Dalhousie University Dalhousie University Faculty of Medicine Department of Pharmacology
   
 



Faculty

Harold Robertson, PhD

Professor Emeritus

Professor of Medicine (Neurology) and Psychiatry
Adjunct Professor, Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island

BA, MSc (Western Ontario), PhD (Cantab)

Keywords

Parkinson's disease, neural transplantation, olfaction, neurogenesis, dopamine, sonic hedgehog, c-fos, immediate early genes

Current Research

I am interested in the treatment of neurological and psychiatric disorders. Currently I focus on the treatment of Parkinson's disease and work closely with Ivar Mendez and others in the Brain Repair Centre Halifax. Parkinson's disease (PD) is a progressive neurodegenerative disorder of the central nervous system (CNS) that affects about 1% of those over 65 years old. Although other systems are also affected, the main underlying pathology is a progressive loss of dopaminergic neurons in the ventral mesencephalon (VM), particularly the cells of the substantia nigra pars compacta (SNc). This leads to a loss of dopaminergic innervation of the striatum, especially the putamen and as the disease progresses, patients experience trembling, muscle rigidity, difficulty walking, and problems with balance and coordination. The most effective symptomatic treatment of PD includes the administration of the DA precursor L-dopa. While this pharmacological approach is highly effective in the initial stages of the disease, chronic therapy is complicated with the development of dyskinesia (abnormal uncontrolled movements, usually of head and arms) and non-motor symptoms such as dementia. In addition, pharmacological treatment with dopaminergic drugs does not slow progression of the disease nor alleviate non-motor symptoms such as dementia. There is therefore a need for the development of new treatments for Parkinsons disease.

The main research projects in my laboratory are:
Project I: NEURAL TRANSPLANTATION IN THE TREATMENT OF PATIENTS WITH PARKINSON'S DISEASE.
This is a large international collaborative project with Roger Barker (Cambridge) and Anders Björklund (Lund) as Principal Investigators. Ivar Mendez is the Principal Investigator in Halifax. Collaborators include Steve Dunnett, Huw Morris, Anne Rosser, Nick Allen (Cardiff, Wales), Paola Piccini, Niall Quinn, Patricia Limousin, David Brooks (London, UK), Anders Björklund, Olle Lindvall, Hakan Widner, Patrick Brundin, Deniz Kirik (Lund, Sweden), Pierre Cesaro, Stephane Palfi (Paris, France), Guido Nikkhah, Christian Winkler (Freiburg, Germany); Stan Fahn, David Eidelberg, Thomas Freedman (USA), Ivar Mendez, Harold Robertson (Halifax, Canada).
Funding: Framework 7, European Union

This object of this project is to improve effectiveness and reliability of neural transplantation as a treatment for Parkinson's disease (see Science 16 OCTOBER 2009 VOL 326 www.sciencemag.org). This international collaborative group has been working since Spring of 2006 to determine the reasons for the poor outcome in the previous trials of neural transplantation for the treatment of Parkinson's disease. The group has now received a grant of 12 million Euros for a two-phase clinical trial; other funding will be applied for in future. Among the changes that will be made in the study will be recruitment of subjects with earlier stage Parkinson's disease. Early diagnosis of Parkinson's disease will be crucial for these trials. This led us to a search for ways to detect Parkinsons disease in early stages.

PROJECT II. DIAGNOSIS OF PRECLINICAL PARKINSON'S DISEASE.
PI: H.A. Robertson, PhD
Collaborators: Tyler Rolheiser, PhD, Ron Leslie, PhD, Kim Good, PhD, Kerrie Schoffer, MD, Roger McKelvey, MD, Naeem Khan, MD, John Fisk, PhD, Ben Rusak, PhD
Funding: Parkinson Society Canada, Department of Psychiatry Research Fund, CIHR

As with many diseases and disorders, early diagnosis of Parkinson's disease is critical to effective treatment. This may not be true for symptomatic treatments like L-Dopa but it is increasingly obvious that for neurorestorative treatments like neural transplantation or deep brain stimulation (DBS), early diagnosis and treatment are desirable. Interventions that halt or reverse the progression of Parkinson's disease (PD) remain a crucial unmet medical need. Current therapies (drugs, cell transplantation, deep brain stimulation) for PD are only applied after clinical diagnosis, when damage is probably irreparable. Therapies that halt progression are urgently required, but equally important is the need for biomarkers for preclinical stages of PD, to enable effective testing of therapies directed at halting progression. It is clear that preclinical PD antedates diagnosis by 4-6 years, involving pathological changes to brain anterior olfactory structures; most patients with PD (about 90%) have olfactory deficits at the earliest clinical stages of the disorder. As olfactory dysfunction is probably profound before it is evident, subtle changes may occur a decade or more before diagnosis. So close is the relationship between olfaction and PD that it has been argued that an absence of changes in the sense of smell is good reason to question a diagnosis of PD. Recent studies have suggested that olfactory testing, in the presence of other indicators of risk, might identify subjects that have a propensity to develop PD. Diffusion weighted magnetic resonance imaging (DWI, similar to DTI), which provides a measure the integrity of neural tissue, has confirmed a disruption of the olfactory tract in early stages of the disorder , a finding congruent with the known neuropathological changes in anterior olfactory structures. Clinical diagnosis only detects PD when about 80% of the dopamine in the striatum is lost and 50-70% of the dopamine neurons in the substantia nigra pars compacta have died. Damage to the system at this point may be largely irreparable. Consequently, neuroprotective strategies such as rasagiline treatment or neurorestorative strategies such as neural transplantation or deep brain stimulation (DBS) are generally only applied late in the course of the disease. This is now recognized in peer-reviewed clinical trials currently recruiting early stage PD for DBS and neural transplantation. Preclinical diagnosis may improve the treatment of PD whether treatment is neuroprotective or neurorestorative. The goal of this research project is to find ways of diagnosing PD in preclinical stages, before the damage is extensive. Possible ways of diagnosing preclinical PD include studying changes in olfactory function and in imaging that might occur many years before clinical presentation. Olfactory dysfunction especially if combined with imaging techniques, might be a useful diagnostic tool. We propose using olfactory testing combined with diffusion tensor imaging (DTI) of a) the olfactory tract and bulb and b) the caudal substantia nigra to determine whether such testing can detect subjects in the preclinical stages of PD. While both olfactory dysfunction and imaging techniques have been studied previously, only one study has examined olfaction and imaging (SPECT, not DTI) in the same subjects; the Ponsen study is also the only one to attempt to identify subjects with preclinical PD. Our study will for the first time examine olfaction and DTI in the same subjects and screen for preclinical PD. Objective 1 will examine olfaction and DTI in newly diagnosed PD subjects and will correlate olfactory function, determined using the University of Pennsylvania Smell Identification Test (UPSIT), with DTI of the olfactory tract and the caudal substantia nigra. Study 2 will use the UPSIT to screen an at risk population for subjects with possible preclinical PD and determine whether subjects with olfactory dysfunction have DTI changes characteristic of PD.
So how will that make a difference?
We are already pretty sure that early diagnosis will be important for neurorestorative treatments like neural transplantation and DBS. Although we have no drugs yet that I believe work effectively to halt or reverse the progression of Parkinson's disease, I believe that such drugs may be on the way. It is claimed that rasagiline for example might be such a drug. Other possible drugs to halt progression might be substances like ginseng. In future, GP's could administer the olfaction test at very low cost and then request a MRI for follow-up. In developing substances that are neuroprotective, early diagnosis will be crucial in allowing us to test drugs that halt progression early.

Contact Information

Brain Repair Centre
Dalhousie University
Life Sciences Research Institute
1348 Summer Street, North Tower
Halifax, NS B3H 4R2
Canada

Phone: (902) 494-4010

Fax: (902) 494-4013

Email: har1@dal.ca