Dataset Information

Modifiable Risk Factors and Brain Positron Emission Tomography Measures of Amyloid and Tau in Nondemented Adults with Memory Complaints.

ABSTRACT: OBJECTIVE:Exercise and diet impact body composition, but their age-related brain effects are unclear at the molecular imaging level. To address these issues, the authors determined whether body mass index (BMI), physical activity, and diet relate to brain positron emission tomography (PET) of amyloid plaques and tau tangles using 2-(1-(6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile (FDDNP). METHODS:Volunteers (N?=?44; mean age: 62.6?±?10.7 years) with subjective memory impairment (N?=?24) or mild cognitive impairment (MCI; N?=?20) were recruited by soliciting for memory complaints. Levels of physical activity and extent of following a Mediterranean-type diet were self-reported. FDDNP-PET scans assessed plaque/tangle binding in Alzheimer disease-associated regions (frontal, parietal, medial and lateral temporal, posterior cingulate). Mixed models controlling for known covariates examined BMI, physical activity, and diet in relation to FDDNP-PET. RESULTS:MCI subjects with above normal BMI (>25) had higher FDDNP-PET binding compared with those with normal BMI (1.11(0.03) versus 1.08(0.03), ES?=?1.04, t(35)?=?3.3, p?=?0.002). Greater physical activity was associated with lower FDDNP-PET binding in MCI subjects (1.07(0.03) versus 1.11(0.03), ES?=?1.13, t(35)?=?-3.1, p?=?0.004) but not in subjects with subjective memory impairment (1.07(0.03) versus 1.07(0.03), ES?=?0.02, t(35)?=?-0.1, p?=?0.9). Healthier diet related to lower FDDNP-PET binding, regardless of cognitive status (1.07(0.03) versus 1.09(0.02), ES?=?0.72, t(35)?=?-2.1, p?=?0.04). CONCLUSION:These preliminary findings are consistent with a relationship between risk modifiersand brain plaque/tangle deposition in nondemented individuals and supports maintenance of normal body weight, regular physical activity, and healthy diet to protect the brain during aging. (clinicaltrials.gov; NCT00355498).

SUBMITTER: Merrill DA

PROVIDER: S-EPMC5003686 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Modifiable Risk Factors and Brain Positron Emission Tomography Measures of Amyloid and Tau in Nondemented Adults with Memory Complaints.

Merrill David A DA Siddarth Prabha P Raji Cyrus A CA Emerson Natacha D ND Rueda Florangel F Ercoli Linda M LM Miller Karen J KJ Lavretsky Helen H Harris Laurel M LM Burggren Alison C AC Bookheimer Susan Y SY Barrio Jorge R JR Small Gary W GW

The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 20160513 9

<h4>Objective</h4>Exercise and diet impact body composition, but their age-related brain effects are unclear at the molecular imaging level. To address these issues, the authors determined whether body mass index (BMI), physical activity, and diet relate to brain positron emission tomography (PET) of amyloid plaques and tau tangles using 2-(1-(6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile (FDDNP).<h4>Methods</h4>Volunteers (N = 44; mean age: 62.6 ± 10.7 years) with s ...[more]

PMID: 27421618

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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.

Project description:ImportanceAn increased tau positron emission tomography (PET) signal in the medial temporal lobe (MTL) has been observed in older individuals in the absence of amyloid-β (Aβ) pathology. Little is known about the longitudinal course of this condition, and its association with Alzheimer disease (AD) remains unclear.ObjectiveTo study the pathologic and clinical course of older individuals with PET-evidenced MTL tau deposition (TMTL+) in the absence of Aβ pathology (A-), and the association of this condition with the AD continuum.Design, setting, and participantsA multicentric, observational, longitudinal cohort study was conducted using pooled data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and the AVID-A05 study, collected between July 2, 2015, and August 23, 2021. Participants in the ADNI, HABS, and AVID-A05 studies (N = 1093) with varying degrees of cognitive performance were deemed eligible if they had available tau PET, Aβ PET, and magnetic resonance imaging scans at baseline. Of these, 128 participants did not meet inclusion criteria based on Aβ PET and tau PET biomarker profiles (A+ TMTL-).ExposuresTau and Aβ PET, magnetic resonance imaging, cerebrospinal fluid biomarkers, and cognitive assessments.Main outcomes and measuresCross-sectional and longitudinal measures for tau and Aβ PET, cortical atrophy, cognitive scores, and core AD cerebrospinal fluid biomarkers (Aβ42/40 and tau phosphorylated at threonine 181 p-tau181 available in a subset).ResultsAmong the 965 individuals included in the study, 503 were women (52.1%) and the mean (SD) age was 73.9 (8.1) years. A total of 51% of A- individuals and 78% of A+ participants had increased tau PET signal in the entorhinal cortex (TMTL+) compared with healthy younger (aged <39 years) controls. Compared with A- TMTL-, A- TMTL+ participants showed statistically significant, albeit moderate, longitudinal (mean [SD], 1.83 [0.84] years) tau PET increases that were largely limited to the temporal lobe, whereas those with A+ TMTL+ showed faster and more cortically widespread tau PET increases. In contrast to participants with A+ TMTL+, those with A- TMTL+ did not show any noticeable Aβ accumulation over follow-up (mean [SD], 2.36 [0.76] years). Complementary cerebrospinal fluid analysis confirmed longitudinal p-tau181 increases in A- TMTL+ in the absence of increased Aβ accumulation. Participants with A- TMTL+ had accelerated MTL atrophy, whereas those with A+ TMTL+ showed accelerated atrophy in widespread temporoparietal brain regions. Increased MTL tau PET uptake in A- individuals was associated with cognitive decline, but at a significantly slower rate compared with A+ TMTL+.Conclusions and relevanceIn this study, individuals with A- TMTL+ exhibited progressive tau accumulation and neurodegeneration, but these processes were comparably slow, remained largely restricted to the MTL, were associated with only subtle changes in global cognitive performance, and were not accompanied by detectable accumulation of Aβ biomarkers. These data suggest that individuals with A- TMTL+ are not on a pathologic trajectory toward AD.

Project description:ImportanceCerebrospinal fluid phosphorylated tau (p-tau) 181, p-tau217, and p-tau231 are associated with neuropathological outcomes, but a comparison of these p-tau isoforms in blood samples is needed.ObjectiveTo conduct a head-to-head comparison of plasma p-tau181 and p-tau231 measured on the single-molecule array (Simoa) platform and p-tau181 and p-tau217 measured on the Meso Scale Discovery (MSD) platform on amyloid and tau positron emission tomography (PET) measures, neurodegeneration, vascular pathology, and cognitive outcomes.Design, setting, and participantsThis study included data from the Mayo Clinic Study on Aging collected from March 1, 2015, to September 30, 2017, and analyzed between December 15, 2020, and May 17, 2021. Associations between the 4 plasma p-tau measures and dichotomous amyloid PET, metaregion of interest tau PET, and entorhinal cortex tau PET were analyzed using logistic regression models; the predictive accuracy was summarized using area under the receiver operating characteristic curve (AUROC) statistic. Of 1329 participants without dementia and with p-tau181 and p-tau217 on MSD, 200 participants with plasma p-tau181 and p-tau231 on Simoa and magnetic resonance imaging and amyloid and tau PET data at the same study visit were eligible.Main outcomes and measuresPrimary outcomes included amyloid (greater than 1.48 standardized uptake value ratio) and tau PET, white matter hyperintensities, white matter microstructural integrity (fractional anisotropy genu of corpus callosum and hippocampal cingulum bundle), and cognition.ResultsOf 200 included participants, 101 (50.5%) were male, and the median (interquartile range [IQR]) age was 79.5 (71.1-84.1) years. A total of 177 were cognitively unimpaired (CU) and 23 had mild cognitive impairment. Compared with amyloid-negative CU participants, among amyloid-positive CU participants, the median (IQR) Simoa p-tau181 measure was 49% higher (2.58 [2.00-3.72] vs 1.73 [1.45-2.13] pg/mL), MSD p-tau181 measure was 53% higher (1.22 [0.91-1.56] vs 0.80 [0.66-0.97] pg/mL), MSD p-tau217 measure was 77% higher (0.23 [0.17-0.34] vs 0.13 [0.09-0.18] pg/mL), and Simoa p-tau231 measure was 49% higher (20.21 [15.60-25.41] vs 14.27 [11.27-18.10] pg/mL). There were no differences between the p-tau species for amyloid PET and tau PET metaregions of interest. However, among CU participants, both MSD p-tau181 and MSD p-tau217 more accurately predicted abnormal entorhinal cortex tau PET than Simoa p-tau181 (MSD p-tau181: AUROC, 0.80 vs 0.70; P = .046; MSD p-tau217: AUROC, 0.81 vs 0.70; P = .04). MSD p-tau181 and p-tau217 and Simoa p-tau181, but not p-tau231, were associated with greater white matter hyperintensity volume and lower white matter microstructural integrity.Conclusions and relevanceIn this largely presymptomatic population, these results suggest subtle differences across plasma p-tau species and platforms for the prediction of amyloid and tau PET and magnetic resonance imaging measures of cerebrovascular and Alzheimer-related pathology.

Project description:Alzheimer's disease (AD), the most common cause of dementia, has limited treatment options. Emerging disease modifying therapies are targeted at clearing amyloid-β (Aβ) aggregates and slowing the rate of amyloid deposition. However, amyloid burden is not routinely evaluated quantitatively for purposes of disease progression and treatment response assessment. Statistical Parametric Mapping (SPM) is a technique comparing single-subject Positron Emission Tomography (PET) to a healthy cohort that may improve quantification of amyloid burden and diagnostic performance. While primarily used in 2-[18F]-fluoro-2-deoxy-D-glucose (FDG)-PET, SPM's utility in amyloid PET for AD diagnosis is less established and uncertainty remains regarding optimal normal database construction. Using commercially available SPM software, we created a database of 34 non-APOE ε4 carriers with normal cognitive testing (MMSE > 25) and negative cerebrospinal fluid (CSF) AD biomarkers. We compared this database to 115 cognitively normal subjects with variable AD risk factors. We hypothesized that SPM based on our database would identify more positive scans in the test cohort than the qualitatively rated [11C]-PiB PET (QR-PiB), that SPM-based interpretation would correlate better with CSF Aβ42 levels than QR-PiB, and that regional z-scores of specific brain regions known to be involved early in AD would be predictive of CSF Aβ42 levels. Fisher's exact test and the kappa coefficient assessed the agreement between SPM, QR-PiB PET, and CSF biomarkers. Logistic regression determined if the regional z-scores predicted CSF Aβ42 levels. An optimal z-score cutoff was calculated using Youden's index. We found SPM identified more positive scans than QR-PiB PET (19.1 vs. 9.6%) and that SPM correlated more closely with CSF Aβ42 levels than QR-PiB PET (kappa 0.13 vs. 0.06) indicating that SPM may have higher sensitivity than standard QR-PiB PET images. Regional analysis demonstrated the z-scores of the precuneus, anterior cingulate and posterior cingulate were predictive of CSF Aβ42 levels [OR (95% CI) 2.4 (1.1, 5.1) p = 0.024; 1.8 (1.1, 2.8) p = 0.020; 1.6 (1.1, 2.5) p = 0.026]. This study demonstrates the utility of using SPM with a "true normal" database and suggests that SPM enhances diagnostic performance in AD in the clinical setting through its quantitative approach, which will be increasingly important with future disease-modifying therapies.

Dataset Information

Modifiable Risk Factors and Brain Positron Emission Tomography Measures of Amyloid and Tau in Nondemented Adults with Memory Complaints.

Publications

Modifiable Risk Factors and Brain Positron Emission Tomography Measures of Amyloid and Tau in Nondemented Adults with Memory Complaints.

Similar Datasets

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