Dalhousie University Dalhousie University Faculty of Medicine Department of Pharmacology


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), FRSC

Current Research

Research interests

As professor emeritus, I dont use the term retired to describe my situation. I prefer to think of it as on a sabbatical without term. I no longer have my own laboratory so I do research by collaboration with colleagues in the Departments of Psychiatry and Medicine-Neurology. I still hold a CIHR operating grant as PI and do mainly clinically-focused research using the expertise of my colleagues and Capital District Health Authoritys (CDHA) equipment for magnetic resonance imaging. I also do research through collaboration with a biotechnology company, Neurodyn Inc, where I have several projects related to my major research interest, the treatment of neurological disorders such as Parkinsons disease (PD), Alzheimers disease (AD), amyotrophic lateral sclerosis (ALS) and Huntingtons disease (HD).

Research at Capital District Health Authority and Dalhousie University

Neurological disorders are progressive and all involve protein misfolding and loss of neurons in specific parts of the brain and spinal cord. With the exception of HD, which is inherited in an autosomal dominant fashion with complete penetrance, they are largely idiopathic but all have some familial forms. Neurological disorders, except for HD, are also hard to diagnose because irreparable neuron loss occurs before symptoms appear. For example, Parkinsons disease (PD) is only clinically diagnosed when motor systems are involved. By this time, 80% of the dopamine in the striatum is lost and treatment difficult. Replacement of lost neurons by neuronal transplantation for the treatment of PD is one of the only options left at this point. I remain part of the group led by Dr. Ivar Mendez, now at the University of Saskatchewan and Ole Isacson at Harvard Medical School who are preparing for clinical trials of cell replacement therapy for PD (1,2).

In reviewing the results of all neural transplantation procedures, it was concluded that patients with mild to moderate PD benefited from the transplantation procedure while those older patients benefited least (3). This implied that early diagnosis could be important for successful treatment so we began studies funded by the Parkinson Society Canada and the Canadian Institutes of Health Research to search for better diagnostic tools. It has recently been recognized that several biomarkers precede the motor symptoms in PD. These include loss of the sense of smell, constipation and sleep disturbances. Loss of sense of smell in particular occurs in almost all PD patients but also in AD patients (sensitive but not specific). Smell testing was easy and inexpensive but we needed a secondary screen to confirm PD. In the past decade, the work of Braak and others has suggested that deposition of Lewy bodies and neurites occurs first not in the substantia nigra but in the olfactory bulb. We confirmed that PD patients in the earliest stages have changes in diffusion tensor imaging in olfactory bulb (decreased fractional anisotropy or FA) and now we are screening 1,200 subjects at risk for PD using smell testing (4). Subjects with decreased sense of smell will be scanned using MRI to determine whether we can use this as a tool to detect early (preclinical) stages of PD. This study will be completed in 2017-18. In the meanwhile we are searching for other biomarkers for PD and other neurological disorders.

1. Mendez, I., Vinuela, A., Astradsson, A., Mukhida, K., Hallett, P., Robertson, H., Tierney, T., Holness, R., Dagher, A., Trojanowski, J.Q., et al. (2008). Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years. Nat Med 14, 507-509.

2. Hallett, P.J., Cooper, O., Sadi, D., Robertson, H., Mendez, I., and Isacson, O. (2014). Long-term health of dopaminergic neuron transplants in Parkinson's disease patients. Cell Rep 7, 1755-1761.

3. Barker, R.A., Barrett, J., Mason, S.L., and Bjorklund, A. (2013). Fetal dopaminergic transplantation trials and the future of neural grafting in Parkinson's disease. Lancet Neurol 12, 84-91.

4. Braak, H., Bohl, J.R., Muller, C.M., Rub, U., de Vos, R.A., and Del Tredici, K. (2006). Stanley Fahn Lecture 2005: The staging procedure for the inclusion body pathology associated with sporadic Parkinson's disease reconsidered. Mov Disord 21, 2042-2051.

5. Rolheiser, T.M., Fulton, H.G., Good, K.P., Fisk, J.D., McKelvey, J.R., Scherfler, C., Khan, N.M., Leslie, R.A., and Robertson, H.A. (2011). Diffusion tensor imaging and olfactory identification testing in early-stage Parkinson's disease. J Neurol 258, 1254-1260.

Research at Neurodyn Inc (in collaboration with Drs. Jackalina Van Kampen, Denis G. Kay)

1) A new more valid and comprehensive rat model for Parkinsons disease.

Currently there is no animal model for Parkinsons disease (PD) capable of replicating all of the features of human idiopathic PD. Prodromal changes, such as olfaction, are not generally observed. Changes in TH and other dopamine markers do not always occur in transgenic mouse models, while aggregation of a-synuclein almost never is seen in toxin models. Cognitive deficits are rarely observed and, when they are, occur early and are not associated with histopathology typical of PD dementia. We believe that we have developed a more comprehensive rodent model for Parkinsons disease (the BSSG model). This model represents a major step forward in modeling Parkinsons disease in the rat. Laboratories at the University of Maryland, the University of British Columbia and the Atlantic Veterinary College in Charlottetown, Prince Edward Island, Canada have repeated preliminary work on the model but we would like to see the model widely tested, replicated and verified. To this end we have discussed research projects that would accomplish this while also extending our understanding of this model and its applicability to PD research. Importantly, the model is based on a neurotoxin, ²-sitosterol ²-d-glucoside (BSSG), that is probably at least partly responsible for the ALS-Parkinsonism dementia complex (ALS-PDC) of Guam and thus, may produce the symptoms reminiscent of Parkinsons disease with dementia in humans. In rats fed BSSG, it produces a progressive model of Parkinsons disease, developing slowly over time, with the majority of pathological hallmarks only beginning to appear long after BSSG exposure is terminated. This promises to make it a useful model of Parkinsons disease progression. Like idiopathic Parkinsons disease, the model first exhibits non-motor symptoms (hyposmia), then asymmetrical motor symptoms and histopathology (as in human Hoehn and Yahr stage 1). This is followed by increased inflammation and deposition of alpha-synuclein that displays a region-to-region spread over time (olfactory bulb to substantia nigra to hippocampus and cortex). Most animal models for Parkinsons disease do not exhibit alpha-synuclein deposition. As the phenotype evolves, both sides of the body are affected, making this model a potentially useful model for studying the development of dyskinesias. Finally, animals exhibit late-stage cognitive deficits, coincident with the spread of pathology to hippocampal and cortical regions, making this a potential model for studying dementia in Parkinsons disease.

The progressive nature of this model, as well as the recapitulation of multiple features characteristic of PD, will be critical for screening candidates for neuroprotection. In addition, once prodromal biomarkers become effective tools for early diagnosis of PD, this model will be useful for screening such neuroprotectants at early, pre-motor, time points. In addition, this model is also potentially useful for late-stage issues characteristic of PD, such as PD dementia and, possibly, dyskinesias.

2) Memogain®: A new pro-drug for the treatment of cognitive dysfunction Memogain® is a derivative of galantamine, one of 4 drugs approved in Canada, the US, Europe and Asia for treatment of mild to moderate Alzheimers disease. Memogain, a pharmacologically inactive pro-drug of the marketed Alzheimer drug galantamine shows improved brain penetration and is cleaved in the brain to active galantamine. The drug then repeatedly interacts with a7 nicotinic acetylcholine receptors (main target) and with cholinesterases (other targets) in the brain, before the equilibrium brain-to-blood ratio reaches a steady state and galantamine levels in the brain decline through efflux to plasma followed by metabolic breakdown. Neurodyn Inc now owns memogain® and has just successfully completed phase 1 clinical trial at the Centre for Human Drug Research in Leiden, The Netherlands. Phase 2 clinical trials will begin in 2014. Potential disease targets are not restricted to AD but may also include dementia associated with PD, HD and schizophrenia.

Collaborations: I have collaborations with scientists in the UK, Sweden, the USA, the Netherlands and, of course, Canada.

Contact Information

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

Phone: (902) 494-4010

Fax: (902) 494-4013

Email: har1@dal.ca