremors, slow movement, muscle stiffness and difficulty speaking. Both also had dystonia, dysarthria, and showed extreme impulsivity. The brothers, ages 24 and 29 at treatment start, had lost the ability to walk independently, and the older sibling required a feeding tube.

Results showed the drug was safe and was well-tolerated by the patients, and meaningful improvements in mobility and stabilized disease progression were reported over 47 weeks of treatment. Improvements were measured using the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), a widely used means of assessing daily life activities and neurological impairment in patients.

No treatment-associated adverse effects were reported, and both men chose to continue taking to RE-024 after the 47 weeks.

“These data add to the growing body of evidence demonstrating the potential of RE-024 in patients with PKAN and support our plans to initiate an efficacy study during the second half of 2016,” Alvin Shih, executive vice president and head of research & development for Retrophin, said in a news release.

Cynapsus presented seven posters at the congress, covering aspects related to “off” episodes in Parkinson’s patients and reporting findings from its soon-to-finish Phase 3 study of APL-130277, a sublingual thin film being evaluated to treat “off” episodes. Findings discussed in the presentations included: over 30 percent of patients and caregivers report “off” episodes in the first year after a Parkinson’s diagnosis, and another 53 percent indicated they began two to three years post-diagnosis; patients are aware of “off” episodes; the APL-130277 dose needed to transition from “off” to “on” cannot be predicted by disease severity, a trial finding; and trial data support starting patients on lower doses.

“These data presented at ICPDMD complement Cynapsus’ positive results shared at prior medical meetings and demonstrate an encouraging clinical profile, and further support the potential opportunity that APL-130277 may have in effectively treating OFF episodes in patients with Parkinson’s disease,” Albert Agro, chief medical officer of Cynapsus, said in a news release. “We expect to share additional clinical data from our pivotal Phase 3 efficacy trial by the end of the third quarter of 2016.”

Acorda also presented data on CVT-301 (levodopa inhalation powder), a self-administered treatment for “off” episodes that is also being evaluated in its Phase 3 clinical trial, expected to finish in September.

Based on trial results, both companies are planning to file applications with the U.S. Food and Drug Administration for the treatments to be approved as therapy options for Parkinson’s “off” episodes.

The Michael J. Fox Foundation for Parkinson’s Research helped to support early development work in these two investigational therapies.

http://parkinsonsnewstoday.com/2016/06/24/parkinsons-disease-therapies-to-control-motor-symptoms-pharma-announced-new-data/

ADHD Drug Fails to Boost Cognition in Parkinson's

By Kristina Fiore 
June 24, 2016

But patients reported improvements in impulsivity, inattention

BERLIN.

A drug used to treat attention deficit-hyperactivity disorder didn't improve cognition in Parkinson's patients with mild cognitive impairment (MCI), researchers reported here.

In a single-center randomized controlled trial, patients on atomoxetine didn't have any benefits on neuropsychological testing for attention, working memory, information processing speed, and set-shifting, according to Vanessa Hinson, MD, PhD, of the Medical University of South Carolina in Charleston, and colleagues.

 But they did have improvements in self-reported measures of inattention and impulsivity compared with those on placebo, they reported at the Movement Disorders Society meeting here.

"Our patients were on the advanced spectrum of Parkinson's MCI, which is why the objective measures failed to show benefit," Hinson told MedPage Today. "We are excited and encouraged about the positive subjective measures [on the CAARS instrument] despite the advanced MCI stage in this group. The next step is to study ATM in patients who are less cognitively impaired."

Mild cognitive impairment is common in Parkinson's disease and may be a precursor of dementia, which occurs in about 80% of Parkinson's patients over the course of their disease.

There is currently no treatment for the cognitive problems that arise in Parkinson's, but it's an area that's garnering more research interest, Hinson said.

"Cognitive impairment in Parkinson's is a huge problem for patients and there is only one FDA-approved medication for Parkinson's dementia and none for Parkinson's MCI," she added

So she and colleagues conducted a 12-week, single-center, double-blind, placebo-controlled, parallel-group study of the norepinephrine reuptake inhibitor atomoxetine in 30 patients who had a mean age of 68.

They were randomized to 80 mg of the drug – starting at 40 mg and then uptitrated – or to a matching placebo.

All patients had neuropsychological testing at 10 weeks, after which the drug was discontinued and all were assessed again at 12 weeks for safety.

The primary endpoint was an effect on a composite of attention, working memory, information processing speed, and set-shifting.

Five patients withdrew because of side effects: four in the atomoxetine group, and one in the placebo group.

Overall, the researchers saw no significant differences in scores on neuropsychological testing between the drug and placebo groups (99.5 and 117.5, P=0.25).

Nor did they see any differences between groups on any of the individual measures in the primary endpoint.

They did, however, see statistically and clinically significant subjective improvements for those on the drug on subscales for inattention (CAARS A) and impulsivity (CAARS C), with a mean improvement of -5.7 points for impulsivity and -5.4 points for inattention. No changes occurred on these measures among those in the placebo group.

"Treatment with atomoxetine produced subjective, but not objective, improvements in executive function in Parkinson's patients with mild cognitive impairment," they reported, adding that the drug was generally well tolerated and didn't worsen Parkinson's severity.

Hinson said it's possible that patients in the study were too severely impaired to show change in the selected outcome measures and that a less severely impaired population might improve with atomoxetine in objective measures of cognition.

Claudia Trenkwalder, MD, of the University of Gottingen, who was not involved in the study, noted that this was the "first study ever to look at MCI in Parkinson's."

"No one is sure if this would really develop into dementia or not," Trenkwalder said, "so this is a real pilot trial."

http://www.medpagetoday.com/MeetingCoverage/MDS/58746?

Mutant fruit flies provide insight into origins of Parkinson's disease

Published on June 24, 2016

MRC researchers at University of Leicester investigate ‘mutant flies’

The neurodegeneration that occurs in Parkinson’s disease is a result of stress on the endoplasmic reticulum in the cell rather than failure of the mitochondria as previously thought, according to a study in fruit flies. It was found that the death of neurons associated with the disease was prevented when chemicals that block the effects of endoplasmic reticulum stress were used.

The team from the MRC Toxicology Unit at the University of Leicester. Credit: University of Leicester

Some inherited forms of early-onset Parkinson’s disease have typically been blamed on poorly functioning mitochondria, the powerhouses of cells. Without reliable sources of energy, neurons wither and die. This may not be the complete picture of what is happening within cells affected by Parkinson’s. Researchers from the MRC Toxicology Unit at the University of Leicester used a common fruit fly to investigate this further; fruit flies were used because they provide a good genetic model for humans.

Studies on human subjects are of limited use for elucidating the signaling pathways and cellular processes underlying the neurodegenerative process. This is because both ethical and technical constraints limit the extent to which genetic analysis can be performed in humans.

Flies are a well-established model animal to understand the molecular mechanisms of human diseases. This is because about 75% of human disease-causing genes are found in the fly in a similar form. Also, they are easy to work with, breed quickly and many tools are available to manipulate any genes in the fly. In flies, potential therapeutic drugs can be mixed with food and readily tested.

It was found that the bulk of the damage to neurons with damaged mitochondria stems from a related but different source - the neighbouring maze-like endoplasmic reticulum (ER).

The ER has the important job of folding proteins so that they can do the vast majority of work within cells. Misfolded proteins are recognized by the cell as being dangerous. Cells halt protein production if there are too many of these harmful proteins present. While this system is protective, it also stalls the manufacture of vital proteins, and this eventually results in the death of neurons.

To find out if ER stress might be at play in Parkinson’s, a team led by Dr Miguel Martins analyzed fruit flies with mutant forms of the pink1 or parkin genes. Mutant forms of pink1 and parkin are already known to starve neurons from energy by preventing the disposal of defective mitochondria. These genes are also mutated in humans and result in hereditary versions of the disease. Much like Parkinson’s patients, flies with either mutation move more slowly and have weakened muscles. The insects struggle to fly and they lose dopaminergic neurons in their brains – a classic feature of Parkinson’s.

Compared to normal flies, Miguel’s team found that the mutants experienced large amounts of ER stress. The mutant flies did not manufacture proteins as quickly as the non-mutants. They also had elevated levels of the protein-folding molecule BiP, a telltale sign of stress.

One function of pink1 and parkin genes is to help degrade mitofusin - a protein that tethers the endoplasmic reticulum to mitochondria. Mutant flies have an abundance of this protein. It was found that the mutants had more of their mitochondria attached to the ER than normal flies. For this reason, the researchers suggest that ER stress is related to extra tethering of mitochondria, thereby preventing the removal of defective versions of the organelle.

Mutant flies, which have more of these tethers, have fewer dopaminergic neurons, which can have an adverse effect on the brain. By reducing the number of these tethers it is possible to prevent the loss of the neurons. When the researchers experimentally lowered the amount of mitofusin in the mutants, the number of tethers fell and the neuron number increased again (see figure). The flies’ muscles also remained healthy despite the mitochondria themselves still being defective.

These results suggest that the neurodegeneration seen in Parkinson’s is a result of ER stress rather than a general failure of the mitochondria. The scientists were able to prevent neurodegeneration in mutant flies not only by reducing mitofusin, but also with chemicals that block the effects of ER stress.

Dr Miguel Martins said:

This research challenges the current held belief the Parkinson’s disease is a result of malfunctioning mitochondria. By identifying and preventing ER stress in a model of the disease it was possible for us to prevent neurodegeneration. Lab experiments, like this, allow us to see what effect ER stress has on Parkinson’s disease. While the finding so far only applies to fruit flies, we believe further research could find that a similar intervention in people might help treat certain forms of Parkinson’s.

Source:

https://le.ac.uk/
http://www.news-medical.net/news/20160624/Mutant-fruit-flies-provide-insight-into-origins-of-Parkinsons-disease.aspx?

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