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IMPORTANCE: Adults with Down syndrome (DS) are at high-risk of revealing Alzheimer's disease (AD) pathology, in part due to the triplication of chromosome 21 encoding the amyloid precursor protein. Adults with DS are uniformly affected by AD pathology by their 30's and have a 70% to 80% chance of clinical dementia by their 60's. Our previous studies have assessed longitudinal changes in amyloid beta (Aß) accumulation in DS. OBJECTIVE: The goal of the present study was to assess the presence of brain tau using [18F]AV-1451 positron emission tomography (PET) in DS and to assess the relationship of brain tau pathology to Aß using Pittsburgh Compound B (PiB)-PET. DESIGN: Cohort study. SETTING: Multi-center study. PARTICIPANTS: Participants consisted of a sample of individuals with DS and sibling controls recruited from the community; exclusion criteria included contraindications for magnetic resonance imaging (MRI) and/or a medical or psychiatric condition that impaired cognitive functioning. EXPOSURES: PET brain scans to assess Aß ([11C]PiB) and tau ([18F]AV-1451) burden. MAIN OUTCOMES AND MEASURES: Multiple linear regression models (adjusted for chronological age, sex and performance site) were used to examine associations between regional [18F]AV-1451 standard uptake value ratio (SUVR) (based on regions associated with Braak stages 1-6) and global [11C]PiB SUVR (as both a continuous and dichotomous variable). RESULTS: A cohort of 156 participants (mean age = 39.05, SD(8.4)) were examined. These results revealed a significant relationship between in vivo Aß and tau pathology in DS. As a dichotomous variable, [18F]AV-1451 retention was higher in each Braak region in PiB(+) participants. We also found, based on our statistical models, starting with the Braak 3 region of interest (ROI), an acceleration of [18F]AV-1451 SUVR deposition with [11C]PiB SUVR increases.
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The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in the pathophysiology of mood and anxiety disorders and is a potential treatment target in major depressive disorder (MDD). This study compared brain mGluR5 binding in elderly patients suffering from MDD with that in elderly healthy volunteers using positron emission tomography (PET) and [(11)C]ABP688. Twenty elderly (mean age: 63.0 ± 6.3) subjects with MDD and twenty-two healthy volunteers in the same age range (mean age: 66.4 ± 7.3) were examined with PET after a single bolus injection of [(11)C]ABP688, with many receiving arterial sampling. PET images were analyzed on a region of interest and a voxel level to compare mGluR5 binding in the brain between the two groups. Differences in [(11)C]ABP688 binding between patients with early- and late-onset depression were also assessed. In contrast to a previously published report in a younger cohort, no significant difference in [(11)C]ABP688 binding was observed between elderly subjects with MDD and healthy volunteers. [(11)C]ABP688 binding was also similar between subgroups with early- or late-onset depression. We believe this is the first study to examine mGluR5 expression in depression in the elderly. Although future work is required, results suggest potential differences in the pathophysiology of elderly depression versus depression earlier in life.
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Encéfalo/metabolismo , Radioisótopos de Carbono , Transtorno Depressivo Maior/metabolismo , Oximas , Tomografia por Emissão de Pósitrons , Piridinas , Receptor de Glutamato Metabotrópico 5/metabolismo , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
The amyloid imaging agent, Pittsburgh Compound-B, binds with high affinity to ß-amyloid (Aß) in the brain, and it is well established that PiB also shows non-specific retention in white matter (WM). However, little is known about retention of PiB in areas of white matter hyperintensities (WMH), abnormalities commonly seen in older adults. Further, it is hypothesized that WMH are related to both cognitive dysfunction and Aß deposition. The goal of the present study was to explore PiB retention in both normal-appearing WM (NAWM) and WMH in a group of elderly, cognitively normal individuals. In a group of cognitively normal elderly (n = 64; 86.5 ± 2.6 years) two analyses were applied: (1) ROIs were placed over periventricular areas in which WMH caps are commonly seen on all subjects, regardless of WMH burden or size. (2) Subject-specific maps of NAWM and WMH were co-registered with the PiB-PET images and mean SUVR values were calculated in these NAWM and WMH maps. PiB retention was significantly reduced in the ROIs of subjects with high WMH compared to subjects with low WMH. Additionally, in subjects with high WMH, there was significantly lower PiB retention in subject-specific maps of WMH compared to NAWM, which was not observed in subjects with low WMH, likely because of the small size of WMH maps in this group. These data suggest that WM in areas of WMH binds PiB less effectively than does normal WM. Further exploration of this phenomenon may lead to insights about the molecular basis of the non-specific retention of amyloid tracers in white matter.
Assuntos
Compostos de Anilina/farmacocinética , Ventrículos Cerebrais/diagnóstico por imagem , Ventrículos Cerebrais/patologia , Tomografia por Emissão de Pósitrons/métodos , Tiazóis/farmacocinética , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Idoso de 80 Anos ou mais , Ventrículos Cerebrais/metabolismo , Feminino , Humanos , Masculino , Substância Branca/metabolismoRESUMO
OBJECTIVE: This study examined the relationship between postmortem precuneus cholinergic enzyme activity, Pittsburgh compound B (PiB) binding, and soluble amyloid-ß concentration in mild cognitive impairment (MCI) and Alzheimer disease (AD). METHODS: Choline acetyltransferase (ChAT) activity, [(3)H]PiB binding, and soluble amyloid-ß(1-42) (Aß42) concentration were quantified in precuneus tissue samples harvested postmortem from subjects with no cognitive impairment (NCI), MCI, and mild AD and correlated with their last antemortem Mini-Mental State Examination (MMSE) score and postmortem pathologic evaluation according to the National Institute on Aging-Reagan criteria, recommendations of the Consortium to Establish a Registry for Alzheimer's Disease, and Braak stage. RESULTS: Precuneus ChAT activity was lower in AD than in NCI and was comparable between MCI and NCI. Precuneus [(3)H]PiB binding and soluble Aß42 levels were elevated in MCI and significantly higher in AD than in NCI. Across all case subjects, reduced ChAT activity was associated with increased [(3)H]PiB binding, increased soluble Aß42, lower MMSE score, presence of the APOE*4 allele, and more advanced AD pathology. CONCLUSIONS: Despite accumulating amyloid burden, cholinergic enzyme activity is stable in the precuneus during prodromal AD. A decline in precuneus ChAT activity occurs only in clinical AD, when PiB binding and soluble Aß42 levels are substantially elevated compared with those in MCI. Anti-amyloid interventions in MCI case subjects with a positive PiB PET scan may aid in reducing cholinergic deficits and cognitive decline later in the disease process.
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Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Lobo Parietal/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Compostos de Anilina , Benzotiazóis/farmacocinética , Estudos de Casos e Controles , Colina O-Acetiltransferase/metabolismo , Feminino , Humanos , Masculino , Emaranhados Neurofibrilares/patologia , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Mudanças Depois da Morte , Escalas de Graduação Psiquiátrica , Ensaio Radioligante , Cintilografia , Tiazóis , Trítio/farmacocinéticaRESUMO
OBJECTIVE: To investigate whether longitudinal declines in cognition are associated with higher fibrillar amyloid-beta (Abeta) deposition in vivo in individuals without dementia. METHOD: [(11)C]PiB images were obtained to measure fibrillar Abeta burden in 57 participants without dementia from the Baltimore Longitudinal Study of Aging. Participants (33 men, 24 women) had a mean (SD) age of 78.7 (6.2) years. Six participants (4 men, 2 women) had mild cognitive impairment defined as Clinical Dementia Rating = 0.5. To measure [(11)C]PiB retention, distribution volume ratios (DVR) for 15 regions of interest were estimated by fitting a simplified reference tissue model to the measured time activity curves. Mixed effects regression was used to predict cognitive trajectories over time using data before and including time of PiB (mean follow-up 10.8 years), with mean cortical DVR, age at baseline, sex, and education as independent predictors. Voxel-based analysis identified local associations. RESULTS: [(11)C]PiB retention was higher in older individuals. Greater declines over time in mental status and verbal learning and memory, but not visual memory, were associated significantly with higher PiB retention. Voxel-based analysis showed significant associations in frontal and lateral temporal regions. CONCLUSIONS: Higher Abeta deposition is associated with greater longitudinal decline in mental status and verbal memory in the preceding years. The differential association for verbal but not visual memory may reflect the greater reliance of verbal word list learning on prefrontal regions, which show early Abeta deposition. Prospective imaging may help distinguish between individuals with evolving neuropathology who develop accelerated cognitive decline vs those with normal aging.
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Amiloide/metabolismo , Compostos de Anilina , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/metabolismo , Tiazóis , Idoso , Idoso de 80 Anos ou mais , Mapeamento Encefálico , Radioisótopos de Carbono , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética/métodos , Masculino , Entrevista Psiquiátrica Padronizada , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons/métodos , Estudos RetrospectivosRESUMO
BACKGROUND: PET imaging using [(18)F]fluorodeoxyglucose (FDG) and [(11)C]Pittsburgh compound B (PIB) have been proposed as biomarkers of Alzheimer disease (AD), as have CSF measures of the 42 amino acid beta-amyloid protein (Abeta(1-42)) and total and phosphorylated tau (t-tau and p-tau). Relationships between biomarkers and with disease severity are incompletely understood. METHODS: Ten subjects with AD, 11 control subjects, and 34 subjects with mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative underwent clinical evaluation; CSF measurement of Abeta(1-42), t-tau, and p-tau; and PIB-PET and FDG-PET scanning. Data were analyzed using continuous regression and dichotomous outcomes with subjects classified as "positive" or "negative" for AD based on cutoffs established in patients with AD and controls from other cohorts. RESULTS: Dichotomous categorization showed substantial agreement between PIB-PET and CSF Abeta(1-42) measures (91% agreement, kappa = 0.74), modest agreement between PIB-PET and p-tau (76% agreement, kappa = 0.50), and minimal agreement for other comparisons (kappa <0.3). Mini-Mental State Examination score was significantly correlated with FDG-PET but not with PIB-PET or CSF Abeta(1-42). Regression models adjusted for diagnosis showed that PIB-PET was significantly correlated with Abeta(1-42), t-tau, and p-tau(181p), whereas FDG-PET was correlated only with Abeta(1-42). CONCLUSIONS: PET and CSF biomarkers of Abeta agree with one another but are not related to cognitive impairment. [(18)F]fluorodeoxyglucose-PET is modestly related to other biomarkers but is better related to cognition. Different biomarkers for Alzheimer disease provide different information from one another that is likely to be complementary.
Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Biomarcadores/metabolismo , Transtornos Cognitivos/diagnóstico por imagem , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Compostos de Anilina/metabolismo , Biomarcadores/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Estudos de Casos e Controles , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/metabolismo , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Masculino , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Escalas de Graduação Psiquiátrica , Tiazóis/metabolismo , Proteínas tau/líquido cefalorraquidianoRESUMO
AIMS: One promising approach for treatment of Alzheimer's disease (AD) is use of anti-amyloid therapies, based on the hypothesis that increases in amyloid-beta (Aß) deposits in brain are a major cause of AD. Several groups have focused on Aß immunotherapy with some success. Small molecules derivatives of Congo red have been shown to inhibit Aß aggregation and protect against Aß neurotoxicity in vitro. The agents described here are all small molecule Aß-binding agents (SMAßBA's) derivatives of Congo red. MAIN METHODS: Here, we have explored the anti-amyloid properties of these SMAßBA's in mice doubly transgenic for human prensenilin-1 (PS1) and APP gene mutations that cause early-onset AD. Mice were treated with either methoxy-X04, X:EE:B34 and X:034-3-OMe1. After treatment, brains were examined for Aß-deposition, using histochemistry, and soluble and insoluble Aß levels were determined using ELISA. KEY FINDINGS: A range of anti-amyloid activity was observed with these three compounds. PS1/APP mice treated with methoxy-X04 and X:EE:B34 showed decrease in total Aß load, a decrease in Aß fibril load, and a decrease in average plaque size. Treatment with methoxy-X04 also resulted in a decrease in insoluble Aß levels. The structurally similar compound, X:034:3-OMe1, showed no significant effect on any of these measures. The effectiveness of the SMAßBA's may be related to a combination of binding affinity for Aß and entry into brain, but other factors appear to apply as well. SIGNIFICANCE: These data suggest that SMAßBA's may significantly decrease amyloid burden in brain during the pathogenesis of AD and could be useful therapeutics alone, or in combination with immunotherapy.
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Although beta-amyloid (Abeta) plaques are a primary diagnostic criterion for Alzheimer's disease, this pathology is commonly observed in the brains of non-demented older individuals. To explore the importance of this pathology in the absence of dementia, we compared levels of amyloid deposition (via 'Pittsburgh Compound-B' (PIB) positron emission tomography (PET) imaging) to hippocampus volume (HV) and episodic memory (EM) in three groups: (i) normal controls (NC) from the Berkeley Aging Cohort (BAC NC, n = 20); (ii) normal controls (NC) from the Alzheimer's disease neuroimaging initiative (ADNI NC, n = 17); and (iii) PIB+ mild cognitive impairment subjects from the ADNI (ADNI PIB+ MCI, n = 39). Age, gender and education were controlled for in each statistical model, and HV was adjusted for intracranial volume (aHV). In BAC NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.0016) and worse EM (P = 0.0086). Within ADNI NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.047) but not EM (P = 0.60); within ADNI PIB+ MCI, elevated PIB uptake was significantly associated with both smaller aHV (P = 0.00070) and worse EM (P = 0.046). To further understand these relationships, a recursive regression procedure was conducted within all ADNI NC and PIB+ MCI subjects (n = 56) to test the hypothesis that HV mediates the relationship between Abeta and EM. Significant correlations were found between PIB index and EM (P = 0.0044), PIB index and aHV (P < 0.0001), as well as between aHV and EM (P < 0.0001). When both aHV and PIB were included in the same model to predict EM, aHV remained significant (P = 0.0015) whereas PIB index was no longer significantly associated with EM (P = 0.50). These results are consistent with a model in which Abeta deposition, hippocampal atrophy, and EM occur sequentially in elderly subjects, with Abeta deposition as the primary event in this cascade. This pattern suggests that declining EM in older individuals may be caused by Abeta-induced hippocampus atrophy.
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Peptídeos beta-Amiloides/análise , Hipocampo/patologia , Transtornos da Memória/patologia , Fatores Etários , Idoso , Envelhecimento/fisiologia , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Compostos de Anilina , Atrofia , Radioisótopos de Carbono , Estudos de Casos e Controles , Escolaridade , Feminino , Hipocampo/química , Hipocampo/diagnóstico por imagem , Humanos , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Transtornos da Memória/diagnóstico por imagem , Transtornos da Memória/psicologia , Pessoa de Meia-Idade , Análise Multivariada , Tamanho do Órgão , Tomografia por Emissão de Pósitrons/métodos , Escalas de Graduação Psiquiátrica , Compostos Radiofarmacêuticos , Fatores Sexuais , TiazóisRESUMO
BACKGROUND: Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD). OBJECTIVES: To determine whether amyloid deposition, as assessed by PET imaging with the beta-amyloid-binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features. METHODS: Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio. RESULTS: Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function. CONCLUSIONS: Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that beta-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
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Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Demência/metabolismo , Doença por Corpos de Lewy/psicologia , Doença de Parkinson/psicologia , Tomografia por Emissão de Pósitrons , Idoso , Compostos de Anilina , Encéfalo/diagnóstico por imagem , Cognição , Demência/diagnóstico , Demência/diagnóstico por imagem , Demência/etiologia , Diagnóstico Diferencial , Feminino , Humanos , Doença por Corpos de Lewy/fisiopatologia , Masculino , Pessoa de Meia-Idade , Movimento , Testes Neuropsicológicos , Doença de Parkinson/fisiopatologia , Tiazóis , Distribuição TecidualRESUMO
Input functions required for positron emission tomography (PET) tracer kinetic modeling are often obtained from arterial blood. In some situations, using short-lived radiotracers, e.g. [(15)O]water, rapid sample handling is required. A method used at several facilities is to pump blood through a detector system at a constant rate. We investigate the suitability of a commercial radiochromatography module (IN/US Posi-RAM) for this new use. The Posi-RAM consists of two 2.5 cm (length) x 2.5 cm (diameter) cylindrical bismuth germanate (BGO) detectors that can operate in coincidence mode. Arterial blood is transported through the system via a length of tubing with flow rate controlled by a peristalsis pump. A custom-counting loop and support frame were designed for the Posi-RAM for PET studies. System sensitivity was determined to be 1.1 x 10(4) cps/(MBq ml(-1)). Dead time as a function of count-rate was found to be less than 1% for concentrations below 3.5 MBq ml(-1), a range encompassing all human-study values. In a human study, the performance of the device was found to be similar to that of the facility's current blood monitor (Siemens Fluid Monitor). We conclude that the Posi-RAM has the necessary sensitivity and count-rate capabilities to be used as a real-time blood activity monitor.
Assuntos
Artérias/metabolismo , Análise Química do Sangue/instrumentação , Sangue/diagnóstico por imagem , Cromatografia/instrumentação , Tomografia por Emissão de Pósitrons/instrumentação , Radiometria/instrumentação , Compostos Radiofarmacêuticos/sangue , Processamento de Sinais Assistido por Computador/instrumentação , Análise Química do Sangue/métodos , Cromatografia/métodos , Desenho de Equipamento , Análise de Falha de Equipamento , Humanos , Radioquímica/instrumentação , Radioquímica/métodos , Radiometria/métodos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: To compare brain beta-amyloid (Abeta) burden measured with [(11)C]Pittsburgh Compound B (PIB) PET in normal aging, Alzheimer disease (AD), and other dementias. METHODS: Thirty-three subjects with dementia (17 AD, 10 dementia with Lewy bodies [DLB], 6 frontotemporal dementia [FTD]), 9 subjects with mild cognitive impairment (MCI), and 27 age-matched healthy control subjects (HCs) were studied. Abeta burden was quantified using PIB distribution volume ratio. RESULTS: Cortical PIB binding was markedly elevated in every AD subject regardless of disease severity, generally lower and more variable in DLB, and absent in FTD, whereas subjects with MCI presented either an "AD-like" (60%) or normal pattern. Binding was greatest in the precuneus/posterior cingulate, frontal cortex, and caudate nuclei, followed by lateral temporal and parietal cortex. Six HCs (22%) showed cortical uptake despite normal neuropsychological scores. PIB binding did not correlate with dementia severity in AD or DLB but was higher in subjects with an APOE-epsilon4 allele. In DLB, binding correlated inversely with the interval from onset of cognitive impairment to diagnosis. CONCLUSIONS: Pittsburgh Compound B PET findings match histopathologic reports of beta-amyloid (Abeta) distribution in aging and dementia. Noninvasive longitudinal studies to better understand the role of amyloid deposition in the course of neurodegeneration and to determine if Abeta deposition in nondemented subjects is preclinical AD are now feasible. Our findings also suggest that Abeta may influence the development of dementia with Lewy bodies, and therefore strategies to reduce Abeta may benefit this condition.
Assuntos
Envelhecimento/metabolismo , Peptídeos beta-Amiloides/análise , Compostos de Anilina , Química Encefálica , Radioisótopos de Carbono , Transtornos Cognitivos/diagnóstico por imagem , Demência/diagnóstico por imagem , Compostos Radiofarmacêuticos , Tiazóis , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Apolipoproteínas E/genética , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Demência/metabolismo , Demência/patologia , Feminino , Giro do Cíngulo/química , Giro do Cíngulo/diagnóstico por imagem , Humanos , Doença por Corpos de Lewy/diagnóstico por imagem , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neocórtex/química , Neocórtex/diagnóstico por imagem , CintilografiaRESUMO
AIM: To investigate the relationship between ratings of depressive symptoms and in vivo cortical acetylcholinesterase (AChE) activity in subjects with Parkinson's disease (PD) and parkinsonian dementia (PDem). METHODS: Subjects (with PD, n = 18, including subjects with PDem, n = 6, and normal controls, n = 10) underwent [11C]methyl-4-piperidinyl propionate AChE positron emission tomography imaging and clinical assessment including the Cornell Scale for Depression in Dementia (CSDD). RESULTS: Subjects with PD and PDem had higher scores on the CSDD compared with normal controls: 7.3 (5.4) and 2.8 (2.6), respectively (F = 6.9, p = 0.01). Pooled analysis demonstrated a significant inverse correlation between cortical AChE activity and CSDD scores: R = -0.5, p = 0.007. This correlation remained significant after controlling for Mini-Mental State Examination scores. CONCLUSION: Depressive symptomatology is associated with cortical cholinergic denervation in PD that tends to be more prominent when dementia is present.
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Acetilcolinesterase/metabolismo , Colinérgicos/metabolismo , Demência/fisiopatologia , Transtorno Depressivo/fisiopatologia , Doença de Parkinson/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Córtex Cerebral/fisiopatologia , Demência/diagnóstico por imagem , Demência/etiologia , Transtorno Depressivo/diagnóstico por imagem , Transtorno Depressivo/etiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Degeneração Neural/diagnóstico por imagem , Degeneração Neural/fisiopatologia , Testes Neuropsicológicos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Receptores Colinérgicos/metabolismoRESUMO
BACKGROUND: The PET tracer (11)C-labeled Pittsburgh Compound-B ((11)C-PIB) specifically binds fibrillar amyloid-beta (Abeta) plaques and can be detected in Alzheimer disease (AD). We hypothesized that PET imaging with (11)C-PIB would discriminate AD from frontotemporal lobar degeneration (FTLD), a non-Abeta dementia. METHODS: Patients meeting research criteria for AD (n = 7) or FTLD (n = 12) and cognitively normal controls (n = 8) underwent PET imaging with (11)C-PIB (patients and controls) and (18)F-fluorodeoxyglucose ((18)F-FDG) (patients only). (11)C-PIB whole brain and region of interest (ROI) distribution volume ratios (DVR) were calculated using Logan graphical analysis with cerebellum as a reference region. DVR images were visually rated by a blinded investigator as positive or negative for cortical (11)C-PIB, and summed (18)F-FDG images were rated as consistent with AD or FTLD. RESULTS: All patients with AD (7/7) had positive (11)C-PIB scans by visual inspection, while 8/12 patients with FTLD and 7/8 controls had negative scans. Of the four PIB-positive patients with FTLD, two had (18)F-FDG scans that suggested AD, and two had (18)F-FDG scans suggestive of FTLD. Mean DVRs were higher in AD than in FTLD in whole brain, lateral frontal, precuneus, and lateral temporal cortex (p < 0.05), while DVRs in FTLD did not significantly differ from controls. CONCLUSIONS: PET imaging with (11)C-labeled Pittsburgh Compound-B ((11)C-PIB) helps discriminate Alzheimer disease (AD) from frontotemporal lobar degeneration (FTLD). Pathologic correlation is needed to determine whether patients with PIB-positive FTLD represent false positives, comorbid FTLD/AD pathology, or AD pathology mimicking an FTLD clinical syndrome.
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Doença de Alzheimer/diagnóstico por imagem , Benzotiazóis , Encéfalo/diagnóstico por imagem , Demência/diagnóstico por imagem , Aumento da Imagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Idoso , Compostos de Anilina , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , TiazóisRESUMO
BACKGROUND: Beta-amyloid (Abeta) plaques are the hallmark of Alzheimer disease (AD). A PET imaging tracer that binds to Abeta plaques in vivo, N-methyl-[(11)C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (or [(11)C]PIB for "Pittsburgh Compound-B"), has significantly higher binding in subjects diagnosed with dementia of the Alzheimer type (DAT) compared to nondemented controls. The authors used this imaging technique to investigate whether abnormal binding occurs in clinically normal individuals, prior to the development of cognitive changes. METHODS: Forty-one nondemented subjects (age range 20 to 86 years) and 10 patients with DAT (age range 66 to 86 years) underwent [(11)C]PIB PET scanning. Regions of interest were drawn on the MRI over the cerebellar, prefrontal, lateral temporal, occipital, gyrus rectus, precuneus, and striatal cortex. Binding potential values (BPs), proportional to the density of [(11)C]PIB-Abeta binding sites, were calculated using the Logan graphical analysis and the cerebellar cortex for a reference tissue. RESULTS: Patients with DAT had elevated BP values vs nondemented subjects (p < 0.0001). Four of the 41 nondemented subjects had elevated cortical BP values and their BP values as a group were not significantly different from the DAT subjects' BP values. Two of these four nondemented subjects had [(11)C]PIB uptake, both visually and quantitatively, that was indistinguishable from the DAT subjects. CONCLUSIONS: Elevated [(11)C]PIB binding in nondemented subjects suggests that [(11)C]PIB amyloid imaging may be sensitive for detection of a preclinical Alzheimer disease state. Longitudinal studies will be required to determine the association of elevated [(11)C]PIB binding and risk of developing dementia of the Alzheimer type.
Assuntos
Doença de Alzheimer/diagnóstico , Benzotiazóis , Compostos Radiofarmacêuticos , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Compostos de Anilina , Biomarcadores , Radioisótopos de Carbono , Humanos , Pessoa de Meia-Idade , TiazóisAssuntos
Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo Genético , Receptor 5-HT1A de Serotonina/genética , Tonsila do Cerebelo/fisiologia , Feminino , Genótipo , Humanos , Neurônios/fisiologia , Valores de Referência , Proteínas da Membrana Plasmática de Transporte de Serotonina , Estatísticas não ParamétricasRESUMO
OBJECTIVES: To determine in vivo cortical acetylcholinesterase (AChE) activity and cognitive effects in subjects with mild Alzheimer's disease (AD, n = 14) prior to and after 12 weeks of donepezil therapy. METHODS: Cognitive and N-[(11)C]methyl-piperidin-4-yl propionate ([(11)C]PMP) AChE positron emission tomography (PET) assessments before and after donepezil therapy. RESULTS: Analysis of the PET data revealed mean (temporal, parietal, and frontal) cortical donepezil induced AChE inhibition of 19.1% (SD 9.4%) (t = -7.9; p<0.0001). Enzyme inhibition was most robust in the anterior cingulate cortex (24.2% (6.9%), t = -14.1; p<0.0001). Donepezil induced cortical inhibition of AChE activity correlated with changes in the Stroop Color Word interference scores (R(2) = 0.59, p<0.01), but not with primary memory test scores. Analysis of the Stroop test data indicated that subjects with AChE inhibition greater than the median value (>22.2%) had improved scores on the Stroop Color Word Test compared with subjects with less inhibition who had stable to worsening scores (t = -2.7; p<0.05). CONCLUSIONS: Donepezil induced inhibition of cortical AChE enzyme activity is modest in patients with mild AD. The degree of cortical enzyme inhibition correlates with changes in executive and attentional functions.
Assuntos
Acetilcolinesterase/efeitos dos fármacos , Acetilcolinesterase/farmacologia , Doença de Alzheimer/tratamento farmacológico , Córtex Cerebral/enzimologia , Inibidores da Colinesterase/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Indanos/farmacologia , Piperidinas/farmacologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Atenção/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Donepezila , Feminino , Humanos , Masculino , Tomografia por Emissão de PósitronsRESUMO
The development of radioligands to image beta-amyloid (A beta) plaques and neurofibrillary tangles (NFTs) in vivo in the aging human brain is an important and active area of radiopharmaceutical design. When used in combination with positron emission tomography (Pet) or single photon emission computed tomography (spect), amyloid-imaging tracers could facilitate the evaluation of the efficacy of anti-amyloid therapies currently under intense development by many major pharmaceutical companies throughout the world. Amyloid-imaging agents could also serve as surrogate markers in early diagnosis and neuropathogenesis studies of Alzheimer's disease and other aging-related neurodegenerative disorders. In this review article, the design and biological evaluation of amyloid-imaging agents are discussed. The structures of these agents vary from large proteins and peptides such as radiolabeled A beta peptides and monoclonal antibodies to small molecules derived from Congo red, Chrysamine-G, thioflavin-T, and Acridine Orange. In vitro studies indicate that amyloid plaques contain multiple binding sites that can accommodate structurally diverse compounds, providing flexibility for radiopharmaceutical design of amyloid imaging agents. Compared to large biomolecules, small molecule radiotracers are often readily accessible through chemical synthesis and can display superior brain permeability. Several small molecule amyloid-imaging radioligands display high binding affinities to A beta and sufficient brain penetration for imaging studies. Recent studies demonstrate the feasibility of imaging amyloid plaques in vivo in human subjects with PET. Imaging NFTs, separately or in concert with A beta plaques, is not as far advanced as imaging A beta plaques and remains to be fully characterized and demonstrated.
Assuntos
Envelhecimento/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Emaranhados Neurofibrilares/metabolismo , Placa Amiloide/metabolismo , Peptídeos beta-Amiloides/análise , Animais , Diagnóstico por Imagem/métodos , Humanos , Emaranhados Neurofibrilares/química , Placa Amiloide/químicaRESUMO
In vivo assessment of the beta-sheet proteins deposited in amyloid plaques (A beta peptide) or neurofibrillary tangles (tau protein) presents a target for the development of biological markers for Alzheimer's disease (AD). In an effort to develop in vivo beta-sheet imaging probes, derivatives of thioflavin-T (ThT) were synthesized and evaluated. These compounds lack the positively charged quaternary heterocyclic nitrogen of ThT and are therefore uncharged at physiological pH. They are 600-fold more lipophilic than ThT. These ThT derivatives bind to A beta(1-40) fibrils with higher affinity (Ki = 20.2 nM) than ThT (Ki = 890 nM). The uncharged ThT derivatives stained both plaques and neurofibrillary tangles in post-mortem AD brain, showing some preference for plaque staining. A carbon-11 labeled compound, [N-methyl-11C]6-Me-BTA-1, was prepared, and its brain entry and clearance were studied in Swiss-Webster mice. This compound entered the brain at levels comparable to commonly used neuroreceptor imaging agents (0.223 %ID-kg/g or 7.61 %ID/g at 2 min post-injection) and showed good clearance of free and non-specifically bound radioactivity in normal rodent brain tissue (brain clearance t(1,2) = 20 min). The combination of relatively high affinity for amyloid, specificity for staining plaques and neurofibrillary tangles in post-mortem AD brain, and good brain entry and clearance makes [N-methyl-11C]6-Me-BTA-1 a promising candidate as an in vivo positron emission tomography (PET) beta-sheet imaging agent.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Tiazóis/metabolismo , Doença de Alzheimer/metabolismo , Animais , Benzotiazóis , Fenômenos Químicos , Físico-Química , Feminino , Corantes Fluorescentes , Histocitoquímica , Concentração de Íons de Hidrogênio , Camundongos , Ligação Proteica , Solubilidade , Espectrometria de Fluorescência , Tomografia Computadorizada de EmissãoRESUMO
Imaging serotonin-2A (5-HT(2A)) neuroreceptors with positron emission tomography (PET) and [(18)F]altanserin has been the focus of a series of PET studies, as [(18)F]altanserin is one of the most selective 5-HT(2A) antagonist radiotracers. Previous animal studies showed that radiolabeled metabolites (radiometabolites) of [(18)F]altanserin crossed the blood-brain barrier (BBB) to localize nonspecifically in brain, consistent with a constant radioactivity "background." In this work, we evaluated human bolus injection [(18)F]altanserin PET data with detailed consideration of the impact of BBB-permeable metabolites on the specific binding parameters. Data were quantified using either single (parent radiotracer), dual (parent radiotracer and radiometabolites), or no arterial input function(s) (cerebellum as reference tissue input function). A step-gradient high-performance liquid chromatography (HPLC) analysis provided distinct separation of [(18)F]altanserin and four radiolabeled components in plasma. After [(18)F]altanserin injection, the step-gradient data showed that the major BBB-permeable radiometabolites approached constant levels in plasma (>50 min), consistent with a constant metabolite "background." The single-input Logan graphical results were highly correlated with the dual-input results and its bias was fairly constant across regions and subjects, as similarly observed for a nongraphical reference tissue method. The most comprehensive and quantitatively valid analysis for bolus [(18)F]altanserin PET data was the dual-input method that specifically accounted for BBB-permeable metabolites, although the Logan analysis was preferred because it provided a good compromise between validity, sensitivity, and reliability of implementation. Further study is needed to better understand how the cerebellar kinetics of [(18)F]altanserin and its radiometabolites impact the reference tissue measures.
Assuntos
Radioisótopos de Flúor/farmacocinética , Ketanserina/análogos & derivados , Ketanserina/farmacocinética , Modelos Biológicos , Receptores de Serotonina/metabolismo , Tomografia Computadorizada de Emissão/métodos , Adolescente , Adulto , Idoso , Barreira Hematoencefálica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor 5-HT2A de SerotoninaRESUMO
Positron emission tomography (PET) has been used to study serotonin 2A (5-HT(2A)) receptor binding in human brain using the 5-HT(2A) antagonist, [(18)F]altanserin. Previous analyses of bolus injection [(18)F]altanserin data provided 5-HT(2A) specific binding measures that were highly correlated with the in vitro distribution of 5-HT(2A) receptors and reflected decreased binding after ketanserin (5-HT(2A) antagonist) administration. These observations were made in the presence of a nonspecific tissue component that was consistent with blood-brain barrier (BBB) passage of radiolabeled metabolites (radiometabolites). In this work, we evaluated the in vivo kinetics of [(18)F]altanserin and two major radiometabolites of [(18)F]altanserin, focusing on the kinetics of free and nonspecifically-bound radioactivity. PET studies were performed in baboons after the bolus injection of [(18)F]altanserin or one of its major radiometabolites, either [(18)F]altanserinol or [(18)F]4-(4-fluorobenzoyl)piperidine, at baseline and after pharmacologic receptor blockade (blocking data). The cerebellar and blocking data were analyzed using either single (parent radiotracer) or dual (parent radiotracer and radiometabolites) input function methods. After bolus injection of either [(18)F]altanserin metabolite, radioactivity crossed the BBB and localized nonspecifically. The radio- metabolites were found to contribute to nonspecific "background" radioactivity that was similar in receptor-poor and receptor-rich regions. After bolus injection in baboons, two of the major radiometabolites of [(18)F]altanserin crossed the BBB and contributed to a fairly uniform background of nonspecific radioactivity. This uniformity suggests that conventional analyses are appropriate for human bolus injection [(18)F]altanserin PET data, although these methods may overestimate [(18)F]altanserin nonspecific binding.