RESUMEN
BACKGROUND: In Parkinson disease (PD), the benefit of levodopa therapy becomes less marked over time, perhaps because degeneration of nigrostrial neurons causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa into dopamine. In a primate model of PD, intrastriatal infusion of an adeno-associated viral type 2 vector containing the human AADC gene (AAV-hAADC) results in robust response to low-dose levodopa without the side effects associated with higher doses. These data prompted a clinical trial. METHODS: Patients with moderately advanced PD received bilateral intraputaminal infusion of AAV-hAADC vector. Low-dose and high-dose cohorts (5 patients in each) were studied using standardized clinical rating scales at baseline and 6 months. PET scans using the AADC tracer [(18)F]fluoro-L-m-tyrosine (FMT) were performed as a measure of gene expression. RESULTS: The gene therapy was well tolerated, but 1 symptomatic and 2 asymptomatic intracranial hemorrhages followed the operative procedure. Total and motor rating scales improved in both cohorts. Motor diaries also showed increased on-time and reduced off-time without increased "on" time dyskinesia. At 6 months, FMT PET showed a 30% increase of putaminal uptake in the low-dose cohort and a 75% increase in the high-dose cohort. CONCLUSION: This study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson's Disease Rating Scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache.
Asunto(s)
Descarboxilasas de Aminoácido-L-Aromático/genética , Descarboxilasas de Aminoácido-L-Aromático/uso terapéutico , Terapia Genética , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/terapia , Putamen/fisiopatología , Anciano , Estudios de Cohortes , Discinesias/fisiopatología , Discinesias/terapia , Femenino , Estudios de Seguimiento , Terapia Genética/efectos adversos , Humanos , Hemorragias Intracraneales/etiología , Masculino , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos/efectos adversos , Enfermedad de Parkinson/cirugía , Tomografía de Emisión de Positrones , Putamen/diagnóstico por imagen , Putamen/cirugía , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: In a primate model of Parkinson disease (PD), intrastriatal infusion of an adeno-associated viral (AAV) vector containing the human aromatic l-amino acid decarboxylase (hAADC) gene results in robust gene expression. After gene transfer, low doses of systemically administered l-dopa are converted to dopamine in the transduced striatal neurons, resulting in behavioral improvement without the side effects typically associated with higher doses of l-dopa. These studies led to the initiation of a phase I safety trial. Here we report the findings for the first cohort of five patients. METHODS: Patients with moderate to advanced PD received bilateral infusion of a low dose of the AAV-hAADC vector into the putamen. PET scans using the AADC tracer, 6-[18F]fluoro-l-m-tyrosine (FMT), were performed at baseline and at 1 and 6 months after infusion as an in vivo measure of gene expression. RESULTS: PET results showed an average 30% increase in FMT uptake (K(i)(c)) in the putamen after gene transfer. Preliminary analysis of clinical data indicates a modest improvement, but absence of a control and the nonblinded analyses make interpretation difficult. CONCLUSIONS: Thus far, this gene therapy approach has been well tolerated and shows PET evidence of sustained gene expression. These initial findings demonstrate the safety of the therapy; higher doses of adeno-associated viral vector containing the human aromatic l-amino acid decarboxylase gene in the next cohort of patients may further increase dopamine production in the putamen and provide more profound clinical benefit.
Asunto(s)
Descarboxilasas de Aminoácido-L-Aromático/genética , Terapia Genética/métodos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/terapia , Anciano , Femenino , Expresión Génica , Terapia Genética/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Tomografía de Emisión de Positrones , Putamen/diagnóstico por imagen , Resultado del TratamientoAsunto(s)
Expresión Génica , Enfermedad de Parkinson/diagnóstico por imagen , Tomografía Computarizada de Emisión , Animales , Descarboxilasas de Aminoácido-L-Aromático/genética , Descarboxilasas de Aminoácido-L-Aromático/metabolismo , Modelos Animales de Enfermedad , Modelos Lineales , Macaca mulatta , Neuronas/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/terapia , Radiografía , Transducción Genética , Transgenes/fisiologíaRESUMEN
Few studies have examined gender differences in hippocampal volumes, and the potential effect of estrogen on these measures has not been well studied. We used MRI to measure hippocampal volumes in elderly Mexican American men and women subjects in order to determine if there were gender differences and if estrogen replacement therapy (ERT) had an effect on hippocampal volume in postmenopausal women. MRI measures of hippocampal volumes (normalized to intracranial volume) were compared in 59 women and 38 men. Further comparisons were made between men subjects, women subjects taking ERT, and women subjects not taking ERT. There were no significant effects of gender on normalized hippocampal volumes. However, women subjects taking ERT had larger right hippocampal volumes than women subjects not taking ERT and larger anterior hippocampal volumes than men subjects and women subjects not taking ERT. These findings suggest a neuroprotective effect of estrogen.
Asunto(s)
Terapia de Reemplazo de Estrógeno/métodos , Estrógenos/uso terapéutico , Hipocampo/patología , Anciano , Anciano de 80 o más Años , Atrofia/metabolismo , Atrofia/prevención & control , Femenino , Lateralidad Funcional , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Imagen por Resonancia Magnética/instrumentación , Imagen por Resonancia Magnética/métodos , Masculino , Americanos Mexicanos , Persona de Mediana Edad , Posmenopausia/metabolismo , Caracteres SexualesRESUMEN
BACKGROUND: Previous studies using PET to measure cerebral glucose metabolism in AD have found metabolic reductions in the temporoparietal and posterior cingulate cortices in individuals with dementia and those at risk of developing it. This study was designed to extend this finding to individuals selected from a population-based cohort of Mexican Americans with a wide spectrum of cognitive ability. METHODS: A group of 93 individuals was selected from the Sacramento Area Latino Study on Aging, and subjects were categorized into four groups of increasing levels of cognitive impairment: normal, memory impaired, cognitively impaired but not demented (CIND), and demented. PET was performed with the tracer [(18)F]-fluorodeoxyglucose, and data were analyzed with both statistical parametric mapping and an atrophy-corrected volume of interest approach. RESULTS: Individuals with dementia had metabolic reductions that were most robust in the posterior cingulate cortex, whereas CIND subjects had less statistically robust reductions in the posterior cingulate cortex. Cingulate hypometabolism increased the risk of dementia and was a significant risk factor for dementia in logistic regression models that also incorporated MR measures of hippocampal volume and white matter hyperintensities. CONCLUSION: Posterior cingulate cortical hypometabolism is clearly detected in individuals with dementia who are selected from a population with lower education and a high prevalence of cerebrovascular risk factors, supporting the generalizability of this finding. These metabolic reductions occur prior to the onset of dementia but only in those persons with relatively advanced symptoms.
Asunto(s)
Envejecimiento/fisiología , Envejecimiento/psicología , Encéfalo/fisiología , Trastornos del Conocimiento , Recolección de Datos , Americanos Mexicanos , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , California/epidemiología , Trastornos del Conocimiento/diagnóstico por imagen , Trastornos del Conocimiento/epidemiología , Trastornos del Conocimiento/psicología , Intervalos de Confianza , Recolección de Datos/estadística & datos numéricos , Demencia/diagnóstico por imagen , Demencia/epidemiología , Demencia/psicología , Femenino , Giro del Cíngulo/diagnóstico por imagen , Giro del Cíngulo/metabolismo , Humanos , Modelos Logísticos , Masculino , Americanos Mexicanos/psicología , Americanos Mexicanos/estadística & datos numéricos , Persona de Mediana Edad , Oportunidad Relativa , Factores de Riesgo , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/metabolismo , Tomografía Computarizada de Emisión/métodos , Tomografía Computarizada de Emisión/estadística & datos numéricosRESUMEN
BACKGROUND: Previous studies have found that hippocampal atrophy and white matter hyperintensities (WMH) on MRI are linked to cognitive impairment and dementia. The authors measured these variables in a population-based cohort of older Mexican Americans with a wide spectrum of cognitive ability, ranging from normal cognition to dementia. OBJECTIVE: To investigate whether these structural brain changes were seen in individuals prior to the development of dementia and how these changes were related to the presence of dementia. METHODS: A sample of 122 subjects was selected from the Sacramento Area Latino Study on Aging, and subjects were categorized into four groups of increasing levels of cognitive impairment: normal, memory impaired (MI), cognitively impaired but not demented (CIND), and demented. Hippocampal volume was quantified using a region of interest approach. WMH was rated on a semiquantitative scale as the percent of total volume of white matter. RESULTS: Hippocampal volume was significantly reduced in CIND and demented individuals, and WMH were significantly increased in demented subjects. MI subjects did not have any significant changes in hippocampal volume or WMH. The risk for developing dementia was significantly and comparably increased in subjects with either hippocampal atrophy or high WMH. However, the risk for dementia increased dramatically in subjects with both hippocampal atrophy and a high degree of WMH. CONCLUSION: Reductions in hippocampal volume may be present before dementia but not until cognitive impairment is relatively severe. Because there is a synergistic effect between high WMH and hippocampal atrophy, interactions between vascular and degenerative processes may be important determinants of dementia.
Asunto(s)
Envejecimiento/fisiología , Envejecimiento/psicología , Encéfalo/patología , Trastornos del Conocimiento/diagnóstico , Recolección de Datos , Americanos Mexicanos , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Atrofia , Distribución de Chi-Cuadrado , Trastornos del Conocimiento/epidemiología , Estudios de Cohortes , Intervalos de Confianza , Recolección de Datos/métodos , Recolección de Datos/estadística & datos numéricos , Femenino , Hipocampo/patología , Humanos , Modelos Logísticos , Imagen por Resonancia Magnética , Masculino , Americanos Mexicanos/psicología , Americanos Mexicanos/estadística & datos numéricos , Persona de Mediana Edad , Oportunidad RelativaRESUMEN
BACKGROUND: A proportion of patients with subcortical lacunes will suffer progressive cognitive dysfunction, but the basis for this decline is controversial and little is known about predicting cognitive decline in these patients. Studies of Alzheimer disease have shown that imaging measures of temporal and parietal metabolism and blood flow predict disease course. OBJECTIVE: To determine whether regional cerebral glucose metabolism predicts cognitive decline by testing 2 opposing hypotheses: (1) temporoparietal activity predicts decline (based on the idea that concomitant Alzheimer disease causes decline) vs (2) frontal hypometabolism predicts decline (based on evidence that subcortical frontal circuits are especially vulnerable to small vessel ischemia). DESIGN: Prospective cohort study. SETTING: University outpatient dementia center. PATIENTS: A convenience sample of 26 patients with radiologically defined lacunes and baseline cognitive function ranging from normal to moderately demented. MAIN OUTCOME MEASURES: Regional cerebral metabolism was quantitated in the form of atrophy-corrected positron emission tomographic activity ratios in cortical regions that were defined a priori. Patients were followed up at a mean of 1.8 years, and the dependent variable was rate of change in the Mini-Mental State Examination score. RESULTS: Bilateral and right hemisphere dorsolateral frontal metabolism significantly predicted cognitive decline, with right dorsolateral frontal metabolism explaining 19% of the variance. No other positron emission tomographic region was a significant predictor, nor were demographic variables or baseline Mini-Mental State Examination scores significant predictors. CONCLUSION: Cognitive decline in patients with lacunes may result in part from progressive vascular compromise in subcortical frontal circuits.
Asunto(s)
Infarto Encefálico/metabolismo , Trastornos del Conocimiento/metabolismo , Metabolismo Energético , Lóbulo Frontal/metabolismo , Anciano , Anciano de 80 o más Años , Infarto Encefálico/diagnóstico , Trastornos del Conocimiento/diagnóstico , Femenino , Humanos , Masculino , Análisis Multivariante , Valor Predictivo de las Pruebas , Estudios Prospectivos , Escalas de Valoración PsiquiátricaRESUMEN
Unilateral intracarotid artery (ICA) MPTP infusion, along with sequential systemic doses of MPTP, produces near complete degeneration of the nigrostriatal pathway on the side of infusion (ipsilateral) and variable levels of damage in the contralateral hemisphere accompanied by varying levels of parkinsonism (overlesioned hemiparkinsonian model). Positron emission tomography and the dopamine (DA) metabolism tracer [(18)F]6-fluoro-l-m-tyrosine (FMT) were used to evaluate the relationship between DA metabolism and clinical features of parkinsonism in 14 overlesioned hemiparkinsonian monkeys. Monkeys were rated on a parkinsonian scale that included ratings of bradykinesia, fine motor skills (FMS), and rest tremor. Because the monkeys tended to show more severe clinical signs on the side of the body contralateral to ICA MPTP infusion, we calculated asymmetry scores for each of the clinical features as well as for FMT uptake (K(i)) in the caudate and putamen. Tremor asymmetry was associated with FMT uptake asymmetry in the putamen. No such relationship was observed for FMS or bradykinesia. The overall severity of tremor (mild, moderate/severe) was associated with FMT uptake in the caudate and putamen. Postmortem biochemical analysis for a subset of monkeys showed that the monkeys with moderate/severe tremor had significantly lower DA levels in both caudate and putamen than those with mild tremor. In addition, K(i) values were significantly correlated with DA levels in both caudate and putamen. These findings support the idea that nigrostriatal degeneration contributes to rest tremor.
Asunto(s)
Núcleo Caudado/metabolismo , Dopamina/metabolismo , Putamen/metabolismo , Degeneración Estriatonigral/metabolismo , Temblor/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Núcleo Caudado/diagnóstico por imagen , Dopaminérgicos , Femenino , Macaca mulatta , Masculino , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/diagnóstico por imagen , Enfermedad de Parkinson Secundaria/metabolismo , Putamen/diagnóstico por imagen , Degeneración Estriatonigral/inducido químicamente , Degeneración Estriatonigral/diagnóstico por imagen , Tomografía Computarizada de Emisión , Temblor/inducido químicamente , Temblor/diagnóstico por imagenRESUMEN
PET was used to evaluate the effect of estrogen use on regional cerebral glucose metabolism in postmenopausal women. Women receiving estrogen replacement therapy (ERT+), women not receiving estrogen (ERT-), and women with AD were studied. The ERT- group showed metabolic ratios that were intermediate to the ERT+ and AD groups, although they did not show any signs of cognitive impairment. These findings show an effect of estrogen depletion on brain metabolic activity.
Asunto(s)
Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Estrógenos/farmacología , Glucosa/metabolismo , Posmenopausia/metabolismo , Anciano , Femenino , Humanos , Persona de Mediana Edad , Tomografía Computarizada de EmisiónRESUMEN
Patients with extensive subcortical cerebrovascular disease may have impaired memory, often despite the absence of medial temporal or diencephalic strokes. In this group, episodic memory failure may arise from frontal lobe dysfunction based on disruption of frontosubcortical loops caused by lacunae. We tested this idea by studying cognitively impaired subcortical stroke (CIS) patients and Alzheimer's disease (AD) patients with [18F]-fluorodeoxyglucose positron emission tomography using a continuous verbal memory task during the period of tracer uptake. Patients were matched on severity of cognitive impairment and overall memory task performance. As hypothesized, we found a double dissociation in the relations between metabolism and memory in these groups, such that memory in CIS (but not in AD) correlates with prefrontal lobe metabolism, whereas in AD (but not in CIS), memory correlates with left hippocampal and temporal lobe metabolism. Analysis of memory subscores showed that CIS patients made more errors on short-delay trials, which is consistent with working memory failure. It seems that different pathogenic mechanisms underlie episodic memory failure in subcortical cerebrovascular disease and AD.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/fisiopatología , Trastornos de la Memoria/diagnóstico por imagen , Trastornos de la Memoria/fisiopatología , Memoria/fisiología , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/fisiopatología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/psicología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Femenino , Humanos , Masculino , Cintigrafía , Análisis y Desempeño de TareasRESUMEN
Using an approach that combines gene therapy with aromatic l-amino acid decarboxylase (AADC) gene and a pro-drug (l-dopa), dopamine, the neurotransmitter involved in Parkinson's disease, can be synthesized and regulated. Striatal neurons infected with the AADC gene by an adeno-associated viral vector can convert peripheral l-dopa to dopamine and may therefore provide a buffer for unmetabolized l-dopa. This approach to treating Parkinson's disease may reduce the need for l-dopa/carbidopa, thus providing a better clinical response with fewer side effects. In addition, the imbalance in dopamine production between the nigrostriatal and mesolimbic dopaminergic systems can be corrected by using AADC gene delivery to the striatum. We have also demonstrated that a fundamental obstacle in the gene therapy approach to the central nervous system, i.e., the ability to deliver viral vectors in sufficient quantities to the whole brain, can be overcome by using convection-enhanced delivery. Finally, this study demonstrates that positron emission tomography and the AADC tracer, 6-[(18)F]fluoro-l-m-tyrosine, can be used to monitor gene therapy in vivo. Our therapeutic approach has the potential to restore dopamine production, even late in the disease process, at levels that can be maintained during continued nigrostriatal degeneration.
Asunto(s)
Dependovirus/genética , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Enfermedad de Parkinson Secundaria/genética , Enfermedad de Parkinson Secundaria/terapia , Tirosina/análogos & derivados , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Descarboxilasas de Aminoácido-L-Aromático/genética , Descarboxilasas de Aminoácido-L-Aromático/metabolismo , Descarboxilasas de Aminoácido-L-Aromático/uso terapéutico , Carbidopa/uso terapéutico , Cateterismo/métodos , Núcleo Caudado/diagnóstico por imagen , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/patología , Línea Celular , Dopamina/metabolismo , Vías de Administración de Medicamentos , Combinación de Medicamentos , Radioisótopos de Flúor , Vectores Genéticos/genética , Vectores Genéticos/farmacocinética , Levodopa/metabolismo , Levodopa/uso terapéutico , Macaca mulatta , Imagen por Resonancia Magnética , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/diagnóstico , Profármacos/uso terapéutico , Putamen/diagnóstico por imagen , Putamen/efectos de los fármacos , Putamen/patología , Tomografía Computarizada de Emisión , Tirosina/farmacocinética , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The in vivo neuronal contribution to human cerebral metabolic rate of glucose (CMRglc), measured by 18FDG-PET, is unknown. Examining the effect of 1H MRSI-derived N-acetyl aspartate (NAA) concentration on positron emission tomography (PET) measures of metabolic activity might indicate the relationship of CMRglc to neuron density. In a population of 19 demented, cognitively impaired, and control subjects, the Miller-Gartner algorithm was applied to whole-brain PET data to isolate the PET signal originating in cortical gray matter alone (GMPET). An analogous procedure applied to multislice proton MRSI data yielded the N-acetyl aspartate concentration in cortical gray matter (GMNAA). In 18 of 19 subjects, a significant linear regression (P < 0.05) resulted when GMPET was plotted against GMNAA, whereby GMPET was higher for higher GMNAA. This suggests that CMRglc rises linearly with increasing neuron density in gray matter. This method may be used to investigate the relationship of CMRglc to neurons in various conditions.
Asunto(s)
Fluorodesoxiglucosa F18 , Espectroscopía de Resonancia Magnética/métodos , Radiofármacos , Tomografía Computarizada de Emisión/métodos , Anciano , Algoritmos , Análisis de Varianza , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Encéfalo/metabolismo , Trastornos del Conocimiento/metabolismo , Demencia/metabolismo , Femenino , Glucosa/metabolismo , Humanos , Espectroscopía de Resonancia Magnética/instrumentación , Espectroscopía de Resonancia Magnética/estadística & datos numéricos , Valores de Referencia , Tomografía Computarizada de Emisión/instrumentación , Tomografía Computarizada de Emisión/estadística & datos numéricosRESUMEN
BACKGROUND: The mechanism of dementia in subcortical cerebral infarction is incompletely understood. OBJECTIVE: To determine how cognitive function is related to cortical metabolism in patients with subcortical infarction and a continuum of cognitive impairment. METHODS: We used positron emission tomography (PET) and the glucose metabolic tracer fludeoxyglucose F 18 to study 8 patients with subcortical stroke and normal cognitive function (S-CN), 5 patients with subcortical stroke and cognitive impairment (S-CI) who did not have dementia, 8 patients with subcortical stroke and dementia (S-D), and 11 controls with no cognitive impairment or stroke. A subset of patients had absolute regional cerebral metabolic rate of glucose (CMRglc) determined, while in all subjects regional tracer uptake normalized to whole brain tracer uptake was calculated. PET data were analyzed by constructing volumes of interest using coregistered magnetic resonance imaging data and correcting the PET data for atrophy. RESULTS: Global CMRglc was significantly lower in the patients with S-D than in the control and S-CN groups, with S-CI rates intermediate to those of the S-D and S-CN groups. Absolute regional CMRs of glucose were similar in the S-D and S-CI groups and in the control and S-CN groups. The regional pattern, however, showed lower right frontal regional CMRglc ratios in all stroke groups compared with the controls. There were modest correlations between performance on the Mini-Mental State Examination and whole brain CMRglc when all 4 groups were included. CONCLUSIONS: These results demonstrate that subcortical infarction produces global cerebral hypometabolism, which is related to the clinical status of the patients. In addition, specific frontal lobe hypometabolism also appears to be a feature of subcortical infarction. Taken together, both global and regional effects on cortical function mediate the production of clinical symptoms in patients with subcortical strokes.
Asunto(s)
Infarto Cerebral/complicaciones , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/metabolismo , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Glucosa/metabolismo , Anciano , Atrofia/patología , Encéfalo/patología , Trastornos del Conocimiento/diagnóstico , Femenino , Lóbulo Frontal/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Pruebas Neuropsicológicas , Índice de Severidad de la Enfermedad , Tomografía Computarizada de Emisión , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Single photon emission computed tomography (SPECT) and the dopamine (DA) transporter tracer, 2 beta-carboxymethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT), were used to determine DA transporter density in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-lesioned monkeys with varying degrees of parkinsonism. The clinical stage of parkinsonism corresponded to SPECT measures of striatal DA transporter density suggesting that more severe parkinsonism was associated with a greater degree of dopaminergic terminal degeneration. These findings are similar to those reported earlier using positron emission tomography (PET) and the DA metabolism tracer, 6-[18F]fluoro-L-m-tyrosine (FMT), indicating that both are good methods for evaluating nigrostriatal degeneration in MPTP primate models.
Asunto(s)
Proteínas Portadoras/metabolismo , Dopaminérgicos/toxicidad , Intoxicación por MPTP , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Enfermedad de Parkinson Secundaria/metabolismo , Animales , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Macaca mulatta , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/diagnóstico por imagen , Tomografía Computarizada de Emisión , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
BACKGROUND: The variability of disease course in patients diagnosed with AD makes prediction of survival difficult, despite the identification of numerous predictors to date. This study evaluated the predictive utility of measurements of regional cerebral blood flow (rCBF) obtained with SPECT in a group of AD patients. METHODS: Fifty AD patients were studied with SPECT and followed longitudinally. SPECT measures of relative rCBF were calculated by measuring radioactivity densities in dorsolateral frontal, orbitofrontal, temporal, and parietal cortex normalized to occipital cortical radioactivity density. Subjects were classified into three tertiles of rCBF ratios for each region. These rCBF ratios were used as predictors of survival in life-table and proportional hazard models to predict survival. RESULTS: Right parietal rCBF was a significant predictor of survival in the life-table analysis, with subjects in the lowest tertile having shortest survivals. No other brain region was a significant predictor of survival. In a proportional hazards model when a variety of other potential predictors were accounted for, right parietal rCBF ratio remained a significant predictor. CONCLUSIONS: These results demonstrate that brain perfusion in the right parietal lobe is a significant predictor of survival in patients with AD even when other predictors are taken into consideration. This suggests that SPECT perfusion imaging may provide additional useful information on disease prognosis in AD.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/mortalidad , Corteza Cerebral/irrigación sanguínea , Circulación Cerebrovascular , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Análisis de Supervivencia , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Positron emission tomography (PET) and the dopamine (DA) metabolism tracer, [18F]6-fluoro-L-m-tyrosine (FMT) were used to evaluate the relationship between DA metabolism and the clinical stage of parkinsonism monkeys following either unilateral ICA MPTP infusion or unilateral ICA MPTP infusion and subsequent varying sequential systemic doses of MPTP. Clinical stage corresponded to PET measures of striatal DA metabolism, showing the usefulness of the overlesioned hemiparkinsonian monkey as a stable model of various stages of Parkinson's disease (PD).
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Dopaminérgicos , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/fisiopatología , Animales , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Dopamina/metabolismo , Macaca mulatta , Enfermedad de Parkinson Secundaria/diagnóstico por imagen , Tomografía Computarizada de Emisión , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
In vivo brain microdialysis was used to monitor 6-[18F]fluoro-L-m-tyrosine (FMT) uptake and metabolism in the striatum of conscious freely moving rats for 3 hours after FMT injection (25 mg/kg, i.v.). Microdialysate collected 20 to 120 min post-dose, contained FMT at a concentration (0.2 to 0.3 nM) approximately ten-fold below that of its metabolite [18F]fluoro-3-hydroxyphenylacetic acid (FPAC; 3.2 to 3.3 nM). D-amphetamine (2.5 mg/kg, i.p.) injected 120 min after significantly increased microdialysate FPAC (3.27 +/- 0.31 nM to 4.51 +/- 0.45 nM) in control but not reserpinized rats. Taken together these data demonstrate FMT is heavily metabolized following its entry into the striatum yielding FPAC which appears to be stored, at least in part, in reserpine sensitive cytoplasmic vesicles. Presynaptic retention of FPAC may contribute to the preferential accumulation of FMT positron emission tomography (PET) signaling in dopaminergic brain areas.
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Cuerpo Estriado/metabolismo , Radioisótopos de Flúor/farmacocinética , Tirosina/análogos & derivados , Animales , Transporte Biológico , Biotransformación , Cuerpo Estriado/efectos de los fármacos , Dextroanfetamina/farmacología , Cinética , Masculino , Microdiálisis/métodos , Fenilacetatos/farmacocinética , Ratas , Ratas Wistar , Reserpina/farmacología , Factores de Tiempo , Tirosina/farmacocinéticaRESUMEN
Studies of Alzheimer's disease using single-photon emission computed tomography (SPECT) and positron emission tomography (PET) have found reductions in blood flow and glucose metabolism in temporal and parietal cortex. In 50 AD patients who underwent neuropsychological testing and SPECT perfusion imaging, we found significant correlations between perfusion and performance on the Mini-Mental Status Examination in the frontal and parietal lobes. In addition, specific correlations between perfusion in the frontal lobes and performance on tests of frontal lobe ability were noted. These findings, while suggesting the importance of perfusion measures in determining clinical features of the disease, do not clearly define perfusion changes as primary, since similar findings have been seen when metabolism is studied. In a separate group of 5 AD patients and 16 controls, we used PET with the perfusion tracer HIPDM and examined cerebrovascular reactivity to carbon dioxide inhalation. We found that in multiple brain regions, including the temporal lobes, AD patients showed robust and significant increases in perfusion in response to carbon dioxide that did not differ from the response seen in the controls. Taken together, these results show that while perfusion changes are important in AD, they are not clearly either primary or limiting.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Circulación Cerebrovascular , Cognición , Humanos , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Volume-of-interest (VOI) extraction for radionuclide and anatomical measurements requires correct identification and delineation of the anatomical feature being studied. We have developed a toolset for specifying three-dimensional (3-D) VOI's on a multislice positron emission tomography (PET) dataset. The software is particularly suited for specifying cerebral cortex VOI's which represent a particular gyrus or deep brain structure. A registered 3-D magnetic resonance image (MRI) dataset is used to provide high-resolution anatomical information, both as oblique two-dimensional (2-D) sections and as volume renderings of a segmented cortical surface. VOI's are specified indirectly in two dimensions by drawing a stack of 2-D regions on the MRI data. The regions are tiled together to form closed triangular mesh surface models, which are subsequently transformed into the observation space of the PET scanner. Quantification by this method allows calculation of radionuclide activity in the VOI's, as well as their statistical uncertainties and correlations. The methodology for this type of analysis and validation results are presented.
Asunto(s)
Corteza Cerebral , Procesamiento de Imagen Asistido por Computador/métodos , Tomografía Computarizada de Emisión/métodos , Encéfalo/anatomía & histología , Encéfalo/diagnóstico por imagen , Corteza Cerebral/anatomía & histología , Corteza Cerebral/diagnóstico por imagen , Procesamiento Automatizado de Datos , Humanos , Imagen por Resonancia Magnética/métodos , Reproducibilidad de los ResultadosRESUMEN
MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is a neurotoxin that produces degeneration of nigrostriatal dopaminergic neurons and a chronic parkinsonian condition in primates. Positron emission tomography (PET) studies of rhesus macaques at various time points following unilateral MPTP administration demonstrated a different time course of degeneration in the dopaminergic terminals in the putamen and in the cell bodies in the substantia nigra, consistent with other evidence of retrograde degeneration. In addition, the substantia nigra showed a transient upregulation in dopaminergic function in the lesioned hemisphere indicating functional compensation. This plasticity has important implications for the therapeutic effects of growth factors and other potential treatments for neurodegenerative diseases.