A BS TRACT: Background: The serotonergic system is known to contribute to levodopa-derived dopami... more A BS TRACT: Background: The serotonergic system is known to contribute to levodopa-derived dopamine release in advanced Parkinson's disease. Objective: We investigated the role of the serotonergic system in determining response to treatment in early disease and risk for complications concurrently with dopaminergic alterations. Methods: Eighteen patients with early and stable Parkinson's disease underwent multitracer positron emission tomography using [ 11 C]dihydrotetrabenazine (vesicular monoamine transporter 2 marker), [ 11 C] methylphenidate (dopamine transporter marker), [ 11 C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile (DASB, serotonin transporter marker), and [ 11 C]raclopride (D2 marker) to investigate relationships between striatal dopaminergic and serotonergic alterations and levodopa-induced dopamine release, related to motor response to treatment and risk for dyskinesias, using a novel joint pattern analysis. Results: The joint pattern analysis revealed correlated spatial patterns conceptually related to abnormal dopamine turnover in the putamen (higher dopamine release associated with dopaminergic and serotonergic denervation); response to treatment significantly inversely correlated with turnover-related dopamine release (P < 10 −5). Patterns identified without inclusion of the DASB data showed no correlation with clinical data, indicating an important contribution from the serotonergic system to a clinically relevant abnormal dopamine release in early disease. Subjects who experienced dyskinesia 3 years after baseline scans showed higher turnover-related dopamine release compared with subjects who remained stable (P < 0.01). Conclusions: Joint analysis of dopaminergic and serotonergic data identified a turnover-related dopamine release component, strongly related to motor response to levodopa in early disease and contributing to higher risk for dyskinesia. These findings suggest that the contribution of the serotonergic system to dopamine release not only increases the risk for motor complications but also fails to provide sustained therapeutic advantage in early disease.
Most cases of Parkinson's disease (PD) are idiopathic, but some characteristics, such as earl... more Most cases of Parkinson's disease (PD) are idiopathic, but some characteristics, such as early onset or a positive family history, raise suspicions of an inherited form of the disease. In the last decades several genes have been linked to parkinsonism, with different patterns of inheritance and different clinical phenotypes. Positron emission tomography (PET) imaging has helped to characterize genetic-linked parkinsonism, thanks to the availability of dopaminergic and nondopaminergic tracers. On the other hand, investigation of molecular changes in mutation carriers, even at preclinical stages, has provided a deeper comprehension of the pathogenesis of PD and of the compensatory mechanisms that take place in the very early stages of the disease.
Objective: To investigate if subjects that carry LRRK2 mutations, a known risk factor for Parkins... more Objective: To investigate if subjects that carry LRRK2 mutations, a known risk factor for Parkinson’s disease (PD), exhibit increased neuroinflammation compared to age matched healthy controls. Background: LRRK2 is known to play a role in the regulation of the innate immune system and response to inflammation. Similarly, neuroinflammation is hypothesized to be a likely contributor to PD origin and its progression. Thus, we investigated if increased neuroinflammation could be a mechanism by which LRRK2 mutations increase the risk of PD. Methods: In this pilot study we imaged 4 Healthy Controls (HC) (age 44 ± 16, mean, std; range 24-63) and 3 age matched unaffected LRRK2 G2019S mutation carriers (UC)(age 51 ± 12, mean, std; range 37-61) with 11C-PBR28, a second generation TSPO binding PET ligand. All subjects were mixed affinity binders (MAB). 38 MRI guided regions of interest were placed on the PET images. The primary outcome measures were standard uptake values (SUV), previously cro...
The concept of repairing the brain with growth factors has been pursued for many years in a varie... more The concept of repairing the brain with growth factors has been pursued for many years in a variety of neurodegenerative diseases including primarily Parkinson's disease (PD) using glial cell line-derived neurotrophic factor (GDNF). This neurotrophic factor was discovered in 1993 and shown to have selective effects on promoting survival and regeneration of certain populations of neurons including the dopaminergic nigrostriatal pathway. These observations led to a series of clinical trials in PD patients including using infusions or gene delivery of GDNF or the related growth factor, neurturin (NRTN). Initial studies, some of which were open label, suggested that this approach could be of value in PD when the agent was injected into the putamen rather than the cerebral ventricles. In subsequent double-blind, placebo-controlled trials, the most recent reporting in 2019, treatment with GDNF did not achieve its primary end point. As a result, there has been uncertainty as to whether GDNF (and by extrapolation, related GDNF family neurotrophic factors) has merit in the future treatment of PD. To critically appraise the existing work and its future, a special workshop was held to discuss and debate this issue. This paper is a summary of that meeting with recommendations on whether there is a future for this therapeutic approach and also what any future PD trial involving GDNF and other GDNF family neurotrophic factors should consider in its design.
BackgroundThe objective of this study was to examine the effects of aerobic exercise on evoked do... more BackgroundThe objective of this study was to examine the effects of aerobic exercise on evoked dopamine release and activity of the ventral striatum using positron emission tomography and functional magnetic resonance imaging in Parkinson's disease (PD).MethodsThirty‐five participants were randomly allocated to a 36‐session aerobic exercise or control intervention. Each participant underwent an functional magnetic resonance imaging scan while playing a reward task before and after the intervention to determine the effect of exercise on the activity of the ventral striatum in anticipation of reward. A subset of participants (n = 25) completed [11C] raclopride positron emission tomography scans to determine the effect of aerobic exercise on repetitive transcranial magnetic stimulation‐evoked release of endogenous dopamine in the dorsal striatum. All participants completed motor (MDS‐UPDRS part III, finger tapping, Timed‐up‐and‐go) and nonmotor assessments (Starkstein Apathy Scale,...
Most neurodegenerative diseases are known to affect several aspects of brain function, including ... more Most neurodegenerative diseases are known to affect several aspects of brain function, including neurotransmitter systems, metabolic and functional connectivity. Diseases are generally characterized by common clinical characteristics across subjects, but there are also significant inter-subject variations. It is thus reasonable to expect that in terms of brain function, such clinical behaviors will be related to a general overall multi-system pattern of disease-induced alterations and additional brain system-specific abnormalities; these additional abnormalities would be indicative of a possible unique system response to disease or subject-specific propensity to a specific clinical progression. Based on the above considerations we introduce and validate the use of a joint pattern analysis approach, canonical correlation analysis and orthogonal signal correction, to analyze multi-tracer PET data to identify common (reflecting functional similarities) and unique (reflecting functional differences) information provided by each tracer/target. We apply the method to [ 11 C]-DTBZ (VMAT2 marker) and [ 11 C]-MP (DAT marker) data from 15 early Parkinson's disease (PD) subjects; the behavior of these two tracers/targets is well characterized providing robust reference information for the method's outcome. Highly significant common subject profiles were identified that decomposed the characteristic dopaminergic changes into three distinct orthogonal spatial patterns: 1) disease-induced asymmetry between the less and more affected dorsal striatum; 2) disease-induced gradient with caudate and ventral striatum being relatively spared compared to putamen; 3) progressive loss in the less affected striatum, which correlated significantly with disease duration (p < 0.01 for DTBZ, p < 0.05 for MP). These common spatial patterns reproduce all known aspects of these two targets/tracers. In addition, orthogonality of the patterns may indicate different mechanisms underlying disease initiation or progression. Information unique to each tracer revealed a residual striatal asymmetry when targeting VMAT2, consistent with the notion that VMAT2 density is highly related to terminal degeneration; and a residual DAT disease-induced gradient in the striatum with relative DAT preservation in the substantia nigra. This finding may be indicative either of a possible DAT specific early disease compensation and/or related to disease origin. These results demonstrate the applicability and relevance of the joint pattern analysis approach to datasets obtained with two PET tracers; this data driven method, while recapitulating known aspects of the PD-induced tracer/target behaviour, was found to be statistically more robust and provided additional information on (i) correlated behaviors of the two systems, identified as orthogonal patterns, possibly reflecting different diseaseinduced alterations and (ii) system specific effects of disease. It is thus expected that this approach will be very well suited to the analysis of multi-tracer and/or multi-modality data and to relating the outcomes to different aspects of disease.
Background: Intraputamenal glial cell line-derived neurotrophic factor (GDNF), administered every... more Background: Intraputamenal glial cell line-derived neurotrophic factor (GDNF), administered every 4 weeks to patients with moderately advanced Parkinson's disease, did not show significant clinical improvements against placebo at 40 weeks, although it significantly increased [ 18 F]DOPA uptake throughout the entire putamen. Objective: This open-label extension study explored the effects of continued (prior GDNF patients) or new (prior placebo patients) exposure to GDNF for another 40 weeks. Methods: Using the infusion protocol of the parent study, all patients received GDNF without disclosing prior treatment allocations (GDNF or placebo). The primary outcome was the percentage change from baseline to Week 80 in the OFF state Unified Parkinson's Disease Rating Scale (UPDRS) motor score. Results: All 41 parent study participants were enrolled. The primary outcome decreased by 26.7 ± 20.7% in patients on GDNF for 80 weeks (GDNF/GDNF; N = 21) and 27.6 ± 23.6% in patients on placebo for 40 weeks followed by GDNF for 40 weeks (placebo/GDNF, N = 20; least squares mean difference: 0.4%, 95% CI:-13.9, 14.6, p = 0.96). Secondary endpoints did not show significant differences between the groups at Week 80 either. Prespecified comparisons between GDNF/GDNF at Week
ABSTRACTBackgroundThe benefits of exercise in PD have been linked to enhanced dopamine (DA) trans... more ABSTRACTBackgroundThe benefits of exercise in PD have been linked to enhanced dopamine (DA) transmission in the striatum.ObjectiveTo examine differences in DA release, reward signaling, and clinical features between habitual exercisers and sedentary subjects with PD.MethodsEight habitual exercisers and 9 sedentary subjects completed [11C]raclopride PET scans before and after stationary cycling to determine exercise‐induced release of endogenous DA in the dorsal striatum. Additionally, functional MRI assessed ventral striatum activation during reward anticipation. All participants completed motor (UPDRS III; finger tapping; and timed‐up‐and‐go) and nonmotor (Beck Depression Inventory; Starkstein Apathy Scale) assessments.Results[11C]Raclopride analysis before and after stationary cycling demonstrated greater DA release in the caudate nuclei of habitual exercisers compared to sedentary subjects (P < 0.05). Habitual exercisers revealed greater activation of ventral striatum during t...
We used positron emission tomography imaging with [ 11 C]-3-amino-4-(2-dimethylaminomethylphenyls... more We used positron emission tomography imaging with [ 11 C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile (DASB) and principal component analysis to investigate whether a specific Parkinson's disease (PD)related spatial covariance pattern could be identified for the serotonergic system. We also explored if nonmanifesting leucine-rich repeat kinase 2 (LRRK2) mutation carriers, with normal striatal dopaminergic innervation as measured with [ 11 C]-dihydrotetrabenazine (DTBZ), exhibit a distinct spatial covariance pattern compared to healthy controls and subjects with manifest PD. 15 subjects with sporadic PD, eight subjects with LRRK2 mutation-associated PD, nine LRRK2 non-manifesting mutation carriers, and nine healthy controls participated in the study. The analysis was applied to the DASB non-displaceable binding potential values evaluated in 42 pre-defined regions of interest. PD was found to be associated with a specific spatial covariance pattern, comprising relatively decreased DASB binding in the caudate, putamen and substantia nigra and relatively preserved binding in the hypothalamus and hippocampus; the expression of this pattern in PD subjects was significantly higher than in healthy controls (P < 0.001) and correlated significantly with disease duration (P < 0.01) and with DTBZ binding in the more affected putamen (P < 0.01). The LRRK2 non-manifesting mutation carriers expressed a different pattern, also significantly different from healthy controls (P < 0.001), comprising relatively decreased DASB binding in the pons, pedunculopontine nucleus, thalamus and rostral raphe nucleus, and with relatively preserved binding in the hypothalamus, amygdala, hippocampus and substantia nigra. This pattern was not present in either sporadic or LRRK2 mutation-associated PD subjects. These findings, although obtained with a relatively limited number of subjects, suggest that specific and overall distinct spatial serotonergic patterns may be associated with PD and LRRK2 mutations. Alterations in regions where relative upregulation is observed in both patterns may be indicative of compensatory mechanisms preceding or protecting from disease manifestation. 1. Introduction Parkinson's disease (PD) is the second most frequent progressive neurodegenerative disorder (de Lau and Breteler, 2006). The cardinal features are motor deficits, including tremor, rigidity and bradykinesia, traditionally associated with dopaminergic denervation in the substantia nigra (Stoessl et al., 2012). There is however increased recognition of the importance of the disease-induced non-motor symptoms. Some of these non-motor abnormalities, including autonomic dysfunction, sleep disturbance, cognitive impairment and depression, can precede the motor deficits by years or even decades (Schrag et al., 2015). The bases for these non-motor deficits are still unclear, but it is suggested that many of them may be associated with alterations of nondopaminergic neurotransmitter systems (Stoessl, 2009). In particular, several in-vivo and post-mortem studies support the hypothesis that progressive alterations of the serotonergic system may contribute to a number of such non-motor alterations (Politis and Loane, 2011). A large body of evidence has indeed been gathered from in-vivo PET studies
People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic a... more People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinson's disease and individuals with sporadic Parkinson's disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes. We did two cross-sectional PET studies at the Pacific Parkinson's Research Centre in Vancouver, BC, Canada. We included LRRK2 mutation carriers with or without manifest Parkinson's disease, people with sporadic Parkinson's disease, and age-matched healthy controls, all aged 18 years or older. People with Parkinson's disease were diagnosed by a neurologist with movement disorder training, in accordance with the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. In the first study, LRRK2 mutation c...
The main goal of dopamine cell replacement therapy in Parkinson's disease (PD) is to provide ... more The main goal of dopamine cell replacement therapy in Parkinson's disease (PD) is to provide clinical benefit mediated by graft survival with nigrostriatal reinnervation. We report a dichotomy between graft structure and clinical function in a patient dying sixteen years following fetal nigral grafting. A 55-year-old levodopa-responsive woman with PD received bilateral putamenal fetal mesencephalic grafts as part of an NIH-sponsored double-blind sham-controlled trial. The patient never experienced clinical benefit and her course was complicated by the development of graft-related dyskinesias. Fluorodopa positron emission tomography (FD-PET) demonstrated significant increases post-grafting bilaterally. She experienced worsening of parkinsonism with severe dyskinesias, and underwent STN-DBS 8 years after grafting. She died 16-years post-transplantation. Post-mortem analyses confirmed the diagnosis of PD and demonstrated >300,000 tyrosine hydroxylase (TH) positive grafted cells ...
Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2002
Background:We describe nine females with Rett Syndrome (RS), aged 14 to 26 years. All had had dev... more Background:We describe nine females with Rett Syndrome (RS), aged 14 to 26 years. All had had developmental delay before the end of their first year and had subsequently regressed to profound dementia with apraxia, ataxia, irregular respirations and often also seizures.Methods:The Revised Gesell developmental assessment and Alpern-Boll Developmental Profile were used in modified form. Volumetric measurements of basal ganglia using MRI were compared with the findings in nine age-matched volunteer females. Positron emission scans with [18F]-6-fluorodopa and [11C]-raclopride were performed under light anesthesia with intravenous Propofol, and the findings were compared with those in healthy control girls. Bidirectional sequencing of the coding regions of the MECP2 gene was investigated in blood samples for mutational analyses.Results:The RS females functioned at a mental age level ranging from about 4 to 15 months. The scores correlated with height, weight and head circumference. Magne...
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...
Objective-To describe clinical, positron emission tomography (PET), pathological, and genetic fin... more Objective-To describe clinical, positron emission tomography (PET), pathological, and genetic findings of a large kindred with progressive neurodegenerative phenotypes in which the proband had autopsy-confirmed corticobasal degeneration (CBD). Methods-Five family members, including the proband, were examined neurologically. Clinical information from the other family members was collected by questionnaires. Three individuals underwent PET with 11 C-dihydrotetrabenazine and 18 F-fludeoxyglucose. The proband was examined post-mortem. Genetic studies were performed. Results-The pedigree contains 64 individuals, including 8 affected patients. The inheritance is likely autosomal dominant with reduced penetrance. The proband developed progressive speech and language difficulties at the age of 64 years. Upon examination at the age of 68 years, she showed non-fluent aphasia, word-finding difficulties, circumlocution, frontal release signs, and right-sided bradykinesia, rigidity, and pyramidal signs. She died 5 years after disease onset. The neuropathology was consistent with CBD, including many cortical and subcortical astrocytic plaques. Other family members had progressive neurodegenerative phenotypes-two were
Background: To date, statistical methods that take into account fully the non-linear, longitudina... more Background: To date, statistical methods that take into account fully the non-linear, longitudinal and multivariate aspects of clinical data have not been applied to the study of progression in Parkinson's disease (PD). In this paper, we demonstrate the usefulness of such methodology for studying the temporal and spatial aspects of the progression of PD. Extending this methodology further, we also explore the presymptomatic course of this disease. Methods: Longitudinal Positron Emission Tomography (PET) measurements were collected on 78 PD patients, from 4 subregions on each side of the brain, using 3 different radiotracers. Non-linear, multivariate, longitudinal random effects modelling was applied to analyze and interpret these data. Results: The data showed a non-linear decline in PET measurements, which we modelled successfully by an exponential function depending on two patient-related covariates duration since symptom onset and age at symptom onset. We found that the degree of damage was significantly greater in the posterior putamen than in the anterior putamen throughout the disease. We also found that over the course of the illness, the difference between the less affected and more affected sides of the brain decreased in the anterior putamen. Younger patients had significantly poorer measurements than older patients at the time of symptom onset suggesting more effective compensatory mechanisms delaying the onset of symptoms. Cautious extrapolation showed that disease onset had occurred some 8 to 17 years prior to symptom onset. Conclusions: Our model provides important biological insights into the pathogenesis of PD, as well as its preclinical aspects. Our methodology can be applied widely to study many other chronic progressive diseases.
A BS TRACT: Background: The serotonergic system is known to contribute to levodopa-derived dopami... more A BS TRACT: Background: The serotonergic system is known to contribute to levodopa-derived dopamine release in advanced Parkinson's disease. Objective: We investigated the role of the serotonergic system in determining response to treatment in early disease and risk for complications concurrently with dopaminergic alterations. Methods: Eighteen patients with early and stable Parkinson's disease underwent multitracer positron emission tomography using [ 11 C]dihydrotetrabenazine (vesicular monoamine transporter 2 marker), [ 11 C] methylphenidate (dopamine transporter marker), [ 11 C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile (DASB, serotonin transporter marker), and [ 11 C]raclopride (D2 marker) to investigate relationships between striatal dopaminergic and serotonergic alterations and levodopa-induced dopamine release, related to motor response to treatment and risk for dyskinesias, using a novel joint pattern analysis. Results: The joint pattern analysis revealed correlated spatial patterns conceptually related to abnormal dopamine turnover in the putamen (higher dopamine release associated with dopaminergic and serotonergic denervation); response to treatment significantly inversely correlated with turnover-related dopamine release (P < 10 −5). Patterns identified without inclusion of the DASB data showed no correlation with clinical data, indicating an important contribution from the serotonergic system to a clinically relevant abnormal dopamine release in early disease. Subjects who experienced dyskinesia 3 years after baseline scans showed higher turnover-related dopamine release compared with subjects who remained stable (P < 0.01). Conclusions: Joint analysis of dopaminergic and serotonergic data identified a turnover-related dopamine release component, strongly related to motor response to levodopa in early disease and contributing to higher risk for dyskinesia. These findings suggest that the contribution of the serotonergic system to dopamine release not only increases the risk for motor complications but also fails to provide sustained therapeutic advantage in early disease.
Most cases of Parkinson's disease (PD) are idiopathic, but some characteristics, such as earl... more Most cases of Parkinson's disease (PD) are idiopathic, but some characteristics, such as early onset or a positive family history, raise suspicions of an inherited form of the disease. In the last decades several genes have been linked to parkinsonism, with different patterns of inheritance and different clinical phenotypes. Positron emission tomography (PET) imaging has helped to characterize genetic-linked parkinsonism, thanks to the availability of dopaminergic and nondopaminergic tracers. On the other hand, investigation of molecular changes in mutation carriers, even at preclinical stages, has provided a deeper comprehension of the pathogenesis of PD and of the compensatory mechanisms that take place in the very early stages of the disease.
Objective: To investigate if subjects that carry LRRK2 mutations, a known risk factor for Parkins... more Objective: To investigate if subjects that carry LRRK2 mutations, a known risk factor for Parkinson’s disease (PD), exhibit increased neuroinflammation compared to age matched healthy controls. Background: LRRK2 is known to play a role in the regulation of the innate immune system and response to inflammation. Similarly, neuroinflammation is hypothesized to be a likely contributor to PD origin and its progression. Thus, we investigated if increased neuroinflammation could be a mechanism by which LRRK2 mutations increase the risk of PD. Methods: In this pilot study we imaged 4 Healthy Controls (HC) (age 44 ± 16, mean, std; range 24-63) and 3 age matched unaffected LRRK2 G2019S mutation carriers (UC)(age 51 ± 12, mean, std; range 37-61) with 11C-PBR28, a second generation TSPO binding PET ligand. All subjects were mixed affinity binders (MAB). 38 MRI guided regions of interest were placed on the PET images. The primary outcome measures were standard uptake values (SUV), previously cro...
The concept of repairing the brain with growth factors has been pursued for many years in a varie... more The concept of repairing the brain with growth factors has been pursued for many years in a variety of neurodegenerative diseases including primarily Parkinson's disease (PD) using glial cell line-derived neurotrophic factor (GDNF). This neurotrophic factor was discovered in 1993 and shown to have selective effects on promoting survival and regeneration of certain populations of neurons including the dopaminergic nigrostriatal pathway. These observations led to a series of clinical trials in PD patients including using infusions or gene delivery of GDNF or the related growth factor, neurturin (NRTN). Initial studies, some of which were open label, suggested that this approach could be of value in PD when the agent was injected into the putamen rather than the cerebral ventricles. In subsequent double-blind, placebo-controlled trials, the most recent reporting in 2019, treatment with GDNF did not achieve its primary end point. As a result, there has been uncertainty as to whether GDNF (and by extrapolation, related GDNF family neurotrophic factors) has merit in the future treatment of PD. To critically appraise the existing work and its future, a special workshop was held to discuss and debate this issue. This paper is a summary of that meeting with recommendations on whether there is a future for this therapeutic approach and also what any future PD trial involving GDNF and other GDNF family neurotrophic factors should consider in its design.
BackgroundThe objective of this study was to examine the effects of aerobic exercise on evoked do... more BackgroundThe objective of this study was to examine the effects of aerobic exercise on evoked dopamine release and activity of the ventral striatum using positron emission tomography and functional magnetic resonance imaging in Parkinson's disease (PD).MethodsThirty‐five participants were randomly allocated to a 36‐session aerobic exercise or control intervention. Each participant underwent an functional magnetic resonance imaging scan while playing a reward task before and after the intervention to determine the effect of exercise on the activity of the ventral striatum in anticipation of reward. A subset of participants (n = 25) completed [11C] raclopride positron emission tomography scans to determine the effect of aerobic exercise on repetitive transcranial magnetic stimulation‐evoked release of endogenous dopamine in the dorsal striatum. All participants completed motor (MDS‐UPDRS part III, finger tapping, Timed‐up‐and‐go) and nonmotor assessments (Starkstein Apathy Scale,...
Most neurodegenerative diseases are known to affect several aspects of brain function, including ... more Most neurodegenerative diseases are known to affect several aspects of brain function, including neurotransmitter systems, metabolic and functional connectivity. Diseases are generally characterized by common clinical characteristics across subjects, but there are also significant inter-subject variations. It is thus reasonable to expect that in terms of brain function, such clinical behaviors will be related to a general overall multi-system pattern of disease-induced alterations and additional brain system-specific abnormalities; these additional abnormalities would be indicative of a possible unique system response to disease or subject-specific propensity to a specific clinical progression. Based on the above considerations we introduce and validate the use of a joint pattern analysis approach, canonical correlation analysis and orthogonal signal correction, to analyze multi-tracer PET data to identify common (reflecting functional similarities) and unique (reflecting functional differences) information provided by each tracer/target. We apply the method to [ 11 C]-DTBZ (VMAT2 marker) and [ 11 C]-MP (DAT marker) data from 15 early Parkinson's disease (PD) subjects; the behavior of these two tracers/targets is well characterized providing robust reference information for the method's outcome. Highly significant common subject profiles were identified that decomposed the characteristic dopaminergic changes into three distinct orthogonal spatial patterns: 1) disease-induced asymmetry between the less and more affected dorsal striatum; 2) disease-induced gradient with caudate and ventral striatum being relatively spared compared to putamen; 3) progressive loss in the less affected striatum, which correlated significantly with disease duration (p < 0.01 for DTBZ, p < 0.05 for MP). These common spatial patterns reproduce all known aspects of these two targets/tracers. In addition, orthogonality of the patterns may indicate different mechanisms underlying disease initiation or progression. Information unique to each tracer revealed a residual striatal asymmetry when targeting VMAT2, consistent with the notion that VMAT2 density is highly related to terminal degeneration; and a residual DAT disease-induced gradient in the striatum with relative DAT preservation in the substantia nigra. This finding may be indicative either of a possible DAT specific early disease compensation and/or related to disease origin. These results demonstrate the applicability and relevance of the joint pattern analysis approach to datasets obtained with two PET tracers; this data driven method, while recapitulating known aspects of the PD-induced tracer/target behaviour, was found to be statistically more robust and provided additional information on (i) correlated behaviors of the two systems, identified as orthogonal patterns, possibly reflecting different diseaseinduced alterations and (ii) system specific effects of disease. It is thus expected that this approach will be very well suited to the analysis of multi-tracer and/or multi-modality data and to relating the outcomes to different aspects of disease.
Background: Intraputamenal glial cell line-derived neurotrophic factor (GDNF), administered every... more Background: Intraputamenal glial cell line-derived neurotrophic factor (GDNF), administered every 4 weeks to patients with moderately advanced Parkinson's disease, did not show significant clinical improvements against placebo at 40 weeks, although it significantly increased [ 18 F]DOPA uptake throughout the entire putamen. Objective: This open-label extension study explored the effects of continued (prior GDNF patients) or new (prior placebo patients) exposure to GDNF for another 40 weeks. Methods: Using the infusion protocol of the parent study, all patients received GDNF without disclosing prior treatment allocations (GDNF or placebo). The primary outcome was the percentage change from baseline to Week 80 in the OFF state Unified Parkinson's Disease Rating Scale (UPDRS) motor score. Results: All 41 parent study participants were enrolled. The primary outcome decreased by 26.7 ± 20.7% in patients on GDNF for 80 weeks (GDNF/GDNF; N = 21) and 27.6 ± 23.6% in patients on placebo for 40 weeks followed by GDNF for 40 weeks (placebo/GDNF, N = 20; least squares mean difference: 0.4%, 95% CI:-13.9, 14.6, p = 0.96). Secondary endpoints did not show significant differences between the groups at Week 80 either. Prespecified comparisons between GDNF/GDNF at Week
ABSTRACTBackgroundThe benefits of exercise in PD have been linked to enhanced dopamine (DA) trans... more ABSTRACTBackgroundThe benefits of exercise in PD have been linked to enhanced dopamine (DA) transmission in the striatum.ObjectiveTo examine differences in DA release, reward signaling, and clinical features between habitual exercisers and sedentary subjects with PD.MethodsEight habitual exercisers and 9 sedentary subjects completed [11C]raclopride PET scans before and after stationary cycling to determine exercise‐induced release of endogenous DA in the dorsal striatum. Additionally, functional MRI assessed ventral striatum activation during reward anticipation. All participants completed motor (UPDRS III; finger tapping; and timed‐up‐and‐go) and nonmotor (Beck Depression Inventory; Starkstein Apathy Scale) assessments.Results[11C]Raclopride analysis before and after stationary cycling demonstrated greater DA release in the caudate nuclei of habitual exercisers compared to sedentary subjects (P < 0.05). Habitual exercisers revealed greater activation of ventral striatum during t...
We used positron emission tomography imaging with [ 11 C]-3-amino-4-(2-dimethylaminomethylphenyls... more We used positron emission tomography imaging with [ 11 C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile (DASB) and principal component analysis to investigate whether a specific Parkinson's disease (PD)related spatial covariance pattern could be identified for the serotonergic system. We also explored if nonmanifesting leucine-rich repeat kinase 2 (LRRK2) mutation carriers, with normal striatal dopaminergic innervation as measured with [ 11 C]-dihydrotetrabenazine (DTBZ), exhibit a distinct spatial covariance pattern compared to healthy controls and subjects with manifest PD. 15 subjects with sporadic PD, eight subjects with LRRK2 mutation-associated PD, nine LRRK2 non-manifesting mutation carriers, and nine healthy controls participated in the study. The analysis was applied to the DASB non-displaceable binding potential values evaluated in 42 pre-defined regions of interest. PD was found to be associated with a specific spatial covariance pattern, comprising relatively decreased DASB binding in the caudate, putamen and substantia nigra and relatively preserved binding in the hypothalamus and hippocampus; the expression of this pattern in PD subjects was significantly higher than in healthy controls (P < 0.001) and correlated significantly with disease duration (P < 0.01) and with DTBZ binding in the more affected putamen (P < 0.01). The LRRK2 non-manifesting mutation carriers expressed a different pattern, also significantly different from healthy controls (P < 0.001), comprising relatively decreased DASB binding in the pons, pedunculopontine nucleus, thalamus and rostral raphe nucleus, and with relatively preserved binding in the hypothalamus, amygdala, hippocampus and substantia nigra. This pattern was not present in either sporadic or LRRK2 mutation-associated PD subjects. These findings, although obtained with a relatively limited number of subjects, suggest that specific and overall distinct spatial serotonergic patterns may be associated with PD and LRRK2 mutations. Alterations in regions where relative upregulation is observed in both patterns may be indicative of compensatory mechanisms preceding or protecting from disease manifestation. 1. Introduction Parkinson's disease (PD) is the second most frequent progressive neurodegenerative disorder (de Lau and Breteler, 2006). The cardinal features are motor deficits, including tremor, rigidity and bradykinesia, traditionally associated with dopaminergic denervation in the substantia nigra (Stoessl et al., 2012). There is however increased recognition of the importance of the disease-induced non-motor symptoms. Some of these non-motor abnormalities, including autonomic dysfunction, sleep disturbance, cognitive impairment and depression, can precede the motor deficits by years or even decades (Schrag et al., 2015). The bases for these non-motor deficits are still unclear, but it is suggested that many of them may be associated with alterations of nondopaminergic neurotransmitter systems (Stoessl, 2009). In particular, several in-vivo and post-mortem studies support the hypothesis that progressive alterations of the serotonergic system may contribute to a number of such non-motor alterations (Politis and Loane, 2011). A large body of evidence has indeed been gathered from in-vivo PET studies
People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic a... more People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinson's disease and individuals with sporadic Parkinson's disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes. We did two cross-sectional PET studies at the Pacific Parkinson's Research Centre in Vancouver, BC, Canada. We included LRRK2 mutation carriers with or without manifest Parkinson's disease, people with sporadic Parkinson's disease, and age-matched healthy controls, all aged 18 years or older. People with Parkinson's disease were diagnosed by a neurologist with movement disorder training, in accordance with the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. In the first study, LRRK2 mutation c...
The main goal of dopamine cell replacement therapy in Parkinson's disease (PD) is to provide ... more The main goal of dopamine cell replacement therapy in Parkinson's disease (PD) is to provide clinical benefit mediated by graft survival with nigrostriatal reinnervation. We report a dichotomy between graft structure and clinical function in a patient dying sixteen years following fetal nigral grafting. A 55-year-old levodopa-responsive woman with PD received bilateral putamenal fetal mesencephalic grafts as part of an NIH-sponsored double-blind sham-controlled trial. The patient never experienced clinical benefit and her course was complicated by the development of graft-related dyskinesias. Fluorodopa positron emission tomography (FD-PET) demonstrated significant increases post-grafting bilaterally. She experienced worsening of parkinsonism with severe dyskinesias, and underwent STN-DBS 8 years after grafting. She died 16-years post-transplantation. Post-mortem analyses confirmed the diagnosis of PD and demonstrated >300,000 tyrosine hydroxylase (TH) positive grafted cells ...
Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2002
Background:We describe nine females with Rett Syndrome (RS), aged 14 to 26 years. All had had dev... more Background:We describe nine females with Rett Syndrome (RS), aged 14 to 26 years. All had had developmental delay before the end of their first year and had subsequently regressed to profound dementia with apraxia, ataxia, irregular respirations and often also seizures.Methods:The Revised Gesell developmental assessment and Alpern-Boll Developmental Profile were used in modified form. Volumetric measurements of basal ganglia using MRI were compared with the findings in nine age-matched volunteer females. Positron emission scans with [18F]-6-fluorodopa and [11C]-raclopride were performed under light anesthesia with intravenous Propofol, and the findings were compared with those in healthy control girls. Bidirectional sequencing of the coding regions of the MECP2 gene was investigated in blood samples for mutational analyses.Results:The RS females functioned at a mental age level ranging from about 4 to 15 months. The scores correlated with height, weight and head circumference. Magne...
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...
Objective-To describe clinical, positron emission tomography (PET), pathological, and genetic fin... more Objective-To describe clinical, positron emission tomography (PET), pathological, and genetic findings of a large kindred with progressive neurodegenerative phenotypes in which the proband had autopsy-confirmed corticobasal degeneration (CBD). Methods-Five family members, including the proband, were examined neurologically. Clinical information from the other family members was collected by questionnaires. Three individuals underwent PET with 11 C-dihydrotetrabenazine and 18 F-fludeoxyglucose. The proband was examined post-mortem. Genetic studies were performed. Results-The pedigree contains 64 individuals, including 8 affected patients. The inheritance is likely autosomal dominant with reduced penetrance. The proband developed progressive speech and language difficulties at the age of 64 years. Upon examination at the age of 68 years, she showed non-fluent aphasia, word-finding difficulties, circumlocution, frontal release signs, and right-sided bradykinesia, rigidity, and pyramidal signs. She died 5 years after disease onset. The neuropathology was consistent with CBD, including many cortical and subcortical astrocytic plaques. Other family members had progressive neurodegenerative phenotypes-two were
Background: To date, statistical methods that take into account fully the non-linear, longitudina... more Background: To date, statistical methods that take into account fully the non-linear, longitudinal and multivariate aspects of clinical data have not been applied to the study of progression in Parkinson's disease (PD). In this paper, we demonstrate the usefulness of such methodology for studying the temporal and spatial aspects of the progression of PD. Extending this methodology further, we also explore the presymptomatic course of this disease. Methods: Longitudinal Positron Emission Tomography (PET) measurements were collected on 78 PD patients, from 4 subregions on each side of the brain, using 3 different radiotracers. Non-linear, multivariate, longitudinal random effects modelling was applied to analyze and interpret these data. Results: The data showed a non-linear decline in PET measurements, which we modelled successfully by an exponential function depending on two patient-related covariates duration since symptom onset and age at symptom onset. We found that the degree of damage was significantly greater in the posterior putamen than in the anterior putamen throughout the disease. We also found that over the course of the illness, the difference between the less affected and more affected sides of the brain decreased in the anterior putamen. Younger patients had significantly poorer measurements than older patients at the time of symptom onset suggesting more effective compensatory mechanisms delaying the onset of symptoms. Cautious extrapolation showed that disease onset had occurred some 8 to 17 years prior to symptom onset. Conclusions: Our model provides important biological insights into the pathogenesis of PD, as well as its preclinical aspects. Our methodology can be applied widely to study many other chronic progressive diseases.
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Papers by Jon Stoessl