Detection of amyloid in Alzheimer's disease with positron emission tomography using [11C]AZD2184.
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ABSTRACT:
SUBMITTER: Nyberg S
PROVIDER: S-EPMC2764092 | biostudies-other | 2009 Nov
REPOSITORIES: biostudies-other
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Project description:Antibody-mediated imaging of amyloid ? (A?) in Alzheimer's disease (AD) offers a promising strategy to detect and monitor specific A? species, such as oligomers, that have important pathological and therapeutic relevance. The major current limitation of antibodies as a diagnostic and imaging device is poor blood-brain-barrier permeability. A classical anti-A? antibody, 6E10, is modified with 10 kDa polyethylene glycol (PEG) and a positron emitting isotope, Copper-64 (t(½)?=?12.7 h), and intravenously delivered to the TgCRND8 mouse model of Alzheimer's disease. Modification of 6E10 with PEG (6E10-PEG) increases accumulation of 6E10 in brain tissue in both TgCRND8 and wild type control animals. 6E10-PEG differentiates TgCRND8 animals from wild type controls using positron emission tomography (PET) and provides a framework for using antibodies to detect pathology using non-invasive medical imaging techniques.
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Project description:Imaging of type 1 metabotropic glutamate receptor (mGluR1) has recently become possible using positron emission tomography (PET). To date, little evidence exists on the role of mGluR1 in the pathophysiology of Alzheimer's disease (AD). We aimed to examine mGluR1 availability in patients with AD. Ten patients with AD (78.9 ± 5.9 years) and 12 age-matched volunteers (74.6 ± 2.6 years) underwent PET using an mGluR1 radiotracer. All patients were anti-dementia drug-naive. Volumes-of-interest were placed on the anterior and posterior lobes and vermis in the cerebellum and frontal, parietal, and temporal cortices. The binding potential (BPND) was calculated to estimate mGluR1 availability, and partial volume correction was applied to the BPND values. Mini Mental State Examination (MMSE) scores were also obtained (22.0 ± 4.8). No significant difference was observed in BPND between the AD and control groups in the anterior lobe (p = .30), posterior lobe (p = .95), vermis (p = .96), frontal cortex (p = .61), parietal cortex (p = .59), or temporal cortex (p = .27). No significant correlation was observed between BPND and MMSE scores in the anterior lobe (p = .59), posterior lobe (p = .35), vermis (p = .92), frontal cortex (p = .78), parietal cortex (p = .83), or temporal cortex (p = .82). In conclusions, this study suggests that mGluR1 availability is unchanged in the relatively early stage of AD. However, because regional mGluR1 availability may change with the progression of AD, further longitudinal follow-up is necessary.
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Project description:ObjectiveTo understand the neurotoxic effects of manganese (Mn) exposure on monoaminergic function, utilizing [C]dihydrotetrabenazine (DTBZ) positron emission tomography (PET) to measure vesicular monoamine transporter 2 (VMAT2).MethodsBasal ganglia and thalamic DTBZ binding potentials (BPND) were calculated on 56 PETs from 41 Mn-exposed workers. Associations between cumulative Mn exposure, regional BPND, and parkinsonism were examined by mixed linear regression.ResultsThalamic DTBZ BPND was inversely associated with exposure in workers with less than 3 mg Mn/m-yrs, but subsequently remained stable. Pallidal DTBZ binding increased in workers with less than 2 mg Mn/m-yrs of exposure, but decreased thereafter. Thalamic DTBZ binding was inversely associated with parkinsonism (P = 0.003).ConclusionMn-dose-dependent associations with thalamic and pallidal DTBZ binding indicate direct effects on monoaminergic VMAT2. Thalamic DTBZ binding was also associated with parkinsonism, suggesting potential as an early biomarker of Mn neurotoxicity.
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Project description:INTRODUCTION:Due to the high cost and high failure rate of ascertaining amyloid positron emission tomography positivity (PET+) in patients with earlier stage Alzheimer's disease (AD), an effective pre-screening tool for amyloid PET scans is needed. METHODS:Patients with mild cognitive impairment (n?=?33, 24.2% PET+, 42% females, age 74.4?±?7.5, MMSE 26.8?±?1.9) and mild dementia (n?=?19, 63.6% PET+, 36.3% females, age 73.0?±?9.3, MMSE 22.6?±?2.0) were recruited. Amyloid PET imaging, Apolipoprotein E (APOE) genotyping, and plasma amyloid ? (A?)1-40, A?1-42, and total tau protein quantification by immunomagnetic reduction (IMR) method were performed. Receiver operating characteristics (ROC) analysis and Youden's index were performed to identify possible cut-off points, clinical sensitivities/specificities, and areas under the curve (AUCs). RESULTS:Amyloid PET+ participants had lower plasma A?1-42 levels than amyloid PET-negative (PET-) subjects. APOE ?4 carriers had higher plasma A?1-42 than non-carriers. We developed an algorithm involving the combination of plasma A?1-42 and APOE genotyping. The success rate for detecting amyloid PET+ patients effectively increased from 42.3 to 70.4% among clinically suspected MCI and mild dementia patients. CONCLUSIONS:Our results demonstrate the possibility of utilizing APOE genotypes in combination with plasma A?1-42 levels as a pre-screening tool for predicting the positivity of amyloid PET findings in early stage dementia patients.
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Project description:ImportanceThe recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies of Alzheimer disease (AD): amyloid-β plaques and tau neurofibrillary tangles.ObjectiveTo determine whether cerebrospinal fluid (CSF) and plasma p-tau biomarkers preferentially reflect cerebral β-amyloidosis or neurofibrillary tangle aggregation measured with positron emission tomography (PET).Design, setting, and participantsThis was a cross-sectional study of 2 observational cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) study, with data collected between October 2017 and August 2021, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), with data collected between September 2015 and November 2019. TRIAD was a single-center study, and ADNI was a multicenter study. Two independent subsamples were derived from TRIAD. The first TRIAD subsample comprised individuals assessed with CSF p-tau (p-tau181, p-tau217, p-tau231, p-tau235), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. The second TRIAD subsample included individuals assessed with plasma p-tau (p-tau181, p-tau217, p-tau231), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. An independent cohort from ADNI comprised individuals assessed with CSF p-tau181, [18F]florbetapir PET, and [18F]flortaucipir PET. Participants were included based on the availability of p-tau and PET biomarker assessments collected within 9 months of each other. Exclusion criteria were a history of head trauma or magnetic resonance imaging/PET safety contraindications. No participants who met eligibility criteria were excluded.ExposuresAmyloid PET, tau PET, and CSF and plasma assessments of p-tau measured with single molecule array (Simoa) assay or enzyme-linked immunosorbent assay.Main outcomes and measuresAssociations between p-tau biomarkers with amyloid PET and tau PET.ResultsA total of 609 participants (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) were included in the study. For all 4 phosphorylation sites assessed in CSF, p-tau was significantly more closely associated with amyloid-PET values than tau-PET values (p-tau181 difference, 13%; 95% CI, 3%-22%; P = .006; p-tau217 difference, 11%; 95% CI, 3%-20%; P = .003; p-tau231 difference, 15%; 95% CI, 5%-22%; P < .001; p-tau235 difference, 9%; 95% CI, 1%-19%; P = .02) . These results were replicated with plasma p-tau181 (difference, 11%; 95% CI, 1%-22%; P = .02), p-tau217 (difference, 9%; 95% CI, 1%-19%; P = .02), p-tau231 (difference, 13%; 95% CI, 3%-24%; P = .009), and CSF p-tau181 (difference, 9%; 95% CI, 1%-21%; P = .02) in independent cohorts.Conclusions and relevanceResults of this cross-sectional study of 2 observational cohorts suggest that the p-tau abnormality as an early event in AD pathogenesis was associated with amyloid-β accumulation and highlights the need for careful interpretation of p-tau biomarkers in the context of the amyloid/tau/neurodegeneration, or A/T/(N), framework.
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Project description:BackgroundRecognizing clinical manifestations heralding the development of Alzheimer's disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults.MethodsThis prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n?=?2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [18F]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1?years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change.ResultsWeight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00-1.61, p?=?0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19-1.89, p?=?0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25-2.20, p?=?0.001) and was greater among participants with an A+T+ profile (p?<?0.01) at follow-up. Weight change was positively associated with CSF A?42/40 ratio (??=?0.099, p?=?0.032) and negatively associated with CSF p-tau (??=?-?0.141, p?=?0.005), t-tau (??=?-?0.147 p?=?0.004) and neurogranin levels (??=?-?0.158, p?=?0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only.ConclusionsWeight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-? accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment.Trial registrationNCT01835717 , NCT02485730 , NCT02685969 .
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Project description:This study examines the relationship between fibrillar beta-amyloid (A?) deposition and reduced glucose metabolism, a proxy for neuronal dysfunction, in cognitively normal (NL) individuals with a parent affected by late-onset Alzheimer's disease (AD). Forty-seven 40-80-year-old NL received positron emission tomography (PET) with (11)C-Pittsburgh compound B (PiB) and 18F-fluoro-2-deoxy-d-glucose (FDG). These included 19 NL with a maternal history (MH), 12 NL with a paternal history (PH), and 16 NL with negative family history of AD (NH). Automated regions of interest, statistical parametric mapping, voxel-wise intermodality correlations, and logistic regressions were used to examine cerebral-to-cerebellar PiB and FDG standardized uptake value ratios across groups. The MH group showed higher PiB retention and lower metabolism in AD regions compared with NH and PH, which were negatively correlated in posterior cingulate, frontal, and parieto-temporal regions (Pearson r ? -0.57, p ? 0.05). No correlations were observed in NH and PH. The combination of A? deposition and metabolism yielded accuracy ? 69% for MH vs. NH and ? 71% for MH vs. PH, with relative risk = 1.9-5.1 (p values < 0.005). NL individuals with AD-affected mothers show co-occurring A? increases and hypometabolism in AD-vulnerable regions, suggesting an increased risk for AD.
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