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The role of neurotensin (NT) in a putative model of tardive dyskinesia (TD) was examined in the rat. When administered directly into the ventrolateral striatum of neuroleptic-naive animals, NT (2.5 micrograms/side) elicited vacuous... more
The role of neurotensin (NT) in a putative model of tardive dyskinesia (TD) was examined in the rat. When administered directly into the ventrolateral striatum of neuroleptic-naive animals, NT (2.5 micrograms/side) elicited vacuous chewing movements. This response was not seen following administration of NT into other striatal regions or the substantia nigra and was suppressed by the NT antagonist SR 48692 (100 micrograms/kg i.p.). Vacuous chewing movements were also seen following chronic administration of fluphenazine decanoate. These movements were likewise suppressed by SR 48692 (10-100 micrograms/kg i.p.), which failed to affect other behavioural responses and was without effect in neuroleptic-naive animals. Our data suggest that increased levels of endogenous NT within the ventrolateral striatum may play a critical role in the development of TD following chronic neuroleptic administration and that NT antagonists may be beneficial for the treatment of this disorder.
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Symptomatic management of Parkinson’s disease (PD) is complex and many symptoms, especially non-motor symptoms, are not effectively addressed with current medications. In the US, cannabis has become more widely available for medical and... more
Symptomatic management of Parkinson’s disease (PD) is complex and many symptoms, especially non-motor symptoms, are not effectively addressed with current medications. In the US, cannabis has become more widely available for medical and recreational use, permitting those in the PD community to try alternative means of symptom control. However, little is known about the attitudes towards, and experiences with, cannabis use among those living with PD. To address this shortcoming, we distributed an anonymous survey to 7,607 people with PD in January 2020 and received 1,339 responses (17.6%). 1,064 complete responses were available for analysis. Respondents represented 49 states with a mean age of 71.2 years (± 8.3) and mean PD duration of 7.4 years (± 6.2). About a quarter of respondents (24.5%) reported cannabis use within the previous six months. Age and gender were found to be predictors of cannabis use in this sample (Age OR = 0.95, 95% CI 0.93 to 0.97; Male OR = 1.44, 95% CI 1.03 ...
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Significant insights have been gained into the neural mechanisms of acute placebo responses. However, little is known about the mechanisms of long-term placebo responses, such as those seen in clinical trials, or the interactions between... more
Significant insights have been gained into the neural mechanisms of acute placebo responses. However, little is known about the mechanisms of long-term placebo responses, such as those seen in clinical trials, or the interactions between these mechanisms and brain disease. We examined morphological brain correlates of placebo responses in a randomized clinical trial of the liberation procedure, a controversial endovascular treatment for multiple sclerosis (MS). Patients were randomized to receive either balloon or sham extracranial venoplasty and followed for 48 weeks. The trial did not support therapeutic efficacy of venoplasty, but a subset of both venoplasty and sham patients reported a transient improvement in health-related quality of life, indicating a placebo response. Graph theoretical analysis of cortical thickness (CT) covariance showed that placebo non-responders had a more homogenous regional CT pattern with denser clustering and a more small-world-like architecture. In ...
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Markers of neuroinflammation are increased in some patients with LRRK2 Parkinson's disease compared with individuals with idiopathic Parkinson's disease, suggesting possible differences in disease pathogenesis. Previous PET... more
Markers of neuroinflammation are increased in some patients with LRRK2 Parkinson's disease compared with individuals with idiopathic Parkinson's disease, suggesting possible differences in disease pathogenesis. Previous PET studies have suggested amplified dopamine turnover and preserved serotonergic innervation in LRRK2 mutation carriers. We postulated that patients with LRRK2 mutations might show abnormalities of central cholinergic activity, even before the diagnosis of Parkinson's disease. Between June, 2009, and December, 2015, we recruited participants from four movement disorder clinics in Canada, Norway, and the USA. Patients with Parkinson's disease were diagnosed by movement disorder neurologists on the basis of the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. We used the PET tracer N-C-methyl-piperidin-4-yl propionate to scan for acetylcholinesterase activity. The primary out...
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Functional imaging may be useful for both the early diagnosis as well as preclinical detection of neurodegenerative disease. Additionally, while structural imaging has traditionally been regarded as a tool to exclude alternate diagnoses,... more
Functional imaging may be useful for both the early diagnosis as well as preclinical detection of neurodegenerative disease. Additionally, while structural imaging has traditionally been regarded as a tool to exclude alternate diagnoses, recent advances in magnetic resonance show promise for greater diagnostic specificity. The role of MR and radionuclide imaging in early diagnosis and preclinical detection of dementia and parkinsonism are reviewed here.
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To determine the impact of age-related decline in dopamine transporter (DAT) expression on motor function in the elderly. About 33 normal individuals of a wide age range were scanned with PET employing d-threo-[(11)C]-methylphenidate (MP,... more
To determine the impact of age-related decline in dopamine transporter (DAT) expression on motor function in the elderly. About 33 normal individuals of a wide age range were scanned with PET employing d-threo-[(11)C]-methylphenidate (MP, a marker of DAT) and [(11)C]-dihydrotetrabenazine (DTBZ, that binds to the vesicular monoamine transporter Type 2). Motor function was assessed using the Purdue Pegboard Test (PPB). We analyzed the relationship between [(11)C]-MP and motor performance. Age ranged from 27- to 77-year old (mean +/- SD, 54.75 +/- 14.14). There was no age-related decline in binding potentials (BP) for [(11)C]-DTBZ. In contrast, [(11)C]-MP BP was inversely related to age in all striatal regions analyzed (caudate: reduction of 11.2% per decade, P < 0.0001, r = -0.86; putamen: reduction of 10.5% per decade, P < 0.0001, r = -0.80). A differential effect of [(11)C]-MP on PPB could be observed according to age group. There was a positive relation between the PPB and [(11)C]-MP in young individuals (coefficient = 13.56), whereas in individuals greater than 57 years this relationship was negative (coefficient = -19.53, P = 0.031). Our findings confirm prior observations of age-related DAT decline and suggest that this phenomenon is independent of changes in VMAT2. After the fifth decade of life, this reduction in DAT binding is associated with a motor performance comparable to mid-adult life. These findings imply that biochemical processes associated with healthy aging may offset the naturaldecline in motor function observed in the elderly.
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Two patients with acquired dystonia were studied by computed imaging techniques and found to have lesions predominantly involving the putamen. The implications of these findings are discussed, and it is concluded that, for the genesis of... more
Two patients with acquired dystonia were studied by computed imaging techniques and found to have lesions predominantly involving the putamen. The implications of these findings are discussed, and it is concluded that, for the genesis of dystonia, a relative increase of other inputs to the pallidum may be important, such as those from the caudate and subthalamic nuclei.
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The integrity of the dopaminergic system can be studied using positron emission tomography. The presynaptic tracers [11C]-methylphenidate and [11C]dihydrotetrabenazine (DTBZ) are used to investigate the dopamine transporter availability,... more
The integrity of the dopaminergic system can be studied using positron emission tomography. The presynaptic tracers [11C]-methylphenidate and [11C]dihydrotetrabenazine (DTBZ) are used to investigate the dopamine transporter availability, the dopamine vesicular transporter integrity; the post-synaptic tracers [11C]-raclopride and [11C]-Schering 23990 (SCH) are used to probe the D2 and D1 receptors. These are reversible tracers, where the binding potential (BP) = Bmax/Kd often is used to quantify the amount of their specific binding to the sites of interest. The simplified tissue input methods to calculate BP are attractive, since they do not require a blood input function. The suitability and performance of two such methods were evaluated: the Logan graphical tissue method, and the Lammertsma reference tissue method (RTM). The BP estimates obtained with the two methods were nearly identical in most cases, with similar reliability and reproducibility indicating that all four tracers s...
Research Interests: Chemistry, Neurology, Metabolism, Kinetics, Medicine, and 15 moreDopamine, Neuropeptides, Humans, Flow, Brain Circulation, Membrane transport proteins, Clinical Sciences, Aged, Middle Aged, Adult, Dopamine Transporter, Boolean Satisfiability, Methylphenidate, Dopamine antagonists, and Cardiovascular medicine and haematology
Positron emission tomography and single photon emission computed tomography have been used to measure receptor concentration and function through the use of a variety of radiotracers and data analysis techniques. Changes in presynaptic... more
Positron emission tomography and single photon emission computed tomography have been used to measure receptor concentration and function through the use of a variety of radiotracers and data analysis techniques. Changes in presynaptic function and postsynaptic receptor concentration reflect both loss due to disease and compensatory responses.
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Abstract Since 1989, four Canadian Consensus Conferences on the Diagnosis and Treatment of Dementia (CCCDTDs) have provided evidence‐based dementia diagnostic and treatment guidelines for Canadian clinicians and researchers. We present... more
Abstract Since 1989, four Canadian Consensus Conferences on the Diagnosis and Treatment of Dementia (CCCDTDs) have provided evidence‐based dementia diagnostic and treatment guidelines for Canadian clinicians and researchers. We present the results from the Neuroimaging and Fluid Biomarkers Group of the 5th CCCDTD (CCCDTD5), which addressed topics chosen by the steering committee to reflect advances in the field and build on our previous guidelines. Recommendations on Imaging and Fluid Biomarker Use from this Conference cover a series of different fields. Prior structural imaging recommendations for both computerized tomography (CT) and magnetic resonance imaging (MRI) remain largely unchanged, but MRI is now more central to the evaluation than before, with suggested sequences described here. The use of visual rating scales for both atrophy and white matter anomalies is now included in our recommendations. Molecular imaging with [18F]‐fluorodeoxyglucose ([18F]‐FDG) Positron Emisson Tomography (PET) or [99mTc]‐hexamethylpropyleneamine oxime/ethylene cysteinate dimer ([99mTc]‐HMPAO/ECD) Single Photon Emission Tomography (SPECT), should now decidedly favor PET. The value of [18F]‐FDG PET in the assessment of neurodegenerative conditions has been established with greater certainty since the previous conference, and it has now been recognized as a useful biomarker to establish the presence of neurodegeneration by a number of professional organizations around the world. Furthermore, the role of amyloid PET has been clarified and our recommendations follow those from other groups in multiple countries. SPECT with [123I]‐ioflupane (DaTscanTM) is now included as a useful study in differentiating Alzheimer's disease (AD) from Lewy body disease. Finally, liquid biomarkers are in a rapid phase of development and, could lead to a revolution in the assessment AD and other neurodegenerative conditions at a reasonable cost. We hope these guidelines will be useful for clinicians, researchers, policy makers, and the lay public, to inform a current and evidence‐based approach to the use of neuroimaging and liquid biomarkers in clinical dementia evaluation and management.
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Molecular imaging has proven to be a powerful tool for investigation of parkinsonian disorders. One current challenge is to identify biomarkers of early changes that may predict the clinical trajectory of parkinsonian disorders. Exciting... more
Molecular imaging has proven to be a powerful tool for investigation of parkinsonian disorders. One current challenge is to identify biomarkers of early changes that may predict the clinical trajectory of parkinsonian disorders. Exciting new tracer developments hold the potential for in vivo markers of underlying pathology. Herein, we provide an overview of molecular imaging advances and how these approaches help us to understand PD and atypical parkinsonisms. © 2016 International Parkinson and Movement Disorder Society.
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Movement disorders can be hypokinetic (e.g., parkinsonism), hyperkinetic, or dystonic in nature and commonly arise from altered function in nuclei of the basal ganglia or their connections. As obvious structural changes are often limited,... more
Movement disorders can be hypokinetic (e.g., parkinsonism), hyperkinetic, or dystonic in nature and commonly arise from altered function in nuclei of the basal ganglia or their connections. As obvious structural changes are often limited, standard imaging plays less of a role than in other neurologic disorders. However, structural imaging is indicated where clinical presentation is atypical, particularly if the disorder is abrupt in onset or remains strictly unilateral. More recent advances in magnetic resonance imaging (MRI) may allow for differentiation between Parkinson's disease and atypical forms of parkinsonism. Functional imaging can assess regional cerebral blood flow (functional MRI (fMRI), positron emission tomography (PET), or single-photon emission computed tomography (SPECT)), cerebral glucose metabolism (PET), neurochemical and neuroreceptor status (PET and SPECT), and pathologic processes such as inflammation or abnormal protein deposition (PET) (Table 49.1). Cerebral blood flow can be assessed at rest, during the performance of motor or cognitive tasks, or in response to a variety of stimuli. In appropriate situations, the correct imaging modality and/or combination of modalities can be used to detect early disease or even preclinical disease, and to monitor disease progression and the effects of disease-modifying interventions. Various approaches are reviewed here.
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A major risk-factor for developing Parkinson's disease (PD) is genetic variability in leucine-rich repeat kinase 2 (LRRK2), most notably the p.G2019S mutation. Examination of the effects of this mutation is necessary to determine the... more
A major risk-factor for developing Parkinson's disease (PD) is genetic variability in leucine-rich repeat kinase 2 (LRRK2), most notably the p.G2019S mutation. Examination of the effects of this mutation is necessary to determine the etiology of PD and to guide therapeutic development. Assess the behavioral consequences of LRRK2 p.G2019S overexpression in transgenic rats as they age and test the functional integrity of the nigro-striatal dopamine system. Conduct positron emission tomography (PET) neuroimaging to compare transgenic rats with previous data from human LRRK2 mutation carriers. Rats overexpressing human LRRK2 p.G2019S were generated by BAC transgenesis and compared to non-transgenic (NT) littermates. Motor skill tests were performed at 3, 6 and 12 months-of-age. PET, performed at 12 months, assessed the density of dopamine and vesicular monoamine transporters (DAT and VMAT2, respectively) and measured dopamine synthesis, storage and availability. Brain tissue was ass...
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Research Interests: Cognitive Science, Depression, Positron Emission Tomography, Medicine, Movement disorders, and 15 moreSerotonin, Dopamine, Humans, Mutation, Sulfides, Clinical Sciences, Middle Aged, Single Photon Emission Computed Tomography, Adult, Hypoventilation, aniline Compounds, Tetrabenazine, Raclopride, Corpus striatum, and parkinsonian disorders
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Research Interests: Psychology, Placebo Effect, Positron Emission Tomography, Medicine, Dopamine, and 15 moreHumans, Female, Male, Placebos, British Columbia, Levodopa, Aged, Middle Aged, Basal ganglia, Archives General Psychiatry, Parkinson Disease, Clinical Trials as Topic, attitude to health, Psychology and Cognitive Sciences, and Medical and Health Sciences
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Thirty-four advanced PD patients were randomly assigned to receive bilateral transplantation with 1 donor per side (n = 11), 4 donors per side (n = 12), or a placebo procedure (n = 11). Prior to entry into the study, all patients signed... more
Thirty-four advanced PD patients were randomly assigned to receive bilateral transplantation with 1 donor per side (n = 11), 4 donors per side (n = 12), or a placebo procedure (n = 11). Prior to entry into the study, all patients signed an institutional review board-approved informed ...
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With increased understanding of disease pathogenesis and the foreseeable reality of disease-modifying therapies, there is a growing need to find biomarkers that will allow early (preferably preclinical) detection of disease and that will... more
With increased understanding of disease pathogenesis and the foreseeable reality of disease-modifying therapies, there is a growing need to find biomarkers that will allow early (preferably preclinical) detection of disease and that will provide an independent readout of disease progression. In this article, we review a variety of markers, with a focus on functional imaging techniques, which while imperfect, currently provide the best approach to this problem. We consider the limitations of functional imaging of the dopamine system in assessing the progression of Parkinson's Disease (PD) as well as the potential use of structural imaging and emerging progress in other biochemical and molecular markers. While there is no single biomarker that will satisfy all requirements, some combination is likely to be of great use in identifying those subjects most likely to benefit from neuroprotective therapies, as well as in monitoring the effects of these interventions.
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Abstract. Fluphenazine decanoate (25 mg/kg IM every 3 weeks x 6) resulted in spontaneous vacuous chewing mouth movements and jaw tremor in male Sprague-Dawley rats. These movements could be suppressed by the selective D1 or D2 dopamine... more
Abstract. Fluphenazine decanoate (25 mg/kg IM every 3 weeks x 6) resulted in spontaneous vacuous chewing mouth movements and jaw tremor in male Sprague-Dawley rats. These movements could be suppressed by the selective D1 or D2 dopamine antagonists SCH 23390 (0.5 ...
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Neurodegeneration of Parkinson's disease (PD) starts in an insidious manner, 30-50% of dopaminergic neurons have been lost in the substantia nigra before clinical diagnosis. Prodromal stage of the disease, during which the disease... more
Neurodegeneration of Parkinson's disease (PD) starts in an insidious manner, 30-50% of dopaminergic neurons have been lost in the substantia nigra before clinical diagnosis. Prodromal stage of the disease, during which the disease pathology has started but is insufficient to result in clinical manifestations, offers a valuable window for disease-modifying therapies. The most focused underlying mechanisms linking the pathological pattern and clinical characteristics of prodromal PD are the prion hypothesis of alpha-synuclein and the selective vulnerability of neurons. In this review, we consider the two potential portals, the vagus nerve and the olfactory bulb, through which abnormal alpha-synuclein can access the brain. We review the clinical, pathological and neuroimaging evidence of the parasympathetic nervous system and the olfactory system in the neurodegenerative process and using the two systems as models to discuss the internal homogeneity and heterogeneity of the prodrom...
Mutations in dynactin DCTN1 (p150(glued)) have previously been linked to familial motor neuron disease or Perry syndrome (PS) consisting of depression, parkinsonism and hypoventilation. We sequenced DCTN1 in 636 Caucasian patients with... more
Mutations in dynactin DCTN1 (p150(glued)) have previously been linked to familial motor neuron disease or Perry syndrome (PS) consisting of depression, parkinsonism and hypoventilation. We sequenced DCTN1 in 636 Caucasian patients with parkinsonism (Parkinson's disease and Parkinson-plus syndromes) and 508 healthy controls. Variants (MAF < 0.01) were subsequently genotyped in Caucasian (1360 cases and 1009 controls) and Asian cohorts (1046 cases and 830 controls), and the functional implications of pathogenic variants were assessed. We identified 17 rare variants leading to non-synonymous amino-acid substitutions. Four of the variants were only observed in control subjects, four in both cases and controls and the remaining nine in cases only. One of the variants, DCTN1 p.K56R, was present in two patients with progressive supranuclear palsy (PSP) with a shared minimal 2.2 Mb haplotype. Both subjects have parkinsonism as the most prominent symptom with abnormal ocular movements, moderate cognitive impairment and little to no l-dopa response. Neither subject presents with depression, central hypoventilation or weight loss. For one of the subjects MRI shows symmetrical atrophy of temporal and frontoparietal lobes. In HEK293 cells mutant p150(glued) (p.K56R) shows less affinity for microtubules than wild-type, with a more diffuse cytoplasmic distribution. We have identified DCTN1 p.K56R in patients with PSP. This variant is immediately adjacent to the N-terminal p150(glued) 'CAP-Gly' domain, affects a highly conserved amino acid and alters the protein's affinity to microtubules and its cytoplasmic distribution.
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The diagnosis of Parkinson's disease (PD) currently relies on the appearance of certain clinical features. However, these features appear only years after the loss of nigral... more
The diagnosis of Parkinson's disease (PD) currently relies on the appearance of certain clinical features. However, these features appear only years after the loss of nigral dopaminergic neurons. The progression of PD may be measured using clinical rating scales that are subjective and that have a variable inter-rater consistency. There is a growing need for a biomarker that will allow for early detection of the disease as well as provide a measure of disease progression. In this article, we review different biomarkers, with a focus on functional imaging techniques, which while imperfect, currently provide the best approach to this problem. We also discuss the use of structural imaging and emerging progress in other biochemical and molecular markers. While there is no single biomarker that will satisfy all requirements, a combination is likely to be of great use in identifying those subjects most likely to benefit from neuroprotective therapies, as well as in monitoring the effects of any interventions.
Research Interests: Neuroimaging, Magnetic Resonance Imaging, Biomarkers, Diffusion Tensor Imaging, Inflammation, and 15 moreOxidative Stress, Positron Emission Tomography, Alpha Synuclein, Brain, Humans, Mutation, Substantia nigra, Single Photon Emission Computed Tomography, Functional Neuroimaging, Disease Progression, Neurosciences, Dopaminergic Neurons, Parkinson Disease, Tau proteins, and Pharmacology and pharmaceutical sciences
Since structural imaging has generally failed to demonstrate consistent abnormalities in Parkinsons disease (PD), from an imaging perspective, the diagnosis has typically been based upon the demonstration of impaired striatal dopamine... more
Since structural imaging has generally failed to demonstrate consistent abnormalities in Parkinsons disease (PD), from an imaging perspective, the diagnosis has typically been based upon the demonstration of impaired striatal dopamine (DA) function. Radiotracer imaging techniques such as positron emission tomography (PET) and single photon emission computerized tomography (SPECT) allow thein vivoassessment of nigrostriatal DA function as well as regional cerebral blood flow, glucose metabolism, and functional connectivity, and changes in these measures have been used to infer disease progression. Pre-synaptic radiotracer imaging (RTI) has shown that striatal dopaminergic hypofunction follows a negative exponential pattern with the fastest rate of decline in early disease. Moreover, while striatal subregions remain differentially affected throughout the course of disease, with the posterior putamen affected more than anterior structures, the rate of deterioration is similar in all s...
ABSTRACT Positron emission tomography (PET) studies of Parkinson's disease (PD) have largely focused on agents used to study the nigrostriatal dopamine projections. These studies have consistently demonstrated asymmetric reduction... more
ABSTRACT Positron emission tomography (PET) studies of Parkinson's disease (PD) have largely focused on agents used to study the nigrostriatal dopamine projections. These studies have consistently demonstrated asymmetric reduction in dopaminergic integrity, affecting the caudal more than the rostral striatum. Studies with dopamine receptor ligands reveal relatively limited changes in receptor density in PD, but can be used to great advantage to assess dopamine release in response to a variety of stimuli. Recently, PET has been used to study other monoaminergic systems in PD, particularly serotonergic innervation. PET can also be used to study cholinergic innervation, of particular relevance to cognitive impairment in PD, and neuropeptide receptors which may be altered in association with motor complications. Studies of cardiac sympathetic innervation may be of diagnostic utility in the assessment of patients with parkinsonism and autonomic dysfunction. Studies of glucose metabolism or cerebral blood flow reveal altered networks in PD and altered patterns of activation associated with motor or cognitive tasks. Disease process such as inflammation or amyloid deposition can also be studied using PET. Such studies can provide useful insights into the pathogenesis of PD and associated treatment-related complications.
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The reproducibility of (+/-)-alpha-[11C] dihydrotetrabenazine (DTBZ) measures in PET was studied in 10 healthy human subjects, aged 22-76 y. The scan-to-scan variation of several measures used in PET data analysis was determined,... more
The reproducibility of (+/-)-alpha-[11C] dihydrotetrabenazine (DTBZ) measures in PET was studied in 10 healthy human subjects, aged 22-76 y. The scan-to-scan variation of several measures used in PET data analysis was determined, including the radioactivity ratio (target-to-reference), plasma-input Logan total distribution volume (DV), plasma-input Logan Bmax/Kd and tissue-input Logan Bmax/Kd values. The radioactivity ratios, plasma-input Bmax/Kd and tissue-input Bmax/Kd all have higher reliability than plasma-input total DV values. In addition, measures using the occipital cortex as the reference region have higher reliability than the same measures using the cerebellum as the reference region. Our results show that DTBZ is a reliable PET tracer that provides reproducible in vivo measurement of striatal vesicular monoamine transporter density. In the selection of reference regions for DTBZ PET data analysis, caution must be exercised in circumstances when DTBZ binding in the occipi...