Donald Calne - Academia.edu (original) (raw)
Papers by Donald Calne
The Canadian Journal of Neurological Sciences Le Journal Canadien Des Sciences Neurologiques, May 1, 1988
We have studied 11 patients with neurological deficits due to the pandemic of encephalitis lethar... more We have studied 11 patients with neurological deficits due to the pandemic of encephalitis lethargica, all of whom had remained in hospital for more than forty years. Retrospective information obtained from physicians and nurses dating back as far as 1931, our own Webster and Northwestern University Disability Rating Scales available from 1976, photographic records, published narrative and hospital charts all indicate that neurological disabilities attributable to basal ganglia damage frequently increase in late life. Deterioration was most marked in motor function and largely spared the intellect, special senses and somatosensory system. The findings are discussed in relation to current hypotheses concerning the aetiology of Parkinson's disease.
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J Neurol Sci, 1989
Cultured human fetal sympathetic ganglion explants or adrenal chromaftin cell aggregates were imp... more Cultured human fetal sympathetic ganglion explants or adrenal chromaftin cell aggregates were implanted into the left striatum of monkeys whose left nigrostriatal pathway had been lesioned with the neurotoxin MPTP. There was no clinical reversal ofparkinsonian symptoms and PET scans did not show increased striatal fluorodopa uptake from pre-implant levels. At sacrifice, left striatal contents of dopamine were not statistically different from MPTP-treated but non-implanted controls. Histological examinations revealed pockets of extrinsic cells which were found at the end of needle tracks. There was no evidence of immune rejection. The extrinsic cells did not stain for tyrosine hydroxylase or neurofilament, suggesting that they were not dopaminergic neurons. The failure to reverse clinical parkinsonian symptoms highlights the stage of infancy of neural implantation in Parkinson's disease.
Jnm the Journal of Nuclear Medicine, 1994
humans to measure scan-to-scan variation in 1G. We also studiedthe variations of individual deter... more humans to measure scan-to-scan variation in 1G. We also studiedthe variations of individual determinants(emission data measured by the PET camera, blood radioactivityand measurements of the peripheral metabolites of FD) and their effectson 1G.
Annals of Neurology, 1994
Linkage studies were performed in three families (A, B, and C) with autosomal dominantly inherite... more Linkage studies were performed in three families (A, B, and C) with autosomal dominantly inherited parkinsonism affecting multiple members in three generations. Affected individuals exhibited the cardinal signs and symptoms of Parkinson's disease, with a mean age of onset of 51,62, and 61 years in Families A, B, and C, respectively. Parkinsonian symptoms responded to L-dopa treatment, and an {'aF76-fluoro-~-dopa positron emission tomography scan in 1 affected member of Family B showed decreased striatal uptake typical of Parkinson's disease. Ancestors of all three families were traced to a small region in northern Germany and southern Denmark, suggesting the possibility of a common mutation. Linkage studies were performed with polymorphic markers associated with the following candidate genes: the genes for glutathione peroxidase (GPX1, 3ql l), tyrosine hydroxylase (TH, 1 lp15.5), brain-derived neurotrophic factor (BDNF, llp14), catalase (CAT, 1 lp13), amyloid precursor protein (APP, 21q2 l), copper-zinc superoxide dismutase (SOD1, 21q21), and debrisoquin 4-hydroxylase (CYP2D6, 22q13.1). Summed lod scores for all families excluded linkage to the genes GPX1, TH, APP, SOD1, and CYP2D6, as well as to the chromosomal region containing the genes CAT and BDNF. If families were analyzed individually, exclusion was possible for two (Family A), six (Family B), and five (Family C) of the seven candidate genes. There was strong evidence against linkage for the remaining loci in all families analyzed individually, except for TH, which was uninformative in Families A and B, and CYP2D6, which gave slightly positive pairwise lod scores in Family A. Our results indicate that the candidate genes investigated are not involved in the etiology of parkinsonism in these families. Gasser T, Wszolek ZK, Trofatter J, Ozelius L, Uitti RJ, Lee CS, Gusella J, Pfeiffer RF, Calne DB, Breakefield XO. Genetic linkage studies in autosomal dominant parkinsonism: evaluation of seven candidate genes. Ann Neurol 1994;36:387-396 Parkinson's disease (PD) is characterized by a progressive neuronal degeneration, predominantly affecting dopaminergic neurons of the substantia nigra [If. The cause of this selective cell death is unknown. The possibility of a genetic contribution to the pathogenesis of PD recently received increased support [ 2 ) based on several lines of evidence. First, several inherited traits, such as monoamine oxidase A and B [ 3 , 41 and debrisoquin 4-hydroxylase [5], have specific allele states From the "Molecular
American Journal of Industrial Medicine, 1990
We compared personal histories of 57 cases and 122 age-matched controls to identify possible envi... more We compared personal histories of 57 cases and 122 age-matched controls to identify possible environmental determinants of Parkinson's disease (PD). Odds ratios (OR) adjusted for sex, age, and smoking were computed using stepwise logistic regression. We found a statistically significant increased risk for working in orchards (OR = 3.69, p = 0.012, 95% CI = 1.34, 10.27) and a marginally significant increased risk associated with working in planer mills (OR = 4.11, p = 0.065, 95% CI = 0.91, 18.50). A Fisher's exact test of the association between PD development and (1) paraquat contact, and (2) postural tremor gave statistically significant probability estimates of 0.01 and 0.03, respectively. The relative risk of PD decreased with smoking, an inverse relationship supported by many studies.
Annals of Neurology, 1992
Journal of the Neurological Sciences
Parkinsonism & Related Disorders, 2003
This study focuses on the potential protective effects of intracerebral adeno-viral mediated glia... more This study focuses on the potential protective effects of intracerebral adeno-viral mediated glial cell line derived neurotrophic factor (GDNF) gene transfer in a rat model of Parkinson's disease (PD). Thirty-five SD rats were divided into three groups to receive perinigral injections of recombinant adenovirus encoding GDNF (Ad-GDNF), LacZ (Ad-LacZ) or PBS, respectively. One week later, an intrastriatal injection of 6-hydroxydopamine
The Journal of otolaryngology, 2003
The reproducibilityof (±)-a-(11C) dihydrotetrabenazine (DTBZ) measuresin PET was studied in 10 h... more The reproducibilityof (±)-a-(11C) dihydrotetrabenazine (DTBZ) measuresin PET was studied in 10 healthyhumansubjects, aged22â€"76 y. Methods: The scan-to-scanvariationof several measuresusedin PETdataanalysiswasdetermined,including the radioactivityratio (target-to-reference), plasma-inputLogan total distributionvolume(DV),plasma-inputLogan @ and tissue-inputLogan B@JKIJ values. Results: The radioactivity ratios, plasma-inputB@,JK,J and tissue-inputBr,@R,JKJ all have higherreliabilitythan plasma-inputtotal DV values.In addition, measuresusingtheoccipitalcortexasthe referenceregionhave higherreliabilitythan the samemeasuresusingthe cerebellum as the referenceregion. Conclusion: Our results show that DTBZis
Advances in Behavioral Biology, 2008
Synapse, 1988
R. W M.), and the UBC/TRIUMF PET Project (M.J.A., TJ. R.), Vancouuer, British Columbia, Canada V ... more R. W M.), and the UBC/TRIUMF PET Project (M.J.A., TJ. R.), Vancouuer, British Columbia, Canada V 6 T 1 W5 KEY WORDS Parkinsonism, Nigrostriatal injury, In vivo detection
Synapse, 2003
The clinical evolution of Parkinson&a... more The clinical evolution of Parkinson's disease (PD) is known to be partly dependent on the age of onset. For example, motor complications associated with chronic dopaminomimetic treatment occur more often in younger patients. However, few attempts have been made to characterize the functional pathological differences underlying this age effect. We investigated the relationship between age and severity of nigrostriatal damage at onset of PD. Twenty patients with early PD (symptom duration <or=5 years) with onset before age 50 (n = 10) and with onset after age 50 (n = 10) were studied. The two groups were compared with respect to severity of nigrostriatal damage as evaluated by positron emission tomography (PET) scanning with 6-[(18)F]fluoro-L-dopa ([(18)F]-dopa), (+/-)-alpha-[(11)C]dihydrotetrabenazine ([(11)C]DTBZ), and d-threo-[(11)C]methylphenidate ([(11)C]MP). We found no significant differences between younger- and older-onset PD patients with regard to any of the three presynaptic markers. For putamen, the P-values corresponding to the different PET measurements ranged from P = 0.34 ([(18)F]-dopa) to P = 0.79 ([(11)C]DTBZ). However, after adjusting for treatment and PD duration, regression analysis showed that [(18)F]-dopa uptake correlated positively with age of onset (r = 0.59; P = 0.010). No correlation was found between [(11)C]DTBZ and [(11)C]MP binding potentials and age of onset (P = 0.26 and P = 0.90, respectively). These data suggest that age-of-onset-dependent differences in clinical evolution are not likely to reflect early differences in nigrostriatal pathology in PD. Age-related differences in [(18)F]-dopa uptake may be related to changes in dopamine turnover.
Synapse, 1998
Radioligand binding studies in animals have demonstrated age-related loss of dopamine receptors i... more Radioligand binding studies in animals have demonstrated age-related loss of dopamine receptors in the caudate and putamen. In humans, while age-related declines in dopamine D2 receptors have been consistently reported, the effects of ageing on D1 receptors have been controversial. We used positron emission tomography (PET) with [11C]SCH 23390 to investigate dopamine D1 receptor binding in 21 normal volunteers aged 22-74 years. We also assessed their motor function with a Modified Columbia Score (MCS) and the Purdue Pegboard Test (PPBT). D1 binding potentials were derived using a graphical analysis with a cerebellar tissue input function. Standard linear regression techniques were used to determine the age-related rate of decline of D1 binding. We found an age-dependent decrease of D1 receptor binding in the caudate (6.9% per decade) and putamen (7.4% per decade). There was also a significant inverse correlation between [11C]SCH 23390 binding in the occipital cortex and age (8.6% decline per decade). PPBT score also decreased with age (P = 0.007). There was a direct correlation between PPBT score and D1 binding potential. We conclude that dopamine D1 receptor density declines with age and that the effects of physiological ageing may play a role in the expression of extrapyramidal disorders in the elderly.
Synapse, 2003
dopamine turnover; [ 11 C]dihydrotetrabenazine; [ 11 C]raclopride ABSTRACT Dopa-responsive dyston... more dopamine turnover; [ 11 C]dihydrotetrabenazine; [ 11 C]raclopride ABSTRACT Dopa-responsive dystonia (DRD) is a lifelong disorder in which dopamine deficiency is not associated with neuronal loss and therefore it is an ideal human model for investigating the compensatory changes that occur in response to this biochemical abnormality. Using positron emission tomography (PET), we examined the (Ϯ)-␣-[ 11 C]dihydrotetrabenazine ([ 11 C]DTBZ) binding potential of untreated DRD patients and normal controls. Two other PET markers of presynaptic nigrostriatal function, d-threo-[ 11 C]methylphenidate ([ 11 C]MP) and 6-[ 18 F]fluoro-L-dopa ([ 18 F]-dopa), and [ 11 C]raclopride were also used in the study. We found increased [ 11 C]DTBZ binding potential in the striatum of DRD patients. By contrast, no significant changes were detected in either [ 11 C]MP binding potential or [ 18 F]-dopa uptake rate constant. In addition, we found evidence for increased dopamine turnover in one DRD patient by examining changes in [ 11 C]raclopride binding potential in relation to levodopa treatment. We propose that the increase in [ 11 C]DTBZ binding likely reflects the dramatic decrease in the intravesicular concentration of dopamine that occurs in DRD; upregulation of vesicular monoamine transporter type 2 (VMAT2) expression may also contribute. Our findings suggest that the striatal expression of VMAT2 (as estimated by [ 11 C]DTBZ binding) is not coregulated with dopamine synthesis. This is in keeping with a role for VMAT2 in other cellular processes (i.e., sequestration and release from the cell of potential toxic products), in addition to its importance for the quantal release of monoamines. Synapse 49:20 -28, 2003.
Parkinsonism & Related Disorders, 2009
Patients with Leucine-rich repeat kinase 2 (LRRK2) linked Parkinson&a... more Patients with Leucine-rich repeat kinase 2 (LRRK2) linked Parkinson's disease (PD) clinically present with typical idiopathic PD. However, LRRK2-linked PD displays a pleomorphic neuropathology and high variability in age at disease onset (AAO) which suggests that environmental and/or genetic factors other than the mutation itself influence the course of the disease. We investigated the modulation of AAO by genetic factors including the mutation-containing domain and PD associated polymorphisms in the gene coding alpha-synuclein (SNCA) and tau (MAPT) in 44 patients from 19 affected families. Using this limited number of available LRRK2 mutation carriers, we provide evidence that mutations in the kinase domain of Lrrk2 significantly decrease AAO compared to mutations in the ROC (Ras/GTPase of complex proteins) domain. Furthermore, polymorphic variations in MAPT show a significant association with AAO in individuals with LRRK2 mutations. Our results await replication in future studies with a larger number of LRRK2 mutation carriers, but indicate an association of mutation-affected protein domain and mutation-extrinsic genetic factors with AAO and suggest that these factors could contribute to explain the phenotypic heterogeneity observed in LRRK2-linked PD.
Parkinsonism & Related Disorders, 2004
Genetically-derived neurodegenerative disorders offer a rare opportunity to test validity of neur... more Genetically-derived neurodegenerative disorders offer a rare opportunity to test validity of neuropathological criteria for diagnosis. Implications regarding an autosomal dominant neurodegenerative disorder (PARK 8) in which four different neuropathological diagnoses were found at autopsy are discussed. We suggest that just as there is currently no clinical 'gold standard' for Parkinson's disease, there is no pathological 'gold standard.' We conclude that in certain circumstances genetic studies may provide definitive arbitration of validity of clinical and pathological diagnostic criteria.
Parkinsonism & Related Disorders, 2009
Objective-Autosomal dominant parkinsonism, hypoventilation, depression and severe weight loss (Pe... more Objective-Autosomal dominant parkinsonism, hypoventilation, depression and severe weight loss (Perry syndrome) is an early-onset rapidly progressive disease. At autopsy, previous studies have found severe neuronal loss in the substantia nigra without Lewy bodies. Transactive response DNAbinding protein of 43 kDa (TDP-43) has recently been identified as a major ubiquitinated constituent of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. This study reports clinical, genetic and neuropathologic investigations of Perry syndrome.
Parkinsonism & Related Disorders, 2003
We examined the clinical features of familial (n = 26) and sporadic (n = 52) Parkinson's ... more We examined the clinical features of familial (n = 26) and sporadic (n = 52) Parkinson's disease (PD) in patients presenting over the age of 40 years. Familial PD cases were tested for alpha-synuclein or parkin mutations as appropriate. No mutations were found in any of the families investigated. We found no between-group differences in the age at onset of PD, the pattern or severity of parkinsonian features, the dose of antiparkinsonian medications or treatment related complications. Cases of familial and sporadic PD in our cohort of patients display similar clinical features. This may suggest similar etiologies for both familial and sporadic PD.
The Canadian Journal of Neurological Sciences Le Journal Canadien Des Sciences Neurologiques, May 1, 1988
We have studied 11 patients with neurological deficits due to the pandemic of encephalitis lethar... more We have studied 11 patients with neurological deficits due to the pandemic of encephalitis lethargica, all of whom had remained in hospital for more than forty years. Retrospective information obtained from physicians and nurses dating back as far as 1931, our own Webster and Northwestern University Disability Rating Scales available from 1976, photographic records, published narrative and hospital charts all indicate that neurological disabilities attributable to basal ganglia damage frequently increase in late life. Deterioration was most marked in motor function and largely spared the intellect, special senses and somatosensory system. The findings are discussed in relation to current hypotheses concerning the aetiology of Parkinson's disease.
J Neurol Sci, 1989
Cultured human fetal sympathetic ganglion explants or adrenal chromaftin cell aggregates were imp... more Cultured human fetal sympathetic ganglion explants or adrenal chromaftin cell aggregates were implanted into the left striatum of monkeys whose left nigrostriatal pathway had been lesioned with the neurotoxin MPTP. There was no clinical reversal ofparkinsonian symptoms and PET scans did not show increased striatal fluorodopa uptake from pre-implant levels. At sacrifice, left striatal contents of dopamine were not statistically different from MPTP-treated but non-implanted controls. Histological examinations revealed pockets of extrinsic cells which were found at the end of needle tracks. There was no evidence of immune rejection. The extrinsic cells did not stain for tyrosine hydroxylase or neurofilament, suggesting that they were not dopaminergic neurons. The failure to reverse clinical parkinsonian symptoms highlights the stage of infancy of neural implantation in Parkinson's disease.
Jnm the Journal of Nuclear Medicine, 1994
humans to measure scan-to-scan variation in 1G. We also studiedthe variations of individual deter... more humans to measure scan-to-scan variation in 1G. We also studiedthe variations of individual determinants(emission data measured by the PET camera, blood radioactivityand measurements of the peripheral metabolites of FD) and their effectson 1G.
Annals of Neurology, 1994
Linkage studies were performed in three families (A, B, and C) with autosomal dominantly inherite... more Linkage studies were performed in three families (A, B, and C) with autosomal dominantly inherited parkinsonism affecting multiple members in three generations. Affected individuals exhibited the cardinal signs and symptoms of Parkinson's disease, with a mean age of onset of 51,62, and 61 years in Families A, B, and C, respectively. Parkinsonian symptoms responded to L-dopa treatment, and an {'aF76-fluoro-~-dopa positron emission tomography scan in 1 affected member of Family B showed decreased striatal uptake typical of Parkinson's disease. Ancestors of all three families were traced to a small region in northern Germany and southern Denmark, suggesting the possibility of a common mutation. Linkage studies were performed with polymorphic markers associated with the following candidate genes: the genes for glutathione peroxidase (GPX1, 3ql l), tyrosine hydroxylase (TH, 1 lp15.5), brain-derived neurotrophic factor (BDNF, llp14), catalase (CAT, 1 lp13), amyloid precursor protein (APP, 21q2 l), copper-zinc superoxide dismutase (SOD1, 21q21), and debrisoquin 4-hydroxylase (CYP2D6, 22q13.1). Summed lod scores for all families excluded linkage to the genes GPX1, TH, APP, SOD1, and CYP2D6, as well as to the chromosomal region containing the genes CAT and BDNF. If families were analyzed individually, exclusion was possible for two (Family A), six (Family B), and five (Family C) of the seven candidate genes. There was strong evidence against linkage for the remaining loci in all families analyzed individually, except for TH, which was uninformative in Families A and B, and CYP2D6, which gave slightly positive pairwise lod scores in Family A. Our results indicate that the candidate genes investigated are not involved in the etiology of parkinsonism in these families. Gasser T, Wszolek ZK, Trofatter J, Ozelius L, Uitti RJ, Lee CS, Gusella J, Pfeiffer RF, Calne DB, Breakefield XO. Genetic linkage studies in autosomal dominant parkinsonism: evaluation of seven candidate genes. Ann Neurol 1994;36:387-396 Parkinson's disease (PD) is characterized by a progressive neuronal degeneration, predominantly affecting dopaminergic neurons of the substantia nigra [If. The cause of this selective cell death is unknown. The possibility of a genetic contribution to the pathogenesis of PD recently received increased support [ 2 ) based on several lines of evidence. First, several inherited traits, such as monoamine oxidase A and B [ 3 , 41 and debrisoquin 4-hydroxylase [5], have specific allele states From the "Molecular
American Journal of Industrial Medicine, 1990
We compared personal histories of 57 cases and 122 age-matched controls to identify possible envi... more We compared personal histories of 57 cases and 122 age-matched controls to identify possible environmental determinants of Parkinson's disease (PD). Odds ratios (OR) adjusted for sex, age, and smoking were computed using stepwise logistic regression. We found a statistically significant increased risk for working in orchards (OR = 3.69, p = 0.012, 95% CI = 1.34, 10.27) and a marginally significant increased risk associated with working in planer mills (OR = 4.11, p = 0.065, 95% CI = 0.91, 18.50). A Fisher's exact test of the association between PD development and (1) paraquat contact, and (2) postural tremor gave statistically significant probability estimates of 0.01 and 0.03, respectively. The relative risk of PD decreased with smoking, an inverse relationship supported by many studies.
Annals of Neurology, 1992
Journal of the Neurological Sciences
Parkinsonism & Related Disorders, 2003
This study focuses on the potential protective effects of intracerebral adeno-viral mediated glia... more This study focuses on the potential protective effects of intracerebral adeno-viral mediated glial cell line derived neurotrophic factor (GDNF) gene transfer in a rat model of Parkinson's disease (PD). Thirty-five SD rats were divided into three groups to receive perinigral injections of recombinant adenovirus encoding GDNF (Ad-GDNF), LacZ (Ad-LacZ) or PBS, respectively. One week later, an intrastriatal injection of 6-hydroxydopamine
The Journal of otolaryngology, 2003
The reproducibilityof (±)-a-(11C) dihydrotetrabenazine (DTBZ) measuresin PET was studied in 10 h... more The reproducibilityof (±)-a-(11C) dihydrotetrabenazine (DTBZ) measuresin PET was studied in 10 healthyhumansubjects, aged22â€"76 y. Methods: The scan-to-scanvariationof several measuresusedin PETdataanalysiswasdetermined,including the radioactivityratio (target-to-reference), plasma-inputLogan total distributionvolume(DV),plasma-inputLogan @ and tissue-inputLogan B@JKIJ values. Results: The radioactivity ratios, plasma-inputB@,JK,J and tissue-inputBr,@R,JKJ all have higherreliabilitythan plasma-inputtotal DV values.In addition, measuresusingtheoccipitalcortexasthe referenceregionhave higherreliabilitythan the samemeasuresusingthe cerebellum as the referenceregion. Conclusion: Our results show that DTBZis
Advances in Behavioral Biology, 2008
Synapse, 1988
R. W M.), and the UBC/TRIUMF PET Project (M.J.A., TJ. R.), Vancouuer, British Columbia, Canada V ... more R. W M.), and the UBC/TRIUMF PET Project (M.J.A., TJ. R.), Vancouuer, British Columbia, Canada V 6 T 1 W5 KEY WORDS Parkinsonism, Nigrostriatal injury, In vivo detection
Synapse, 2003
The clinical evolution of Parkinson&a... more The clinical evolution of Parkinson's disease (PD) is known to be partly dependent on the age of onset. For example, motor complications associated with chronic dopaminomimetic treatment occur more often in younger patients. However, few attempts have been made to characterize the functional pathological differences underlying this age effect. We investigated the relationship between age and severity of nigrostriatal damage at onset of PD. Twenty patients with early PD (symptom duration <or=5 years) with onset before age 50 (n = 10) and with onset after age 50 (n = 10) were studied. The two groups were compared with respect to severity of nigrostriatal damage as evaluated by positron emission tomography (PET) scanning with 6-[(18)F]fluoro-L-dopa ([(18)F]-dopa), (+/-)-alpha-[(11)C]dihydrotetrabenazine ([(11)C]DTBZ), and d-threo-[(11)C]methylphenidate ([(11)C]MP). We found no significant differences between younger- and older-onset PD patients with regard to any of the three presynaptic markers. For putamen, the P-values corresponding to the different PET measurements ranged from P = 0.34 ([(18)F]-dopa) to P = 0.79 ([(11)C]DTBZ). However, after adjusting for treatment and PD duration, regression analysis showed that [(18)F]-dopa uptake correlated positively with age of onset (r = 0.59; P = 0.010). No correlation was found between [(11)C]DTBZ and [(11)C]MP binding potentials and age of onset (P = 0.26 and P = 0.90, respectively). These data suggest that age-of-onset-dependent differences in clinical evolution are not likely to reflect early differences in nigrostriatal pathology in PD. Age-related differences in [(18)F]-dopa uptake may be related to changes in dopamine turnover.
Synapse, 1998
Radioligand binding studies in animals have demonstrated age-related loss of dopamine receptors i... more Radioligand binding studies in animals have demonstrated age-related loss of dopamine receptors in the caudate and putamen. In humans, while age-related declines in dopamine D2 receptors have been consistently reported, the effects of ageing on D1 receptors have been controversial. We used positron emission tomography (PET) with [11C]SCH 23390 to investigate dopamine D1 receptor binding in 21 normal volunteers aged 22-74 years. We also assessed their motor function with a Modified Columbia Score (MCS) and the Purdue Pegboard Test (PPBT). D1 binding potentials were derived using a graphical analysis with a cerebellar tissue input function. Standard linear regression techniques were used to determine the age-related rate of decline of D1 binding. We found an age-dependent decrease of D1 receptor binding in the caudate (6.9% per decade) and putamen (7.4% per decade). There was also a significant inverse correlation between [11C]SCH 23390 binding in the occipital cortex and age (8.6% decline per decade). PPBT score also decreased with age (P = 0.007). There was a direct correlation between PPBT score and D1 binding potential. We conclude that dopamine D1 receptor density declines with age and that the effects of physiological ageing may play a role in the expression of extrapyramidal disorders in the elderly.
Synapse, 2003
dopamine turnover; [ 11 C]dihydrotetrabenazine; [ 11 C]raclopride ABSTRACT Dopa-responsive dyston... more dopamine turnover; [ 11 C]dihydrotetrabenazine; [ 11 C]raclopride ABSTRACT Dopa-responsive dystonia (DRD) is a lifelong disorder in which dopamine deficiency is not associated with neuronal loss and therefore it is an ideal human model for investigating the compensatory changes that occur in response to this biochemical abnormality. Using positron emission tomography (PET), we examined the (Ϯ)-␣-[ 11 C]dihydrotetrabenazine ([ 11 C]DTBZ) binding potential of untreated DRD patients and normal controls. Two other PET markers of presynaptic nigrostriatal function, d-threo-[ 11 C]methylphenidate ([ 11 C]MP) and 6-[ 18 F]fluoro-L-dopa ([ 18 F]-dopa), and [ 11 C]raclopride were also used in the study. We found increased [ 11 C]DTBZ binding potential in the striatum of DRD patients. By contrast, no significant changes were detected in either [ 11 C]MP binding potential or [ 18 F]-dopa uptake rate constant. In addition, we found evidence for increased dopamine turnover in one DRD patient by examining changes in [ 11 C]raclopride binding potential in relation to levodopa treatment. We propose that the increase in [ 11 C]DTBZ binding likely reflects the dramatic decrease in the intravesicular concentration of dopamine that occurs in DRD; upregulation of vesicular monoamine transporter type 2 (VMAT2) expression may also contribute. Our findings suggest that the striatal expression of VMAT2 (as estimated by [ 11 C]DTBZ binding) is not coregulated with dopamine synthesis. This is in keeping with a role for VMAT2 in other cellular processes (i.e., sequestration and release from the cell of potential toxic products), in addition to its importance for the quantal release of monoamines. Synapse 49:20 -28, 2003.
Parkinsonism & Related Disorders, 2009
Patients with Leucine-rich repeat kinase 2 (LRRK2) linked Parkinson&a... more Patients with Leucine-rich repeat kinase 2 (LRRK2) linked Parkinson's disease (PD) clinically present with typical idiopathic PD. However, LRRK2-linked PD displays a pleomorphic neuropathology and high variability in age at disease onset (AAO) which suggests that environmental and/or genetic factors other than the mutation itself influence the course of the disease. We investigated the modulation of AAO by genetic factors including the mutation-containing domain and PD associated polymorphisms in the gene coding alpha-synuclein (SNCA) and tau (MAPT) in 44 patients from 19 affected families. Using this limited number of available LRRK2 mutation carriers, we provide evidence that mutations in the kinase domain of Lrrk2 significantly decrease AAO compared to mutations in the ROC (Ras/GTPase of complex proteins) domain. Furthermore, polymorphic variations in MAPT show a significant association with AAO in individuals with LRRK2 mutations. Our results await replication in future studies with a larger number of LRRK2 mutation carriers, but indicate an association of mutation-affected protein domain and mutation-extrinsic genetic factors with AAO and suggest that these factors could contribute to explain the phenotypic heterogeneity observed in LRRK2-linked PD.
Parkinsonism & Related Disorders, 2004
Genetically-derived neurodegenerative disorders offer a rare opportunity to test validity of neur... more Genetically-derived neurodegenerative disorders offer a rare opportunity to test validity of neuropathological criteria for diagnosis. Implications regarding an autosomal dominant neurodegenerative disorder (PARK 8) in which four different neuropathological diagnoses were found at autopsy are discussed. We suggest that just as there is currently no clinical 'gold standard' for Parkinson's disease, there is no pathological 'gold standard.' We conclude that in certain circumstances genetic studies may provide definitive arbitration of validity of clinical and pathological diagnostic criteria.
Parkinsonism & Related Disorders, 2009
Objective-Autosomal dominant parkinsonism, hypoventilation, depression and severe weight loss (Pe... more Objective-Autosomal dominant parkinsonism, hypoventilation, depression and severe weight loss (Perry syndrome) is an early-onset rapidly progressive disease. At autopsy, previous studies have found severe neuronal loss in the substantia nigra without Lewy bodies. Transactive response DNAbinding protein of 43 kDa (TDP-43) has recently been identified as a major ubiquitinated constituent of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. This study reports clinical, genetic and neuropathologic investigations of Perry syndrome.
Parkinsonism & Related Disorders, 2003
We examined the clinical features of familial (n = 26) and sporadic (n = 52) Parkinson's ... more We examined the clinical features of familial (n = 26) and sporadic (n = 52) Parkinson's disease (PD) in patients presenting over the age of 40 years. Familial PD cases were tested for alpha-synuclein or parkin mutations as appropriate. No mutations were found in any of the families investigated. We found no between-group differences in the age at onset of PD, the pattern or severity of parkinsonian features, the dose of antiparkinsonian medications or treatment related complications. Cases of familial and sporadic PD in our cohort of patients display similar clinical features. This may suggest similar etiologies for both familial and sporadic PD.