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July 2010 Charles Holme

Edition 56

Chair

This article is for members and appears in the printed version only

To have access to the articles for members, you may join SPRING - see page 2.

Continued on Page 3 >>

In this edition: View from the Chair

Charles Holme on recent and forth-coming events

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About SPRING

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Member Involvement in Research Activities Charles Holme on future possibilities for SPRING members

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Who's Who in the Research Directorate Photos of the Parkinson's UK staff and their roles Research Funding Programme Three ways for members to help fund research through Parkinson's UK

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Exercise: Treadmills and Cross Trainers Michael Kelly describes their benefits Blue Tinted Glasses Harry Pearman relates their odd effect on movement disorders Disease Modifying Drugs Flora Hill and John Telford look at some recent developments On the Lighter Side: Harry muses on some useful things to do with a hand tremor

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Feedback: The Future of SPRING and SPRING Times? Some of your views Web Watch Notes on research developments since we last reported them

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Immunotherapy for Parkinson's John Telford follows up the article in the last edition Duodopa Chris Hill describes this relatively new way of administering levodopa

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About SPRING SPRING is constituted within the Parkinson’s Disease Society of the United Kingdom* as a special interest group which seeks to further medical research into Parkinson’s disease. Particular emphasis is placed upon the need to search for a ‘cure’, for better drugs and to find the cause of the disease. In using the word Parkinson’s, SPRING means to signify the ‘classical’ Parkinson’s disease plus other neurological conditions presenting similar signs and symptoms which are together described as Parkinsonism. Chair Vice-chair Treasurer Secretary Membership

Charles Holme (Vacant) Louise Pearson Liz Roberts Liz Roberts

Committee members and co-optees: Flora Hill, Hilary Elliott, Richard Hill, Tony Cox, Shirley Ratcliffe, John Telford, Colin Tucker SPRING Times Editor John Telford Web site Web master Alun Morgan

SPRING Times is published quarterly. Publication of information or opinions in SPRING Times should not be construed as necessarily conveying approval or endorsement by the SPRING Committee. Qualified medical advice should always be sought before acting on such information or opinions. The Editorial group of SPRING Times endeavours to check the factual accuracy of all articles and submits reports of presentations to those who gave them for their approval. *Parkinson’s Disease Society of the United Kingdom. Charity Registered in England and Wales No. 258197 and in Scotland No SCO37554. A company limited by guarantee. Registered No. 948776 (London). Registered Office: 215 Vauxhall Bridge Road, London, SW1V 1EJ. Tel 020 7931 8080 email enquiries@parkinsons.org.uk web site: http://www.parkinsons.org.uk PDS Research:

http://www.parkinsons.org.uk/research.aspx

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All enquiries and offers of help to: secretary@spring.parkinsons.org.uk or phone 01403 730 163 or write to:

Letters to the editor to: editor@spring.parkinsons.org.uk Send membership subscriptions direct to: SPRING: 15 Silver Park Close, Church Crookham, Fleet, Hants, GU52 6BP e-mail: secretary@spring.parkinsons.org.uk

SPRING website: http://spring.parkinsons.org.uk Material in this edition of SPRING Times may be reproduced without prior permission provided that any article is used in its entirety and not out of context and is attributed to both SPRING Times and its author. Prior permission must be sought where only part of an article is to be reproduced and for articles not written by SPRING members.

If you are reading this and would like to receive your own copy of SPRING Times regularly, clip out the slip below and send it in to learn about SPRING and how to become a member. Members receive SPRING Times free and are informed of all the members’ forums and other events that take place throughout the year. Alternatively you can phone 01403 730 163 or email secretary@spring.parkinsons.org.uk Please send me details about joining SPRING and an application form. Name…………………………………………………….......... Address……………………………………………….......... . ………………………………………………………………........... Clip out this slip and send it to: SPRING, PO Box 440, Horsham, West Sussex RH13 0YE


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Charles Holme

- CONTINUED Chair

This article is for members and appears in the printed version only

To have access to the articles for members, you may join SPRING - see page 2.

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SPRING Times

Member involvement in research activities – the future is approaching quickly now! Charles Holme Chair of SPRING This article is for members and appears in the printed version only To have access to the articles for members, you may join SPRING - see page 2.

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SPRING Times

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July 2010

This article is for members and appears in the printed version only

To have access to the articles for members, you may join SPRING - see page 2.

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Over recent years, Parkinson's UK has redoubled its commitment to research. This has meant that a lot more work has to be done and now there is a sizeable professional staff in place to do it. Communication and liaison with members and with the public now feature strongly, but the main thrust is still to raise funds and to select the highest quality projects to channel them to. The work of the Directorate is set within a detailed Research Strategy and because it is necessary to keep up with the progress being achieved through the world to ensure that new projects build on an up to date picture of what is now known about Parkinson's, a Research Development Manager is on the point of being appointed – maybe we shall have his or her photo in the next edition! Thus the Research and Development Directorate operates a number of different grant schemes which enable researchers to apply for funding for all kinds of Parkinson’s research. The team is responsible for the coordination and management of this funding process, and for ensuring that each grant application undergoes a rigorous assessment process during which relevant experts, including people affected by Parkinson’s, review the applications. The Directorate is also accountable for all communication pertaining to these research projects, keeping people informed of these results and the results of ongoing research into Parkinson’s from around the world. The members of the team introduce themselves below:

I have been Director of Research and Development at Parkinson’s UK since March 2005. My role is to work with Parkinson’s researchers to stimulate new and innovative research towards the development of a cure for the condition. I’m also responsible for the development of the Charity’s research strategy. I work with the Parkinson’s research community, both in the UK and internationally, to ensure that we remain one of the leading charitable funders of Parkinson’s research worldwide. I also liaise directly with other UK funding bodies and am a member of the Executive Council of the Association of Medical Research Charities.

I am responsible for overseeing the process by which local branches can give money to Parkinson’s research, and am the point of contact for local branch and brain bank visits. I also have a number of administrative duties within the team, such as making sure the mailing list for Progress Magazine is up-to-date, and helping Kieran manage his busy schedule.

I oversee the management of Research Operations (including all queries to do with finance), and have particular responsibility for the project grants and themed research schemes.


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I am responsible for the administration of the career development awards scheme, which helps to promote and expand a diverse research community by encouraging researchers from a range of disciplines to develop their specific skills in Parkinson's research. I am also responsible for our PhD studentships scheme, which enables outstanding students to complete a PhD in research related to Parkinson’s, and our innovation grants scheme which funds high-risk, high-reward research that tests bold new ideas that have the potential to transform the lives of people with Parkinson's.

Stacey and I are working closely with members of the Research Network and SPRING Committee to develop one new group of volunteers interested in getting involved with our research.

I am responsible for managing our research volunteers. I also organise our site visits for the research projects we fund, and am currently organising our 2010 research conference.

I produce Progress magazine and the research pages of The Parkinson, along with lay summaries of the charity’s research grants.

I am the point of contact for research enquiries, and I manage the research section of the website.

I analyse the data from the 2007 members’ survey to support campaigns and the research teams. I also manage the Parkinson’s audit, in which geriatricians and neurologists can participate, and am planning the Parkinson’s incidence and prevalence study.


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Parkinson's UK announces measures to make research funding more appealing and relevant to members During last year's Annual Branch Meeting (ABM), a workshop was held on Parkinson's research called “Help us help you”. Members were asked for their ideas and opinions and excellent feedback and suggestions were received. One clear message was that members wanted to choose how to give to research and get updates on how the research they helped fund was progressing.

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Help us make breakthrough

July 2010

our

next

research

We want everyone with Parkinson’s to be able to live their lives completely free of symptoms. So, over the next five years we plan to invest more than £25million in research to bring us closer to a cure. But our research is totally dependent on donations - so we need your help to make sure high-quality research work is not lost through lack of funding.

Parkinson's UK

Everyone's feedback has been taken on board and the Research Directorate is working hard to make changes. They are now piloting a new programme called the Research Funding Programme to members and local groups. The Research Funding Programme gives options - so you can choose how you give to research:

Option 1 – Gift to research (any amount)

You can give any amount of money you can afford to support research taking place in universities and hospitals across the UK. You’ll help fund projects that have the greatest potential to find a cure and improve life for everyone affected by With a single donation of £500 or more, you can Parkinson’s. Your money will be used support the vital work of the Parkinson’s UK Brain where the need is greatest and can cover Bank in London. Our Brain Bank is the biggest in the the cost of equipment, the salaries of UK that is dedicated to Parkinson's. Every year, we researchers and the materials necessary to need £200,000 to cover the costs and keep the Brain carry out high-quality research. Bank running. People with and without Parkinson's can pledge to donate their brain to research by joining our Brain Donor Register. Our scientists collect the brains of people who have died and look at the tissue under the microscope to find out what has gone wrong. The donated brain tissue and anonymous donor information is then used by researchers around the world who are With a single donation of £2,000 or more, you can searching for better treatments and a help fund a Parkinson’s UK project of your choice. cure for Parkinson’s. You can support the research project that means the most to you. For example, projects taking place If you choose to support our Brain Bank, at a local university or on a certain topic. we’ll invite you to visit our laboratories to meet our expert team and see how your We’ll help you follow the developments of your gift is making a difference. chosen project and invite you to the project site visit. This will be your opportunity to go behind-thescenes, meet the scientists and find out what progress is being made.


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The Ashford (Kent) Branch has been one of the first local groups to take part in the Research Funding Programme. They raised £3,000 for Dr Frank Hirth’s research project at King’s College London. David Endersby, who is the Committee Member responsible for research, describes why they got involved. “Our Branch wanted to be more involved in research that was relevant to us. We were a little frustrated with the previous 'shopping list' scheme. This is because by the time we had made up our mind about which item of research equipment to buy, the goods had already been purchased by another branch. “We then submitted a question to last year’s ABM about participating in larger projects and shared our views at the research workshop. We were delighted with the outcome and the new Research Funding Programme for members and local groups. “Our Branch decided to make a donation to a specific research project. The benefit is that we’ve had direct contact with the researchers. We visited their laboratories at Kings College London and met the research leaders and their teams. We were able to come back to our Branch and pass on the information to others, which I believe makes our Branch members more enthusiastic about research. “Our Branch was subsequently visited by two of the research leaders from Kings College London and Claire Bale, Research Communications Officer from National Office. They gave us a very enlightening afternoon, after which we presented our cheque for research. “We’ve also been able to encourage people from other organisations to support our project. One of our Branch members, who visited the Kings College London research team, was speaking with his sister who donated a sum of £1,170 to our project. This money had been raised by the Inner Wheel of Tunbridge Wells of which she was the President. She was able to give her members almost first hand knowledge of what went on and how the donation would be spent. I think this is making more people aware of Parkinson's and the importance of research.”

Contact Rebecca Fulton, Research Administrator • Telephone 020 7963 9313 or 020 7932 1332 • Email research@parkinsons.org.uk • Write to us at Parkinson’s UK, 215 Vauxhall Bridge Road, London SW1V 1EJ We’ll get back to you within seven working days to talk about your gift and what to do next. Thank you for your support.

Adapted from an article in a recent Branch mailing


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Michael Kelly, diagnosed with Parkinson’s disease 16 years ago, uses a cross trainer and treadmill at home, especially in the winter months, to maintain a basic fitness level. He is convinced that the effort is rewarded by an enhanced sense of well-being and the ability to continue with activities of daily living without major disruption.

Exercise: trainers

Treadmills

and

Cross

By Michael Kelly At the conference that took place in September 2009 near Gatwick Airport, extensive coverage was given to the role of exercise as a means of alleviating some of the symptoms of PD. Readers are referred to http://spring.parkinsons.org.uk/springdocs/NieuwboerPage.html

and to http://spring.parkinsons.org.uk/springdocs/ZigmondPage.html, both excellent videos of the keynote presentations. The benefits of exercise, meantime proven in a variety of studies, are not just marginally interesting in some limited cases; the evidence points to extensive, long lasting effects extending even into the neuroprotective field. This article aims at giving a comparison between two exercise devices, namely treadmills (TMs) and so-called cross trainers (CTs), often referred to as elliptical trainers. A question that arises at the very beginning is:

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why do indoor training at all? Why not go out-of –doors, walking, jogging etc. The answer ranges over a wide spectrum; there are those who are not capable of walking or jogging. Furthermore, for those of above average fitness, there is a limit to the level of exercise provided by walking. The time of year and weather conditions play a role. The convenience of being able to select the time of exercising is of major importance. The increasing popularity of sport and fitness centres, with their extensive array of exercise devices, is testimony to the attractiveness of indoor workouts. Another point needs to be made at the outset. No exercise device, no matter how sophisticated and elaborate it may be, will bring any benefit if it is not used regularly. The unquestionably large numbers of devices languishing unused in cellars and garages up and down the country is testimony to good intentions on purchasing. It is frequently asserted that a scientifically founded benefit would help to assure regular usage and indeed the studies referred to in the conference cited above are a step in that direction. Regardless of the best approach, it is essential that the willpower and discipline necessary to ensure regular use is there from the start. (Regular use would typically involve a 30 minute moderate to intensive workout two to three times per week). The intensity level needs to be defined to suit the situation of the user, suffice to say that the aim should be to exercise at about 1.5 times basal metabolic rates (energy expenditure level at rest).

Cross Trainer

Treadmill


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Most investigations of exercise devices, both in terms of their benefits to PD patients as well as their use in other applications such as spinal injuries and the like, focus on treadmills. This is somewhat surprising in as far as treadmills have some major drawbacks, especially for more seriously handicapped or elderly users. The predominance of treadmills may relate to the fact that they have been around for a long time; cross trainers have come into use only as of 1995, having been developed by Precor in the USA (http://www.precor.com). Some of these drawbacks might be summarised as follows: 1. The danger of falling or misplacing a step on a treadmill is high, especially when the arms swing free while not holding on to a support or positioner. A temporary lapse in concentration, coupled with an unsteady gait, such as often occurs with PD, can result in a foot landing outside the belt area, with potentially serious consequences. This danger diminishes somewhat when the treadmill is larger, like the units used in fitness centres. Home units are generally smaller 2. To circumvent this danger, an elaborate support harness needs to be employed or alternatively a number of staff has to be in attendance which makes this labour intensive and again less suitable for home use. 3. A major drawback of treadmills is joint impact shock loading arising when the foot lands on the belt. This has undesirable consequences for ankles, knees and spine, not to mention noise when exercising in an apartment environment. It is generally held that shock loading is up to 20 times the level of soft landing so this feature takes on considerable importance for the elderly, for those with joint problems and for those carrying excess weight. It also means that footwear has to be of high quality, whereas it is possible to use a CT barefoot. 4. The consequences of this, together with safety aspects, are such as to outweigh all other considerations, giving CT a very clear advantage. Cross trainers, or elliptical trainers as they are sometimes called, have the feet positioned on straight struts, one end of which being attached to the periphery of a wheel following a circular path. The other end is suspended and follows an

11 oscillating path, the net result of being that the feet follow an elliptical path and the hands, gripping two uprights, move contra-lateral to the feet, while at the same time making an energy contribution to assist the legs. The net result is a complex movement, involving a side to side sway and activation of many muscle groups, including those of the upper body. The movement action of a CT is smooth and even, without any of the shock impacts associated with treadmills. Both devices can be purchased with a considerable amount of electronics enabling one to vary resistance by electromagnetic braking with a turn-down ratio of 1/15(CT), or alter speed (usually in the range 0-12km/h TM). Some TM units have electrically adjustable slope selection and practically all TMs have soft start features providing slow speed ramp-up. All units cover very broad exercise intensity ranges catering for different levels of fitness to suit everybody. Somewhat unexpectedly, energy expenditure and thus calorific burn-off overlaps to a great extent for any given speed or resistance in both devices so that the exercise effect per unit time is largely similar. This has been found to be the case in numerous investigations. (See reference below, for example) The cross trainer has the advantage that one can reverse the direction of rotation and thus bring additional muscle groups into play. The comparability of exercise arises despite the fact that CT can have variable speed and resistance levels whereas TM can vary speed only (and possibly slope in some cases) Finding sufficient space for a unit at home is often a problem. A CT tends to have a smaller footprint than a TM but nevertheless requires space of about 140x70x160 (LxBXH)cm. A TM can be folded into a compact, upright position when not in use but this requires considerable strength; better quality devices especially are quite heavy. Depending on your age, you may be able to use TMs and CTs free at your local authority leisure centre if you are reluctant to join a fitness club. But you might want to buy your own for home use. Prices vary considerably. A new goodquality CT unit will cost ÂŁ400-500 and upwards. A


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TM generally will be more expensive, usually up to double the price of a CT depending on size and complexity. As mentioned above, however, there are a considerable number of CTs and TMs gathering dust so if one is prepared to wait and look at the likes of eBay occasionally, it is relatively easy to obtain barely used units at much lower prices. A word of caution: it is essential when beginning to exercise for the first time or after a long layoff to get professional assessment of your state of health particularly in regard to the cardiovascular system. Over-exertion can lead to serious complications. It is important to begin slowly and build up gradually. Having persisted in reaching and maintaining a higher degree of fitness, the rewards come in the

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form of improved well-being and a sense of control by adopting an active role in managing the disease. Based on the results of published research and supported by investigations described in the videos of the two keynote speakers referred to above, there can be little doubt about the overall benefits of exercise. A CT is to be preferred over a TM for the many reasons cited above. Reference: Dalleck et al, Maximal exercise testing using elliptical cross trainers and treadmills, Journal of exercise Physiology, vol 7, number 3, June 2004. http://www.asep.org/files/DalleckV2.pdf

One of the easiest ways of determining intensity of exercise is to measure heart rate. Maximum Heart Rate. (MHR) is defined as 220 minus your age. A percentage of the resulting figure is then used to indicate the intensity of physical activity - see table below:

Exercise intensity - MHR Maximun Heart Rate

%MHR

Physical State

Low

40-50

No appreciable change in breathing or perspiration

Medium

50-70

Faster breathing with persoiration after 10 minutes

High

Above 70

Rapid breathing, perspiring freely after 5 minutes

Blue Tinted Glasses may help to offset movement disorders. By Harry Pearman In 1995 Tom Reiss made a posting to an on-line discussion group called the Parkinsons Information Exchange Network On-line. (PIENO). He suggested that there was evidence that stimulating the optic nerves with dark blue light activated neural pathways which helped some people with Parkinson's (PwPs) overcome movement disorders.

a hard time opening his eyes during an OFF state. This relaxed his eye lids thus allowing him to open up his eyes. The shades slightly reduced the stiffness of his muscles... ...Try them, they do work.

An undated posting by Rita Weeks says:-

their

This unleashed a rash of postings of anecdotal evidence, which has rumbled around ever since without resolution. On 9.1.1995 H. M. Laswi wrote:I purchased a pair of Blue Glasses for my father who is a PD patient. The first reaction that my father had when he wore these glasses was better ability to open his eyes. He usually had

I am 50 year old woman with PD. My greatest problem with my PD used to occur when trying to walk (or breathe) in bright afternoon sunlight. I tried the blue filters and now have a pair of my prescription glasses tinted blue. I have dramatic improvement in my movement while wearing blue glasses. I have a dramatic reduction in my rigidity, and fine motor skills when wearing the blue glasses. Do not know what is causing the change in movement. I have discussed this with several neurologists as of yet we have no answers. Try dark blue

On 10.1.1995 Jeffrey Romanyshyn wrote:I had the fortunate experience of trying a pair of blue glasses several months ago. My father


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was an observer and he was amazed at how much better I walked, without any dyskinesia or twitching. I am 27.

A further posting by Rita Weeks on 12.1.1995 described how she went about her experiments:I tried cellophane, first using report covers then overhead projector transparencies. If you wear glasses anyway, just cut a piece to fit behind your glasses to see if you have any improvement in movement. I next moved on to Bright Blue camera filters.....looking for something more durable than cellophane.....again plopping these behind my regular prescription glasses. My next stop was to buy "blue glasses" from a street vendor in Amsterdam (by the way, he was wearing purple glasses at the time!). My daughter (the juvenile probation officer) tells me that these blue glasses are the ones regularly worn by cocaine users.....check with your local drug supplier for accessory purchases I guess!! Finally, I went to the optician and got a dark blue tint on my prescription lens. My one complaint is that my bright blue lens produce better improvement in movement than the prescription tint......which is a cosmetically better colour....less colour distortion in real life..........a dark sunglasses tint. If I had 90% improvement with the bright blue lens/cellophane/camera filters then I am probably at a 70-75% improvement with the standard tint. I do not suffer from dyskinesia. My problem is more lack of movement or impaired movement. I have exactly the same response to the blue glasses whether I am on or off on my mediations. Some mornings when I could not raise my arms to begin to dress myself, my husband will slip on my blue glasses and I am off and moving for the day in an instant. Take off the glasses and I am back to an immobile mannequin.

On 1.2.1885 RobertA Martone wrote:My wife Nancy went to her optometrist last week and had a pair of glasses tinted blue. This was done after experimenting with a felt tipped blue marker pen on a pair of her older glasses. The experiment did seem to provide relief from the drug induced dyskenisia that she suffers from taking Sinemet for 14 years. The optometrist tinted a pair of Nancy’s glasses so the peripheral vision received a darker blue than the central vision but

13 cosmetically the tinting looks uniform and quite normal. After three days of use it is clear that these glasses are generating measurable benefits. The dyskenetic lateral movement of her head and the twisting of her upper torso has been reduced in frequency and in magnitude. Head movement while eating has been a major source of frustration as well as embarrassment. This movement often would span 6 inches to 12 inches and with a frequency of approximately one per second. During the three nights we have had dinner together those movements have been reduced to maybe three inches and to 1 per five second interval. Tonight at dinner there was no dyskenisia at all. This was after wearing the blue glasses virtually all day outside on a bright and sunny 65 degree Fahrenheit day.

After a time the postings petered out. A school of Optometry in New York City on 42nd street was said to be prescribing blue glasses for PwPs and The Parkinson’s Institute at Sunnyvale, California was appealing for funds to enable it to research the subject scientifically. This was all 15 years ago. The topic has been resurrected by the posting to YouTube of a video showing a PD patient experimenting with blue light. The man sits in a room and is plainly suffering from extreme dyskinesia, bradykinesia and tremor. He lurches across the room to a floor marker and back to the seat with limbs and upper torso flailing wildly about. Then with the greatest difficulty he manages to put on a pair of blue-tinted spectacles. Immediately his movements calm down and he is able to repeat the walk with some semblance of a normal gait. He then removes the glasses and the disorders return. He is handed a sheet of blue tinted plastic and when he succeeds with difficulty in getting it in front of his eyes his movements calm down again. A nurse then takes the sheet from him and walks backwards. There is a direct correlation between the distance and the degree of movement disorder exhibited. At the moment the only active interest in this topic seems to be in the United States but you can check out the video for yourself at http://tinyurl.com/y7kfqrf and read the commentary at http://tinyurl.com/3yqclkp


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Disease modifying drugs: a distant dream or a reality? Flora Hill and John Telford Over recent years evidence has been accumulating that some drugs - existing ones as well as new ones - might actually modify the progressive nature of Parkinson's by slowing, halting or even reversing the degeneration of nerve cells. Here we report on Cogane, a new drug which has shown much promise in animal models (i.e. where animals are given a toxin which produces a condition which resembles Parkinson's). But there are other drugs which are already clinically prescribed which may have an effect on the Parkinson's disease process itself. Some of these are used for Parkinson's symptom control and others are used for entirely different conditions.

The latest on cogane Last July Charles Holme reported in SPRING Times (http://spring.parkinsons.org.uk/images/stories/S pringDigest/2009/ST52Web.pdf page 16) that he had been to a meeting about a promising new drug that was under development called Cogane. This has shown promise for protecting and even restoring the neurons that degenerate in Parkinson's. At that point this effect had only been demonstrated in animal models. It has now been announced that the US Food and Drugs Administration has approved the protocol for a Phase II trail to be carried out and this will go ahead over the next couple of years. This trial will test 'the proof of concept' – i.e. that the drug is effective in humans and is also safe and tolerable. The full press release can be found http://www.phytopharm.com/assets/Newsreleases/Rel-163-Final-100610.pdf

at:

The trial, which will be carried out in several countries including the USA and the UK, will be looking for an improvement in symptoms in patients given the drug as measured by the Unified Parkinson's Disease Rating Scale Parts II and III. They will also be assessing other physiological indicators. The press release describes Cogane as a small molecule that can be taken orally and that

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readily crosses the Blood Brain Barrier and induces the release of innate neurotrophic (i.e. nerve-nourishing) factors. In animals which were given a Parkinson's-like condition by the administration of a neurotoxin, the loss of dopamine neurons was reversed and it is hoped a similar effect will occur in Parkinson's patients. So keep an eye on the Phytopharm website over the next two years ...

Additional benefit from COMT inhibitors? In order to prevent the loss of dopaminergic neurons, and thereby treat or slow the progression of Parkinson’s disease (Pd), researchers at the Swiss Federal Institute of Technology (EPFL) aim to develop compounds that block alpha-synuclein aggregation. In a paper published in the Journal of Biological Chemistry (PMID: 20150427) in February 2010, they state that inhibitors of the enzyme COMT (catechol-0-methyltransferase) may not only prolong the availability of levodopa by inhibiting this enzyme, but also have other benefits – namely that they hamper the formation of fibrils of alpha-synuclein and Abeta, a protein that forms fibrils in Alzheimers. The researchers tested a number of catechol containing compounds for their ability to hamper the fibrillization of alpha-synuclein and Abeta and found that both Tolcapone (Tasmar) and Entacapone (Comtan, which is also in Stalevo together with levodopa) were potent inhibitors of alpha-synuclein and Abeta oligomerization. They seem to act as chaperones for these proteins. Tasmar and Entecapone belong to the class of nitro-catechol compounds. The researchers conclude that the inhibitory properties, mode of action and structural properties of these types of compound provide promising leads for further optimization of their action to inhibit protein aggregation.

Non Steroid (NSAIDs)

Anti-Inflammatory

Drugs

In June 2006 SPRING proposed that the Society fund a study to investigate whether Non Steroid Anti-Inflammatory Drugs (NSAIDs), taken after the onset of motor symptoms, would slow down the progression of Parkinson's. This proposal was based on the findings that: - people who took NSAIDs regularly had a reduced


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chance of developing Parkinson's - evidence of an inflammatory process was found in brain tissue of Parkinson's patients - there were no reported studies on the effects of NSAIDs in Parkinson's. Meanwhile another study (in this case a metaanalysis or an aggregation of other studies) has reported that regular use of the NSAID Ibuprofen reduces the risk of developing Parkinson's (PMID: 20308684 ). This means that these persons are less likely to go on to develop the motor systems that are characteristic for Parkinson's and end up with a diagnosis of the disease. This does not mean that they could not have aggregated alphasynuclein somewhere in their bodies. Pathological investigations have shown that many individuals, who die without any clear symptoms of any neurological illness have Lewy bodies in their brains that are distributed in a way that is characteristic for early (pre-motor symptoms) of Parkinson's according to the Braak model.

Anti-hypertension drugs

15 Strategy Group) shortly and we shall bring you a full summary. The reason SPRING took an interest in these classes of drug is because if they were found to have anti-Parkinson's effects, getting them into the clinic for Parkinson's would be quicker than for a new drug because they have already been shown to be safe for clinical use for other conditions. Where the reviews show that there are still gaps in knowledge about their effectiveness for Parkinson's, we hope Parkinson's UK could be persuaded to offer grants to researchers to fill in the missing bits.

On the lighter side On the theory that every problem creates an opportunity, Harry Pearman has come up with:

TEN USEFUL THINGS TO DO WITH A HAND TREMOR

In 2007 SPRING submitted a proposal to investigate the disease modifying properties of drugs prescribed to counter high blood pressure. A class of these, the so-called calcium channel blockers, are of particular interest because of evidence of their anti-Parkinson's effect.

1. Learn to play the maracas and castanets – become the leader of a Latin-American dance band.

Systematic Reviews

3. Take down shorthand from someone who s-sstutters.

Systematic review by the PDS of all available literature for both types of drugs (NSAIDs and Anti-hypertension drugs) has been proceeding over the last couple of years. The results are expected to be presented to the RSG (Research

2. Take up turntable pottery making – produce some interesting spiral effects.

4. Send Morse code messages from ships in Force 9 gales. 5. Do cake decorating in an earthquake zone. 6. Serve soup on high speed trains. 7. Knit Fair Isle pullovers. 8. Play the “Flight of the Bumble Bee” on the piano accordion. 9. Sieve icing sugar in a cake factory. 10. Paint stormy seascapes. Do you have any suggestions to beat these on this or other topics?!


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Feedback The Future of SPRING and SPRING Times Patrick Mark of Dalkeith writes: The January edition asked for views on the continuation of SPRING Times... My view is yes. There is a place for it and I would regret its passing. Why? * The sense of urgency and personal commitment of its contributors makes it uniquely compelling. * The lack of jazzy graphics can make it a more relaxing and focussed read. * The often idiosyncratic views and ideas are stimulating and thought provoking. * It is able to focus on issues - such as exercise - and stir up interest and concern. * It is independent of what is at times a centrist attitude at HQ. I hope these random thoughts are helpful. And thanks to SPRING Times for a number of very thought provoking articles which have strongly influenced me over the years

Joan New writes: I was interested that one reader wrote in the April SPRING Times: "..Any marked advance in the treatment for the disease is sure to be published in the national press or the media generally - which will be quite enough for me.." I strongly disagree. The media is notorious for mis-reporting and overhyping both advances and set-backs. I never feel happy about accepting a press report, until I've seen it confirmed in a more level-headed scientific context. Last week there was a typical example (not PD-related) when we read about the creation of the world's first synthetic life form. Had the biologist created life? No, he hadn't - the life factor was provided by a bacterium - but you wouldn't guess that from the hysteria that followed. I value SPRING Times for its accurate, balanced - and often refreshingly simple reporting of what is actually going on.

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Charles Holme reports: I was speaking to Guildford branch last week and members of SPRING were saying how they value ST. It is useful to hear what the 'customers' say and how they recommend us to others.

Marion Koebner wondered for how much longer SPRING would exist as a separate entity? Charles Holme has answered that in his article on Page 4, but he also responded to her: So do we still need members and should you pay your membership fee? I would say yes for 2 reasons: 1 The discussions may not be successful. The trials may not work as we intend. We are stepping into the future here. Until there is evidence that convinces our members that the new arrangements work as intended then SPRING exists and continues its work. For example we are currently planning the SPRING scientific conference for 2011. SPRING Times is still going out. We are following up the Exercise Conference. We are going to take a part in the World Parkinson's Congress. We fund students, etc 2 We need SPRING members to come forward to take part in the trials and if they are successful to develop the new arrangements. After all we are the ones who have believed in a cure strongly enough to do something about it in the past, to give our time as you have done, to believe that a cure is possible when one Neurologist said we should not be speaking about a cure, and so on. We have the values that will drive this new organisation forward and I trust will attract many more members to join it. It will not be SPRING under another name. SPRING has done a great job. The new organisation can do a different and more important job. The new brand offers us an opportunity. It would be uncharacteristic of SPRING members to sit back and watch as others play the game So renew your membership, continue to play a part in SPRING, watch out for the opportunities the new arrangements bring to your region and go ahead, so we look back from 2015 on SPRING as a launch pad from which new and different initiatives have developed.


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Web Watch

Rapamycin ‘cure’

Harry Pearman has compiled these notes to follow up some accounts of recently published research which we reported in SPRING Times.

SPRING Times edition 54 p15 [8] recorded that Dr. Alex Whitworth of Sheffield University had reversed Parkinson symptoms in mice with induced hereditary forms of the disease by the use of the drug Rapamycin.

External Spinal Column Stimulation In 2009 reports were circulated [1] of a successful experiment at Duke University, North Carolina. A mouse with induced dopamine depletion was ‘cured’ of consequent movement disorders, more or less instantaneously, by an external electrical pulse transmitted through its spinal column. It is now possible see a video of this experiment. [2] It shows a mouse with a neurological pacemaker fastened to it back. It is sitting in a corner of a cage looking rather fed up. Then the pacemaker is switched on and it perks up straight away and starts wandering around the cage. The work came about as a spin-off of research into epileptic seizures. It raises the possibility that an inexpensive and less invasive alternative to Deep Brain Stimulation might be possible. The published account of the work includes the following statement:The Duke team is collaborating with neuroscientists at the Edmond and Lily Safra International Institute of Neuroscience in Natal, Brazil, to test the new procedure in primate models of Parkinson's disease prior to initiating clinical studies. Neuroscientists from the Brain and Mind Institute at the Swiss Institute of Technology (EPFL), in Lausanne, Switzerland, will also participate in this international research effort to translate these new findings into clinical practice.

The same approach has been adopted independently by a research team at the Institute of Neuroscience and Medicine at Julich, Germany [3],[4]. The account of their work published in December 2009 states:We present an external trial DBS device capable of administering effectively desynchronizing stimulation techniques developed with methods from nonlinear dynamics and statistical physics according to a model-based approach.

He has now been given a grant by the P.D.S. to continue with his research. [5],[6].

Reversal of PD symptoms SPRING Times edition 54 p16 [8] recorded that Dr Susan Lindquist of M.I.T. has found 6 compounds that reverse PD symptoms in brewer’s yeast with an induced Parkinsonian condition. She has also had some success at treating Parkinsonian roundworms and laboratory rat neurons with these compounds. A detailed paper has now been published on this work, which identifies the 6 compounds.[7] Remarkably these compounds also protected neurons from rotenone-induced toxicity. (See SPRING Times edition 54 p17 [8] for an account of the rotenone models of PD.) References: External Spinal Column Stimulation: 1 http://tinyurl.com/yferowc Duke University 2 http://tinyurl.com/yjn2wuq Video of mouse with External Spinal Column Stimulation 3 http://tinyurl.com/yztjb4l Similar work at Institute of Neuroscience and Medicine at Julich 4 http://tinyurl.com/yf94z3l Ditto Rapamycin - PDS Grant to Dr Whitworth: 5 http://tinyurl.com/pds-grant 6 http://tinyurl.com/yjov4qx Susan Lindquist – drugs to counter aggregated alpha synuclein toxicity: 7 http://tinyurl.com/pd-c-u-r-e 8 SPRING Times edition 54: http://spring.parkinsons.org.uk/images/stories/SpringDigest/2010/ ST54Web.pdf

But what about this: Cycling for the freezing of gait If the effect of blue glasses is extraordinary (see Page 12), so is the report that a man who is unable to walk because of his Parkinson's can ride a bike fluently. Check out the videos at this web address: http://content.nejm.org/cgi/content/full/362/13/e46


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Immunotherapy for Parkinson's John Telford In the last edition I reported on the work of Professor Howard E Gendleman and his team at the University of Nebraska Medical School in Omaha. (SPRING Times 55 page 15: Parkinson's Vaccination.) Since then he has been kind enough to reply to some of my questions about this exciting research. But why is this research so exciting? Prof Gendleman said that the role of the adaptive immune system in Parkinson's is really only in the early stages of investigation and, until their work, it was not known that the body reacted to itself in this way to speed neurodegeneration. This insight has far-reaching implications both for the understanding of the disease and for therapy. Here is a summary of what their investigations have led them to conclude: - One or more of the modified species of alphasynuclein produced when it aggregates promotes an inflammatory reaction from the microglia which are the front-line immune cells in the central nervous system. Such an inflammatory reaction also speeds more modifications of alpha synuclein so that the process feeds on itself. - This attracts certain cells of the immune system called T effector cells (Teff) to cross the bloodbrain barrier to attack and destroy, in a very targeted way, this form of alpha-synuclein because it is perceived as an antigen and a 'nonself' protein. Normally such T effector cells are produced to eliminate harmful microbes from the body that the body sees as foreign but somehow the changes in alpha-synuclein trick the body's immune system into attacking itself. - The Teffs themselves amplify the inflammatory state in the damaged brain reinforcing oxidative stress and producing other biochemical factors which cause neurons to die. - Dying neurons in turn produce pro-inflammatory substances. The microglia, which were likely to have been responsible for the initial inflammatory reaction in response to a perceived attack of one sort or another, get locked into an inflammatory state and persistent inflammation sets in which feeds the disease process. Thus,

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there are several different processes that are going on at the same time that speed the inflammatory state, increase the changes in form and substance of alpha-synuclein and lead to more neuronal injury and death. - It would be expected at this point that another type of immune cell, the regulatory T-cells (Tregs), would now be produced to constrain the inflammation and switch on a repair and restore mechanism. But there arises what they call an immune deficit characterised a clear dysfunction of the Tregs. The consequence of this is the chronic, progressive nature of Parkinson's and other degenerative diseases. Simply stated there is nothing to brake the vicious cycle of inflammation, alpha synuclein aggregation and neuronal death. The exciting development is that the Omaha team believes it has found a way to raise the level and, most importantly, the function of the missing Tregs. This has delivered neuroprotection in a mouse model of Parkinson's and gives hope that this can be repeated in humans by administering a vaccine produced in essentially the the same way as with the mouse model. Animal models, i.e. experimental set-ups where animals are given a condition that resembles the disease in humans, clearly have their limitations and Prof Gendelman is keen to work with patients with Parkinson's at the earliest opportunity. I am sure we'd all support this enthusiasm if it could reach a cure faster. They have therefore begun to look for the 'immune deficit' in Parkinson's patients – even using Sundays to analyse their data, I was told! The next stages, which probably determines their work for the next few years, will be, first, to determine the safety of the vaccine, second, to assess its effectiveness and then to come up with the optimum formulation and dose. Not a trivial task. Not without potential show-stopping setbacks either because, for example, one can imagine the disastrous consequences if by increasing the regulatory T-cells to a level that quenched the chronic inflammation the whole immune system was compromised. Now there are good reasons why this should not happen, but there are always unforeseen effects of any intervention of this kind. For instance there was hope that simply giving non-steroidal anti-


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inflammatory drugs (NSAIDs) could be effective in an Alzheimer's prevention trial but patients were found to have an increased risk of cardiovascular events that prompted its discontinuation1. At about the same time that this edition of SPRING Times comes out, Prof Gendleman and his team will be publishing a review of their work so far in the Journal of Neurochemistry. This pulls together all the work that has been reported in separate papers and outlines the work they are planning to do. Prof Gendleman will also be at the World Parkinson Congress in Glasgow this autumn where he will be presenting the data that they are acquiring right now2. A good reason for you to register to go! If successful, this immunotherapy would stop the progression of the disease process. Alphasynuclein aggregation would cease and further neural degeneration would be arrested. It is possible that deposited alpha-synuclein would be

Duodopa Chris Hill A new drug delivery system is now available in the UK for Parkinson’s patients who are experiencing the long term side effects of levodopa including motor fluctuations (on-off effects) and dyskinesia. I have been following the progress of Duodopa with particular interest ever since meeting a ‘Duodopa patient’ at an EPDA conference in Slovenia in 2002. I recently attended a Duodopa Information Day organized by the Netherlands Parkinson Patienten Vereniging. Speakers included neurologist Prof EC Wolters from Amsterdam VU and Antonio Melendez, Duodopa patient and chair of the Duodopa workgroup of the Parkinson Patienten Vereniging.

Background The disabling motor fluctuations and dyskinesia which affect patients who have been taking levodopa by mouth for some years are thought to result from the ‘pulsatile’ way in which the drug reaches the brain. In an attempt to smooth out the delivery of the

19 disaggregated by macrophages and then disposed of by the usual mechanisms that are disrupted in Parkinson's. If the restoration of the Treg cells also achieved the switching back on of the trophic (nourishing) functions of the microglia and astrocytes with the production of growth factors such as GDNF and BDNF then it is feasible that ailing neurons could be rescued and returned to functionality. One can be excused for being excited over this prospect because we are not merely talking about prevention.

1 Meinert, C. L., McCaffrey, L. D. and Breitner, J. C. (2009) Alzheimer's Disease Anti-inflammatory Prevention Trial: design, methods, and baseline results. Alzheimers Dement, 93-104. PMID: 19328435 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866447/ 2 World Parkinson Congress, Day 1, Wednesday, September 29, 2010, Parallel Session #10 Non-Autonomous Cell Death In PD: 17:35 Talk: Vaccination for PD . Speaker: Howard Gendelman (US) http://www.worldpdcongress.org/Program/program.cfm

drug to the brain many patients are either prescribed levodopa in a ‘controlled release’ formulation, or advised to take levodopa in smaller doses at more frequent intervals. However the time taken for each dose to pass from the mouth, through the oesophagus and the stomach to the duodenum (which is the first location at which the levodopa can be absorbed into the bloodstream) can still vary considerably. The last leg of the journey, in which the drug has to pass from the blood into the brain, is similarly complex but can be optimized with additives such as carbidopa.

Duodopa - a new formulation of an existing drug The drug Duodopa contains levodopa and carbidopa, the same active constituents as Sinemet tablets but now in the form of a gel designed for continuous infusion directly into the duodenum with the objective of smoothing out the rate of absorption of the drug into the bloodstream. The concept of continuous levodopa infusion was developed primarily in Sweden, where trials began in 1990 and considerable ‘history’ is now available.


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The Duodopa System The whole System comprises: - a battery-driven pump and a cassette (reservoir) containing Duodopa gel, which can be carried either fixed to the patient’s waist belt or in a ‘shoulder holster’. The total weight, with a full cassette, is 500g. A full cassette contains the equivalent of 2000mg levodopa which is for most patients enough for one day. The cassette is replaced daily and unused gel is discarded. The pump rate can be adjusted by the patient. - a PEG tube (Percutaneous Endoscopic Gastrostomy) which penetrates the stomach wall and enters the stomach. - a smaller tube which is passed through the PEG into the stomach and from there into the duodenum. The Duodopa rights are held by Solvay Pharma who launched Duodopa in twelve Western EU countries in 2005. The UK had to wait a while longer but are now catching up.

Practical aspects A hospital stay of some 10 days is required for tests to confirm a patient’s suitability for Duodopa, and to complete the installation of the System. The most common complications are associated with the injection tube. With time the injection

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tube may be displaced, either up (ie back into the stomach) or down (into the large bowel). These events will be detected by the patient, who will notice a return of both his Parkinson symptoms and his motor fluctuations. In some patients the position of the tube may need to be corrected several times before it settles down. In many patients, however, the tube stays safely in place for years. Skin irritation or minor infections may occur at the injection site. These can be effectively treated. Many patients find that they can reduce or even completely stop the other Parkinson drugs – dopamine agonists etc – which they were taking before starting Duodopa. The operation is reversible. If desired, the PEG and tubes can be removed at any time and the injection site allowed to heal, without leaving any residual damage.

Costs The costs of the operation and the Duodopa cassettes are high, but these may reduce with increasing demand. The annual cost of the cassettes is believed to be some GBP 25-30k. If any of our readers are on the Duodopa system, would you like to write in and tell us of your experience with it? - Editor

Test setup

Permanent setup using PEG

Oesophagus Stomach PEG

Duodenum

Pump

Cassette with Duodopa gel

Adapted from Solvay Pharma source


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