Movement disorders can be hypokinetic (e.g., parkinsonism), hyperkinetic, or dystonic in nature a... 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.
A major risk-factor for developing Parkinson's disease (PD) is genetic variability in leucine... 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...
The role of neurotensin (NT) in a putative model of tardive dyskinesia (TD) was examined in the r... 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.
Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2020
Abstract Since 1989, four Canadian Consensus Conferences on the Diagnosis and Treatment of Dement... more Abstract Since 1989, four Canadian Consensus Conferences on the Diagnosis and Treatment of Dementia (CCCDTDs) have provided evidenceābased 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]āfluorodeoxyglucose ([18F]āFDG) Positron Emisson Tomography (PET) or [99mTc]āhexamethylpropyleneamine oxime/ethylene cysteinate dimer ([99mTc]āHMPAO/ECD) Single Photon Emission Tomography (SPECT), should now decidedly favor PET. The value of [18F]āFDG 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]āioflupane (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 evidenceābased approach to the use of neuroimaging and liquid biomarkers in clinical dementia evaluation and management.
Levodopa remains the mainstay of treatment for Parkinson disease (PD), but its use is associated ... more Levodopa remains the mainstay of treatment for Parkinson disease (PD), but its use is associated with dyskinesias (LID) in many patients. LID likely reflect dysregulated release of dopamine combined with altered postsynaptic mechanisms due to pulsatile dopamine receptor stimulation. Dopamine D3 receptors are increased in animal models of LID, and experimental LID is attenuated by suppression of D3 signaling, but the relevance to LID in humans is uncertain.1 Payer et al.2 used PET with the D3-preferring dopamine receptor agonist [11C]PHNO. Compared to patients with PD without LID, those with LID had increased binding in the globus pallidus and decreased binding in the ventral striatum. In the dorsal striatum, PHNO binding was increased in both PD groups, but the difference between PD-stable and PD-LID was not significant. However, [11C]raclopride binding to D2 and D3 receptors was increased in patients with LID when controlling for levodopa dose.
Movement disorders can be hypokinetic (e.g., parkinsonism), hyperkinetic, or dystonic in nature a... 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.
A major risk-factor for developing Parkinson's disease (PD) is genetic variability in leucine... 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...
The role of neurotensin (NT) in a putative model of tardive dyskinesia (TD) was examined in the r... 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.
Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2020
Abstract Since 1989, four Canadian Consensus Conferences on the Diagnosis and Treatment of Dement... more Abstract Since 1989, four Canadian Consensus Conferences on the Diagnosis and Treatment of Dementia (CCCDTDs) have provided evidenceābased 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]āfluorodeoxyglucose ([18F]āFDG) Positron Emisson Tomography (PET) or [99mTc]āhexamethylpropyleneamine oxime/ethylene cysteinate dimer ([99mTc]āHMPAO/ECD) Single Photon Emission Tomography (SPECT), should now decidedly favor PET. The value of [18F]āFDG 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]āioflupane (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 evidenceābased approach to the use of neuroimaging and liquid biomarkers in clinical dementia evaluation and management.
Levodopa remains the mainstay of treatment for Parkinson disease (PD), but its use is associated ... more Levodopa remains the mainstay of treatment for Parkinson disease (PD), but its use is associated with dyskinesias (LID) in many patients. LID likely reflect dysregulated release of dopamine combined with altered postsynaptic mechanisms due to pulsatile dopamine receptor stimulation. Dopamine D3 receptors are increased in animal models of LID, and experimental LID is attenuated by suppression of D3 signaling, but the relevance to LID in humans is uncertain.1 Payer et al.2 used PET with the D3-preferring dopamine receptor agonist [11C]PHNO. Compared to patients with PD without LID, those with LID had increased binding in the globus pallidus and decreased binding in the ventral striatum. In the dorsal striatum, PHNO binding was increased in both PD groups, but the difference between PD-stable and PD-LID was not significant. However, [11C]raclopride binding to D2 and D3 receptors was increased in patients with LID when controlling for levodopa dose.
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Papers by A Jon Stoessl