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Kirk A Frey - One of the best experts on this subject based on the ideXlab platform.

  • A JOURNAL OF NEUROLOGY Assessment of mild dementia with amyloid and dopamine terminal positron emission tomography
    2016
    Co-Authors: James F Burke, Roger L Albin, Bruno Giordani, Michael R Kilbourn, Sid Gilman, Kirk A Frey
    Abstract:

    We assessed the relationship between consensus clinical diagnostic classification and neurochemical positron emission tomography imaging of striatal vesicular monoamine transporters and cerebrocortical deposition of ab-amyloid in mild dementia. Seventy-five subjects with mild dementia (Mini-Mental State Examination score5 18) underwent a conventional clinical evaluation followed by 11C-Dihydrotetrabenazine positron emission tomography imaging of striatal vesicular monoamine trans-porters and 11C-Pittsburgh compound-B positron emission tomography imaging of cerebrocortical ab-amyloid deposition. Clinical classifications were assigned by consensus of an experienced clinician panel. Neuroimaging classifications were assigned as Alzheimer’s disease, frontotemporal dementia or dementia with Lewy bodies on the basis of the combined 11C-Dihydrotetrabenazine and 11C-Pittsburgh compound-B results. Thirty-six subjects were classified clinically as having Alzheimer’s disease, 25 as having frontotemporal dementia and 14 as having dementia with Lewy bodies. Forty-seven subjects were classified by positron emission tomography neuroimaging as having Alzheimer’s disease, 15 as having dementia with Lewy bodies and 13 as having frontotemporal dementia. There was only moderate agreement between clinical consensus and neuroimaging classifications across all dementia subtypes, with discordant classifications in 35 % of subjects (Cohen’s = 0.39). Discordant classifications were least frequent in clinical consensus Alzheimer’s disease (17%), followed by dementi

  • advanced age cardiovascular risk burden and timed up and go test performance in parkinson disease
    Journals of Gerontology Series A-biological Sciences and Medical Sciences, 2014
    Co-Authors: Vikas Kotagal, Roger L Albin, Robert A Koeppe, Kirk A Frey, Martijn L T M Muller, Stephanie A Studenski, Nicolaas I Bohnen
    Abstract:

    Background Cardiovascular comorbidities are a known risk factor for impaired mobility in elderly individuals. Motor impairments in Parkinson disease are conventionally ascribed to nigrostriatal dopaminergic denervation although progressive gait and balance impairments become more common with aging and often show limited response to dopaminergic replacement therapies. Methods We explored the association between elevated cardiovascular risk factors and performance on the Timed Up and Go test in cross-sectional of Parkinson disease subjects (n = 83). Cardiovascular risk factor status was estimated using the Framingham General Cardiovascular Disease risk-scoring algorithm in order to dichotomize the cohort into those with and without elevated modifiable cardiovascular risk compared with normative scores for age and gender. All subjects underwent clinical and neuroimaging evaluations including a 3-m Timed Up and Go test, [(11)C]Dihydrotetrabenazine positron emission tomography imaging to estimate nigrostriatal dopamine terminal loss, and an magnetic resonance imaging assessment of leukoaraiosis. A similar analysis was performed in 49 healthy controls. Results After adjusting for disease duration, leukoaraiosis, and nigrostriatal dopaminergic denervation, Parkinson disease subjects with elevated Framingham risk scores (n = 61) displayed slower Timed Up and Go test performance (β = 1.86, t = 2.41, p = .018) compared with subjects with normal range Framingham risk scores (n = 22). When age ≥65 was added to the model in a post hoc analysis, the strength of effect seen with older age (β = 1.51, t = 2.44, p = .017) was similar to that of elevated Framingham risk scoring (β = 1.87, t = 2.51, p = .014). In a multivariable regression model studying the healthy control population, advanced age (t = 2.15, p = .037) was a significant predictor of Timed Up and Go speed though striatal [(11)C]Dihydrotetrabenazine (t = -1.30, p = .19) and elevated Framingham risk scores (t = 1.32, p = .19) were not. Conclusions Modifiable cardiovascular risk factors and older age may independently exacerbate balance-related disability in Parkinson disease and may exert additive or synergistic pathological effects. The pathophysiology of these impairments cannot be explained completely by nigrostriatal dopaminergic denervation or leukoaraiosis burden and may relate to systemic factors seen with accelerated aging.

  • assessment of mild dementia with amyloid and dopamine terminal positron emission tomography
    Brain, 2011
    Co-Authors: James F Burke, Roger L Albin, Robert A Koeppe, Bruno Giordani, Michael R Kilbourn, Sid Gilman, Kirk A Frey
    Abstract:

    We assessed the relationship between consensus clinical diagnostic classification and neurochemical positron emission tomography imaging of striatal vesicular monoamine transporters and cerebrocortical deposition of aβ-amyloid in mild dementia. Seventy-five subjects with mild dementia (Mini-Mental State Examination score ≥ 18) underwent a conventional clinical evaluation followed by 11C-Dihydrotetrabenazine positron emission tomography imaging of striatal vesicular monoamine transporters and 11C-Pittsburgh compound-B positron emission tomography imaging of cerebrocortical aβ-amyloid deposition. Clinical classifications were assigned by consensus of an experienced clinician panel. Neuroimaging classifications were assigned as Alzheimer’s disease, frontotemporal dementia or dementia with Lewy bodies on the basis of the combined 11C-Dihydrotetrabenazine and 11C-Pittsburgh compound-B results. Thirty-six subjects were classified clinically as having Alzheimer’s disease, 25 as having frontotemporal dementia and 14 as having dementia with Lewy bodies. Forty-seven subjects were classified by positron emission tomography neuroimaging as having Alzheimer’s disease, 15 as having dementia with Lewy bodies and 13 as having frontotemporal dementia. There was only moderate agreement between clinical consensus and neuroimaging classifications across all dementia subtypes, with discordant classifications in ∼35% of subjects (Cohen’s κ = 0.39). Discordant classifications were least frequent in clinical consensus Alzheimer’s disease (17%), followed by dementia with Lewy bodies (29%) and were most common in frontotemporal dementia (64%). Accurate clinical classification of mild neurodegenerative dementia is challenging. Though additional post-mortem correlations are required, positron emission tomography imaging likely distinguishes subgroups corresponding to neurochemically defined pathologies. Use of these positron emission tomography imaging methods may augment clinical classifications and allow selection of more uniform subject groups in disease-modifying therapeutic trials and other prospective research involving subjects in the early stages of dementia. * Abbreviations : APOE4  :  apolipoprotein e 4 allele DVR  :  distribution volume ratio PiB  :  Pittsburgh compound B

  • comparing fludeoxyglucose f18 pet assessment of regional cerebral glucose metabolism and 11c Dihydrotetrabenazine pet in evaluation of early dementia and mild cognitive impairment
    JAMA Neurology, 2010
    Co-Authors: Roger L Albin, James F Burke, Robert A Koeppe, Bruno Giordani, Michael R Kilbourn, Sid Gilman, Kirk A Frey
    Abstract:

    Objective To compare assessment of regional cerebral metabolic changes with [ 11 C]Dihydrotetrabenazine (DTBZ)–positron emission tomography (PET) measurement of regional cerebral blood flow (K 1 ) and fludeoxyglucose F18 (FDG)–PET measurement of regional cerebral glucose uptake (CMR glc ) in a clinically representative sample of subjects with mild dementia and mild cognitive impairment (MCI). Design [ 11 C]Dihydrotetrabenazine-PET K 1 and FDG-PET CMR glc measurements were performed. Setting University-based cognitive disorders clinic. Participants Fifty subjects with either mild dementia (Mini-Mental State Examination score ≥ 18) or MCI. Their results were compared with those of 80 normal control subjects. Main Outcome Measures The DTBZ-PET regional K 1 and FDG-PET CMR glc measurements were compared with standard correlation analysis. The overall patterns of DTBZ-PET K 1 and FDG-PET CMR glc deficits were assessed with stereotaxic surface projections (SSPs) of parametric images. Results The DTBZ-PET regional K 1 and FDG-PET CMR glc measurements were highly correlated, both within and between subjects. The SSP maps of deficits in DTBZ-PET regional K 1 and FDG-PET CMR glc measurements were markedly similar. The DTBZ-PET K 1 SSP maps exhibited a mild decrease in sensitivity relative to FDG-PET CMR glc maps. Conclusions Both DTBZ-PET K 1 and FDG-PET CMR glc measurements provide comparable information in assessment of regional cerebral metabolic deficits in mild dementia and MCI. Blood flow measures can assess regional cerebral metabolism deficits accurately in mild dementia and MCI. Blood flow assessments of regional cerebral metabolic deficits can be combined with tracer binding results to improve utility of PET imaging in mild dementia and MCI.

  • in vivo 11c Dihydrotetrabenazine binding in rat striatum sensitivity to dopamine concentrations
    Nuclear Medicine and Biology, 2010
    Co-Authors: Michael R Kilbourn, Phillip Sherman, Elizabeth R Butch, Timothy J Desmond, Paul L Harris, Kirk A Frey
    Abstract:

    Abstract Introduction The sensitivity of the in vivo binding of [ 11 C]Dihydrotetrabenazine ([ 11 C]DTBZ) and [ 11 C]methylphenidate ([ 11 C]MPH) to their respective targets — vesicular monoamine transporter type 2 (VMAT2) and neuronal membrane dopamine transporter — after alterations in endogenous levels of dopamine was examined in the rat brain. Methods In vivo binding of [ 11 C]DTBZ and [ 11 C]MPH was determined using a bolus+infusion protocol. The in vitro number of VMAT2 binding sites was determined by autoradiography. Results Repeated dosing with α-methyl- p -tyrosine (AMPT) at doses that significantly (−75%) depleted brain tissue dopamine levels resulted in increased (+36%) in vivo [ 11 C]DTBZ binding to VMAT2 in the striatum. The increase in binding could be completely reversed via treatment with l-DOPA/benserazide to restore dopamine levels. There were no changes in the total number of VMAT2 binding sites, as measured using in vitro autoradiography. No changes were observed for in vivo [ 11 C]MPH binding to the dopamine transporter in the striatum following AMPT pretreatment. Conclusion These results indicate that large reductions in dopamine concentrations in the rat brain can produce modest but significant changes in the binding of radioligands to VMAT2, which can be reversed by replenishment of dopamine using exogenous l-DOPA.

Michael R Kilbourn - One of the best experts on this subject based on the ideXlab platform.

  • In Vivo Measures of Dopaminergic Radioligands in the Rat Brain: Equilibrium Infusion Studies
    2016
    Co-Authors: Michael R Kilbourn, Phillip S. Sherman, Kyle Kuszpit
    Abstract:

    KEY WORDS transporter; dopamine; vesicular monoamine; carbon radioisotopes ABSTRACT The application of an equilibrium infusion method for measuring spe-cific in vivo radioligand binding in the conscious rat brain was evaluated for two ligands of the dopaminergic system, (1)-a-[11C]Dihydrotetrabenazine (DTBZ) and d-threo-[11C]methylphenidate (MePhen). Both radioligands can be successfully utilized to reach equilibrium distributions in rat brain within 1 h; combinations of tritiated and carbon-11-labeled radiotracers can furthermore be used to obtain simultaneous measures of the neuronal membrane dopamine transporter (using [3H]MePhen) and vesicular mono-amine transporter (using [11C]DTBZ) in the same animal. These studies provided quantitative measures of distribution volume ratios, which represent specific radioli-gand binding. Stereospecificity of in vivo binding was demonstrated using equilibrium infusions of the low-affinity isomers of each ligand, (2)-a-[11C]Dihydrotetrabenazine (DTBZ) and l-threo-[11C]methylphenidate, both of which produced uniform brain distri-butions and no specific binding. Specific binding of (1)-a-[11C]Dihydrotetrabenazine was blocked by co-infusion of tetrabenazine, but was unaffected by administration of meth-ylphenidate, haloperidol, or apomorphine. Specific binding of d-threo-[11C]methylpheni-date, conversely, was blocked with unlabeled methylphenidate but not affected by tetrabenazine or the dopamine receptor ligands. Equilibrium measures of in vivo radio-ligand binding, as utilized in this study, offer a quantitative means to evaluate acute and chronic drug effects on in vivo radioligand binding in the rat brain. Synapse 43: 188–194, 2002. © 2002 Wiley-Liss, Inc

  • A JOURNAL OF NEUROLOGY Assessment of mild dementia with amyloid and dopamine terminal positron emission tomography
    2016
    Co-Authors: James F Burke, Roger L Albin, Bruno Giordani, Michael R Kilbourn, Sid Gilman, Kirk A Frey
    Abstract:

    We assessed the relationship between consensus clinical diagnostic classification and neurochemical positron emission tomography imaging of striatal vesicular monoamine transporters and cerebrocortical deposition of ab-amyloid in mild dementia. Seventy-five subjects with mild dementia (Mini-Mental State Examination score5 18) underwent a conventional clinical evaluation followed by 11C-Dihydrotetrabenazine positron emission tomography imaging of striatal vesicular monoamine trans-porters and 11C-Pittsburgh compound-B positron emission tomography imaging of cerebrocortical ab-amyloid deposition. Clinical classifications were assigned by consensus of an experienced clinician panel. Neuroimaging classifications were assigned as Alzheimer’s disease, frontotemporal dementia or dementia with Lewy bodies on the basis of the combined 11C-Dihydrotetrabenazine and 11C-Pittsburgh compound-B results. Thirty-six subjects were classified clinically as having Alzheimer’s disease, 25 as having frontotemporal dementia and 14 as having dementia with Lewy bodies. Forty-seven subjects were classified by positron emission tomography neuroimaging as having Alzheimer’s disease, 15 as having dementia with Lewy bodies and 13 as having frontotemporal dementia. There was only moderate agreement between clinical consensus and neuroimaging classifications across all dementia subtypes, with discordant classifications in 35 % of subjects (Cohen’s = 0.39). Discordant classifications were least frequent in clinical consensus Alzheimer’s disease (17%), followed by dementi

  • assessment of mild dementia with amyloid and dopamine terminal positron emission tomography
    Brain, 2011
    Co-Authors: James F Burke, Roger L Albin, Robert A Koeppe, Bruno Giordani, Michael R Kilbourn, Sid Gilman, Kirk A Frey
    Abstract:

    We assessed the relationship between consensus clinical diagnostic classification and neurochemical positron emission tomography imaging of striatal vesicular monoamine transporters and cerebrocortical deposition of aβ-amyloid in mild dementia. Seventy-five subjects with mild dementia (Mini-Mental State Examination score ≥ 18) underwent a conventional clinical evaluation followed by 11C-Dihydrotetrabenazine positron emission tomography imaging of striatal vesicular monoamine transporters and 11C-Pittsburgh compound-B positron emission tomography imaging of cerebrocortical aβ-amyloid deposition. Clinical classifications were assigned by consensus of an experienced clinician panel. Neuroimaging classifications were assigned as Alzheimer’s disease, frontotemporal dementia or dementia with Lewy bodies on the basis of the combined 11C-Dihydrotetrabenazine and 11C-Pittsburgh compound-B results. Thirty-six subjects were classified clinically as having Alzheimer’s disease, 25 as having frontotemporal dementia and 14 as having dementia with Lewy bodies. Forty-seven subjects were classified by positron emission tomography neuroimaging as having Alzheimer’s disease, 15 as having dementia with Lewy bodies and 13 as having frontotemporal dementia. There was only moderate agreement between clinical consensus and neuroimaging classifications across all dementia subtypes, with discordant classifications in ∼35% of subjects (Cohen’s κ = 0.39). Discordant classifications were least frequent in clinical consensus Alzheimer’s disease (17%), followed by dementia with Lewy bodies (29%) and were most common in frontotemporal dementia (64%). Accurate clinical classification of mild neurodegenerative dementia is challenging. Though additional post-mortem correlations are required, positron emission tomography imaging likely distinguishes subgroups corresponding to neurochemically defined pathologies. Use of these positron emission tomography imaging methods may augment clinical classifications and allow selection of more uniform subject groups in disease-modifying therapeutic trials and other prospective research involving subjects in the early stages of dementia. * Abbreviations : APOE4  :  apolipoprotein e 4 allele DVR  :  distribution volume ratio PiB  :  Pittsburgh compound B

  • rat pancreas uptake of 11c Dihydrotetrabenazine stereoisomers
    Nuclear Medicine and Biology, 2010
    Co-Authors: Michael R Kilbourn
    Abstract:

    Abstract (+)-α-[ 11 C]Dihydrotetrabenazine ((+)-[ 11 C]DTBZ), a radioligand for the vesicular monoamine transporter type 2 (VMAT2), has been previously proposed as an in vivo marker of beta-cell degeneration in the pancreas. The stereospecificity of uptake of [ 11 C]DTBZ into rat pancreas was examined here using radiolabeled forms of the (+)- and (−)-isomers. Pancreas localization of (+)-[ 11 C]DTBZ could be partially blocked by prior administration of unlabeled (+)-DTBZ. Pancreatic uptake of the (−)-isomer was unexpectedly high and could not be blocked by pretreatment with (+)-DTBZ, but could be significantly reduced by treatment with racemic tetrabenazine, an in vivo source of (−)-DTBZ. These studies indicate that the inactive isomer of DTBZ does not provide a mechanism for defining the nonspecific binding of (+)-DTBZ in rat pancreas.

  • comparing fludeoxyglucose f18 pet assessment of regional cerebral glucose metabolism and 11c Dihydrotetrabenazine pet in evaluation of early dementia and mild cognitive impairment
    JAMA Neurology, 2010
    Co-Authors: Roger L Albin, James F Burke, Robert A Koeppe, Bruno Giordani, Michael R Kilbourn, Sid Gilman, Kirk A Frey
    Abstract:

    Objective To compare assessment of regional cerebral metabolic changes with [ 11 C]Dihydrotetrabenazine (DTBZ)–positron emission tomography (PET) measurement of regional cerebral blood flow (K 1 ) and fludeoxyglucose F18 (FDG)–PET measurement of regional cerebral glucose uptake (CMR glc ) in a clinically representative sample of subjects with mild dementia and mild cognitive impairment (MCI). Design [ 11 C]Dihydrotetrabenazine-PET K 1 and FDG-PET CMR glc measurements were performed. Setting University-based cognitive disorders clinic. Participants Fifty subjects with either mild dementia (Mini-Mental State Examination score ≥ 18) or MCI. Their results were compared with those of 80 normal control subjects. Main Outcome Measures The DTBZ-PET regional K 1 and FDG-PET CMR glc measurements were compared with standard correlation analysis. The overall patterns of DTBZ-PET K 1 and FDG-PET CMR glc deficits were assessed with stereotaxic surface projections (SSPs) of parametric images. Results The DTBZ-PET regional K 1 and FDG-PET CMR glc measurements were highly correlated, both within and between subjects. The SSP maps of deficits in DTBZ-PET regional K 1 and FDG-PET CMR glc measurements were markedly similar. The DTBZ-PET K 1 SSP maps exhibited a mild decrease in sensitivity relative to FDG-PET CMR glc maps. Conclusions Both DTBZ-PET K 1 and FDG-PET CMR glc measurements provide comparable information in assessment of regional cerebral metabolic deficits in mild dementia and MCI. Blood flow measures can assess regional cerebral metabolism deficits accurately in mild dementia and MCI. Blood flow assessments of regional cerebral metabolic deficits can be combined with tracer binding results to improve utility of PET imaging in mild dementia and MCI.

Robert A Koeppe - One of the best experts on this subject based on the ideXlab platform.

  • advanced age cardiovascular risk burden and timed up and go test performance in parkinson disease
    Journals of Gerontology Series A-biological Sciences and Medical Sciences, 2014
    Co-Authors: Vikas Kotagal, Roger L Albin, Robert A Koeppe, Kirk A Frey, Martijn L T M Muller, Stephanie A Studenski, Nicolaas I Bohnen
    Abstract:

    Background Cardiovascular comorbidities are a known risk factor for impaired mobility in elderly individuals. Motor impairments in Parkinson disease are conventionally ascribed to nigrostriatal dopaminergic denervation although progressive gait and balance impairments become more common with aging and often show limited response to dopaminergic replacement therapies. Methods We explored the association between elevated cardiovascular risk factors and performance on the Timed Up and Go test in cross-sectional of Parkinson disease subjects (n = 83). Cardiovascular risk factor status was estimated using the Framingham General Cardiovascular Disease risk-scoring algorithm in order to dichotomize the cohort into those with and without elevated modifiable cardiovascular risk compared with normative scores for age and gender. All subjects underwent clinical and neuroimaging evaluations including a 3-m Timed Up and Go test, [(11)C]Dihydrotetrabenazine positron emission tomography imaging to estimate nigrostriatal dopamine terminal loss, and an magnetic resonance imaging assessment of leukoaraiosis. A similar analysis was performed in 49 healthy controls. Results After adjusting for disease duration, leukoaraiosis, and nigrostriatal dopaminergic denervation, Parkinson disease subjects with elevated Framingham risk scores (n = 61) displayed slower Timed Up and Go test performance (β = 1.86, t = 2.41, p = .018) compared with subjects with normal range Framingham risk scores (n = 22). When age ≥65 was added to the model in a post hoc analysis, the strength of effect seen with older age (β = 1.51, t = 2.44, p = .017) was similar to that of elevated Framingham risk scoring (β = 1.87, t = 2.51, p = .014). In a multivariable regression model studying the healthy control population, advanced age (t = 2.15, p = .037) was a significant predictor of Timed Up and Go speed though striatal [(11)C]Dihydrotetrabenazine (t = -1.30, p = .19) and elevated Framingham risk scores (t = 1.32, p = .19) were not. Conclusions Modifiable cardiovascular risk factors and older age may independently exacerbate balance-related disability in Parkinson disease and may exert additive or synergistic pathological effects. The pathophysiology of these impairments cannot be explained completely by nigrostriatal dopaminergic denervation or leukoaraiosis burden and may relate to systemic factors seen with accelerated aging.

  • assessment of mild dementia with amyloid and dopamine terminal positron emission tomography
    Brain, 2011
    Co-Authors: James F Burke, Roger L Albin, Robert A Koeppe, Bruno Giordani, Michael R Kilbourn, Sid Gilman, Kirk A Frey
    Abstract:

    We assessed the relationship between consensus clinical diagnostic classification and neurochemical positron emission tomography imaging of striatal vesicular monoamine transporters and cerebrocortical deposition of aβ-amyloid in mild dementia. Seventy-five subjects with mild dementia (Mini-Mental State Examination score ≥ 18) underwent a conventional clinical evaluation followed by 11C-Dihydrotetrabenazine positron emission tomography imaging of striatal vesicular monoamine transporters and 11C-Pittsburgh compound-B positron emission tomography imaging of cerebrocortical aβ-amyloid deposition. Clinical classifications were assigned by consensus of an experienced clinician panel. Neuroimaging classifications were assigned as Alzheimer’s disease, frontotemporal dementia or dementia with Lewy bodies on the basis of the combined 11C-Dihydrotetrabenazine and 11C-Pittsburgh compound-B results. Thirty-six subjects were classified clinically as having Alzheimer’s disease, 25 as having frontotemporal dementia and 14 as having dementia with Lewy bodies. Forty-seven subjects were classified by positron emission tomography neuroimaging as having Alzheimer’s disease, 15 as having dementia with Lewy bodies and 13 as having frontotemporal dementia. There was only moderate agreement between clinical consensus and neuroimaging classifications across all dementia subtypes, with discordant classifications in ∼35% of subjects (Cohen’s κ = 0.39). Discordant classifications were least frequent in clinical consensus Alzheimer’s disease (17%), followed by dementia with Lewy bodies (29%) and were most common in frontotemporal dementia (64%). Accurate clinical classification of mild neurodegenerative dementia is challenging. Though additional post-mortem correlations are required, positron emission tomography imaging likely distinguishes subgroups corresponding to neurochemically defined pathologies. Use of these positron emission tomography imaging methods may augment clinical classifications and allow selection of more uniform subject groups in disease-modifying therapeutic trials and other prospective research involving subjects in the early stages of dementia. * Abbreviations : APOE4  :  apolipoprotein e 4 allele DVR  :  distribution volume ratio PiB  :  Pittsburgh compound B

  • comparing fludeoxyglucose f18 pet assessment of regional cerebral glucose metabolism and 11c Dihydrotetrabenazine pet in evaluation of early dementia and mild cognitive impairment
    JAMA Neurology, 2010
    Co-Authors: Roger L Albin, James F Burke, Robert A Koeppe, Bruno Giordani, Michael R Kilbourn, Sid Gilman, Kirk A Frey
    Abstract:

    Objective To compare assessment of regional cerebral metabolic changes with [ 11 C]Dihydrotetrabenazine (DTBZ)–positron emission tomography (PET) measurement of regional cerebral blood flow (K 1 ) and fludeoxyglucose F18 (FDG)–PET measurement of regional cerebral glucose uptake (CMR glc ) in a clinically representative sample of subjects with mild dementia and mild cognitive impairment (MCI). Design [ 11 C]Dihydrotetrabenazine-PET K 1 and FDG-PET CMR glc measurements were performed. Setting University-based cognitive disorders clinic. Participants Fifty subjects with either mild dementia (Mini-Mental State Examination score ≥ 18) or MCI. Their results were compared with those of 80 normal control subjects. Main Outcome Measures The DTBZ-PET regional K 1 and FDG-PET CMR glc measurements were compared with standard correlation analysis. The overall patterns of DTBZ-PET K 1 and FDG-PET CMR glc deficits were assessed with stereotaxic surface projections (SSPs) of parametric images. Results The DTBZ-PET regional K 1 and FDG-PET CMR glc measurements were highly correlated, both within and between subjects. The SSP maps of deficits in DTBZ-PET regional K 1 and FDG-PET CMR glc measurements were markedly similar. The DTBZ-PET K 1 SSP maps exhibited a mild decrease in sensitivity relative to FDG-PET CMR glc maps. Conclusions Both DTBZ-PET K 1 and FDG-PET CMR glc measurements provide comparable information in assessment of regional cerebral metabolic deficits in mild dementia and MCI. Blood flow measures can assess regional cerebral metabolism deficits accurately in mild dementia and MCI. Blood flow assessments of regional cerebral metabolic deficits can be combined with tracer binding results to improve utility of PET imaging in mild dementia and MCI.

  • striatal 11c Dihydrotetrabenazine and 11c methylphenidate binding in tourette syndrome
    Neurology, 2009
    Co-Authors: Roger L Albin, Robert A Koeppe, Michael R Kilbourn, Kirk A Frey, Kristine Wernette, W Zhuang, Thomas E Nichols
    Abstract:

    Objective: Tourette syndrome (TS) is a common neurodevelopmental disorder marked by tics and behavioral comorbidities. Clinical pharmacology suggests that dopaminergic signaling abnormalities are part of the pathophysiology of TS. Prior molecular imaging studies of nigrostriatal dopaminergic terminal markers report conflicting results. Our goal was to characterize the distribution of nigrostriatal dopaminergic terminals in subjects with TS. Methods: Thirty-three adult subjects with TS were studied with PET using [11C]Dihydrotetrabenazine (DTBZ), a ligand for the type 2 vesicular monoamine transporter, and with [11C] methylphenidate (MP), a ligand for the plasmalemmal dopamine transporter. Subjects were characterized with standard rating instruments for tic severity, obsessive-compulsive behaviors, and attentional deficits. Results: We found no differences between subjects with TS and control subjects in DTBZ and MP binding in any striatal region. There was no correlation between binding measures and clinical variables. Ventral striatal DTBZ and MP binding distributions in subjects with TS were normal. Conclusions: We found no evidence of increased striatal dopaminergic innervation in Tourette syndrome (TS). Discrepancy between our present results and those of other studies may be explained by heterogeneity of TS.

  • decreased striatal dopaminergic innervation in rem sleep behavior disorder
    Neurology, 2000
    Co-Authors: Roger L Albin, Robert A Koeppe, Kirk A Frey, Ronald D Chervin, Flavia B Consens, Kristine Wernette, Michael S Aldrich
    Abstract:

    Article abstract—REM sleep behavior disorder (RBD) is a possible herald of neurodegenerative disorders with parkinsonism. The authors determined the density of striatal dopaminergic terminals with [ 11 C]Dihydrotetrabenazine PET in six elderly subjects with chronic idiopathic RBD and 19 age-appropriate controls. In subjects with RBD, there were significant reductions in striatal [ 11 C]Dihydrotetrabenazine binding, particularly in the posterior putamen.

Hank F Kung - One of the best experts on this subject based on the ideXlab platform.

  • deuterated 18f 9 o hexadeutero 3 fluoropropoxyl Dihydrotetrabenazine d6 fp dtbz a vesicular monoamine transporter 2 vmat2 imaging agent
    Nuclear Medicine and Biology, 2018
    Co-Authors: Lin Zhu, Seok Rye Choi, Karl Ploessl, Futao Liu, Zhihao Zha, Hank F Kung
    Abstract:

    Abstract Introduction Vesicular monoamine transporters 2 (VMAT2) in the brain serve as transporter for packaging monoamine in vesicles for normal CNS neurotransmission. Several VMAT2 imaging agents, [ 11 C]-(+)-DTBZ, Dihydrotetrabenazine and [ 18 F]FP-(+)-DTBZ (9-O-fluoropropyl-(+)-dihydro tetrabenazine, a.k.a. [ 18 F]AV-133), are useful for studying the changes in brain function related to monoamine transmission by in vivo imaging. Deuterated analogs have been reported targeting VMAT2 binding sites. Methods A novel deuterated [ 18 F]9-O-hexaduterofluoropropyl-(+)-Dihydrotetrabenazine, [ 18 F]D6-FP-(+)-DTBZ, [ 18 F] 1 , was prepared as a VMAT2 imaging agent. This 18 F agent which targeted VMAT2 was evaluated by in vitro binding, in vivo biodistribution and microPET imaging studies in rodents. Results The one step radiolabeling reaction led to the desired [ 18 F]D6-FP-(+)-DTBZ, [ 18 F] 1 , which showed excellent binding affinity to VMAT2 (Ki = 0.32 ± 0.07 nM) comparable to that of FP-(+)-DTBZ (Ki = 0.33 ± 0.02 nM) using [ 18 F]FP-(+)-DTBZ and rat striatum membrane homogenates. In vivo biodistribution in normal rats showed that 1 , exhibited excellent brain uptake and comparable high ratio of striatum to cerebellum (target/background) ratio at 1 hr after injection (ratio of 6.05 ± 0.43 vs 5.66 ± 0.72 for [ 18 F]FP-(+)-DTBZ vs [ 18 F] 1 , respectively). MicroPET imaging studies in rats further confirm that the striatum with high VMAT2 concentration was clearly delineated in normal rat brain after iv injection of [ 18 F] 1 . We observed minor changes of metabolism in rat plasma between these two agents; however, the changes showed little effect on regional brain uptake and retention. Conclusions The results reported here lend support for using [ 18 F]D6-FP-(+)-DTBZ, [ 18 F] 1 , as in vivo PET imaging agent for VMAT2 binding in the brain.

  • determination of the penetration of 9 fluoropropyl Dihydrotetrabenazine across the blood brain barrier in rats by microdialysis combined with liquid chromatography tandem mass spectrometry
    Journal of Chromatography B, 2011
    Co-Authors: Xue Zhou, Lin Zhu, Jinping Qiao, Wei Yin, Hank F Kung
    Abstract:

    Abstract To evaluate the penetration of the blood–brain barrier by 9-fluoropropyl-(+)-Dihydrotetrabenazine (AV-133), microdialysis probes were implanted simultaneously into rat blood and brain, and a liquid chromatography–tandem mass spectrometric method was developed and validated to monitor the AV-133 concentration in the microdialysates. The chromatographic separation was performed on an XTerra C 18 column (150 mm × 2.1 mm i.d., 5 μm particles) with gradient elution. The mass spectrometer was operated in positive mode using electrospray ionization. The analytes were measured using the multiple-reaction-monitoring mode. The calibration curves were linear over the range of 5.00–1000 ng/mL AV-133, with a coefficient of determination >0.995. The accuracies ranged from 99.5% to 105.0% and the precisions were

  • synthesis and biological evaluation of 3 alkyl Dihydrotetrabenazine derivatives as vesicular monoamine transporter 2 vmat2 ligands
    Bioorganic & Medicinal Chemistry Letters, 2011
    Co-Authors: Pinguan Zheng, Brian P Lieberman, Seok Rye Choi, Karl Ploessl, Hank F Kung
    Abstract:

    Abstract In the search of new probes for in vivo brain imaging of vesicular monoamine transporter type 2 (VMAT2), we have developed an efficient synthesis of a novel series of 3-alkyl-Dihydrotetrabenazine (DTBZ) derivatives. The affinity of VMAT2 was evaluated by an in vitro inhibitory binding assay using [ 125 I]-iodovinyl-TBZ or [ 18 F](+)-FP-DTBZ as radioligands in rat striatal tissue homogenates. New DTBZ derivatives exhibited moderate to good binding affinity to VMAT2. Among these new ligands, compound 4b showed the best affinity for VMAT2 ( K i  = 5.98 nM) and may be a useful lead compound for future structure–activity studies.

  • study the effect of a pseudo carrier on pharmacokinetics of 9 fluoropropyl Dihydrotetrabenazine in rat plasma by ultra performance liquid chromatography tandem mass spectrometry
    Journal of Chromatography B, 2011
    Co-Authors: Xue Zhou, Lin Zhu, Jinping Qiao, Wei Yin, Hank F Kung
    Abstract:

    To evaluate the effect of a pseudo-carrier (9-hydroxypropyl-(+)-Dihydrotetrabenazine, AV-149) on pharmacokinetics of 9-fluoropropyl-(+)-Dihydrotetrabenazine (AV-133), an ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method was developed and validated for the determination of AV-133 and AV-149 in rat plasma. AV-133 and AV-149 were extracted from plasma following protein precipitation. The chromatographic analysis was performed on an ACQUITY UPLC BEH™ C₁₈ column (50 mm x 2.1 mm x 1.7 μm) by a gradient elution. The mass spectrometer was operated in positive mode using electrospray ionization. The analytes were measured using the multiple reaction-monitoring mode (MRM). An external calibration was used, and the calibration curves were linear in the range of 1.00-800 ng/mL for AV-133 and AV-149. The accuracy ranged from 90.8% to 113.2% and the precision ranged from 2.7% to 9.9% for each analyte. The effect of a pseudo-carrier on pharmacokinetics of AV-133 was studied using the presented method.

  • synthesis and evaluation of 2 amino dihydrotetrabenzine derivatives as probes for imaging vesicular monoamine transporter 2
    Bioorganic & Medicinal Chemistry Letters, 2009
    Co-Authors: Lin Zhu, Jingying Liu, Hank F Kung
    Abstract:

    Abstract A novel series of analogs of 2-amino-Dihydrotetrabenazine derivatives, 4–6, targeting the vesicular monoamine transporter have been prepared. In vitro binding was carried out in tissue homogenates prepared from rat striatal tissue homogenates with both [125I]-iodovinyl-TBZ and [3H]DTBZ. There was a good correlation (r2 = 0.925) between the affinities of the different compounds for [125I]-iodovinyl-TBZ and [3H]-DTBZ binding. Compound 5 exhibited a better affinity for the vesicular monoamine transporter (Ki = 8.68 ± 1.26 nM and 7.01 ± 0.07 nM, respectively), which may be a good lead compound for further structural modification to develop useful probes for VMAT2.

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  • A JOURNAL OF NEUROLOGY Assessment of mild dementia with amyloid and dopamine terminal positron emission tomography
    2016
    Co-Authors: James F Burke, Roger L Albin, Bruno Giordani, Michael R Kilbourn, Sid Gilman, Kirk A Frey
    Abstract:

    We assessed the relationship between consensus clinical diagnostic classification and neurochemical positron emission tomography imaging of striatal vesicular monoamine transporters and cerebrocortical deposition of ab-amyloid in mild dementia. Seventy-five subjects with mild dementia (Mini-Mental State Examination score5 18) underwent a conventional clinical evaluation followed by 11C-Dihydrotetrabenazine positron emission tomography imaging of striatal vesicular monoamine trans-porters and 11C-Pittsburgh compound-B positron emission tomography imaging of cerebrocortical ab-amyloid deposition. Clinical classifications were assigned by consensus of an experienced clinician panel. Neuroimaging classifications were assigned as Alzheimer’s disease, frontotemporal dementia or dementia with Lewy bodies on the basis of the combined 11C-Dihydrotetrabenazine and 11C-Pittsburgh compound-B results. Thirty-six subjects were classified clinically as having Alzheimer’s disease, 25 as having frontotemporal dementia and 14 as having dementia with Lewy bodies. Forty-seven subjects were classified by positron emission tomography neuroimaging as having Alzheimer’s disease, 15 as having dementia with Lewy bodies and 13 as having frontotemporal dementia. There was only moderate agreement between clinical consensus and neuroimaging classifications across all dementia subtypes, with discordant classifications in 35 % of subjects (Cohen’s = 0.39). Discordant classifications were least frequent in clinical consensus Alzheimer’s disease (17%), followed by dementi

  • advanced age cardiovascular risk burden and timed up and go test performance in parkinson disease
    Journals of Gerontology Series A-biological Sciences and Medical Sciences, 2014
    Co-Authors: Vikas Kotagal, Roger L Albin, Robert A Koeppe, Kirk A Frey, Martijn L T M Muller, Stephanie A Studenski, Nicolaas I Bohnen
    Abstract:

    Background Cardiovascular comorbidities are a known risk factor for impaired mobility in elderly individuals. Motor impairments in Parkinson disease are conventionally ascribed to nigrostriatal dopaminergic denervation although progressive gait and balance impairments become more common with aging and often show limited response to dopaminergic replacement therapies. Methods We explored the association between elevated cardiovascular risk factors and performance on the Timed Up and Go test in cross-sectional of Parkinson disease subjects (n = 83). Cardiovascular risk factor status was estimated using the Framingham General Cardiovascular Disease risk-scoring algorithm in order to dichotomize the cohort into those with and without elevated modifiable cardiovascular risk compared with normative scores for age and gender. All subjects underwent clinical and neuroimaging evaluations including a 3-m Timed Up and Go test, [(11)C]Dihydrotetrabenazine positron emission tomography imaging to estimate nigrostriatal dopamine terminal loss, and an magnetic resonance imaging assessment of leukoaraiosis. A similar analysis was performed in 49 healthy controls. Results After adjusting for disease duration, leukoaraiosis, and nigrostriatal dopaminergic denervation, Parkinson disease subjects with elevated Framingham risk scores (n = 61) displayed slower Timed Up and Go test performance (β = 1.86, t = 2.41, p = .018) compared with subjects with normal range Framingham risk scores (n = 22). When age ≥65 was added to the model in a post hoc analysis, the strength of effect seen with older age (β = 1.51, t = 2.44, p = .017) was similar to that of elevated Framingham risk scoring (β = 1.87, t = 2.51, p = .014). In a multivariable regression model studying the healthy control population, advanced age (t = 2.15, p = .037) was a significant predictor of Timed Up and Go speed though striatal [(11)C]Dihydrotetrabenazine (t = -1.30, p = .19) and elevated Framingham risk scores (t = 1.32, p = .19) were not. Conclusions Modifiable cardiovascular risk factors and older age may independently exacerbate balance-related disability in Parkinson disease and may exert additive or synergistic pathological effects. The pathophysiology of these impairments cannot be explained completely by nigrostriatal dopaminergic denervation or leukoaraiosis burden and may relate to systemic factors seen with accelerated aging.

  • assessment of mild dementia with amyloid and dopamine terminal positron emission tomography
    Brain, 2011
    Co-Authors: James F Burke, Roger L Albin, Robert A Koeppe, Bruno Giordani, Michael R Kilbourn, Sid Gilman, Kirk A Frey
    Abstract:

    We assessed the relationship between consensus clinical diagnostic classification and neurochemical positron emission tomography imaging of striatal vesicular monoamine transporters and cerebrocortical deposition of aβ-amyloid in mild dementia. Seventy-five subjects with mild dementia (Mini-Mental State Examination score ≥ 18) underwent a conventional clinical evaluation followed by 11C-Dihydrotetrabenazine positron emission tomography imaging of striatal vesicular monoamine transporters and 11C-Pittsburgh compound-B positron emission tomography imaging of cerebrocortical aβ-amyloid deposition. Clinical classifications were assigned by consensus of an experienced clinician panel. Neuroimaging classifications were assigned as Alzheimer’s disease, frontotemporal dementia or dementia with Lewy bodies on the basis of the combined 11C-Dihydrotetrabenazine and 11C-Pittsburgh compound-B results. Thirty-six subjects were classified clinically as having Alzheimer’s disease, 25 as having frontotemporal dementia and 14 as having dementia with Lewy bodies. Forty-seven subjects were classified by positron emission tomography neuroimaging as having Alzheimer’s disease, 15 as having dementia with Lewy bodies and 13 as having frontotemporal dementia. There was only moderate agreement between clinical consensus and neuroimaging classifications across all dementia subtypes, with discordant classifications in ∼35% of subjects (Cohen’s κ = 0.39). Discordant classifications were least frequent in clinical consensus Alzheimer’s disease (17%), followed by dementia with Lewy bodies (29%) and were most common in frontotemporal dementia (64%). Accurate clinical classification of mild neurodegenerative dementia is challenging. Though additional post-mortem correlations are required, positron emission tomography imaging likely distinguishes subgroups corresponding to neurochemically defined pathologies. Use of these positron emission tomography imaging methods may augment clinical classifications and allow selection of more uniform subject groups in disease-modifying therapeutic trials and other prospective research involving subjects in the early stages of dementia. * Abbreviations : APOE4  :  apolipoprotein e 4 allele DVR  :  distribution volume ratio PiB  :  Pittsburgh compound B

  • comparing fludeoxyglucose f18 pet assessment of regional cerebral glucose metabolism and 11c Dihydrotetrabenazine pet in evaluation of early dementia and mild cognitive impairment
    JAMA Neurology, 2010
    Co-Authors: Roger L Albin, James F Burke, Robert A Koeppe, Bruno Giordani, Michael R Kilbourn, Sid Gilman, Kirk A Frey
    Abstract:

    Objective To compare assessment of regional cerebral metabolic changes with [ 11 C]Dihydrotetrabenazine (DTBZ)–positron emission tomography (PET) measurement of regional cerebral blood flow (K 1 ) and fludeoxyglucose F18 (FDG)–PET measurement of regional cerebral glucose uptake (CMR glc ) in a clinically representative sample of subjects with mild dementia and mild cognitive impairment (MCI). Design [ 11 C]Dihydrotetrabenazine-PET K 1 and FDG-PET CMR glc measurements were performed. Setting University-based cognitive disorders clinic. Participants Fifty subjects with either mild dementia (Mini-Mental State Examination score ≥ 18) or MCI. Their results were compared with those of 80 normal control subjects. Main Outcome Measures The DTBZ-PET regional K 1 and FDG-PET CMR glc measurements were compared with standard correlation analysis. The overall patterns of DTBZ-PET K 1 and FDG-PET CMR glc deficits were assessed with stereotaxic surface projections (SSPs) of parametric images. Results The DTBZ-PET regional K 1 and FDG-PET CMR glc measurements were highly correlated, both within and between subjects. The SSP maps of deficits in DTBZ-PET regional K 1 and FDG-PET CMR glc measurements were markedly similar. The DTBZ-PET K 1 SSP maps exhibited a mild decrease in sensitivity relative to FDG-PET CMR glc maps. Conclusions Both DTBZ-PET K 1 and FDG-PET CMR glc measurements provide comparable information in assessment of regional cerebral metabolic deficits in mild dementia and MCI. Blood flow measures can assess regional cerebral metabolism deficits accurately in mild dementia and MCI. Blood flow assessments of regional cerebral metabolic deficits can be combined with tracer binding results to improve utility of PET imaging in mild dementia and MCI.

  • striatal 11c Dihydrotetrabenazine and 11c methylphenidate binding in tourette syndrome
    Neurology, 2009
    Co-Authors: Roger L Albin, Robert A Koeppe, Michael R Kilbourn, Kirk A Frey, Kristine Wernette, W Zhuang, Thomas E Nichols
    Abstract:

    Objective: Tourette syndrome (TS) is a common neurodevelopmental disorder marked by tics and behavioral comorbidities. Clinical pharmacology suggests that dopaminergic signaling abnormalities are part of the pathophysiology of TS. Prior molecular imaging studies of nigrostriatal dopaminergic terminal markers report conflicting results. Our goal was to characterize the distribution of nigrostriatal dopaminergic terminals in subjects with TS. Methods: Thirty-three adult subjects with TS were studied with PET using [11C]Dihydrotetrabenazine (DTBZ), a ligand for the type 2 vesicular monoamine transporter, and with [11C] methylphenidate (MP), a ligand for the plasmalemmal dopamine transporter. Subjects were characterized with standard rating instruments for tic severity, obsessive-compulsive behaviors, and attentional deficits. Results: We found no differences between subjects with TS and control subjects in DTBZ and MP binding in any striatal region. There was no correlation between binding measures and clinical variables. Ventral striatal DTBZ and MP binding distributions in subjects with TS were normal. Conclusions: We found no evidence of increased striatal dopaminergic innervation in Tourette syndrome (TS). Discrepancy between our present results and those of other studies may be explained by heterogeneity of TS.