RESUMO
BACKGROUND: Recent data demonstrate that surgeons overprescribe opioids and vary considerably in the amount of opioids prescribed for common procedures. Limited data exist about why and how surgeons develop certain opioid prescribing habits. We sought to identify surgeons' knowledge, attitudes, and beliefs about opioid prescribing and elicit barriers to guideline-based prescribing. METHODS: We conducted qualitative semistructured interviews accompanied by demographic surveys at an academic medical center. Surgical residents and faculty members were selected by maximum variation purposive sampling. We used thematic analysis to identify themes associated with opioid prescribing. RESULTS: Twenty surgical residents and twenty-one surgical faculty members were interviewed. Characteristics of individual surgeons, patients, health care teams, practice environments, and the complex interplay between these domains drove prescribing habits. Attending-resident communication about opioid prescribing was extremely limited. Surgeons received little training and feedback about opioid prescribing and were rarely aware of negative long-term consequences, limiting motivation to change prescribing habits. Although surgeons frequently interacted with pain management physicians to comanage patients postoperatively, few involved pain management physicians in preoperative planning. Perceived barriers to guideline-based prescribing included the following: limitations to electronic prescribing, cross-coverage problems, inadequate time for patient education, and impediments to use of nonopioid alternatives. CONCLUSIONS: Interventions to improve compliance with opioid prescribing guidelines should include surgeon education and personal feedback. Future interventions should aim to improve attending-resident communication about opioid prescribing, reduce hurdles to electronic prescribing, provide clear pain management plans for cross-covering physicians, assess alternative methods for efficient patient education, and maximize use of nonnarcotic pain medications.
Assuntos
Analgésicos Opioides/efeitos adversos , Prescrições de Medicamentos/estatística & dados numéricos , Fidelidade a Diretrizes/estatística & dados numéricos , Epidemia de Opioides/prevenção & controle , Padrões de Prática Médica/estatística & dados numéricos , Centros Médicos Acadêmicos/normas , Centros Médicos Acadêmicos/estatística & dados numéricos , Adulto , Analgésicos Opioides/administração & dosagem , Competência Clínica/estatística & dados numéricos , Prescrições de Medicamentos/normas , Feminino , Humanos , Internato e Residência/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Transtornos Relacionados ao Uso de Opioides/etiologia , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Manejo da Dor/métodos , Manejo da Dor/normas , Dor Pós-Operatória/tratamento farmacológico , Educação de Pacientes como Assunto , Guias de Prática Clínica como Assunto , Padrões de Prática Médica/normas , Pesquisa Qualitativa , Cirurgiões/estatística & dados numéricos , Inquéritos e Questionários/estatística & dados numéricos , Estados Unidos/epidemiologiaRESUMO
INTRODUCTION: We sought to establish the relationships between standard postmortem measures of AD neuropathology and antemortem [11C]PIB-positron emission tomography ([11C]PIB-PET) analyzed with the Centiloid (CL) method, a standardized scale for Aß-PET quantification. METHODS: Four centers contributed 179 participants encompassing a broad range of clinical diagnoses, PET data, and autopsy findings. RESULTS: CL values increased with each CERAD neuritic plaque score increment (median -3 CL for no plaques and 92 CL for frequent plaques) and nonlinearly with Thal Aß phases (increases were detected starting at phase 2) with overlap between scores/phases. PET-pathology associations were comparable across sites and unchanged when restricting the analyses to the 56 patients who died within 2 years of PET. A threshold of 12.2 CL detected CERAD moderate-to-frequent neuritic plaques (area under the curve = 0.910, sensitivity = 89.2%, specificity = 86.4%), whereas 24.4 CL identified intermediate-to-high AD neuropathological changes (area under the curve = 0.894, sensitivity = 84.1%, specificity = 87.9%). DISCUSSION: Our study demonstrated the robustness of a multisite Centiloid [11C]PIB-PET study and established a range of pathology-based CL thresholds.
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Doença de Alzheimer , Compostos de Anilina , Autopsia , Neuropatologia , Placa Amiloide , Tomografia por Emissão de Pósitrons , Tiazóis , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Feminino , Humanos , Masculino , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/patologia , Estudos RetrospectivosRESUMO
Neuropathological and in vivo studies have revealed a tight relationship between tau pathology and cognitive impairment across the Alzheimer's disease spectrum. However, tau pathology is also intimately associated with neurodegeneration and amyloid pathology. The aim of the present study was therefore to assess whether grey matter atrophy and amyloid pathology contribute to the relationship between tau pathology, as measured with 18F-AV-1451-PET imaging, and cognitive deficits in Alzheimer's disease. We included 40 amyloid-positive patients meeting criteria for mild cognitive impairment due to Alzheimer's disease (n = 5) or probable Alzheimer's disease dementia (n = 35). Twelve patients additionally fulfilled the diagnostic criteria for posterior cortical atrophy and eight for logopenic variant primary progressive aphasia. All participants underwent 3 T magnetic resonance imaging, amyloid (11C-PiB) positron emission tomography and tau (18F-AV-1451) positron emission tomography, and episodic and semantic memory, language, executive and visuospatial functions assessment. Raw cognitive scores were converted to age-adjusted Z-scores (W-scores) and averaged to compute composite scores for each cognitive domain. Independent regressions were performed between 18F-AV-1451 binding and each cognitive domain, and we used the Biological Parametric Mapping toolbox to further control for local grey matter volumes, 11C-PiB uptake, or both. Partial correlations and causal mediation analyses (mediation R package) were then performed in brain regions showing an association between cognition and both 18F-AV-1451 uptake and grey matter volume. Our results showed that decreased cognitive performance in each domain was related to increased 18F-AV-1451 binding in specific brain regions conforming to established brain-behaviour relationships (i.e. episodic memory: medial temporal lobe and angular gyrus; semantic memory: left anterior temporal regions; language: left posterior superior temporal lobe and supramarginal gyrus; executive functions: bilateral frontoparietal regions; visuospatial functions: right more than left occipitotemporal regions). This pattern of regional associations remained essentially unchanged-although less spatially extended-when grey matter volume or 11C-PiB uptake maps were added as covariates. Mediation analyses revealed both direct and grey matter-mediated effects of 18F-AV-1451 uptake on cognitive performance. Together, these results show that tau pathology is related in a region-specific manner to cognitive impairment in Alzheimer's disease. These regional relationships are weakly related to amyloid burden, but are in part mediated by grey matter volumes. This suggests that tau pathology may lead to cognitive deficits through a variety of mechanisms, including, but not restricted to, grey matter loss. These results might have implications for future therapeutic trials targeting tau pathology.
Assuntos
Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Proteínas tau/metabolismo , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/psicologia , Compostos de Anilina , Afasia Primária Progressiva/diagnóstico por imagem , Afasia Primária Progressiva/metabolismo , Afasia Primária Progressiva/psicologia , Benzotiazóis , Encéfalo/diagnóstico por imagem , Carbolinas , Radioisótopos de Carbono , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/psicologia , Feminino , Radioisótopos de Flúor , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Análise de Regressão , TiazóisRESUMO
ß-amyloid (Aß) and tau pathology become increasingly prevalent with age, however, the spatial relationship between the two pathologies remains unknown. We examined local (same region) and non-local (different region) associations between these 2 aggregated proteins in 46 normal older adults using [18F]AV-1451 (for tau) and [11C]PiB (for Aß) positron emission tomography (PET) and 1.5T magnetic resonance imaging (MRI) images. While local voxelwise analyses showed associations between PiB and AV-1451 tracer largely in the temporal lobes, k-means clustering revealed that some of these associations were driven by regions with low tracer retention. We followed this up with a whole-brain region-by-region (local and non-local) partial correlational analysis. We calculated each participant's mean AV-1451 and PiB uptake values within 87 regions of interest (ROI). Pairwise ROI analysis demonstrated many positive PiB-AV-1451 associations. Importantly, strong positive partial correlations (controlling for age, sex, and global gray matter fraction, p<.01) were identified between PiB in multiple regions of association cortex and AV-1451 in temporal cortical ROIs. There were also less frequent and weaker positive associations of regional PiB with frontoparietal AV-1451 uptake. Particularly in temporal lobe ROIs, AV-1451 uptake was strongly predicted by PiB across multiple ROI locations. These data indicate that Aß and tau pathology show significant local and non-local regional associations among cognitively normal elderly, with increased PiB uptake throughout the cortex correlating with increased temporal lobe AV-1451 uptake. The spatial relationship between Aß and tau accumulation does not appear to be specific to Aß location, suggesting a regional vulnerability of temporal brain regions to tau accumulation regardless of where Aß accumulates.
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Envelhecimento/patologia , Peptídeos beta-Amiloides/metabolismo , Lobo Temporal/patologia , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/análise , Compostos de Anilina , Carbolinas , Radioisótopos de Carbono , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tiazóis , Proteínas tau/análiseRESUMO
SEE SARAZIN ET AL DOI101093/BRAIN/AWW041 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The advent of the positron emission tomography tracer (18)F-AV1451 provides the unique opportunity to visualize the regional distribution of tau pathology in the living human brain. In this study, we tested the hypothesis that tau pathology is closely linked to symptomatology and patterns of glucose hypometabolism in Alzheimer's disease, in contrast to the more diffuse distribution of amyloid-ß pathology. We included 20 patients meeting criteria for probable Alzheimer's disease dementia or mild cognitive impairment due to Alzheimer's disease, presenting with a variety of clinical phenotypes, and 15 amyloid-ß-negative cognitively normal individuals, who underwent (18)F-AV1451 (tau), (11)C-PiB (amyloid-ß) and (18)F-FDG (glucose metabolism) positron emission tomography, apolipoprotein E (APOE) genotyping and neuropsychological testing. Voxel-wise contrasts against controls (at P < 0.05 family-wise error corrected) showed that (18)F-AV1451 and (18)F-FDG patterns in patients with posterior cortical atrophy ('visual variant of Alzheimer's disease', n = 7) specifically targeted the clinically affected posterior brain regions, while (11)C-PiB bound diffusely throughout the neocortex. Patients with an amnestic-predominant presentation (n = 5) showed highest (18)F-AV1451 retention in medial temporal and lateral temporoparietal regions. Patients with logopenic variant primary progressive aphasia ('language variant of Alzheimer's disease', n = 5) demonstrated asymmetric left greater than right hemisphere (18)F-AV1451 uptake in three of five patients. Across 30 FreeSurfer-defined regions of interest in 16 Alzheimer's disease patients with all three positron emission tomography scans available, there was a strong negative association between (18)F-AV1451 and (18)F-FDG uptake (Pearson's r = -0.49 ± 0.07, P < 0.001) and less pronounced positive associations between (11)C-PiB and (18)F-FDG (Pearson's r = 0.16 ± 0.09, P < 0.001) and (18)F-AV1451 and (11)C-PiB (Pearson's r = 0.18 ± 0.09, P < 0.001). Voxel-wise linear regressions thresholded at P < 0.05 (uncorrected) showed that, across all patients, younger age was associated with greater (18)F-AV1451 uptake in wide regions of the neocortex, while older age was associated with increased (18)F-AV1451 in the medial temporal lobe. APOE ϵ4 carriers showed greater temporal and parietal (18)F-AV1451 uptake than non-carriers. Finally, worse performance on domain-specific neuropsychological tests was associated with greater (18)F-AV1451 uptake in key regions implicated in memory (medial temporal lobes), visuospatial function (occipital, right temporoparietal cortex) and language (left > right temporoparietal cortex). In conclusion, tau imaging-contrary to amyloid-ß imaging-shows a strong regional association with clinical and anatomical heterogeneity in Alzheimer's disease. Although preliminary, these results are consistent with and expand upon findings from post-mortem, animal and cerebrospinal fluid studies, and suggest that the pathological aggregation of tau is closely linked to patterns of neurodegeneration and clinical manifestations of Alzheimer's disease.
Assuntos
Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Glucose/metabolismo , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Compostos de Anilina , Apolipoproteínas E/genética , Benzotiazóis/metabolismo , Carbolinas/metabolismo , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico por imagem , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , TiazóisRESUMO
Neuropsychiatric symptoms (NPSs) often occur in early-age-of-onset Alzheimer's disease (EOAD) and cluster into sub-syndromes (SSy). The aim of this study was to investigate the association between 18 F-FDG-PET regional and connectivity-based brain metabolic dysfunctions and neuropsychiatric SSy. NPSs were assessed in 27 EOAD using the Neuropsychiatric Inventory and further clustered into four SSy (apathetic, hyperactivity, affective, and psychotic SSy). Eighty-five percent of EOAD showed at least one NPS. Voxel-wise correlations between SSy scores and brain glucose metabolism (assessed with 18 F-FDG positron emission tomography) were studied. Interregional correlation analysis was used to explore metabolic connectivity in the salience (aSN) and default mode networks (DMN) in a larger sample of EOAD (N = 51) and Healthy Controls (N = 57). The apathetic, hyperactivity, and affective SSy were highly prevalent (>60%) as compared to the psychotic SSy (33%). The hyperactivity SSy scores were associated with increase of glucose metabolism in frontal and limbic structures, implicated in behavioral control. A comparable positive correlation with part of the same network was found for the affective SSy scores. On the other hand, the apathetic SSy scores were negatively correlated with metabolism in the bilateral orbitofrontal and dorsolateral frontal cortex known to be involved in motivation and decision-making processes. Consistent with these SSy regional correlations with brain metabolic dysfunction, the connectivity analysis showed increases in the aSN and decreases in the DMN. Behavioral abnormalities in EOAD are associated with specific dysfunctional changes in brain metabolic activity, in particular in the aSN that seems to play a crucial role in NPSs in EOAD. Hum Brain Mapp 37:4234-4247, 2016. © 2016 Wiley Periodicals, Inc.
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Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Encéfalo/metabolismo , Glucose/metabolismo , Afeto/fisiologia , Idade de Início , Doença de Alzheimer/classificação , Doença de Alzheimer/diagnóstico por imagem , Apatia/fisiologia , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/diagnóstico por imagem , Transtornos do Humor/etiologia , Transtornos do Humor/metabolismo , Atividade Motora/fisiologia , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/diagnóstico por imagem , Transtornos Psicóticos/etiologia , Transtornos Psicóticos/metabolismo , Compostos Radiofarmacêuticos , Estudos RetrospectivosRESUMO
Amyloid-ß, a hallmark of Alzheimer's disease, begins accumulating up to two decades before the onset of dementia, and can be detected in vivo applying amyloid-ß positron emission tomography tracers such as carbon-11-labelled Pittsburgh compound-B. A variety of thresholds have been applied in the literature to define Pittsburgh compound-B positron emission tomography positivity, but the ability of these thresholds to detect early amyloid-ß deposition is unknown, and validation studies comparing Pittsburgh compound-B thresholds to post-mortem amyloid burden are lacking. In this study we first derived thresholds for amyloid positron emission tomography positivity using Pittsburgh compound-B positron emission tomography in 154 cognitively normal older adults with four complementary approaches: (i) reference values from a young control group aged between 20 and 30 years; (ii) a Gaussian mixture model that assigned each subject a probability of being amyloid-ß-positive or amyloid-ß-negative based on Pittsburgh compound-B index uptake; (iii) a k-means cluster approach that clustered subjects into amyloid-ß-positive or amyloid-ß-negative based on Pittsburgh compound-B uptake in different brain regions (features); and (iv) an iterative voxel-based analysis that further explored the spatial pattern of early amyloid-ß positron emission tomography signal. Next, we tested the sensitivity and specificity of the derived thresholds in 50 individuals who underwent Pittsburgh compound-B positron emission tomography during life and brain autopsy (mean time positron emission tomography to autopsy 3.1 ± 1.8 years). Amyloid at autopsy was classified using Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria, unadjusted for age. The analytic approaches yielded low thresholds (standard uptake value ratiolow = 1.21, distribution volume ratiolow = 1.08) that represent the earliest detectable Pittsburgh compound-B signal, as well as high thresholds (standard uptake value ratiohigh = 1.40, distribution volume ratiohigh = 1.20) that are more conservative in defining Pittsburgh compound-B positron emission tomography positivity. In voxel-wise contrasts, elevated Pittsburgh compound-B retention was first noted in the medial frontal cortex, then the precuneus, lateral frontal and parietal lobes, and finally the lateral temporal lobe. When compared to post-mortem amyloid burden, low proposed thresholds were more sensitive than high thresholds (sensitivities: distribution volume ratiolow 81.0%, standard uptake value ratiolow 83.3%; distribution volume ratiohigh 61.9%, standard uptake value ratiohigh 62.5%) for CERAD moderate-to-frequent neuritic plaques, with similar specificity (distribution volume ratiolow 95.8%; standard uptake value ratiolow, distribution volume ratiohigh and standard uptake value ratiohigh 100.0%). A receiver operator characteristic analysis identified optimal distribution volume ratio (1.06) and standard uptake value ratio (1.20) thresholds that were nearly identical to the a priori distribution volume ratiolow and standard uptake value ratiolow. In summary, we found that frequently applied thresholds for Pittsburgh compound-B positivity (typically at or above distribution volume ratiohigh and standard uptake value ratiohigh) are overly stringent in defining amyloid positivity. Lower thresholds in this study resulted in higher sensitivity while not compromising specificity.
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Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/análise , Compostos de Anilina , Tomografia por Emissão de Pósitrons/normas , Compostos Radiofarmacêuticos , Tiazóis , Idoso , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Valores de Referência , Adulto JovemRESUMO
OBJECTIVE: To determine the training surgical residents and faculty receive on opioid prescribing, and to identify opportunities for curricula development to fill training gaps. DESIGN: We conducted qualitative semi-structured interviews and surveys. After applying an overarching organizational framework, we used an iterative, team-based process to develop relevant inductive codes. We then performed thematic analyses to identify and catalogue critical domains related to surgeons' education about opioid prescribing. SETTING: Tertiary care academic medical center. PARTICIPANTS: Maximum variation purposive sampling was used to recruit general surgery residents and surgical faculty members. RESULTS: We interviewed 21 attending surgeons and 20 surgical residents. Surgeons reported minimal formal training on pain management and prescribing opioids. A minority of individuals described receiving opioid training in the form of continuing medical education, intern boot camp sessions, and medical school classes. Participants compensated for the lack of formal training during residency by informally learning from senior residents, consulting pain specialists, and seeking external learning resources. Increased surgical experience was correlated with increased comfort with pain management. A majority of surgeons desired formal training. The most commonly requested educational resources were opioid prescribing guidelines for common operations and recommendations for treating chronic pain patients. Residents requested that training occur early in residency to maximize the benefits received. Based on these findings, we developed a conceptual framework to explain how surgeons learn to prescribe opioids and to highlight opportunities for improvement. CONCLUSIONS: Although surgeons routinely prescribe opioids and desire education on opioids, a majority of them do not receive any training. Instituting formal educational programs is critical for improving opioid prescribing practices among surgeons.These programs should include standard prescribing guidelines and address management of acute postoperative pain in patients with chronic pain.
Assuntos
Analgésicos Opioides , Cirurgiões , Analgésicos Opioides/uso terapêutico , Prescrições de Medicamentos , Humanos , Dor Pós-Operatória/tratamento farmacológico , Padrões de Prática MédicaRESUMO
The relationships between ß-amyloid (Aß), tau and neurodegeneration within Alzheimer's Disease pathogenesis are not fully understood. To explore these associations in vivo, we evaluated 30 Aß PET-positive patients (mean ± sd age 62.4 ± 8.3) with mild probable AD and 12 Aß PET-negative healthy controls (HC) (mean ± sd age 77.3 ± 6.9) as comparison. All participants underwent 3 T MRI, 11C-PiB (Aß) PET and 18F-AV1451 (tau) PET. Multimodal correlation analyses were run at both voxel- and region-of-interest levels. 11C-PiB retention in AD showed the most diffuse uptake pattern throughout association neocortex, whereas 18F-AV1451 and gray matter volume reduction (GMR) showed a progressive predilection for posterior cortices (p<0.05 Family-Wise Error-[FWE]-corrected). Voxel-level analysis identified negative correlations between 18F-AV1451 and gray matter peaking in medial and infero-occipital regions (p<0.01 False Discovery Rate-[FDR]-corrected). 18F-AV1451 and 11C-PiB were positively correlated in right parietal and medial/inferior occipital regions (p<0.001 uncorrected). 11C-PiB did not correlate with GMR at the voxel-level. Regionally, 18F-AV1451 was largely associated with local/adjacent GMR whereas frontal 11C-PiB correlated with GMR in posterior regions. These findings suggest that, in mild AD, tau aggregation drives local neurodegeneration, whereas the relationships between Aß and neurodegeneration are not region specific and may be mediated by the interaction between Aß and tau.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Vias Neurais/patologia , Tomografia por Emissão de PósitronsRESUMO
OBJECTIVE: To assess the relationships between fluid and imaging biomarkers of tau pathology and compare their diagnostic utility in a clinically heterogeneous sample. METHODS: Fifty-three patients (28 with clinical Alzheimer disease [AD] and 25 with non-AD clinical neurodegenerative diagnoses) underwent ß-amyloid (Aß) and tau ([18F]AV1451) PET and lumbar puncture. CSF biomarkers (Aß42, total tau [t-tau], and phosphorylated tau [p-tau]) were measured by multianalyte immunoassay (AlzBio3). Receiver operator characteristic analyses were performed to compare discrimination of Aß-positive AD from non-AD conditions across biomarkers. Correlations between CSF biomarkers and PET standardized uptake value ratios (SUVR) were assessed using skipped Pearson correlation coefficients. Voxelwise analyses were run to assess regional CSF-PET associations. RESULTS: [18F]AV1451-PET cortical SUVR and p-tau showed excellent discrimination between Aß-positive AD and non-AD conditions (area under the curve 0.92-0.94; ≤0.83 for other CSF measures), and reached 83% classification agreement. In the full sample, cortical [18F]AV1451 was associated with all CSF biomarkers, most strongly with p-tau (r = 0.75 vs 0.57 for t-tau and -0.49 for Aß42). When restricted to Aß-positive patients with AD, [18F]AV1451 SUVR correlated modestly with p-tau and t-tau (both r = 0.46) but not Aß42 (r = 0.02). On voxelwise analysis, [18F]AV1451 correlated with CSF p-tau in temporoparietal cortices and with t-tau in medial prefrontal regions. Within AD, Mini-Mental State Examination scores were associated with [18F]AV1451-PET, but not CSF biomarkers. CONCLUSION: [18F]AV1451-PET and CSF p-tau had comparable value for differential diagnosis. Correlations were robust in a heterogeneous clinical group but attenuated (although significant) in AD, suggesting that fluid and imaging biomarkers capture different aspects of tau pathology. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, in a clinical sample of patients with a variety of suspected neurodegenerative diseases, both CSF p-tau and [18F]AV1451 distinguish AD from non-AD conditions.
Assuntos
Encéfalo/diagnóstico por imagem , Carbolinas , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/diagnóstico por imagem , Compostos Radiofarmacêuticos , Proteínas tau/líquido cefalorraquidiano , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Área Sob a Curva , Biomarcadores/líquido cefalorraquidiano , Encéfalo/metabolismo , Encéfalo/patologia , Estudos Transversais , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/patologia , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosforilação , Curva ROC , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
Importance: The ability to predict the pathology underlying different neurodegenerative syndromes is of critical importance owing to the advent of molecule-specific therapies. Objective: To determine the rates of positron emission tomography (PET) amyloid positivity in the main clinical variants of primary progressive aphasia (PPA). Design, Setting, and Participants: This prospective clinical-pathologic case series was conducted at a tertiary research clinic specialized in cognitive disorders. Patients were evaluated as part of a prospective, longitudinal research study between January 2002 and December 2015. Inclusion criteria included clinical diagnosis of PPA; availability of complete speech, language, and cognitive testing; magnetic resonance imaging performed within 6 months of the cognitive evaluation; and PET carbon 11-labeled Pittsburgh Compound-B or florbetapir F 18 brain scan results. Of 109 patients referred for evaluation of language symptoms who underwent amyloid brain imaging, 3 were excluded because of incomplete language evaluations, 5 for absence of significant aphasia, and 12 for presenting with significant initial symptoms outside of the language domain, leaving a cohort of 89 patients with PPA. Main Outcomes and Measures: Clinical, cognitive, neuroimaging, and pathology results. Results: Twenty-eight cases were classified as imaging-supported semantic variant PPA (11 women [39.3%]; mean [SD] age, 64 [7] years), 31 nonfluent/agrammatic variant PPA (22 women [71.0%]; mean [SD] age, 68 [7] years), 26 logopenic variant PPA (17 women [65.4%]; mean [SD] age, 63 [8] years), and 4 mixed PPA cases. Twenty-four of 28 patients with semantic variant PPA (86%) and 28 of 31 patients with nonfluent/agrammatic variant PPA (90%) had negative amyloid PET scan results, while 25 of 26 patients with logopenic variant PPA (96%) and 3 of 4 mixed PPA cases (75%) had positive scan results. The amyloid positive semantic variant PPA and nonfluent/agrammatic variant PPA cases with available autopsy data (2 of 4 and 2 of 3, respectively) all had a primary frontotemporal lobar degeneration and secondary Alzheimer disease pathologic diagnoses, whereas autopsy of 2 patients with amyloid PET-positive logopenic variant PPA confirmed Alzheimer disease. One mixed PPA patient with a negative amyloid PET scan had Pick disease at autopsy. Conclusions and Relevance: Primary progressive aphasia variant diagnosis according to the current classification scheme is associated with Alzheimer disease biomarker status, with the logopenic variant being associated with carbon 11-labeled Pittsburgh Compound-B positivity in more than 95% of cases. Furthermore, in the presence of a clinical syndrome highly predictive of frontotemporal lobar degeneration pathology, biomarker positivity for Alzheimer disease may be associated more with mixed pathology rather than primary Alzheimer disease.
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Amiloide/metabolismo , Afasia Primária Progressiva/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Idoso , Compostos de Anilina/farmacocinética , Afasia Primária Progressiva/classificação , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Etilenoglicóis/farmacocinética , Feminino , Humanos , Imageamento Tridimensional , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Estudos Retrospectivos , Índice de Gravidade de Doença , Tiazóis/farmacocinéticaRESUMO
Imaging-pathological correlation studies show that in vivo amyloid-ß (Aß) positron emission tomography (PET) strongly predicts the presence of significant Aß pathology at autopsy. We sought to determine whether regional PiB-PET uptake would improve sensitivity for amyloid detection in comparison with global measures (experiment 1), and to estimate the relative contributions of different Aß aggregates to in vivo PET signal (experiment 2). In experiment 1, 54 subjects with [11C] PiB-PET during life and postmortem neuropathologic examination (85.2% with dementia, interval from PET to autopsy 3.1 ± 1.9 years) were included. We assessed Thal amyloid phase (N = 36) and CERAD score (N = 54) versus both global and regional PiB SUVRs. In experiment 2 (N = 42), PiB SUVR and post-mortem amyloid ß burden was analyzed in five customized regions of interest matching regions sampled at autopsy. We assessed the relative contribution of neuritic plaques (NPs), diffuse plaques (DPs) and cerebral amyloid angiopathy (CAA) to regional PIB SUVR using multi-linear regression. In experiment 1, there were no differences in Area Under the Curve for amyloid phase ≥ A2 and CERAD score ≥ C2 between global and highest regional PiB SUVR (p = 0.186 and 0.230). In experiment 2, when NPs, DPs, and/or CAA were included in the same model, moderate to severe NPs were independently correlated with PiB SUVR in all regions except for the inferior temporal and calcarine ROI (ß = 0.414-0.804, p < 0.05), whereas DPs were independently correlated with PiB SUVR in the angular gyrus ROI (ß = 0.446, p = 0.010). CAA was also associated with PiB SUVR in the inferior temporal and calcarine ROI (ß = 0.222-0.355, p < 0.05). In conclusion, global PiB-PET SUVR performed as well as regional values for amyloid detection in our cohort. The substrate-specific binding of PiB might differ among the brain specific regions.
Assuntos
Envelhecimento , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva , Demência , Tomografia por Emissão de Pósitrons/métodos , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Envelhecimento/patologia , Compostos de Anilina , Benzotiazóis , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Demência/diagnóstico por imagem , Demência/metabolismo , Demência/patologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , TiazóisRESUMO
OBJECTIVE: To compare the values of arterial spin-labeled (ASL) MRI and fluorodeoxyglucose (FDG) PET in the diagnosis of behavioral variant of frontotemporal dementia (bvFTD) and Alzheimer's disease (AD). METHODS: Partial least squares logistic regression was used to identify voxels with diagnostic value in cerebral blood flow (CBF) and cerebral metabolic rate of glucose (CMRgl) maps from patients with bvFTD (n = 32) and AD (n = 28), who were compared with each other and with cognitively normal controls (CN, n = 15). Diagnostic values of these maps were compared with each other. RESULTS: Regions that differentiated each disorder from controls were similar for CBF and CMRgl. For differentiating AD from CN, the areas under the curve (AUC) for CBF (0.89) and CMRgl (0.91) were similar, with similar sensitivity (CBF: 86%, CMRgl: 78%) and specificity (CBF: 92%, CMRgl: 100%). Likewise, for differentiating bvFTD from CN performances of CBF (AUC = 0.83) and CMRgl (AUC = 0.85) were equivalent, with similar sensitivity (CBF: 78%, CMRgl: 79%) and specificity (CBF: 92%, CMRgl: 100%). In differentiating bvFTD from AD, classification was again similar for CBF (AUC = 0.87) and CMRgl (AUC = 0.79), as were sensitivity (CBF: 83%, CMRgl: 89%) and specificity (CBF: 93%, CMRgl: 78%). None of the differences in any performance measure were statistically significant. INTERPRETATION: ASL-MRI has similar diagnostic utility as FDG-PET in the diagnosis of AD and bvFTD. Continued development of ASL-MRI as a diagnostic tool for neurodegenerative dementias is warranted.
RESUMO
OBJECTIVE: To investigate the associations among ß-amyloid (Aß), cortical thickness, and episodic memory in a cohort of cognitively normal to mildly impaired individuals at increased risk of vascular disease. METHODS: In 67 subjects specifically recruited to span a continuum of cognitive function and vascular risk, we measured brain Aß deposition using [(11)C] Pittsburgh compound B-PET imaging and cortical thickness using MRI. Episodic memory was tested using a standardized composite score of verbal memory, and vascular risk was quantified using the Framingham Coronary Risk Profile index. RESULTS: Increased Aß was associated with cortical thinning, notably in frontoparietal regions. This relationship was strongest in persons with high Aß deposition. Increased Aß was also associated with lower episodic memory performance. Cortical thickness was found to mediate the relationship between Aß and memory performance. While age had a marginal effect on these associations, the relationship between Aß and cortical thickness was eliminated after controlling for vascular risk except when examined in only Pittsburgh compound B-positive subjects, in whom Aß remained associated with thinner cortex in precuneus and occipital lobe. In addition, only the precuneus was found to mediate the relationship between Aß and memory after controlling for vascular risk. CONCLUSION: These results suggest strong links among Aß, cortical thickness, and memory. They highlight that, in individuals without dementia, vascular risk also contributes to cortical thickness and influences the relationships among Aß, cortical thickness, and memory.