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BACKGROUND: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU). METHODS: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants' clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials. RESULTS: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial's demographic distribution. Participants' decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome. CONCLUSION: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden.
Assuntos
Doença de Alzheimer , Anticorpos Monoclonais Humanizados , Satisfação do Paciente , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Masculino , Feminino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/uso terapêutico , Método Duplo-Cego , Adulto , Inquéritos e Questionários , Ensaios Clínicos como AssuntoRESUMO
BACKGROUND: Lecanemab is a humanized IgG1 monoclonal antibody binding with high affinity to amyloid-beta protein protofibrils. In phase 3 development, lecanemab has been shown to reduce markers of amyloid in early Alzheimer's disease and reduce decline on clinical endpoints of cognition and function at 18 months. OBJECTIVES: To describe the health-related quality-of-life (HRQoL) results from Clarity AD which were exploratory outcomes in this trial. DESIGN: Clarity AD was an 18-month, multi-center, double-blind, phase 3 trial. SETTING: Early Alzheimer's disease. PARTICIPANTS: Individuals 50-90 years of age with a diagnosis of mild cognitive impairment or mild dementia due to Alzheimer's disease and positron emission tomography or cerebrospinal fluid evidence of cerebral amyloid accumulation. INTERVENTION: Placebo or lecanemab 10-mg/kg IV biweekly. MEASUREMENTS: HRQoL was measured at baseline and every 6 months using the European Quality of Life-5 Dimensions (EQ-5D-5L; by subject) and Quality of Life in AD (QOL-AD; by subject and proxy). Study partner burden was measured using the Zarit Burden Interview (ZBI). RESULTS: A total of 1795 participants were enrolled (lecanemab:898; placebo:897). At month 18, adjusted mean change from baseline in EQ-5D-5L and QOL-AD by subject showed 49% and 56% less decline, respectively. QOL-AD rated by study partner as proxy resulted in 23% less decline. ZBI adjusted mean change from baseline at 18 months resulted in 38% less increase of care partner burden. Individual HRQoL test items and dimensions also showed lecanemab benefit. CONCLUSIONS: Lecanemab was associated with a relative preservation of HRQoL and less increase in caregiver burden, with consistent benefits seen across different quality of life scales and within scale subdomains. These benefits provide valuable patient reported outcomes which, together with previously reported benefits of lecanemab across multiple measures of cognition, function, disease progression, and biomarkers, demonstrate that lecanemab treatment may offer meaningful benefits to patients, care partners, and society.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico , Qualidade de Vida/psicologia , Cuidadores , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
OBJECTIVES: Efficacy and safety results from the EMERGE (NCT02484547) and ENGAGE (NCT02477800) phase 3 studies of aducanumab in early Alzheimer's disease (AD) have been published. In EMERGE, but not in ENGAGE, high-dose aducanumab demonstrated significant treatment effects across primary and secondary endpoints. Low-dose aducanumab results were consistent across studies with non-significant differences versus placebo that were intermediate to the high-dose arm in EMERGE. The present investigation examined data from EMERGE and ENGAGE through post-hoc analyses to determine factors that contributed to discordant results between the high-dose arms of the two studies. DESIGN: EMERGE and ENGAGE were 2 phase 3, randomized, double-blind, placebo-controlled, parallel-group studies. SETTING: EMERGE and ENGAGE were 2 global multicenter studies involving 348 sites in 20 countries. PARTICIPANTS: Participants in EMERGE and ENGAGE were aged 50 to 85 years and had mild cognitive impairment or mild AD dementia with confirmed amyloid pathology. The randomized and dosed population (all randomized patients who received at least one dose of study treatment) included 1638 patients in EMERGE and 1647 in ENGAGE. INTERVENTION: In EMERGE and ENGAGE, participants were randomized to receive low- or high-dose aducanumab or placebo (1:1:1) once every 4 weeks. MEASUREMENTS: In this paper, 4 areas were investigated through post-hoc analyses to understand the discordance in the high-dose arms of the EMERGE and ENGAGE studies: baseline characteristics, amyloid-related imaging abnormalities, non-normality of the data, and dosing/exposure to aducanumab. RESULTS: Post-hoc analyses showed that outcomes in the ENGAGE high-dose group were affected by an imbalance in a small number of patients with extremely rapid progression and by lower exposure to the target dose of 10 mg/kg. These factors were confounded and present in early enrolled patients but were not present in later-enrolled patients who were randomized to the target dosing regimen of 10 mg/kg after titration. Neither baseline characteristics nor amyloid-related imaging abnormalities contributed to the difference in results between the high-dose arms. CONCLUSIONS: Results were consistent across studies in later enrolled patients in which the incidence of rapidly progressing patients was balanced across treatment arms.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
BACKGROUND: Alzheimer's disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. OBJECTIVES: We evaluated the efficacy and safety of aducanumab in early Alzheimer's disease. DESIGN: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer's disease. SETTING: These studies involved 348 sites in 20 countries. PARTICIPANTS: Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50-85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, of which 1812 (55.2%) completed the study. INTERVENTION: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks. MEASUREMENTS: The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints. RESULTS: EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of -0.39 for high-dose aducanumab vs placebo [95% CI, -0.69 to -0.09; P=.012; 22% decrease]) but not in ENGAGE (difference of 0.03, [95% CI, -0.26 to 0.33; P=.833; 2% increase]). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer's disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema. CONCLUSIONS: Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose- and time-dependent reduction in pathophysiological markers of Alzheimer's disease was observed in both trials.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores , HumanosRESUMO
BACKGROUND: ACC-001 is an investigational therapeutic vaccine designed to elicit antibodies against the N-terminal peptide 1-7 of the amyloid-beta peptide, believed to be important in the pathogenesis of Alzheimer's disease. OBJECTIVES: To evaluate safety, immunogenicity, impact on brain amyloid, and other exploratory endpoints in participants receiving ACC-001. DESIGN: Randomized, phase 2, interventional study. TRIAL REGISTRATION: Clinicaltrials.gov ID NCT01227564. PARTICIPANTS: Individuals with early Alzheimer's disease (Mini-Mental State Examination scores ≥25, a global Clinical Dementia Rating of 0.5, and evidence of elevated baseline brain amyloid burden). INTERVENTION: Participants were randomized to ACC-001 3 µg or 10 µg with QS-21 adjuvant (50 µg), or placebo. MEASUREMENTS: The primary endpoint was change in brain amyloid burden by 18F-florbetapir positron emission tomography in composite cortical standard uptake value ratio. RESULTS: A total of 63 participants were randomized and 51 completed the study. At week 104, no significant differences were observed in 18F-florbetapir positron emission tomography composite cortical standard uptake value ratio between either ACC-001 dose compared with placebo. In both ACC-001 + QS-21 treatment groups, following the initial immunization, the anti-amyloid-beta geometric mean titers increased after each subsequent vaccination and then declined, with less apparent decline after the later compared with earlier immunizations. The majority of treatment-emergent adverse events in the ACC-001 + QS-21 groups were injection site reactions, which occurred at a greater rate in active treatment groups than in the placebo group. No amyloid-related imaging abnormalities of edema or effusion were reported. CONCLUSION: No statistically significant differences were observed between groups in the change from baseline brain amyloid burden despite apparently robust systemically measured anti-amyloid-beta antibody response at both dose levels. Insufficient antibody titers, poor quality immune response, short duration of treatment, or small sample size may have resulted in these findings. The safety and tolerability profile was acceptable.
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BACKGROUND: The efficacy of extended-release physostigmine salicylate, an acetylcholinesterase inhibitor, was evaluated in 850 subjects with mild-to-moderate Alzheimer disease (AD) in a multicenter trial. METHODS: Subjects initially entered a dose-enrichment phase in which they received 1 week each of physostigmine salicylate, 24 mg/d and 30 mg/d, and daily placebo. Among the subjects who completed this phase, 35.9% responded to physostigmine treatment, whereas 62.4% were considered nonresponders, and 1.6% could not be evaluated because of missing data. After a 4-week placebo-washout phase, 176 responder subjects were randomized to receive their best dose of physostigmine or placebo in a 12-week double-blind phase. Primary efficacy measures included the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change With Caregiver Input (CIBIC+), and the Clinical Global Impression of Change (CGIC). RESULTS: In the intent-to-treat analysis of the double-blind phase, physostigmine-treated subjects scored -2.02 points better than placebo-treated subjects on the ADAS-Cog (F1,167 = 6.42 [P = .01]) and 0.33 points higher on the CIBIC+ (F1,150 = 5.68 [P = .02]). No significant improvement was observed on the CGIC or the secondary outcome measures. Nausea and vomiting were experienced by 47.0% of all physostigmine-treated subjects during the double-blind phase. CONCLUSIONS: Physostigmine demonstrated a statistically significant benefit compared with placebo on a clinical global rating of change and an objective test of cognitive function. Given the frequency of gastrointestinal side effects, the role of this agent in clinical use remains to be determined.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Fisostigmina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Inibidores da Colinesterase/administração & dosagem , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/psicologia , Preparações de Ação Retardada , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Testes Neuropsicológicos , Fisostigmina/administração & dosagem , Fisostigmina/efeitos adversos , Placebos , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
BACKGROUND: Prior research has suggested reductions in the density of serotonin transporter (SERT) binding sites in blood platelets and post-mortem brain tissue of depressed patients. We sought to determine whether patients with unipolar major depression have diminished SERT availability as assessed by both brainstem [123I] beta-CIT SPECT and platelet [3H]paroxetine binding. METHODS: Drug-free depressed and healthy subjects were injected with 211 +/- 22 MBq [123I] beta-CIT and imaged 24 +/- 2 h later under equilibrium conditions. A ratio of specific to nonspecific brain uptake (V3" = (brainstem-occipital)/occipital), a measure proportional to the binding potential (Bmax/Kd), was used for all comparisons. RESULTS: Results showed a statistically significant reduction in brainstem V3" values in depressed as compared to healthy subjects (3.1 +/- .9 vs. 3.8 +/- .8, p = .02). Platelet [3H]paroxetine binding was not altered (Bmax = 2389 +/- 484 vs. 2415 +/- 538 fmol/mg protein, p = .91) and was not significantly correlated with brainstem [123I] beta-CIT binding (r = -0.14, p = .48). CONCLUSIONS: These data are the first to suggest reductions in the density of brain SERT binding sites in living depressed patients. These findings provide further support for a preeminent role for alterations in serotonergic neurons in the pathophysiology of depression.
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Antidepressivos/farmacocinética , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Proteínas de Transporte/fisiologia , Cocaína/análogos & derivados , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/fisiopatologia , Glicoproteínas de Membrana/fisiologia , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Serotonina/fisiologia , Tomografia Computadorizada de Emissão de Fóton Único , Adulto , Antidepressivos/uso terapêutico , Tronco Encefálico/fisiopatologia , Cocaína/farmacocinética , Cocaína/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paroxetina/sangue , Escalas de Graduação Psiquiátrica , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
The serotonin 5-HT3 receptor antagonists ondansetron and SEC-579 were tested over a wide dose range (0.000001-0.5 mg/kg, PO) for cognitive-enhancing effects in aged rhesus monkeys. Animals were tested on the following cognitive and motor tasks: 1) acquisition of a visual object discrimination; 2) reversal of a visual object discrimination; 3) the delayed response task, a spatial working memory task; and 4) a fine motor task. This study found enhanced acquisition of a visual object discrimination following very low doses (0.000001-0.00001 mg/kg, PO) of either 5-HT3 receptor antagonist. This finding replicates a previous study in marmosets. However, unlike the marmoset research, no reliable improvement was found on the reversal condition. Similarly, no improvement was observed on the delayed response or fine motor tasks. No side effects were observed at any dose, consistent with reports in both animals and humans. These results suggest that 5-HT3 receptor antagonists may be helpful in treating a subset of cognitive functions.
Assuntos
Envelhecimento/psicologia , Cognição/efeitos dos fármacos , Ondansetron/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Quinolonas/farmacologia , Antagonistas da Serotonina/farmacologia , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Aprendizagem por Discriminação/efeitos dos fármacos , Aprendizagem por Discriminação/fisiologia , Discriminação Psicológica/efeitos dos fármacos , Discriminação Psicológica/fisiologia , Feminino , Macaca mulatta , Motivação , Córtex Motor/efeitos dos fármacos , Córtex Motor/crescimento & desenvolvimento , Reversão de Aprendizagem/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologiaRESUMO
Postmortem studies have provided limited and conflicting data regarding aging effects on the central serotonin transporter (SERT). The present study investigated the effect of age on SERT availability in the human brainstem and diencephalon with single photon emission computed tomography (SPECT) using the ligand [(123)I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([(123)I]beta-CIT). Healthy control subjects (n = 126) who ranged in age from 18 to 88 were injected with 6.0 +/- 0.8 (mean +/- SD) mCi [(123)I]beta-CIT and imaged 23.1 +/- 1.9 h later under equilibrium conditions. A ratio of specific to nondisplaceable brain uptake (i.e. , V(3)" = [brainstem-diencephalon -occipital]/occipital), a measure proportional to the binding potential (B(max)/K(D)), was derived. SERT availability (V(3)") showed a significant inverse correlation with age (r = -0.40, P < 0.0001). Linear regression analysis revealed that V(3)" declined by 29.5% over the age range 18 to 88, or approximately 4.2% per decade. These results demonstrate reductions in the availability of central SERT binding sites with age in living human subjects.
Assuntos
Envelhecimento/metabolismo , Química Encefálica/fisiologia , Proteínas de Transporte/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Tomografia Computadorizada de Emissão de Fóton Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Tronco Encefálico/química , Tronco Encefálico/fisiologia , Cocaína/análogos & derivados , Diencéfalo/química , Diencéfalo/fisiologia , Feminino , Humanos , Radioisótopos do Iodo , Masculino , Pessoa de Meia-Idade , Valores de Referência , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
OBJECTIVE: The authors examined whether subjects with Tourette's disorder have greater than normal striatal dopamine transporter densities, as suggested by previous post-mortem findings. METHOD: Single photon emission computed tomography (SPECT) and [123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT) were used to assess dopamine transporter levels in five adult patients with Tourette's disorder and five age- and gender-matched healthy comparison subjects. RESULTS: Striatal [123I]beta-CIT binding was a mean of 37% (range = 6%-79%) higher in the subjects with Tourette's disorder than in the comparison subjects, and each Tourette's disorder patient had a higher level than his or her paired comparison subject. CONCLUSIONS: These findings corroborate post-mortem results and support the hypothesis of a dysregulation in presynaptic dopamine function in Tourette's disorder.
Assuntos
Proteínas de Transporte/metabolismo , Cocaína/análogos & derivados , Corpo Estriado/metabolismo , Dopamina/metabolismo , Radioisótopos do Iodo , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Tomografia Computadorizada de Emissão de Fóton Único , Síndrome de Tourette/metabolismo , Adulto , Fatores Etários , Corpo Estriado/diagnóstico por imagem , Dopamina/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Humanos , Masculino , Fatores Sexuais , Síndrome de Tourette/diagnóstico por imagem , Síndrome de Tourette/fisiopatologiaRESUMO
OBJECTIVE: The authors previously observed an increase in striatal dopamine transmission following amphetamine challenge in 15 untreated patients with schizophrenia compared to 15 matched healthy subjects. The purpose of this study was to replicate this finding in a new cohort of schizophrenic patients and healthy subjects. METHOD: Fifteen patients with schizophrenia and 15 healthy subjects matched for age, gender, ethnicity, and parental socioeconomic status were recruited for this study. Patients fulfilled DSM-IV criteria for schizophrenia, had no history of alcohol or substance abuse or dependence, and were neuroleptic free for a minimum of 21 days. Amphetamine-induced dopamine release was assessed by the reduction in dopamine D2 receptor availability induced by an acute amphetamine challenge (0.3 mg/kg, intravenous bolus). Reduction in D2 receptor availability was measured with single photon emission computed tomography and the D2 receptor radiotracer [123I]IBZM. RESULTS: No differences were observed between patients with schizophrenia and the comparison group in D2 receptor availability at baseline. Patients with schizophrenia exhibited a significantly larger reduction in D2 receptor availability following acute amphetamine challenge than the comparison group. In this study, the effect size was smaller than in the first study. Excess dopamine release following amphetamine was associated with transient emergence or worsening of positive symptoms. CONCLUSIONS: In this new cohort of subjects the authors replicated their initial observation of a dysregulation of striatal dopamine release in schizophrenia.
Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Esquizofrenia/diagnóstico , Transmissão Sináptica/efeitos dos fármacos , Adulto , Anfetamina/farmacologia , Benzamidas , Estudos de Coortes , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinas , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores Dopaminérgicos/metabolismo , Reprodutibilidade dos Testes , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/metabolismo , Transmissão Sináptica/fisiologia , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
OBJECTIVE: The authors examined whether striatal dopamine transporters were altered in acutely (96 hours or less) abstinent cocaine-abusing subjects, as suggested by postmortem studies. METHOD: [123I] beta-CIT and single photon emission computed tomography were used to assess striatal dopamine transporter levels in 28 cocaine-abusing subjects and 24 comparison subjects matched as a group for age and gender. RESULTS: Results showed a significant (approximately 20%) elevation in striatal V3" values in acutely abstinent cocaine-abusing subjects relative to comparison subjects. An inverse correlation between dopamine transporter level and Hamilton Depression Rating Scale score was also observed. CONCLUSIONS: These findings indicate more modest elevations in striatal dopamine transporters in cocaine-abusing subjects than noted in previous postmortem reports and suggest a possible relationship between cocaine-related depression and dopamine transporter binding.
Assuntos
Proteínas de Transporte/metabolismo , Transtornos Relacionados ao Uso de Cocaína/diagnóstico , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Dopamina/metabolismo , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Tomografia Computadorizada de Emissão de Fóton Único , Adulto , Proteínas de Transporte/fisiologia , Cocaína/análogos & derivados , Transtornos Relacionados ao Uso de Cocaína/diagnóstico por imagem , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Comorbidade , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/metabolismo , Dopamina/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Humanos , Radioisótopos do Iodo , MasculinoRESUMO
BACKGROUND: The apolipoprotein E (Apo E) epsilon4 allele has been associated with parietal metabolic abnormalities and asymmetries in asymptomatic subjects at risk for Alzheimer disease (AD). However, previous research has shown minimal effect of the epsilon4 allele on regional cerebral blood flow (rCBF) and metabolism in patients with probable AD. OBJECTIVE: To determine whether the Apo E epsilon4 allele is associated with parietal rCBF abnormalities and asymmetries in patients with probable AD. PATIENTS AND METHODS: Thirty patients with AD with the epsilon4 allele (epsilon4+ AD), 22 patients with AD without the epsilon4 allele (epsilon4- AD), and 14 healthy control subjects underwent single-photon emission computed tomography (SPECT) scanning with 740 MBq technetium Tc 99m hexamethylpropyleneamine oxime. Ratios of parietal-unaffected regions and a left-right parietal asymmetry index were compared between both patient groups. RESULTS: The group with epsilon4- AD was younger (P = .005, Student t test) and had an earlier age of onset (P = .005) than the group with epsilon4+ AD. Analysis of covariance revealed no significant difference in the parietal rCBF ratio, controlling for age of onset and Mini-Mental State Examination score (F(1,48) = 0.06; P = .81). However, contrary to hypothesis, significantly greater parietal rCBF asymmetry was seen in patients with epsilon4- AD (mean +/- SD, 9.7% +/- 5.5%) than those with epsilon4+ AD (6.3% +/- 4.7%; F(1,50) = 5.89; P = .02; analysis of variance). When number of epsilon4 allele copies was considered, this effect appeared to accrue primarily from a difference between patients with 0 and with 2 epsilon4 allele copies. An exploratory analysis of multiple cortical structures suggested that this asymmetry extended to additional regions (superior temporal) and to combined association cortex. CONCLUSIONS: Greater parietal rCBF asymmetry is involved in epsilon4- AD than in epsilon4+ AD. Lack of the epsilon4 allele may be associated with other (as yet undiscovered) genetic or environmental risk factors, which confer greater neuropathological asymmetry.
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Doença de Alzheimer/fisiopatologia , Apolipoproteínas E/genética , Circulação Cerebrovascular/fisiologia , Lobo Parietal/irrigação sanguínea , Idade de Início , Idoso , Alelos , Doença de Alzheimer/genética , Análise de Variância , Mapeamento Encefálico , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Testes Neuropsicológicos , Fatores de Risco , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
Research indicates that norepinephrine enhances the working memory functions of the prefrontal cortex (PFC) through actions at post-synaptic, alpha-2A adrenoceptors. The current study examined the effects of the alpha-2A adrenoreceptor agonist, guanfacine (0.7 mg/kg, i.m.), compared to saline on SPECT measures of regional cerebral blood flow (rCBF) in monkeys performing a spatial working memory task. Animals were infused with the SPECT blood flow tracer, Tcm-99m ECD, through an indwelling intravenous catheter while performing the working memory task. Guanfacine treatment significantly improved cognitive performance of the working memory task, and significantly increased rCBF values in the dorsolateral PFC, the brain region most tightly associated with performance of spatial working memory tasks. In contrast, guanfacine had no significant effect on rCBF in the superior temporal cortex, an auditory association area unrelated to task performance. These data are consistent with the hypothesis that alpha-2A adrenoceptor stimulation preferentially enhances functioning of the PFC.
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Agonistas de Receptores Adrenérgicos alfa 2 , Agonistas alfa-Adrenérgicos/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Guanfacina/farmacologia , Memória/fisiologia , Córtex Pré-Frontal/irrigação sanguínea , Percepção Espacial/fisiologia , Animais , Cognição/efeitos dos fármacos , Cognição/fisiologia , Feminino , Processamento de Imagem Assistida por Computador , Macaca mulatta , Imageamento por Ressonância Magnética , Córtex Pré-Frontal/efeitos dos fármacos , Estimulação Química , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
A 40 base polymorphism of a variable number of tandem repeats (VNTR) has been described in the 3' untranslated region of the gene (SLC6A3) coding for the dopamine transporter (DAT). Despite being located in the untranslated region of the gene, this polymorphism has been associated with clinical phenotypes associated with dysregulation of dopamine transmission, such as attention deficit hyperactivity disorder and cocaine-induced paranoia. To examine the neurochemical phenotype associated with this polymorphism, we compared amphetamine-induced dopamine release (measured as displacement of the radiotracer [123I]IBZM) and DAT expression (measured with [123I]beta-CIT) in the striatum with Single Photon Computerized Emission Tomography (SPECT). Our sample included 59 subjects, 31 healthy controls and 29 patients with schizophrenia. No significant association was found between VNTR polymorphism and amphetamine-induced dopamine release or DAT density in the total sample, nor when each diagnostic group was considered separately. Thus, we did not replicate the findings of two previous studies, which had suggested that the 9 repeat allele was associated with either an increased or decreased DAT expression, albeit in different patient populations.
Assuntos
Proteínas de Transporte/genética , Dopamina/metabolismo , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Repetições Minissatélites/genética , Neostriado/metabolismo , Proteínas do Tecido Nervoso , Polimorfismo Genético/genética , Adulto , Anfetamina/administração & dosagem , Anfetamina/efeitos adversos , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Benzamidas/farmacocinética , Proteínas de Transporte/metabolismo , Cocaína/análogos & derivados , Cocaína/farmacocinética , Transtornos Relacionados ao Uso de Cocaína/genética , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Antagonistas de Dopamina/farmacocinética , Proteínas da Membrana Plasmática de Transporte de Dopamina , Genótipo , Humanos , Radioisótopos do Iodo/farmacocinética , Neostriado/efeitos dos fármacos , Neostriado/fisiopatologia , Fenótipo , Transtornos Psicóticos/genética , Transtornos Psicóticos/metabolismo , Transtornos Psicóticos/fisiopatologia , Pirrolidinas/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Esquizofrenia/genética , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
UNLABELLED: Iodine-123-beta-carbomethoxy-3 beta-(4-iodophenyltropane) (CIT) has been used as a probe of dopamine transporters in Parkinson's disease patients using SPECT. This tracer has a protracted period of striatal uptake enabling imaging 14-24 hr postinjection for stable quantitative measures of dopamine transporters, and it binds with nanomolar affinity to the serotonin transporter. Iodine-123 fluoropropyl (FP)CIT is an analog of [123I]-beta-CIT and has been shown to achieve peak tracer uptake in the brain within hours postinjection and to provide greater selectivity for the dopamine transporter. The purpose of the present study was to compare [123I]-beta-CIT with [123I]-FPCIT in a within-subject design. METHODS: Six Parkinson's disease patients and five healthy control subjects participated in one [123I]-beta-CIT and one [123I]-FPCIT SPECT scan separated by 7-21 days. Controls were imaged at 24 hr postinjection 222 MBq (6 mCi) [123I]-beta-CIT and serially from 1-6 hr postinjection 333 MBq (9 mCi) [123I]-FPCIT. Two imaging outcome measures were evaluated: (a) the ratio of specific striatal activity to nondisplaceable uptake, also designated V"3, at each imaging time point; and (b) the rate of striatal washout of radiotracer expressed as a percent reduction per hr for [123I]-FPCIT. In addition, venous plasma was obtained from the five control subjects after the [123I]-FPCIT injection for analysis of radiometabolites. RESULTS: Both [123I]-FPCIT and [123I]-beta-CIT demonstrated decreased striatal uptake in Parkinson's disease patients compared with the controls with a mean of V"3=3.5 and 6.7 for [123I]-beta-CIT (Parkinson's disease and controls, respectively) and a mean of V"3=1.34 and 3.70 for [123I]-FPCIT (Parkinson's disease and controls, respectively). For [123I]-beta-CIT, the mean Parkinson's disease values represented 52% of the control uptake, while the mean [123I]-FPCIT value for Parkinson's disease patients was 37% of the control values. Analysis of [123I]-FPCIT time-activity curves for specific striatal counts showed washout rates of 8.2%/hr for Parkinson's disease and 4.9%/hr for controls. CONCLUSION: These data suggest that SPECT imaging with [123I]-FPCIT visually demonstrates reductions in striatal uptake similar to [123I]-beta-CIT. iodine-123-FPCIT washed out from striatal tissue 15-20 times faster than [123I]-beta-CIT, and estimates of dopamine transporter loss in Parkinson's disease patients were higher for [123I]-FPCIT than for [123I]-beta-CIT. This was most likely due to the faster rate of striatal washout and establishment of transient equilibrium binding conditions at the dopamine transporter, which the modeling theory suggests produces an overestimation of dopamine transporter density with relatively greater overestimates in healthy control subjects by [123I]-FPCIT.
Assuntos
Proteínas de Transporte/metabolismo , Cocaína/análogos & derivados , Corpo Estriado/diagnóstico por imagem , Dopamina/metabolismo , Radioisótopos do Iodo , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Doença de Parkinson/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único , Tropanos , Idoso , Estudos de Casos e Controles , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Humanos , Masculino , Doença de Parkinson/metabolismo , Fatores de TempoRESUMO
UNLABELLED: The effect of age on human striatal dopamine (DA) transporters was investigated with SPECT using the ligand [123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT). METHODS: Iodine-123-beta-CIT binding in the striatum was examined in 28 healthy human subjects (14 men, 14 women) who ranged in age from 18 to 83 yr. Following injection with [123I]beta-CIT (mean +/- s.d. = 9.9 +/- 1.2 mCi), subjects were scanned with the brain-dedicated CERASPECT camera. A reconstructed transaxial slice 13.3-mm thick at the level of maximal striatal activity was used to determine tracer uptake in striatal and occipital regions of interest. The stability of regional uptake on Day 2 (approximately 18-24 hr postinjection) permitted estimation of the specific-to-nondisplaceable equilibrium partition coefficient: V3", calculated as (striatal--occipital)/occipital uptake at equilibrium. RESULTS: Values of V3" ranged from 3.6 to 11.4 for this sample (6.7 +/- 1.9). V3" showed a significant inverse correlation with age (r = -0.73, n = 28, p < 0.0001). Linear regression analysis revealed that V3" declined by 51% over the age range studied or approximately 8% per decade. CONCLUSION: These findings confirm postmortem reports of dopamine transporter loss with aging. In vivo methodologies may permit the age-related degeneration of dopamine nerve terminals to be studied in relation to the cognitive and motor deficits that occur in normal aging.
Assuntos
Envelhecimento/metabolismo , Proteínas de Transporte/metabolismo , Cocaína/análogos & derivados , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Dopamina/metabolismo , Radioisótopos do Iodo , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Tomografia Computadorizada de Emissão de Fóton Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
UNLABELLED: This study assesses the feasibility of using SPECT to image intrasynaptic dopamine release in human striatum following dextroamphetamine sulfate (d-amphetamine) challenge testing. METHODS: A bolus plus constant infusion administration schedule of the D2 receptor radiotracer [123I]iodobenzamide ([123I]IBZM) was used to obtain a stable baseline for reliable quantitation of the d-amphetamine effect. Eight healthy subjects first underwent a controlled experiment to demonstrate that stable levels of striatal and occipital activities could be maintained from 150 to 420 min during programmed infusion of the tracer. Next, seven subjects underwent the experiment with d-amphetamine. The experimental conditions were identical except that 0.3 mg/kg amphetamine was injected intravenously at 240 min. The behavioral effects of d-amphetamine were measured by self-rating on the following analog scales: euphoria, alertness, restlessness and anxiety. RESULTS: The d-amphetamine injection induced a 15% +/- 4% (mean +/- s.d.) decrease in D2 receptor availability, measured as the specific-to-nonspecific equilibrium partition coefficient (V3"). The d-amphetamine injection induced marked increase in euphoria, alertness and restlessness scores. The intensity of these behavioral responses correlated with the decrease in D2 availability measured with SPECT. In contrast, the anxiety response was milder and not correlated with the decrease in D2 availability. CONCLUSION: These studies demonstrate the feasibility of using [123I]IBZM programmed infusion and SPECT imaging to measure endogenous dopamine release after d-amphetamine challenge and to study brain neurochemical correlates of emotions.
Assuntos
Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Dextroanfetamina/farmacologia , Dopamina/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Adolescente , Adulto , Comportamento/efeitos dos fármacos , Benzamidas , Pressão Sanguínea/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Feminino , Humanos , Radioisótopos do Iodo , Masculino , PirrolidinasRESUMO
UNLABELLED: Iodine-123-beta-CIT has been used as a probe of dopamine transporters in Parkinson's disease patients using SPECT. We studied the test/retest reproducibility of SPECT measures in Parkinson's disease patients and healthy controls obtained after injection of [123I])beta-CIT in part to assess the utility of this tracer for longitudinal evaluation of striatal dopamine transporters as a marker of disease progression. METHODS: Seven Parkinson's disease patients and seven healthy control subjects participated in two [123I]beta-CIT SPECT scans separated by 7-21 days. Subjects were imaged at 24 hr post injection of 360 MBq (9.7 mCi) of [123I]beta-CIT. Two outcome measures were evaluated; 1) the ratio of specific striatal (activity associated with DA transporter binding) to nondisplaceable uptake, also designated V3," and 2) the total specific striatal uptake (%SSU) expressed as a percentage of injected radiotracer dose. For both measures, test/retest variability was calculated as the absolute difference of test minus retest divided by the mean of test/retest and expressed as a percent. In addition, the reproducibility of left and right striatal asymmetry and putamen:caudate ratios were determined. RESULTS: The two outcome measures demonstrated excellent test/retest reproducibility for both the Parkinson's disease and healthy subject groups with variability of striatal V3" = 16.8 +/- 13.3% and percent striatal uptake = 6.8 +/- 3.4% for Parkinson's disease patients and V3" = 12.8 +/- 8.9% and %SSU = 7.0 +/- 3.9% for control subjects. There were no statistically significant differences in test/retest variability between control subjects and Parkinson's disease patients for either outcome measure. The reproducibility of left/right asymmetry indices and putamen-to-caudate ratios showed no patient versus control subject differences. The asymmetry index had greater test/retest variability than the other outcome measures. CONCLUSION: These data suggest that SPECT imaging performed at 24 hr postinjection of [123I]beta-CIT permits calculation of reliable and reproducible measures of dopamine transporters in both Parkinson's disease patients and control subjects and supports the feasibility of using [123I]beta-CIT in the evaluation of disease progression in Parkinson's disease.
Assuntos
Encéfalo/metabolismo , Proteínas de Transporte/análise , Cocaína/análogos & derivados , Dopamina/metabolismo , Radioisótopos do Iodo , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Doença de Parkinson/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Putamen/metabolismo , Reprodutibilidade dos TestesRESUMO
UNLABELLED: [18F]altanserin has been used to label serotonin 5-HT2A receptors, which are believed to be important in the pathophysiology of schizophrenia and depression. The purpose of this study was to test the feasibility of a constant infusion paradigm for equilibrium modeling of [18F]altanserin with PET. Kinetic modeling with [18F]altanserin may be hampered by the presence of lipophilic radiometabolites observed in plasma after intravenous administration. METHODS: Eight healthy volunteers were injected with [18F]altanserin as a bolus (208+/-9 MBq [5.62+/-0.25 mCi]) plus constant infusion (65+/-3 MBq/h [1.76+/-0.08 mCi/h]) ranging from 555 to 626 min (615+/-24 min) after injection. PET acquisitions (10-20 min) and venous blood sampling were performed every 30-60 min throughout the infusion period. RESULTS: Linear regression analysis revealed that time-activity curves for both brain activity and plasma [18F]altanserin and metabolite concentrations stabilized after about 6 h. This permitted equilibrium modeling and estimation of V3' (ratio of specific uptake [cortical-cerebellar] to total plasma parent concentration after 6 h). Values of V3' ranged from 1.57+/-0.38 for anterior cingulate cortex to 1.02+/-0.39 for frontal cortex. The binding potential V3 (ratio of specific uptake to free plasma parent concentration after 6 h, using group mean f1) was also calculated and ranged from 169+/-41 for anterior cingulate cortex to 110+/-42 for frontal cortex. From 6 h onward, the rate of change for V3' and V3 was only 1.11+/-1.69 %/h. CONCLUSION: These results demonstrate the feasibility of equilibrium imaging with [18F]altanserin over more than 5 radioactive half-lives and suggest a method to overcome difficulties associated with lipophilic radiolabeled metabolites. The stability in V3 and V3' once equilibrium is achieved suggests that a single PET acquisition obtained at 6 h may provide a reasonable measure of 5-HT2A receptor density.