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Comparing positron emission tomography imaging and cerebrospinal fluid measurements of ?-amyloid.

ABSTRACT: We examined agreement and disagreement between 2 biomarkers of ?-amyloid (A?) deposition (amyloid positron emission tomography [PET] and cerebrospinal fluid [CSF] A?1-42 ) in normal aging and dementia in a large multicenter study.Concurrently acquired florbetapir PET and CSF A? were measured in cognitively normal, mild cognitive impairment (MCI), and Alzheimer's disease participants (n?=?374) from the Alzheimer's Disease Neuroimaging Initiative. We also compared A? measurements in a separate group with serial CSF measurements over 3.1?±?0.8 years that preceded a single florbetapir session. Additional biomarker and cognitive data allowed us to further examine profiles of discordant cases.Florbetapir and CSF A? were inversely correlated across all diagnostic groups, and dichotomous measurements were in agreement in 86% of subjects. Among subjects showing the most disagreement, the 2 discordant groups had different profiles: the florbetapir(+) /CSF A?(-) group was larger (n?=?13) and was made up of only normal and early MCI subjects, whereas the florbetapir(-) /CSF A?(+) group was smaller (n?=?7) and had poorer cognitive function and higher CSF tau, but no ApoE4 carriers. In the longitudinal sample, we observed both stable longitudinal CSF A? trajectories and those actively transitioning from normal to abnormal, but the final CSF A? measurements were in good agreement with florbetapir cortical retention.CSF and amyloid PET measurements of A? were consistent in the majority of subjects in the cross-sectional and longitudinal populations. Based on our analysis of discordant subjects, the available evidence did not show that CSF A? regularly becomes abnormal prior to fibrillar A? accumulation early in the course of disease.

SUBMITTER: Landau SM

PROVIDER: S-EPMC3748164 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Comparing positron emission tomography imaging and cerebrospinal fluid measurements of β-amyloid.

Landau Susan M SM Lu Ming M Joshi Abhinay D AD Pontecorvo Michael M Mintun Mark A MA Trojanowski John Q JQ Shaw Leslie M LM Jagust William J WJ

Annals of neurology 20131201 6

<h4>Objective</h4>We examined agreement and disagreement between 2 biomarkers of β-amyloid (Aβ) deposition (amyloid positron emission tomography [PET] and cerebrospinal fluid [CSF] Aβ1-42 ) in normal aging and dementia in a large multicenter study.<h4>Methods</h4>Concurrently acquired florbetapir PET and CSF Aβ were measured in cognitively normal, mild cognitive impairment (MCI), and Alzheimer's disease participants (n = 374) from the Alzheimer's Disease Neuroimaging Initiative. We also compared ...[more]

PMID: 23536396

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Project description:Cerebral accumulation of amyloid-? is thought to be the starting mechanism in Alzheimer's disease. Amyloid-? can be detected by analysis of cerebrospinal fluid amyloid-?42 or amyloid positron emission tomography, but it is unknown if any of the methods can identify an abnormal amyloid accumulation prior to the other. Our aim was to determine whether cerebrospinal fluid amyloid-?42 change before amyloid PET during preclinical stages of Alzheimer's disease. We included 437 non-demented subjects from the prospective, longitudinal Alzheimer's Disease Neuroimaging Initiative (ADNI) study. All underwent (18)F-florbetapir positron emission tomography and cerebrospinal fluid amyloid-?42 analysis at baseline and at least one additional positron emission tomography after a mean follow-up of 2.1 years (range 1.1-4.4 years). Group classifications were based on normal and abnormal cerebrospinal fluid and positron emission tomography results at baseline. We found that cases with isolated abnormal cerebrospinal fluid amyloid-? and normal positron emission tomography at baseline accumulated amyloid with a mean rate of 1.2%/year, which was similar to the rate in cases with both abnormal cerebrospinal fluid and positron emission tomography (1.2%/year, P = 0.86). The mean accumulation rate of those with isolated abnormal cerebrospinal fluid was more than three times that of those with both normal cerebrospinal fluid and positron emission tomography (0.35%/year, P = 0.018). The group differences were similar when analysing yearly change in standardized uptake value ratio of florbetapir instead of percentage change. Those with both abnormal cerebrospinal fluid and positron emission tomography deteriorated more in memory and hippocampal volume compared with the other groups (P < 0.001), indicating that they were closer to Alzheimer's disease dementia. The results were replicated after adjustments of different factors and when using different cut-offs for amyloid-? abnormality including a positron emission tomography classification based on the florbetapir uptake in regions where the initial amyloid-? accumulation occurs in Alzheimer's disease. This is the first study to show that individuals who have abnormal cerebrospinal amyloid-?42 but normal amyloid-? positron emission tomography have an increased cortical amyloid-? accumulation rate similar to those with both abnormal cerebrospinal fluid and positron emission tomography and higher rate than subjects where both modalities are normal. The results indicate that cerebrospinal fluid amyloid-?42 becomes abnormal in the earliest stages of Alzheimer's disease, before amyloid positron emission tomography and before neurodegeneration starts.

Project description:Mismatch between CSF and PET amyloid-β biomarkers occurs in up to ≈20% of preclinical/prodromal Alzheimer's disease individuals. Factors underlying mismatching results remain unclear. In this study we hypothesized that CSF/PET discordance provides unique biological/clinical information. To test this hypothesis, we investigated non-demented and demented participants with CSF amyloid-β42 and [18F]Florbetapir PET assessments at baseline (n = 867) and at 2-year follow-up (n = 289). Longitudinal trajectories of amyloid-β positivity were tracked simultaneously for CSF and PET biomarkers. In the longitudinal cohort (n = 289), we found that participants with normal CSF/PET amyloid-β biomarkers progressed more frequently toward CSF/PET discordance than to full CSF/PET positivity (χ2(1) = 5.40; p < 0.05). Progression to CSF+/PET+ status was ten times more frequent in cases with discordant biomarkers, as compared to csf-/pet- cases (χ2(1) = 18.86; p < 0.001). Compared to the CSF+/pet- group, the csf-/PET+ group had lower APOE-ε4ε4 prevalence (χ2(6) = 197; p < 0.001; n = 867) and slower rate of brain amyloid-β accumulation (F(3,600) = 12.76; p < 0.001; n = 608). These results demonstrate that biomarker discordance is a typical stage in the natural history of amyloid-β accumulation, with CSF or PET becoming abnormal first and not concurrently. Therefore, biomarker discordance allows for identification of individuals with elevated risk of progression toward fully abnormal amyloid-β biomarkers, with subsequent risk of neurodegeneration and cognitive decline. Our results also suggest that there are two alternative pathways ("CSF-first" vs. "PET-first") toward established amyloid-β pathology, characterized by different genetic profiles and rates of amyloid-β accumulation. In conclusion, CSF and PET amyloid-β biomarkers provide distinct information, with potential implications for their use as biomarkers in clinical trials.

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 .

Project description:The two primary molecular pathologies in Alzheimer's disease are amyloid-? plaques and tau-immunoreactive neurofibrillary tangles. Investigations into these pathologies have been restricted to cerebrospinal fluid assays, and positron emission tomography tracers that can image amyloid-? plaques. Tau tracers have recently been introduced into the field, although the utility of the tracer and its relationship to other Alzheimer biomarkers are still unknown. Here we examined tau deposition in 41 cognitively normal and 11 cognitively impaired older adults using the radioactive tau ligand (18)F-AV-1451 (previously known as T807) who also underwent a lumbar puncture to assess cerebrospinal fluid levels of total tau (t-tau), phosphorylated tau181 (p-tau181) and amyloid-?42 Voxel-wise statistical analyses examined spatial patterns of tau deposition associated with cognitive impairment. We then related the amount of tau tracer uptake to levels of cerebrospinal fluid biomarkers. All analyses controlled for age and gender and, when appropriate, the time between imaging and lumbar puncture assessments. Symptomatic individuals (Clinical Dementia Rating > 0) demonstrated markedly increased levels of tau tracer uptake. This elevation was most prominent in the temporal lobe and temporoparietal junction, but extended more broadly into parietal and frontal cortices. In the entire cohort, there were significant relationships among all cerebrospinal fluid biomarkers and tracer uptake, notably for tau-related cerebrospinal fluid markers. After controlling for levels of amyloid-?42, the correlations with tau uptake were r = 0.490 (P < 0.001) for t-tau and r = 0.492 (P < 0.001) for p-tau181 Within the cognitively normal cohort, levels of amyloid-?42, but not t-tau or p-tau181, were associated with elevated tracer binding that was confined primarily to the medial temporal lobe and adjacent neocortical regions. AV-1451 tau binding in the medial temporal, parietal, and frontal cortices is correlated with tau-related cerebrospinal fluid measures. In preclinical Alzheimer's disease, there is focal tauopathy in the medial temporal lobes and adjacent cortices.

Project description:ImportanceFluid and imaging biomarkers of Alzheimer disease (AD) are often used interchangeably, but some biomarkers may reveal earlier stages of disease.ObjectiveTo characterize individuals with tau abnormality indicated by cerebrospinal fluid (CSF) assay or positron emission tomography (PET).Design, setting, and participantsBetween 2010 and 2019, 322 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent CSF and PET assessments of tau pathology. Data-driven, clinically relevant thresholds for CSF phosphorylated tau (P-tau) (≥26.64 pg/mL) and flortaucipir-PET meta-regions of interest (ROI) (standard uptake value ratio ≥1.37) indicated participants' tau status as CSF-/PET-, CSF+/PET-, CSF-/PET+, and CSF+/PET+. Of 1659 ADNI participants with a CSF or flortaucipir assessment, 588 had both measures (1071 were excluded). Among these, 266 were further excluded because they did not have flortaucipir and CSF testing within less than 25 months, leaving 322 for analysis. Of these, 213 were cognitively unimpaired (CU); 98 had mild cognitive impairment (MCI); and 11 had AD dementia.Main outcomes and measuresWe compared tau-positive vs tau-negative groups as indicated by either modality or demographic and clinical variables, amyloid β-PET burden, and flortaucipir-PET binding across Braak stage-related ROIs. We also compared 5-year rates of CSF P-tau accumulation and cognitive decline prior to flortaucipir-PET scanning.ResultsAmong the 322 study participants, 180 were women (56%), and the mean (SD) age was 73.08 (7.37) years. Two hundred ten participants were CSF-/PET- (65%); 63 were CSF+/PET- (19.5%); 15 were CSF-/PET+ (4.6%); and 34 were CSF+/PET+ (10.5%). Most CSF-/PET+ participants had measures near CSF or PET tau thresholds. The CSF+/PET- participants showed faster 5-year accrual of P-tau and increased flortaucipir-PET binding in early Braak ROIs but similar memory decline compared with CSF-/PET- participants. Tau-positive individuals by either measure showed increased amyloid β-PET burden. All CSF+/PET+ individuals were amyloid-positive, and 26 had MCI or AD dementia (76%). Compared with the CSF-/PET- group, CSF+/PET+ individuals had experienced faster 5-year accrual of CSF P-tau and decline in memory and executive function, resulting in reduced cognitive abilities at the time of flortaucipir-PET assessment.Conclusions and relevanceSuprathreshold CSF P-tau without flortaucipir-PET abnormality may indicate a stage of AD development characterized by early tau abnormality without measurable loss in cognitive performance. Persons with both tau CSF and PET abnormality appear to have reduced cognitive capacities resulting from faster antecedent cognitive decline. Elevation of CSF P-tau appears to precede flortaucipir-PET positivity in the progression of AD pathogenesis and related cognitive decline.

Dataset Information

Comparing positron emission tomography imaging and cerebrospinal fluid measurements of ?-amyloid.

Publications

Comparing positron emission tomography imaging and cerebrospinal fluid measurements of β-amyloid.

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