Post-Mortem evaluation of amyloid-dopamine terminal positron emission tomography dementia classifications.
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ABSTRACT:
SUBMITTER: Albin RL
PROVIDER: S-EPMC4836870 | biostudies-literature | 2015 Nov
REPOSITORIES: biostudies-literature
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Post-Mortem evaluation of amyloid-dopamine terminal positron emission tomography dementia classifications.
Albin Roger L RL Fisher-Hubbard Amanda A Shanmugasundaram Krithika K Koeppe Robert A RA Burke James F JF Camelo-Piragua Sandra S Lieberman Andrew P AP Giordani Bruno B Frey Kirk A KA
Annals of neurology 20150825 5
Clinical classification of early dementia and mild cognitive impairment (MCI) is imprecise. We reported previously that molecular imaging classification of early dementia and MCI with dual amyloid and dopamine terminal positron emission tomography differs significantly from expert clinical classification. We now report pathological diagnoses in a substantial subset of our previously imaged subjects. Among 36 subjects coming to autopsy, imaging classifications and pathological diagnosis were conc ...[more]
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Project description:BACKGROUND:Pittsburgh compound B ([11C]-PIB) identifies amyloid-? (A?) deposition in vivo. Asymptomatic A? deposition has been reported consistently in some healthy older subjects. Of patients with frontotemporal dementia, those who have later onset have a higher potential for A? deposition. OBJECTIVE:Comparison of A? deposition in Alzheimer's disease (AD), healthy older controls, and patients with early- and late-onset semantic dementia (SD), a subtype of frontotemporal dementia. METHODS:Subjects were recruited from tertiary academic care centers specializing in assessment and management of patients with neurodegenerative disease. We used the radiotracer [11C]-PIB in a high-resolution positron emission tomography scanner to evaluate 11 participants with SD (six with onset before age 65 and five with later onset), 9 with probable AD, and 10 controls over age 60. The main outcome measures were frontal, temporal, parietal, and total [11C]-PIB standardized uptake value ratios to establish PIB-positive (PIB+) cutoff. RESULTS:The five patients with late-onset SD were PIB-negative. Two of six with early-onset SD, seven of nine with AD, and 1 of 10 controls were PIB+. The SD participants who were PIB+ did not have memory or visuospatial deficits that are typical in AD. CONCLUSIONS:A? deposition does not seem to be associated with late-onset SD. Future larger studies might confirm whether a significant minority of early-onset SD patients exhibit A? deposition. Copyright © 2016 John Wiley & Sons, Ltd.
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Project description:Elevated in vivo markers of presynaptic striatal dopamine activity have been a consistent finding in schizophrenia, and include a large effect size elevation in dopamine synthesis capacity. However, it is not known if the dopaminergic dysfunction is limited to the striatal terminals of dopamine neurons, or is also evident in the dopamine neuron cell bodies, which mostly originate in the substantia nigra. The aim of our studies was therefore to determine whether dopamine synthesis capacity is altered in the substantia nigra of people with schizophrenia, and how this relates to symptoms. In a post-mortem study, a semi-quantitative analysis of tyrosine hydroxylase staining was conducted in nigral dopaminergic cells from post-mortem tissue from patients with schizophrenia (n = 12), major depressive disorder (n = 13) and matched control subjects (n = 13). In an in vivo imaging study, nigral and striatal dopaminergic function was measured in patients with schizophrenia (n = 29) and matched healthy control subjects (n = 29) using (18)F-dihydroxyphenyl-L-alanine ((18)F-DOPA) positron emission tomography. In the post-mortem study we found that tyrosine hydroxylase staining was significantly increased in nigral dopaminergic neurons in schizophrenia compared with both control subjects (P < 0.001) and major depressive disorder (P < 0.001). There was no significant difference in tyrosine hydroxylase staining between control subjects and patients with major depressive disorder, indicating that the elevation in schizophrenia is not a non-specific indicator of psychiatric illness. In the in vivo imaging study we found that (18)F-dihydroxyphenyl-L-alanine uptake was elevated in both the substantia nigra and in the striatum of patients with schizophrenia (effect sizes = 0.85, P = 0.003 and 1.14, P < 0.0001, respectively) and, in the voxel-based analysis, was elevated in the right nigra (P < 0.05 corrected for family wise-error). Furthermore, nigral (18)F-dihydroxyphenyl-L-alanine uptake was positively related with the severity of symptoms (r = 0.39, P = 0.035) in patients. However, whereas nigral and striatal (18)F-dihydroxyphenyl-L-alanine uptake were positively related in control subjects (r = 0.63, P < 0.001), this was not the case in patients (r = 0.30, P = 0.11). These findings indicate that elevated dopamine synthesis capacity is seen in the nigral origin of dopamine neurons as well as their striatal terminals in schizophrenia, and is linked to symptom severity in patients.
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Project description:BackgroundDisclosure of amyloid positron emission tomography (PET) results to individuals without dementia has become standard practice in secondary prevention trials and also increasingly occurs in clinical practice. However, this is controversial given the current lack of understanding of the predictive value of a PET result at the individual level and absence of disease-modifying treatments. In this study, we systematically reviewed the literature on the disclosure of amyloid PET in cognitively normal (CN) individuals and patients with mild cognitive impairment (MCI) in both research and clinical settings.MethodsWe performed a systematic literature search of four scientific databases. Two independent reviewers screened the identified records and selected relevant articles. Included articles presented either empirical data or theoretical data (i.e. arguments in favor or against amyloid status disclosure). Results from the theoretical data were aggregated and presented per theme.ResultsOf the seventeen included studies, eleven reported empirical data and six provided theoretical arguments. There was a large variation in the design of the empirical studies, which were almost exclusively in the context of cognitively normal trial participants, comprising only two prospective cohort studies quantitatively assessing the psychological impact of PET result disclosure which showed a low risk of psychological harm after disclosure. Four studies showed that both professionals and cognitively normal individuals support amyloid PET result disclosure and underlined the need for clear disclosure protocols. From the articles presenting theoretical data, we identified 51 'pro' and 'contra' arguments. Theoretical arguments in favor or against disclosure were quite consistent across population groups and settings. Arguments against disclosure focused on the principle of non-maleficence, whereas its psychological impact and predictive value is unknown. Important arguments in favor of amyloid disclosure are the patients right to know (patient autonomy) and that it enables early future decision making.DiscussionBefore amyloid PET result disclosure in individuals without dementia in a research or clinical setting is ready for widespread application, more research is needed about its psychological impact, and its predictive value at an individual level. Finally, communication materials and strategies to support disclosure of amyloid PET results should be further developed and prospectively evaluated.
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2015-02-09 | E-MTAB-3175 | biostudies-arrayexpress
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Project description:ObjectiveThe purpose of this study was to compare the diagnostic accuracy of antemortem 11 C-Pittsburgh compound B (PIB) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) versus autopsy diagnosis in a heterogenous sample of patients.MethodsOne hundred one participants underwent PIB and FDG PET during life and neuropathological assessment. PET scans were visually interpreted by 3 raters blinded to clinical information. PIB PET was rated as positive or negative for cortical retention, whereas FDG scans were read as showing an Alzheimer disease (AD) or non-AD pattern. Neuropathological diagnoses were assigned using research criteria. Majority visual reads were compared to intermediate-high AD neuropathological change (ADNC).ResultsOne hundred one participants were included (mean age = 67.2 years, 41 females, Mini-Mental State Examination = 21.9, PET-to-autopsy interval = 4.4 years). At autopsy, 32 patients showed primary AD, 56 showed non-AD neuropathology (primarily frontotemporal lobar degeneration [FTLD]), and 13 showed mixed AD/FTLD pathology. PIB showed higher sensitivity than FDG for detecting intermediate-high ADNC (96%, 95% confidence interval [CI] = 89-100% vs 80%, 95% CI = 68-92%, p = 0.02), but equivalent specificity (86%, 95% CI = 76-95% vs 84%, 95% CI = 74-93%, p = 0.80). In patients with congruent PIB and FDG reads (77/101), combined sensitivity was 97% (95% CI = 92-100%) and specificity was 98% (95% CI = 93-100%). Nine of 24 patients with incongruent reads were found to have co-occurrence of AD and non-AD pathologies.InterpretationIn our sample enriched for younger onset cognitive impairment, PIB-PET had higher sensitivity than FDG-PET for intermediate-high ADNC, with similar specificity. When both modalities are congruent, sensitivity and specificity approach 100%, whereas mixed pathology should be considered when PIB and FDG are incongruent. ANN NEUROL 2021;89:389-401.
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