Fall 2008 - Cleveland Clinic Lerner Research Institute

More documents

Recommendations

Info

Lerner research instituteThe Self-Repairing BrainMore than 15 years ago, Bruce Trapp, PhD, Chair, Neurosciences, created an approach to studying multiple sclerosis(MS). Rather than being confined to investigating the disease in animals, Dr. Trapp wanted to see how MS actuallydevelops and progresses in the human brain. He started an innovative autopsy program to collect the brains andcentral nervous systems of multiple sclerosis patients after they die.“The rapid autopsy program allowed us to study MS by studyingthe disease itself, not a ‘near second’ in animals. This is muchmore relevant than investigating aspects of the disease in animalmodels,” he said. “In essence, what’s happening in the brainsof MS patients is the only thing that matters.”The approach yielded surprising insights that at the timequestioned conventional wisdom about the cause of permanentneurological disability in MS patients, how neuronal tissue isdamaged in MS brains, and whether or not brain cells andtissues can regenerate.White matter neurons are increased in a subset ofchronic multiple sclerosis lesions. Image shows a highmagnification view of post mortem tissue from amultiple sclerosis patient stained with an antibodythat recognizes neurons (microtubule associatedprotein 2, MAP2). The green line delimits a lesionwith increased neurons (top) from the surrounding,non-lesion white matter (bottom). (Photo: BruceTrapp, PhD, Chair, Neurosciences)“Some of our initialobservations were controversialat the time, but they’ve becomeaccepted by neurologists. Ourwork really created a paradigmshift regarding the pathogenesisof permanent neurologicaldisability, tissue damage andregeneration in MS brains,”Dr. Trapp said.Multiple sclerosis is aninflammatory disease thatdamages the insulation (myelin)that surrounds the nerve fibersof the central nervous systemand is the most common causeof neurologic disability in youngadults. Most patients have progressive neurologic deteriorationthat was thought to be caused by the loss of myelin. The axons,or nerve fibers that transmit electrical impulses, were thoughtto be spared this destructive process.A decade ago, Dr. Trapp examined tissues donated throughthe rapid autopsy program and found that a consistent featureof multiple sclerosis lesions was axons that had been cut (ortransected). Additionally, the frequency of these transected axonsrelated to the degree of inflammation within the lesion.“We were able to show initially that transected axons are commonin the lesions of multiple sclerosis, and eventually established arelationship between axonal loss and neurodegeneration withirreversible neurologic impairment in individuals with MS,”Dr. Trapp said. “This was an understanding of the diseaseprocess that contributed to new research in the area.”Other breakthroughs would emerge from the rapid autopsyprogram. For example, in addition to myelin and axons,inflammation associated with MS also destroys cells calledoligodendrocytes that produce myelin. Most multiple sclerosislesions typically do not regenerate myelin, a process calledremyelination. To remyelinate, the MS brain must generate newoligodendrocytes. Dr. Trapp, in collaboration with Case WesternReserve University and the University of Toledo, recently received$3 million by the Ohio Third Frontier Commission to develop smallmolecules that can enhance repair of the brain in MS, with thegoal of not only delaying the progression of disability but reversingit. The leading compounds will be chemically optimized to obtaincompounds suitable for licensing by major pharmaceuticalcompanies as candidate drugs for future clinical trials in patients.Dr. Trapp found that cells capable of producing myelin — the“premyelinating” oligodendrocytes — are present in chroniclesions of multiple sclerosis. “Our expanding knowledge of thecellular interactions between premyelinating oligodendrocytes,axons and the microenvironment of lesions may lead to effectivestrategies for enhancing remyelination.“For example, a possible therapeutic strategy could perhaps beachieved by transplanting oligodendrocyte-producing cells intothe lesions or developing drugs that will promote an MS brain torepair itself,” Dr. Trapp said.More recently, Dr. Trapp’s research team made an unexpectedand exciting finding: the adult human brain can replace neuronsthat were thought to be destroyed by multiple sclerosis.“Proving that the adult human brain produces new neurons isa tough egg to crack because we cannot perform the definitiveexperiments of injecting radioisotopes in the living patients,” hesaid. “The objective, therefore, was to identify areas of the MSbrain which had increased densities of neurons when comparedto normal brains.”8
Focusing on the patients of tomorrow FALL 2008Because it’s difficult to identify increased neuron density in thegray matter of brains, Dr. Trapp’s study team took a closer look atthe relatively low-density neurons that control blood flow in whitebrain matter. They found that these neurons are destroyed as themyelin is destroyed, forming the white-matter lesions typical ofMS brains. Surprisingly, in tissue sections from some older andmore chronic MS lesions, the concentrations of “stained” neuronswere so dense that they were visible to the naked eye. And these“new neurons” shared characteristics with the mature whitematterneurons in normal brains.“These observations beg the question, ‘How did the new neuronsget there?’ We know the normal adult brain can generate newneurons in certain regions. But it has been controversial andvery difficult to prove that neurogenesis [regeneration of neuronaltissue] occurs in the adult brain in response to neuronaldestruction,” Dr. Trapp said.“Some researchers believe that these new concentrations ofneurons might be caused by migration of mature neuronal cells tothe lesions. But our observations suggest new neuron production,”he said. “For example, we also found a significant increasein immature neurons in the same regions that had increasednumbers of mature neurons. Demyelinated white matter couldcreate a great hospitable environment for neurogenesis.“Our research provides a positive message for MS patients,” saidDr. Trapp. The multiple sclerosis brain never gives up trying toreplace the myelin and neurons that are destroyed by the disease.The findings could lead other investigators to search for signs ofneurogenesis in other brain diseases. Dr. Trapp and his colleaguesare now looking for molecules that could regulate neurogenesis inthe MS brain. In addition, Dr. Trapp’s research team just receiveda $1.5 million grant from the National Institutes of Health toinvestigate the cause of cognitive dysfunction in MS patients.Tracking Disappearing Gray Matter in MS PatientsIt’s known that the brain wastes away slowly as multiple sclerosis progresses, just as thesymptoms become more pronounced over time. It seemed natural to conclude that thewhole brain would atrophy during the disease.But new evidence is showing that this might not be the case.Elizabeth Fisher, PhDThe human brain is composed of twobasic components: gray matter (whichconsists mainly of the nerve cellbodies that generate nerve impulses)and white matter (which consists of nerve cell “wires,” calledaxons, that are covered by a sheath made of myelin and thatcarry nerve impulses).Think of a computer network: regions of gray matter in the brainand nervous system are like computers, and the white matter isthe network that links them. This network allows gray matter toshare and process information and stimuli and to generate nerveimpulses, which are also transmitted by white matter.Throughout the progression of multiple sclerosis, the brain wastesaway an average of 0.5% to 1% yearly. Both white and graymatter seem to diminish equally during the early stages of thedisease, meaning the “whole” brain is involved.But brain imaging of MS patients conducted during the last fouryears by Elizabeth Fisher, PhD, Biomedical Engineering, foundthat gray matter starts to waste away at a faster rate than whitematter as the disease progresses. Her research is in collaborationwith Richard Rudick, MD, Vice Chair of Research at ClevelandClinic’s Neurological Institute and Director of its Mellen Centerfor Multiple Sclerosis Treatment and Research.“We found that atrophy of gray matter accounted entirely for theincreasing rate of atrophy as the disease advanced,” Dr. Fishersaid. “This is the first study to demonstrate that gray matteratrophy speeds up as multiple sclerosis progresses. Initially, whiteand gray matter are affected similarly, but over time atrophy ofthe brain is dominated by the wasting away of gray matter.”If a multiple sclerosis patient’s brain is wasting away, does itreally matter which components are affected the most? Definitely.“Gray matter makes up more than half of the functioning portionof the brain, and tissue damage in gray matter is a large part ofthe overall burden of multiple sclerosis,” Dr. Fisher said. “But,unlike damage in white matter, we can’t see it. ConventionalMRI [magnetic resonance imaging] techniques are not sensitiveto lesions that develop in gray matter, so gray matter atrophymeasurement is one of the only available methods to monitorgray matter tissue damage in multiple sclerosis patients usingstandard MRIs.“Gray matter atrophy may be a clinically relevant way to measuremultiple sclerosis progression,” she said. “Measuring atrophy isimportant because we don’t know yet how and why the brainwastes away at different rates. It can also be useful to test newtreatments — to show whether or not new therapies can actuallyprotect the brain from wasting away.”9
Page 5: Focusing on the patients of tomorro
Page 11 and 12: Focusing on the patients of tomorro
Page 13: Focusing on the patients of tomorro
Page 16 and 17: Lerner research instituteA Bridge t
Page 23 and 24: The Future of Medicine Unfolds Dail

Fall 2008 - Cleveland Clinic Lerner Research Institute

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?