Research file
Study: Freezing of gait (walking movement) in Parkinsons disease may be a problem of space perception.

Researcher:Chad A. Lebold, master of science graduate in Wilfrid LaurierUniversitys department of kinesiology and physical education.

Studyfocus: Lebold designed experiments to determine the underlying causesof motor freezing episodes experienced by some Parkinsons diseasepatients, along with the cues that could lead to an improved quality oflife.

His research project was called: Freezing of Gait in Parkinsons Disease: A Perceptual Cause for a Motor Impairment?

Ourgoal was to challenge current beliefs that freezing is a motorimpairment, instead suggesting that patients are having problems withspace perception because of sensory-perceptual issues that interferewith movement, Lebold said.

Lebold examined the gait of threedifferent groups of subjects those with Parkinsons disease andfreezing episodes, those with Parkinsons disease but no freezing, anda control group) as they walked toward doorways of varying widths. Thegoal was to determine how their behaviour was affected by doorway size.

Parkinsons patients who experience freezing episodes showedthe greatest change in gait as they approached the narrow doorway, withmore gait variability, shorter steps and widening their base ofsupport.

Combining visual feedback aids in perceptuallydemanding conditions gave us a greater understanding of the deficitsassociated with gait in Parkinsons disease, Lebold said.

Wewere surprised to find that even Parkinsons patients who do notexperience freezing were influenced by the perception of a narrowdoorway and exhibited behaviours similar to those with freezing.

Thestudy emphasized the importance of thinking outside the box andquestioning what the underlying mechanism for clinical motorimpairments might be, said Quincy Almeida, study co-author and anassociate professor of kinesiology and physical education, as well asdirector of the Sun Life Financial Movement Disorders Research andRehabilitation Centre.

The results of this research hopefullywill provide a greater understanding of one of the most debilitatingdisorders associated with Parkinsons disease, Lebold said.

Thefindings could also impact the direction of future research, hopefullyleading to successful intervention and prevention strategies for gaitdisorders.

Future research will determine the specific aspects of the doorways that affect subjects walking patterns.

A major discovery is challenging accepted thinking about amyloids thefibrous protein deposits associated with diseases such as Alzheimer'sand Parkinson's and may open up a potential new area for therapeutics.

Itwas believed that amyloid fibrils - rope-like structures made up ofproteins sometimes known as fibres - are inert, but that there may betoxic phases during their formation which can damage cells and causedisease.

But in a paper published today [04 December 2009] inthe Journal of Biological Chemistry, scientists at the University ofLeeds have shown that amyloid fibres are in fact toxic - and that theshorter the fibre, the more toxic it becomes.

"This is a majorstep forward in our understanding of amyloid fibrils which play a rolein such a large number of diseases," said Professor Sheena Radford ofthe Astbury Centre for Structural Molecular Biology and the Faculty ofBiological Sciences.

"We've revisited an old suspect with verysurprising results. Whilst we've only looked in detail at three of the30 or so proteins that form amyloid in human disease, our results showthat the fibres they produce are indeed toxic to cells especially whenthey are fragmented into shorter fibres. "

Amyloid deposits canaccumulate at many different sites in the body or can remain localisedto one particular organ or tissue, causing a range of differentdiseases. Amyloid deposits can be seen in the brain, in diseases suchas Parkinson's and Alzheimer's, whereas in otheramyloid diseases deposits can be found elsewhere in the body, in thejoints, liver and many other organs. Amyloid deposits are also closelylinked to the development of Type II diabetes.

Professor Radfordsaid: "Problems in the self-assembly process that results in theformation of amyloid are a natural consequence of longer life. In fact85 per cent of all cases of disease caused by amyloid deposits are seenin those over the age of sixty or so."

The study was funded bythe Wellcome Trust and the Biotechnology and Biological SciencesResearch Council (BBSRC), supporting a team that included both cellbiologists and biophysicists.

The next stage of this work isto look at a greater number of proteins that form amyloid fibres inorder to consolidate these findings, says co-author and cell biologistDr Eric Hewitt. "What we've discovered is fundamental and offers awhole new area for those working on therapeutics in this area. Weanticipate that when we look at amyloid fibres formed from otherproteins, they may well follow the same rules."

The team also hopes to discover why the shorter amyloid fibres are more toxic that their longer counterparts.

"Itmay be that because they're smaller it's easier for them to infiltratecells," says Dr Hewitt. "We've observed them killing cells, but we'renot sure yet exactly how they do it. Nor do we know whether these shortfibres form naturally when amyloid fibres assemble or whether somemolecular process makes them disassemble or fragment into shorterfibres.These are our next big challenges."

US researchers report finding that ghrelin, a hormone produced in thestomach that regulates appetite and how the body deposits fat, may beused to boost resistance to or slow the development of Parkinson'sdisease.

The study is the work of Dr Tamas Horvath, chair andprofessor of comparative medicine and professor of neurobiology andobstetrics and gynecology at the Yale University School of Medicine,New Haven, Connecticut, and colleagues and was published earlier thismonth in The Journal of Neuroscience.

Parkinson's disease is aneurodegenerative disorder where dopamine neurons in an area of themidbrain known as the substantia nigra, which is responsible fordopamine production, start to die off.

As less dopamine isproduced, the symptoms become more severe, so that eventually peoplewith the disease have difficulty walking, have restricted and delayedmovements, get tremors in their head and limbs, lose their appetite,can't eat properly, and have periods of immobility or "freezing".

Wealready know that ghrelin targets the hypothalamus and affectsappetite, food intake and how the body deposits fat. The authors wrotethat ghrelin receptors at sites outside of the hypothalamus also"promote circuit activity associated with learning and memory, andreward seeking behavior". And recent human studies have shown that bodymass index (BMI), stored fat and diabetes are linked to Parkinson'sdisease.

In this study, Horvath and colleagues discovered that ghrelin also protects the neurons that make dopamine.

"Wealso found that, in addition to its influence on appetite, ghrelin isresponsible for direct activation of the brain's dopamine cells," saidHorvath. He explained that because the hormone is made in the stomach,it circulates normally in the bloodstream, "so it could easily be usedto boost resistance to Parkinson's or it could be used to slow thedevelopment of the disease".

For the study, which was supportedby the Michael J Fox Foundation for Parkinson's Research, Horvath andcolleagues gave one group of mice extra ghrelin, and while anothergroup were genetically engineered to lack the hormone and its receptor.

When compared to a group of control mice, the mice that had impaired ghrelin action in the brain had more dopamine loss.

Theauthors explained that the mice that were given extra ghrelin lostfewer substantia nigra pars compacta dopamine cells and showed"restricted striatal dopamine loss", while the mice that weregenetically engineered to lack the hormone and its receptors lost moresubstantia nigra pars compacta dopamine cells and showed "loweredstriatal dopamine levels". The effect in the genetically engineeredmice was reversed when they switched the ghrelin receptor on.

Theyconcluded that their study supports the idea that ghrelin could be anew therapeutic strategy to fight neurodegeneration, loss of appetiteand body weight linked with Parkinson's disease.

Horvath saidthey could see these results being applicable to humans because theghrelin system is preserved through various species.

Theresearchers are now planning to find out how ghrelin levels differbetween healthy people and people with Parkinsons disease, and whetherchanges in ghrelin levels might serve as a biomarker of diseasesusceptibility and development.