From Improved Diagnosis to Novel Therapies: Advances in Parkinson's Disease at the Hadassah University Medical Center

Thursday, Mar 15 2012

In the Hadassah University Medical Center's Neurology Department--a referral center for the most complex and challenging neurological conditions--physicians are pioneering treatments and conducting research with revolutionary results that are being adopted throughout the world. Among these are new modalities for Parkinson's disease.

Various Hadassah teams are gaining better insight into the causes of Parkinson's; developing diagnostic tools that will identify the disease at an early stage and predict its course; initiating novel therapeutic modalities aimed at stopping or delaying the disease in its early phase; and mitigating symptoms in Parkinson's advanced phase.

Parkinson's is a neurodegenerative disease, where there is selective degeneration of dopaminergic neurons in a pathway of the brain. Prof. Tamir Ben-Hur, Chair of Hadassah's Department of Neurology, explains that "we partially know what goes wrong, but we do not sufficiently understand the reasons why."

The diagnosis of Parkinson's is based on clinical observation. By the time a diagnosis is made, about 50 percent of the dopamine neurons have already been lost. At this quite advanced stage, Prof. Ben-Hur notes, "we are completely in the dark as to the rate of progression that can be expected in the individual patient."

Principal Parkinson's Research Projects currently in process at Hadassah and planned for the future:

Developing biomarkers for early diagnosis and rate of progression of Parkinson's

Because the degeneration of dopaminergic neurons in Parkinson's is a gradual process, the biomarker approach will enable both an early diagnosis of the disease and the monitoring of novel and existing therapies, such as stem cell implantation.

Dr. Rachel Katz-Brull is currently conducting studies aimed at developing a biomarker that will noninvasively and directly detect the rate of dopamine synthesis in the brain. This biomarker will trace the interior routes of neurochemical transport and metabolism related to dopamine synthesis to reflect intracellular enzymatic activity. The expectation is to develop a new biomarker, a metabolic MRI contrast agent, which will be used to noninvasively quantify dopaminergic damage and repair. "This may revolutionize our ability to diagnose the disease at an early stage, monitor its progression, and evaluate the effect of disease-modifying drugs," says Prof. Ben-Hur. "Moreover," he adds, "this technology may serve as a novel tool for real time metabolic imaging of dopaminergic activities in the brain during motor and mental tasks."

Developing cell-based therapies for Parkinson's and neurodegenerative disorders

The possibility that cell transplantation may replace dying dopaminergic neurons in the brain has attracted much hype and hope, but has been set back by the limited supply of transplantable neurons; however, Prof. Ben-Hur relates, "human embryonic stem cells appear to provide the best potential source of cells for therapy."

Pioneering studies by Prof. Benjamin Reubinoff, head of Hadassah's Human Embryonic Stem Cell Research Center, and Prof. Ben-Hur, have produced a major breakthrough in deriving neurons from human embryonic stem cells and showing their beneficial effects in an animal model of Parkinson's. This research has established the technology of obtaining highly enriched populations of midbrain dopamine neurons.

Early translational pre-clinical studies, unfortunately, failed because of very low survival of the transplanted dopamine neurons in the brain. Prof. Reubinoff's ongoing studies, however, are aimed at identifying the optimal developmental stage for transplanting the cells. Such cells will need to maintain their progenitor phenotype while already being committed to the dopamine fate, and survive the transplantation procedure well without carrying a risk for tumor growth. Prof. Ben-Hur's current studies reveal that, over time, neural stem cells lose the neuroprotective characteristics they need to survive in the brain; yet, they continue to exhibit beneficial therapeutic effects on their surroundings. This "aging" of neural stem cells may be the reason the resident stem cells of the adult brain are unable to promote repair processes or guard against degeneration, and the reason that transplanted stem cells lose their therapeutic properties and fail to survive.

Prof. Ben-Hur's studies aim to identify the cellular and brain environmental factors that may reverse or "rejuvenate" stem cells, as a means of improving both cell transplantation strategies and endogenous repair and protective mechanisms.

Identifying new genes associated with Parkinsonism and shedding light on the mechanisms that cause the disease

Genetic studies have identified several key genes associated with familial forms of Parkinson's disease and there is increasing awareness of the disease's complex polygenic background that contributes to its pathologic processes. It is still particularly unclear, however, Prof. Ben-Hur explains, how seemingly unrelated metabolic dysfunctions all result in Parkinsonian pathology.

Prof. Alexander Lossos and Dr. Or Kakhlon are conducting research aimed at elucidating the pathophysiology of several neurological disorders in which metabolic deficiencies are implicated. They are investigating, in particular, late onset disorders with Parkinsonian symptomatology such as Adult Polyglucosan Body Disease (APBD), Hereditary Spastic Paraplegia (HSP), Spinocerebelar Ataxia, and involuntary movement disorders. Their approach is to conduct genetic screens to identify novel mutated genes affecting disease, to generate cell and animal models of the diseases, and to test various therapeutic approaches for treating these as yet incurable diseases. Their research on glycogen aggregation and mitochondrial dysfunction has resulted in a novel, yet simple approach to treating APBD, which is about to be examined in a clinical trial.

Studying the neural basis of rigidity and patient-tailored optimization of Deep Brain Stimulation therapy

Neuromodulation by Deep Brain Stimulation (DBS) has already revolutionized therapy for patients with advanced Parkinson's disease. Joint studies by Prof. Hagai Bergman and Dr. Zvi Israel now aim to further improve the DBS procedure by developing a closed loop system that will sense and respond to abnormal brain activity in real time. Further down the road, smart closed loop systems will rely on adaptive Brain Computer Interfaces that will enable the brain and the machine to interact simultaneously. The brain will learn to respond rapidly to computer algorithms while the computer will simultaneously learn to adaptively modulate its computation to optimize performance.

Eventually, Prof. Ben-Hur explains, these systems--as well as the high resolution electrophysiological mapping of brain activity at the spatial, temporal, and frequency modalities which Dr. Shahar Arzy is working on—will make it possible to identify specific neural signatures of abnormal motor, cognitive, and behavioral symptoms—such as rigidity. To shed more light on the pathophysiology of rigidity, Dr. David Arkadir plans to record electrical activity in multiple muscles simultaneously while patients are performing natural, daily motor tasks. Identification of the complex neural network producing rigidity at the periphery, and correlating it to patterns of brain activity recorded by DBS systems, Prof. Ben-Hur says, "may have enormous implications for the fine tuning of neuromodulatory therapy."

An electromyogram (EMG) measures the electrical activity of muscles. When the EMG signal is highly correlated with rigidity, a closed loop DBS device will frequently adapt the stimulation parameters. Any increased rigidity recorded by the EMG will cause the device to change the stimulation amplitude to achieve symptomatic relief. "We hope and believe this will greatly improve the quality of life for future patients," concludes Prof. Ben-Hur, "by better controlling Parkinson's symptoms and avoiding the disabling hour-by-hour fluctuations."


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