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1.
JAMA Neurol ; 80(6): 614-623, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37155176

RESUMO

Importance: Longitudinal tau positron emission tomography (PET) is a relevant outcome in clinical trials evaluating disease-modifying therapies in Alzheimer disease (AD). A key unanswered question is whether the use of participant-specific (individualized) regions of interest (ROIs) is superior to conventional approaches where the same ROI (group-level) is used for each participant. Objective: To compare group- and participant-level ROIs in participants at different stages of the AD clinical continuum in terms of annual percentage change in tau-PET standardized uptake value ratio (SUVR) and sample size requirements. Design, Setting, and Participants: This was a longitudinal cohort study with consecutive participant enrollment between September 18, 2017, and November 15, 2021. Included in the analysis were participants with mild cognitive impairment and AD dementia from the prospective and longitudinal Swedish Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably 2 (BioFINDER-2) study; in addition, a validation sample (the AVID 05e, Expedition-3, Alzheimer's Disease Neuroimaging Initiative [ADNI], and BioFINDER-1 study cohorts) was also included. Exposures: Tau PET (BioFINDER-2, [18F]RO948; validation sample, [18F]flortaucipir), 7 group-level (5 data-driven stages, meta-temporal, whole brain), and 5 individualized ROIs. Main Outcomes and Measures: Annual percentage change in tau-PET SUVR across ROIs. Sample size requirements in simulated clinical trials using tau PET as an outcome were also calculated. Results: A total of 215 participants (mean [SD] age, 71.4 (7.5) years; 111 male [51.6%]) from the BioFINDER-2 study were included in this analysis: 97 amyloid-ß (Aß)-positive cognitively unimpaired (CU) individuals, 77 with Aß-positive mild cognitive impairment (MCI), and 41 with AD dementia. In the validation sample were 137 Aß-positive CU participants, 144 with Aß-positive MCI, and 125 with AD dementia. Mean (SD) follow-up time was 1.8 (0.3) years. Using group-level ROIs, the largest annual percentage increase in tau-PET SUVR in Aß-positive CU individuals was seen in a composite ROI combining the entorhinal cortex, hippocampus, and amygdala (4.29%; 95% CI, 3.42%-5.16%). In individuals with Aß-positive MCI, the greatest change was seen in the temporal cortical regions (5.82%; 95% CI, 4.67%-6.97%), whereas in those with AD dementia, the greatest change was seen in the parietal regions (5.22%; 95% CI, 3.95%-6.49%). Significantly higher estimates of annual percentage change were found using several of the participant-specific ROIs. Importantly, the simplest participant-specific approach, where change in tau PET was calculated in an ROI that best matched the participant's data-driven disease stage, performed best in all 3 subgroups. For the power analysis, sample size reductions for the participant-specific ROIs ranged from 15.94% (95% CI, 8.14%-23.74%) to 72.10% (95% CI, 67.10%-77.20%) compared with the best-performing group-level ROIs. Findings were replicated using [18F]flortaucipir. Conclusions and Relevance: Finding suggest that certain individualized ROIs carry an advantage over group-level ROIs for assessing longitudinal tau changes and increase the power to detect treatment effects in AD clinical trials using longitudinal tau PET as an outcome.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Masculino , Idoso , Proteínas tau/metabolismo , Estudos Longitudinais , Estudos Prospectivos , Encéfalo/metabolismo , Peptídeos beta-Amiloides/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Biomarcadores
2.
J Labelled Comp Radiopharm ; 66(9): 222-236, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37095603

RESUMO

The beta-site amyloid precursor protein cleaving enzyme (BACE1) is responsible for initiating the generation of beta-amyloid, the major constituent of amyloid plaques in Alzheimer's disease (AD). The purpose of this study was to develop a specific BACE1 radioligand for visualization of the distribution pattern and quantification of the BACE1 protein in the rodent and monkey brain both in vitro by autoradiography and in vivo by positron emission tomography (PET). The BACE1 inhibitor RO6807936 originating from an in-house chemical drug optimization program was selected based on its PET tracer-like physicochemical properties and a favorable pharmacokinetic profile. Saturation binding analysis of [3 H]RO6807936 revealed specific and high-affinity binding (KD = 2.9 nM) and a low Bmax value (4.3 nM) of the BACE1 protein in native rat brain membranes. [3 H]RO6807936 binding showed a ubiquitous distribution on rat brain slices in vitro with higher levels in the CA3 pyramidal cell layer and the granule cell layer of the hippocampus. In a next step, RO6807936 was successfully radiolabeled with carbon-11 and showed acceptable uptake in the baboon brain as well as a widespread and rather homogeneous distribution consistent with rodent data. In vivo blockade studies with a specific BACE1 inhibitor reduced uptake of the tracer to homogenous levels across brain regions and demonstrated specificity of the signal. Our data warrant further profiling of this PET tracer candidate in humans to investigate BACE1 expression in normal individuals and those with AD and as an imaging biomarker for target occupancy studies in clinical drug trials.


Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Ratos , Animais , Humanos , Precursor de Proteína beta-Amiloide/metabolismo , Roedores/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Papio/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Peptídeos beta-Amiloides/metabolismo
3.
Int J Mol Sci ; 24(4)2023 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-36835179

RESUMO

Intrathecal inflammation plays a key role in the pathogenesis of multiple sclerosis (MS). To better elucidate its relationship with peripheral inflammation, we investigated the correlation between cerebrospinal fluid (CSF) and serum levels of 61 inflammatory proteins. Paired CSF and serum samples were collected from 143 treatment-naïve MS patients at diagnosis. A customized panel of 61 inflammatory molecules was analyzed by a multiplex immunoassay. Correlations between serum and CSF expression levels for each molecule were performed by Spearman's method. The expression of sixteen CSF proteins correlated with their serum expression (p-value < 0.001): only five molecules (CXCL9, sTNFR2, IFNα2, Pentraxin-3, and TSLP) showed a Rho value >0.40, suggesting moderate CSF/serum correlation. No correlation between inflammatory serum patterns and Qalb was observed. Correlation analysis of serum expression levels of these sixteen proteins with clinical and MRI parameters pinpointed a subset of five molecules (CXCL9, sTNFR2, IFNα2, IFNß, and TSLP) negatively correlating with spinal cord lesion volume. However, following FDR correction, only the correlation of CXCL9 remained significant. Our data support the hypothesis that the intrathecal inflammation in MS only partially associates with the peripheral one, except for the expression of some immunomodulators that might have a key role in the initial MS immune response.


Assuntos
Inflamação , Esclerose Múltipla , Humanos , Biomarcadores , Inflamação/sangue , Inflamação/líquido cefalorraquidiano , Inflamação/metabolismo , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Bandas Oligoclonais/líquido cefalorraquidiano
4.
Alzheimers Dement ; 19(6): 2497-2507, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36516028

RESUMO

INTRODUCTION: Biomarkers for the prediction of cognitive decline in patients with amnestic mild cognitive impairment (MCI) and amnestic mild dementia are needed for both clinical practice and clinical trials. METHODS: We evaluated the ability of tau-PET (positron emission tomography), cortical atrophy on magnetic resonance imaging (MRI), baseline cognition, apolipoprotein E gene (APOE) status, plasma and cerebrospinal fluid (CSF) levels of phosphorylated tau-217, neurofilament light (NfL), and amyloid beta (Aß)42/40 ratio (individually and in combination) to predict cognitive decline over 2 years in BioFINDER-2 and Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: Baseline tau-PET and a composite baseline cognitive score were the strongest independent predictors of cognitive decline. Cortical thickness and NfL provided some additional information. Using a predictive algorithm to enrich patient selection in a theoretical clinical trial led to a significantly lower required sample size. DISCUSSION: Models including baseline tau-PET and cognition consistently provided the best prediction of change in cognitive function over 2 years in patients with amnestic MCI or mild dementia.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Tomografia por Emissão de Pósitrons/métodos , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano
5.
Pharmaceuticals (Basel) ; 15(12)2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36558900

RESUMO

Bioorthogonal pretargeted imaging using the inverse-electron-demand Diels-Alder (IEDDA) reaction between a tetrazine (Tz) and a trans-cyclooctene (TCO) represents an attractive strategy for molecular imaging via antibodies. The advantages of using a pretargeted imaging approach are on the one hand the possibility to achieve a high signal-to-noise ratio and imaging contrast; on the other hand, the method allows the uncoupling of the biological half-life of antibodies from the physical half-life of short-lived radionuclides. A brain-penetrating antibody (mAb) specific for ß-amyloid (Aß) plaques was functionalized with TCO moieties for pretargeted labeling of Aß plaques in vitro, ex vivo, and in vivo by a tritium-labeled Tz. The overall aim was to explore the applicability of mAbs for brain imaging, using a preclinical model system. In vitro clicked mAb-TCO-Tz was able to pass the blood-brain barrier of transgenic PS2APP mice and specifically visualize Aß plaques ex vivo. Further experiments showed that click reactivity of the mAb-TCO construct in vivo persisted up to 3 days after injection by labeling Aß plaques ex vivo after incubation of brain sections with the Tz in vitro. An attempted in vivo click reaction between injected mAb-TCO and Tz did not lead to significant labeling of Aß plaques, most probably due to unfavorable in vivo properties of the used Tz and a long half-life of the mAb-TCO in the blood stream. This study clearly demonstrates that pretargeted imaging of CNS targets via antibody-based click chemistry is a viable approach. Further experiments are warranted to optimize the balance between stability and reactivity of all reactants, particularly the Tz.

6.
JAMA Neurol ; 79(2): 149-158, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34928318

RESUMO

Importance: There is currently no consensus as to which biomarkers best predict longitudinal tau accumulation at different clinical stages of Alzheimer disease (AD). Objective: To describe longitudinal [18F]RO948 tau positron emission tomography (PET) findings across the clinical continuum of AD and determine which biomarker combinations showed the strongest associations with longitudinal tau PET and best optimized clinical trial enrichment. Design, Setting, and Participants: This longitudinal cohort study consecutively enrolled amyloid-ß (Aß)-negative cognitively unimpaired (CU) participants, Aß-positive CU individuals, Aß-positive individuals with mild cognitive impairment (MCI), and individuals with AD dementia between September 2017 and November 2020 from the Swedish BioFINDER-2 (discovery cohort) and BioFINDER-1 (validation cohort) studies. Exposures: Baseline plasma and cerebrospinal fluid Aß42/Aß40, tau phosphorylated at threonine-217 (p-tau217), p-tau181 and neurofilament light, magnetic resonance imaging, amyloid PET ([18F]flutemetamol), and tau PET ([18F]RO948 in the BioFINDER-2 study; [18F]flortaucipir in the BioFINDER-1 study). Main Outcomes and Measures: Baseline tau PET standardized uptake value ratio (SUVR) and annual percent change in tau PET SUVR across regions of interest derived using a data-driven approach combining clustering and event-based modeling. Regression models were used to examine associations between individual biomarkers and longitudinal tau PET and to identify which combinations best predicted longitudinal tau PET. These combinations were then entered in a power analysis to examine how their use as an enrichment strategy would affect sample size in a simulated clinical trial. Results: Of 343 participants, the mean (SD) age was 72.56 (7.24) years, and 157 (51.1%) were female. The clustering/event-based modeling-based approach identified 5 regions of interest (stages). In Aß-positive CU individuals, the largest annual increase in tau PET SUVR was seen in stage I (entorhinal cortex, hippocampus, and amygdala; 4.04% [95% CI, 2.67%-5.32%]). In Aß-positive individuals with MCI and with AD dementia, the greatest increases were seen in stages II (temporal cortical regions; 4.45% [95% CI, 3.41%-5.49%]) and IV (certain frontal regions; 5.22% [95% CI, 3.95%-6.49%]), respectively. In Aß-negative CU individuals and those with MCI, modest change was seen in stage I (1.38% [95% CI, 0.78%-1.99%] and 1.80% [95% CI, 0.76%-2.84%], respectively). When looking at individual predictors and longitudinal tau PET in the stages that showed most change, plasma p-tau217 (R2 = 0.27, P < .005), tau PET (stage I baseline SUVR; R2 = 0.13, P < .05) and amyloid PET (R2 = 0.10, P < .05) were significantly associated with longitudinal tau PET in stage I in Aß-positive CU individuals. In Aß-positive individuals with MCI, plasma p-tau217 (R2 = 0.24, P < .005) and tau PET (stage II baseline SUVR; R2 = 0.44, P < .001) were significantly associated with longitudinal tau PET in stage II. Findings were replicated in BioFINDER-1 using longitudinal [18F]flortaucipir. For the power analysis component, plasma p-tau217 with tau PET resulted in sample size reductions of 43% (95% CI, 34%-46%; P < .005) in Aß-positive CU individuals and of 68% (95% CI, 61%-73%; P < .001) in Aß-positive individuals with MCI. Conclusions and Relevance: In trials using tau PET as the outcome, plasma p-tau217 with tau PET may prove optimal for enrichment in preclinical and prodromal AD. However, plasma p-tau217 was most important in preclinical AD, while tau PET was more important in prodromal AD.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Proteínas tau , Idoso , Peptídeos beta-Amiloides/análise , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores , Encéfalo/diagnóstico por imagem , Carbolinas , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Sintomas Prodrômicos , Compostos Radiofarmacêuticos , Reprodutibilidade dos Testes , Proteínas tau/líquido cefalorraquidiano
7.
JAMA Neurol ; 78(8): 961-971, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34180956

RESUMO

Importance: Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear. Objective: To examine the prognostic accuracy of baseline fluorine 18 (18F)-flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers. Design, Setting, and Participants: This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-ß [Aß]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aß), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aß). Exposures: [18F]Flortaucipir PET in the discovery cohort (n = 1135) or [18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation. Main Outcomes and Measures: Baseline [18F]flortaucipir/[18F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations. Results: Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [18F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P < .001, bootstrapped for difference) in the Aß-positive MCI group (R2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P < .001, bootstrapped for difference) and in the Aß-positive CU group (R2, 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P < .001, bootstrapped for difference). These findings were replicated in the [18F]RO948 PET cohort. MRI mediated the association between [18F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aß-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aß-positive CU group (3.7% [95% CI, -17.5% to 39.0%]; P = .71). Age (t = -2.28; P = .02), but not sex (t = 0.92; P = .36) or APOE genotype (t = 1.06; P = .29) modified the association between baseline [18F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels. Conclusions and Relevance: The findings of this prognostic study suggest that tau PET is a promising tool for predicting cognitive change that is superior to amyloid PET and MRI and may support the prognostic process in preclinical and prodromal stages of AD.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/análise , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Sintomas Prodrômicos , Proteínas tau/análise , Idoso , Apolipoproteínas E/genética , Carbolinas , Córtex Cerebral/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Neuroimagem , Valor Preditivo dos Testes , Prognóstico , Compostos Radiofarmacêuticos , Resultado do Tratamento
8.
Eur J Nucl Med Mol Imaging ; 48(7): 2245-2258, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33215319

RESUMO

PURPOSE: A substantial proportion of amyloid-ß (Aß)+ patients with clinically diagnosed Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI) are tau PET-negative, while some clinically diagnosed non-AD neurodegenerative disorder (non-AD) patients or cognitively unimpaired (CU) subjects are tau PET-positive. We investigated which demographic, clinical, genetic, and imaging variables contributed to tau PET status. METHODS: We included 2338 participants (430 Aß+ AD dementia, 381 Aß+ MCI, 370 non-AD, and 1157 CU) who underwent [18F]flortaucipir (n = 1944) or [18F]RO948 (n = 719) PET. Tau PET positivity was determined in the entorhinal cortex, temporal meta-ROI, and Braak V-VI regions using previously established cutoffs. We performed bivariate binary logistic regression models with tau PET status (positive/negative) as dependent variable and age, sex, APOEε4, Aß status (only in CU and non-AD analyses), MMSE, global white matter hyperintensities (WMH), and AD-signature cortical thickness as predictors. Additionally, we performed multivariable binary logistic regression models to account for all other predictors in the same model. RESULTS: Tau PET positivity in the temporal meta-ROI was 88.6% for AD dementia, 46.5% for MCI, 9.5% for non-AD, and 6.1% for CU. Among Aß+ participants with AD dementia and MCI, lower age, MMSE score, and AD-signature cortical thickness showed the strongest associations with tau PET positivity. In non-AD and CU participants, presence of Aß was the strongest predictor of a positive tau PET scan. CONCLUSION: We identified several demographic, clinical, and neurobiological factors that are important to explain the variance in tau PET retention observed across the AD pathological continuum, non-AD neurodegenerative disorders, and cognitively unimpaired persons.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Demografia , Humanos , Tomografia por Emissão de Pósitrons , Proteínas tau
9.
JAMA Neurol ; 77(8): 955-965, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32391858

RESUMO

Importance: The diagnostic performance of second-generation tau positron emission tomographic (PET) tracers is not yet known. Objective: To examine the novel tau PET tracer RO948 F 18 ([18F]RO948) performance in discriminating Alzheimer disease (AD) from non-AD neurodegenerative disorders. Design, Setting, and Participants: In this diagnostic study, 613 participants in the Swedish BioFINDER-2 study were consecutively enrolled in a prospective cross-sectional study from September 4, 2017, to August 28, 2019. Participants included 257 cognitively unimpaired controls, 154 patients with mild cognitive impairment, 100 patients with AD dementia, and 102 with non-AD neurodegenerative disorders. Evaluation included a comparison of tau PET tracer [18F]RO948 with magnetic resonance imaging (MRI) and cerebrospinal fluid and a head-to-head comparison between [18F]RO948 and flortaucipir F 18 ([18F]flortaucipir) in patients with semantic variant primary progressive aphasia (svPPA). Exposures: [18F]RO948 (all patients) and [18F]flortaucipir (3 patients with svPPA) tau PET; MRI (hippocampal volume, composite temporal lobe cortical thickness, whole-brain cortical thickness) and cerebrospinal fluid measures (p-tau181 and amyloid Aß42 and Aß40 ratio[Aß42/Aß40], and Aß42/p-tau181 ratio). Main Outcomes and Measures: Standard uptake value ratios (SUVRs) in 4 predefined regions of interest (ROIs) reflecting Braak staging scheme for tau pathology and encompass I-II (entorhinal cortex), III-IV (inferior/middle temporal, fusiform gyrus, parahippocampal cortex, and amygdala), I-IV, and V-VI (widespread neocortical areas), area under the receiver operating characteristic curve (AUC) values, and subtraction images between [18F]RO948 and [18F]flortaucipir. Results: Diagnostic groups among the 613 participants included cognitively unimpaired (mean [SD] age, 65.8 [12.1] years; 117 men [46%]), mild cognitive impairment (age, 70.8 [8.3] years; 82 men [53%]), AD dementia (age, 73.5 [6.7] years; 57 men [57%]), and non-AD disorders (age, 70.5 [8.6] years; 41 men [40%]). Retention of [18F]RO948 was higher in AD dementia compared with all other diagnostic groups. [18F]RO948 could distinguish patients with AD dementia from individuals without cognitive impairment and those with non-AD disorders, and the highest AUC was obtained using the I-IV ROI (AUC = 0.98; 95% CI, 0.96-0.99 for AD vs no cognitive impairment and AUC = 0.97; 95% CI, 0.95-0.99 for AD vs non-AD disorders), which outperformed MRI (highest AUC = 0.91 for AD vs no cognitive impairment using whole-brain thickness, and AUC = 0.80 for AD vs non-AD disorders using temporal lobe thickness) and cerebrospinal fluid measures (highest AUC = 0.94 for AD vs no cognitive impairment using Aß42/p-tau181, and AUC = 0.93 for AD vs non-AD disorders using Aß42/Aß40). Generally, tau PET positivity using [18F]RO948 was observed only in Aß-positive cases or in MAPT R406W mutation carriers. Retention of [18F]RO948 was not pronounced in patients with svPPA, and head-to-head comparison revealed lower temporal lobe uptake than with [18F]flortaucipir. Conclusions and Relevance: In this study, elevated [18F]RO948 SUVRs were most often seen among Aß-positive cases, which suggests that [18F]RO948 has high specificity for AD-type tau and highlights its potential as a diagnostic marker in the differential diagnosis of AD.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Radioisótopos de Flúor/farmacocinética , Doenças Neurodegenerativas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/normas , Proteínas tau/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Disfunção Cognitiva/metabolismo , Estudos Transversais , Diagnóstico Diferencial , Feminino , Humanos , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/metabolismo , Suécia , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo
10.
ChemMedChem ; 15(7): 585-592, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-31797561

RESUMO

Nonspecific binding (NSB) is a key parameter in optimizing PET imaging tracers. We compared the ability to predict NSB of three available methods: LIMBA, rat fu,brain , and CHI(IAM). Even though NSB is often associated with lipophilicity, we observed that logD does not correlate with any of these assays, clearly indicating that lipophilicity, while influencing NSB, is insufficient to predict it. A cross-comparison of the methods showed that all three correlate and are useful predictors of NSB. The three assays, however, rank the molecules slightly differently, illustrating the challenge of comparing molecules within a narrow chemical space. We also noted that CHI(IAM) values more effectively predict VNS , a measure of in vivo NSB in the human brain. CHI(IAM) measurements might be a closer model of the actual physicochemical interaction between PET tracer candidates and cell membranes, and seems to be the method of choice for the optimization of in vivo NSB.


Assuntos
Encéfalo/metabolismo , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/metabolismo , Animais , Humanos , Interações Hidrofóbicas e Hidrofílicas , Compostos Radiofarmacêuticos/química , Ratos
11.
J Nucl Med ; 59(12): 1877-1884, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30097505

RESUMO

The availability of tau PET radioligands enables quantitative assessment of tau density and distribution in the human brain. We evaluated the kinetics of a novel radioligand, 18F-RO-948 (previously referred to as 18F-RO6958948), and its ability to identify tau positivity in individual patients with mild Alzheimer disease (AD). Methods: Eleven subjects with amyloid-positive mild AD, 5 amyloid-negative older control subjects (OC), and 5 younger control subjects (YC) completed 1 or 2 (4 AD and 5 OC) PET scans with 18F-RO-948 for 90, 120, or 200 min. The kinetics of the radioligand was evaluated with standard compartmental and noncompartmental models (with plasma data in 70% of cases), tissue-reference methods, and SUV ratio. These approaches were applied to assess the ability of 18F-RO-948 to discriminate AD subjects from OC subjects. Results: The plasma reference graphical analysis appeared to be the optimal method of quantification for 18F-RO-948, yielding strictly time-consistent values of distribution volume and distribution volume ratio at 90 min against the analyses at 120 and 200 min. The reference tissue graphical analysis and SUV ratio were cross-validated against plasma reference graphical analysis. Test-retest evaluation showed excellent reproducibility. A proposed novel index of tau load, the regional tau-positive fraction, showed high values in the medial and lateral temporal and parietal regions in AD and successfully separated AD subjects from OC and YC subjects with a significant margin. Conclusion:18F-RO-948 appears to be a promising radioligand for quantitative imaging of tau in the brain of AD patients.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Neuroimagem Funcional/métodos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Proteínas tau/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Radioisótopos de Flúor , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Ensaio Radioligante , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Adulto Jovem
12.
Chimia (Aarau) ; 72(7): 477-484, 2018 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-30158010

RESUMO

Glycine transporter-1 (GlyT1) inhibition has been extensively studied both in pharmaceutical companies and academic institutions primarily as a potential new approach to treat schizophrenia, a severe and chronic mental illness. More recently, preclinical results have suggested that this approach could also have therapeutic potential for CNS disorders beyond schizophrenia as well as for non-CNS indications. Over the past 17 years, Roche has been a key player in the GlyT1 field with the discovery and development of bitopertin, the most advanced GlyT1 inhibitor to date and the only one which completed Phase III clinical studies for schizophrenia. In this article, we relate the eventful journey of the discovery and development of bitopertin, from project initiation in 2001 to its evaluation today in patients suffering from beta-thalassemia, a monogenic hereditary haematological disorder.


Assuntos
Desenvolvimento de Medicamentos , Descoberta de Drogas , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Piperazinas/farmacologia , Sulfonas/farmacologia , Animais , Ensaios de Triagem em Larga Escala , Humanos , Piperazinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Sulfonas/uso terapêutico , Talassemia beta/tratamento farmacológico
13.
J Nucl Med ; 59(12): 1869-1876, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29728519

RESUMO

11C-RO-963, 11C-RO-643, and 18F-RO-948 (previously referred to as 11C-RO6924963, 11C-RO6931643, and 18F-RO6958948, respectively) have been reported as promising PET tracers for tau imaging based on in vitro and preclinical PET data. Here we describe the first, to our knowledge, human evaluation of these novel radiotracers. Methods: Amyloid PET-positive Alzheimer disease (AD) subjects and younger controls each received 2 different tau tracers. Dynamic 90-min scans were obtained after bolus injection of 11C-RO-963, 11C-RO-643, or 18F-RO-948. Arterial blood sampling was performed on 11 healthy controls and 11 AD subjects. Regions were defined on MR images, and PET data were quantified by plasma reference graphical analysis (for total distribution volume) and target cerebellum ratio (SUV ratios of 60- to 90-min frames). SUV ratio images were also analyzed voxelwise. Five older controls each underwent 2 scans with 18F-RO-948 for evaluation of test-retest variability. Four AD subjects underwent a repeated 18F-RO-948 scan 6-22 mo after the first scan. Six additional healthy controls (3 men and 3 women; age range, 41-67 y) each underwent 1 whole-body dosimetry scan with 18F-RO-948. Results: In younger controls, SUVpeak was observed in the temporal lobe with values of approximately 3.0 for 11C-RO-963, 1.5 for 11C-RO-643, and 3.5 for 18F-RO-948. Over all brain regions and subjects, the trend was for 18F-RO-948 to have the highest SUVpeak, followed by 11C-RO-963 and then 11C-RO-643. Regional analysis of SUV ratio and total distribution volume for 11C-RO-643 and 18F-RO-948 clearly discriminated the AD group from the healthy control groups. Compartmental modeling confirmed that 11C-RO-643 had lower brain entry than either 11C-RO-963 or 18F-RO-948 and that 18F-RO-948 showed better contrast between (predicted) areas of high versus low tau accumulation. Thus, our subsequent analysis focused on 18F-RO-948. Both voxelwise and region-based analysis of 18F-RO-948 binding in healthy controls versus AD subjects revealed multiple areas where AD subjects significantly differed from healthy controls. Of 22 high-binding regions, 13 showed a significant group difference (after ANOVA, F(1,21) = 45, P < 10-5). Voxelwise analysis also revealed a set of symmetric clusters where AD subjects had higher binding than healthy controls (threshold of P < 0.001, cluster size > 50). Conclusion:18F-RO-948 demonstrates characteristics superior to 11C-RO-643 and 11C-RO-963 for characterization of tau pathology in AD. Regional binding data and kinetic properties of 18F-RO-948 compare favorably with other existing tau PET tracers.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Proteínas tau/metabolismo , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Mapeamento Encefálico , Radioisótopos de Carbono , Estudos de Casos e Controles , Feminino , Radioisótopos de Flúor , Humanos , Masculino , Pessoa de Meia-Idade , Doses de Radiação , Ensaio Radioligante , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual
14.
J Nucl Med ; 59(4): 675-681, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28970331

RESUMO

Tau aggregates and amyloid-ß (Aß) plaques are key histopathologic features in Alzheimer disease (AD) and are considered targets for therapeutic intervention as well as biomarkers for diagnostic in vivo imaging agents. This article describes the preclinical in vitro and in vivo characterization of 3 novel compounds-RO6958948, RO6931643, and RO6924963-that bind specifically to tau aggregates and have the potential to become PET tracers for future human use. Methods: RO6958948, RO6931643, and RO6924963 were identified as high-affinity competitors at the 3H-T808 binding site on native tau aggregates in human late-stage AD brain tissue. Binding of tritiated compounds to brain tissue sections of AD patients and healthy controls was analyzed by macro- and microautoradiography and by costaining of tau aggregates and Aß plaques on the same tissue section using specific antibodies. All 3 tracer candidates were radiolabeled with a PET nuclide and tested in vivo in tau-naïve baboons to assess brain uptake, distribution, clearance, and metabolism. Results:3H-RO6958948, 3H-RO6931643, and 3H-RO6924963 bound with high affinity and specificity to tau aggregates, clearly lacking affinity for concomitant Aß plaques in human AD Braak V tissue sections. The specificity of all 3 radioligands for tau aggregates was supported, first, by binding patterns in AD sections comparable to the tau-specific radioligand 3H-T808; second, by very low nonspecific binding in brain tissue devoid of tau pathology, excluding significant radioligand binding to any other central nervous system target; and third, by macroscopic and microscopic colocalization and quantitative correlation of radioligand binding and tau antibody staining on the same tissue section. RO6958948, RO6931643, and RO6924963 were successfully radiolabeled with a PET nuclide at high specific activity, radiochemical purity, and yield. After intravenous administration of 18F-RO6958948, 11C-RO6931643, and 11C-RO6924963 to baboons, PET scans indicated good brain entry, rapid washout, and a favorable metabolism pattern. Conclusion:18F-RO6958948, 11C-RO6931643, and 11C-RO6924963 are promising PET tracers for visualization of tau aggregates in AD. Head-to-head comparison and validation of these tracer candidates in AD patients and healthy controls will be reported in due course.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Agregados Proteicos , Traçadores Radioativos , Proteínas tau/química , Proteínas tau/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Humanos
15.
J Med Chem ; 60(17): 7350-7370, 2017 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-28654263

RESUMO

Aggregates of tau and beta amyloid (Aß) plaques constitute the histopathological hallmarks of Alzheimer's disease and are prominent targets for novel therapeutics as well as for biomarkers for diagnostic in vivo imaging. In recent years much attention has been devoted to the discovery and development of new PET tracers to image tau aggregates in the living human brain. Access to a selective PET tracer to image and quantify tau aggregates represents a unique tool to support the development of any novel therapeutic agent targeting pathological forms of tau. The objective of the study described herein was to identify such a novel radiotracer. As a result of this work, we discovered three novel PET tracers (2-(4-[11C]methoxyphenyl)imidazo[1,2-a]pyridin-7-amine 7 ([11C]RO6924963), N-[11C]methyl-2-(3-methylphenyl)imidazo[1,2-a]pyrimidin-7-amine 8 ([11C]RO6931643), and [18F]2-(6-fluoropyridin-3-yl)pyrrolo[2,3-b:4,5-c']dipyridine 9 ([18F]RO6958948)) with high affinity for tau neurofibrillary tangles, excellent selectivity against Aß plaques, and appropriate pharmacokinetic and metabolic properties in mice and non-human primates.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Radioisótopos de Carbono/química , Radioisótopos de Flúor/química , Tomografia por Emissão de Pósitrons/métodos , Agregação Patológica de Proteínas/diagnóstico por imagem , Pirimidinas/química , Proteínas tau/análise , Animais , Radioisótopos de Carbono/farmacocinética , Radioisótopos de Flúor/farmacocinética , Humanos , Masculino , Camundongos , Papio , Pirimidinas/farmacocinética
16.
J Pharmacol Exp Ther ; 362(3): 413-423, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28642233

RESUMO

Monoamine oxidase B (MAO-B) has been implicated in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Increased MAO-B expression in astroglia has been observed adjacent to amyloid plaques in AD patient brains. This phenomenon is hypothesized to lead to increased production of hydrogen peroxide and reactive oxygen species (ROS), thereby contributing to AD pathology. Therefore, reduction of ROS-induced oxidative stress via inhibition of MAO-B activity may delay the progression of the disease. In the present study we report the pharmacological properties of sembragiline, a novel selective MAO-B inhibitor specifically developed for the treatment of AD, and on its effect on ROS-mediated neuronal injury and astrogliosis in MAO-B transgenic animals. Sembragiline showed potent and long-lasting MAO-B-selective inhibition and did not inhibit MAO-A at doses where full inhibition of MAO-B was observed. Such selectivity should translate into a favorable clinical safety profile. Indeed, sembragiline neither induced the serotonin syndrome when administered together with the serotonin precursor l-5-hydroxytryptophan in combination with antidepressants such as fluoxetine, nor potentiated the pressor effect of tyramine. Additionally, in experiments using a transgenic animal model conditionally overexpressing MAO-B in astroglia, sembragiline protected against neuronal loss and reduced both ROS formation and reactive astrogliosis. Taken together, these findings warrant further investigation of the potential therapeutic benefit of MAO-B inhibitors in patients with AD and other neurologic disorders.


Assuntos
Acetamidas/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Inibidores da Monoaminoxidase/uso terapêutico , Monoaminoxidase/efeitos dos fármacos , Pirrolidinonas/uso terapêutico , 5-Hidroxitriptofano/farmacologia , Acetamidas/farmacocinética , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Gliose/tratamento farmacológico , Gliose/patologia , Humanos , Hipertensão/induzido quimicamente , Hipertensão/prevenção & controle , Masculino , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacocinética , Atividade Motora/efeitos dos fármacos , Neurotransmissores/metabolismo , Pirrolidinonas/farmacocinética , Ratos , Ratos Transgênicos , Espécies Reativas de Oxigênio/metabolismo , Especificidade por Substrato , Distribuição Tecidual
17.
J Alzheimers Dis ; 58(4): 1217-1228, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28550255

RESUMO

BACKGROUND: Sembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer's disease (AD). OBJECTIVE: To evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD. METHODS: In this Phase II study (NCT01677754), 542 patients with moderate dementia (MMSE 13-20) on background acetylcholinesterase inhibitors with/without memantine were randomized (1:1:1) to sembragiline 1 mg, 5 mg, or placebo once daily orally for 52 weeks. RESULTS: No differences between treated groups and placebo in adverse events or in study completion. The primary endpoint, change from baseline in ADAS-Cog11, was not met. At Week 52, the difference between sembragiline and placebo in ADAS-Cog11 change from baseline was - 0.15 (p = 0.865) and 0.90 (p = 0.312) for 1 and 5 mg groups, respectively. Relative to placebo at Week 52 (but not at prior assessment times), the 1 mg and 5 mg sembragiline groups showed differences in ADCS-ADL of 2.64 (p = 0.051) and 1.89 (p = 0.160), respectively. A treatment effect in neuropsychiatric symptoms (as assessed by the difference between sembragiline and placebo on BEHAVE-AD-FW) was also seen at Week 52 only: - 2.80 (p = 0.014; 1 mg) and - 2.64 (p = 0.019; 5 mg), respectively. A post hoc subgroup analysis revealed greater treatment effects on behavior and functioning in patients with more severe baseline behavioral symptoms (above the median). CONCLUSIONS: This study showed that sembragiline was well-tolerated in patients with moderate AD. The study missed its primary and secondary endpoints. Post hoc analyses suggested potential effect on neuropsychiatric symptoms and functioning in more behaviorally impaired study population at baseline.


Assuntos
Acetamidas/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Antipsicóticos/uso terapêutico , Pirrolidinonas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade
18.
J Nucl Med ; 58(7): 1124-1131, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27908967

RESUMO

18F-AV-1451 is currently the most widely used of several experimental tau PET tracers. The objective of this study was to evaluate 18F-AV-1451 binding with full kinetic analysis using a metabolite-corrected arterial input function and to compare parameters derived from kinetic analysis with SUV ratio (SUVR) calculated over different imaging time intervals. Methods:18F-AV-1451 PET brain imaging was completed in 16 subjects: 4 young healthy volunteers (YHV), 4 aged healthy volunteers (AHV), and 8 Alzheimer disease (AD) subjects. Subjects were imaged for 3.5 h, with arterial blood samples obtained throughout. PET data were analyzed using plasma and reference tissue-based methods to estimate the distribution volume, binding potential (BPND), and SUVR. BPND and SUVR were calculated using the cerebellar cortex as a reference region and were compared across the different methods and across the 3 groups (YHV, AHV, and AD). Results: AD demonstrated increased 18F-AV-1451 retention compared with YHV and AHV based on both invasive and noninvasive analyses in cortical regions in which paired helical filament tau accumulation is expected in AD. A correlation of R2 > 0.93 was found between BPND (130 min) and SUVR-1 at all time intervals. Cortical SUVR curves reached a relative plateau around 1.0-1.2 for YHV and AHV by approximately 50 min, but increased in AD by up to approximately 20% at 110-130 min and approximately 30% at 160-180 min relative to 80-100 min. Distribution volume (130 min) was lower by 30%-35% in the YHV than AHV. Conclusion: Our data suggest that although 18F-AV-1451 SUVR curves do not reach a plateau and are still increasing in AD, an SUVR calculated over an imaging window of 80-100 min (as currently used in clinical studies) provides estimates of paired helical filament tau burden in good correlation with BPND, whereas SUVR sensitivity to regional cerebral blood changes needs further investigation.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Carbolinas/farmacocinética , Modelos Biológicos , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo , Idoso , Doença de Alzheimer/diagnóstico por imagem , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Simulação por Computador , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Cinética , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/farmacocinética , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição Tecidual
19.
Mov Disord ; 32(1): 108-114, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27709757

RESUMO

BACKGROUND: Progressive supranuclear palsy (PSP) is difficult to diagnose accurately. The recently developed tau PET tracers may improve the diagnostic work-up of PSP. METHODS: Regional tau accumulation was studied using 18 F-AV-1451 PET in 11 patients with PSP and 11 age-matched healthy controls in the Swedish BioFinder study. RESULTS: 18 F-AV-1451 standard uptake volume ratios were significantly higher in the basal ganglia in PSP patients when compared with controls (globus pallidus 1.75 vs 1.50; putamen 1.51 vs 1.35). Retention in the basal ganglia was correlated with age in both groups (r = .43-.78, P < .05). In PSP, we observed a significant correlation between clinical deterioration measured with the PSP rating scale and standard uptake volume ratios in the globus pallidus (r = .74, P < .05). However, no 18 F-AV-1451 retention was observed in the cerebral cortex or white matter of either PSP patients or controls, and autoradiography did not reveal any specific binding of AV-1451 to PSP tau aggregates. CONCLUSION: We found higher 18 F-AV-1451 retention in the basal ganglia of PSP patients when compared with healthy elderly controls, but also increases with age in both controls and patients. As a result of the overlap in retention between diagnostic groups and the age-dependent increase present also in controls, 18 F-AV-1451 PET might not reliably distinguish individual patients with PSP from controls. However, further studies are needed to evaluate whether 18 F-AV-1451 PET might be useful as a progression marker in clinical PSP trials. © The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Gânglios da Base/metabolismo , Carbolinas , Córtex Cerebral/metabolismo , Paralisia Supranuclear Progressiva/metabolismo , Paralisia Supranuclear Progressiva/fisiopatologia , Proteínas tau/metabolismo , Fatores Etários , Idoso , Gânglios da Base/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Humanos , Tomografia por Emissão de Pósitrons , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Suécia
20.
Neuropsychopharmacology ; 41(5): 1319-28, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26354045

RESUMO

A growing body of evidence indicates that neuronal oscillations in the gamma frequency range (30-80 Hz) are disturbed in schizophrenic patients during cognitive processes and may represent an endophenotype of the disease. N-methyl-D-aspartate (NMDA) receptor antagonists have been used experimentally to induce schizophrenia-like symptoms including cognitive deficits in animals and humans. Here we characterized neuronal oscillations and event-related potentials (ERPs) in Cynomolgus macaques fully trained to perform a continuous performance test (CPT) in the presence and absence of the NMDA antagonist phencyclidine (PCP). Macaques (n=8) were trained to touch 'target' stimuli and ignore 'distractor' stimuli presented randomly on a touchscreen. Subsequently, all subjects were implanted with epidural EEG electrodes over frontal (FC) and parietal cortices (PC) and later tested under vehicle (saline, i.m.) or acute PCP (0.1-0.3 mg/kg, i.m.) conditions. Compared with vehicle treatment, PCP produced a significant dose-dependent decrease in CPT performance accuracy and increased reaction times. Furthermore, PCP elevated the amplitudes of 'low' (30-50 Hz) and 'high' (51-80 Hz) gamma oscillations in FC and PC around target presentations for all correct responses. The CPT accuracy was inversely correlated with the gamma band amplitude in the presence of PCP. Additionally, PCP delayed the N100 peak latency in FC, and prolonged and suppressed the cognitively relevant P300 component of mean ERPs in FC and PC, respectively. The NMDA receptor antagonist-induced alteration in neuronal oscillations and ERPs may contribute to the observed cognitive deficits in macaques, and enhance our understanding of EEG recordings as a translatable biomarker.


Assuntos
Atenção/fisiologia , Lobo Frontal/fisiologia , Ritmo Gama , Lobo Parietal/fisiologia , Fenciclidina/administração & dosagem , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Esquizofrenia/fisiopatologia , Animais , Atenção/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eletroencefalografia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Lobo Frontal/efeitos dos fármacos , Ritmo Gama/efeitos dos fármacos , Macaca fascicularis , Masculino , Lobo Parietal/efeitos dos fármacos
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