Cognitive reserve associated with FDG-PET in preclinical Alzheimer disease.
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ABSTRACT: Objective
To examine the effect of education (a surrogate measure of cognitive reserve) on FDG-PET brain metabolism in elderly cognitively healthy (HC) subjects with preclinical Alzheimer disease (AD).Methods
Fifty-two HC subjects (mean age 75 years) with FDG-PET and CSF measurement of Aβ1-42 were included from the prospective Alzheimer's Disease Neuroimaging Initiative biomarker study. HC subjects received a research classification of preclinical AD if CSF Aβ1-42 was <192 pg/mL (Aβ1-42 [+]) vs HC with normal Aβ (Aβ1-42 [-]). In regression analyses, we tested the interaction effect between education and CSF Aβ1-42 status (Aβ1-42 [+] vs Aβ1-42 [-]) on FDG-PET metabolism in regions of interest (ROIs) (posterior cingulate, angular gyrus, inferior/middle temporal gyrus) and the whole brain (voxel-based).Results
An interaction between education and CSF Aβ1-42 status was observed for FDG-PET in the posterior cingulate (p < 0.001) and angular gyrus ROIs (p = 0.03), but was not significant for the inferior/middle temporal gyrus ROI (p = 0.06), controlled for age, sex, and global cognitive ability (Alzheimer's Disease Assessment Scale-cognitive subscale). The interaction effect was such that higher education was associated with lower FDG-PET in the Aβ1-42 (+) group, but with higher FDG-PET in the Aβ1-42 (-) group. Voxel-based analysis showed that this interaction effect was primarily restricted to temporo-parietal and ventral prefrontal brain areas.Conclusions
Higher education was associated with lower FDG-PET in preclinical AD (Aβ1-42 [+]), suggesting that cognitive reserve had a compensatory function to sustain cognitive ability in presence of early AD pathology that alters FDG-PET metabolism.
SUBMITTER: Ewers M
PROVIDER: S-EPMC3691784 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and purposeThe hippocampus is a widely recognized area of early change in AD, yet voxelwise analyses of FDG-PET activity differences between AD and CN controls have consistently failed to identify hippocampal hypometabolism. In this article, we propose a high-dimensional PET-specific analysis framework to determine whether important hippocampal metabolic FDG-PET activity differences between patients with AD and CN subjects are embedded in the Jacobian information generated during spatial normalization.Materials and methodsResting FDG-PET data were obtained from 102 CN and 92 participants with AD from the ADNI data base. A PET-study-specific template was constructed using symmetric diffeomorphic registration. Spatially normalized raw FDG maps, Jacobian determinant maps, and modulated maps were generated for all subjects. Statistical parametric mapping and tensor-based morphometry were performed, comparing patients with AD with CN subjects.ResultsWhole-brain spatially normalized raw FDG maps demonstrated robust hypometabolism in cingulate gyrus and bilateral parietal areas. No hippocampal differences were present, except on ROI-based analyses with a hippocampal mask. Whole-brain modulated maps demonstrated robust bilateral hippocampal hypometabolism, and some hypometabolism in the posterior cingulate. Tensor-based morphometry demonstrated robust hippocampal differences only.ConclusionsThese results demonstrate that hippocampal metabolic differences are embedded in the Jacobian information from the spatial normalization procedure. We introduce a voxelwise PET-specific analysis framework based on the use of a PET-population-specific template, high-dimensional symmetric diffeomorphic normalization, and the use of Jacobian information, which can provide substantially increased statistical power and an order of magnitude decrease in imaging costs.
| S-EPMC7964612 | biostudies-literature
Project description:This study examined whether cognitive reserve (CR) alters the relationship between magnetic resonance imaging (MRI) measures of cortical thickness and risk of progression from normal cognition to the onset of clinical symptoms associated with mild cognitive impairment (MCI). The analyses included 232 participants from the BIOCARD study. Participants were cognitively normal and largely middle aged (M age = 56.5) at their baseline MRI scan. After an average of 11.8 years of longitudinal follow-up, 48 have developed clinical symptoms of MCI or dementia (M time from baseline to clinical symptom onset = 7.0 years). Mean thickness was measured over eight 'AD vulnerable' cortical regions, and cognitive reserve was indexed by a composite score consisting of years of education, reading, and vocabulary measures. Using Cox regression models, CR and cortical thickness were each independently associated with risk of clinical symptom onset within 7 years of baseline, suggesting that the neuronal injury occurring proximal to symptom onset has a direct association with clinical outcomes, regardless of CR. In contrast, there was a significant interaction between CR and mean cortical thickness for risk of progression more than 7 years from baseline, suggesting that individuals with high CR are better able to compensate for cortical thinning that is beginning to occur at the very earliest phase of AD.
| S-EPMC5743433 | biostudies-literature
Project description:Clinical trials testing treatments for Alzheimer disease (AD) are increasingly focused on cognitively normal individuals in the preclinical phase of the disease. To optimize observing a treatment effect, such trials need to enroll cognitively normal individuals likely to show cognitive decline over the duration of the trial.To identify which group of cognitively normal individuals shows the greatest cognitive decline over time based on their cerebrospinal fluid biomarker profile.In this cohort study, cognitively normal participants were classified into 1 of the following 4 hypothetical preclinical AD groups using baseline cerebrospinal fluid levels of A? and tau or A? and phosphorylated tau (p-tau): stage 0 (high A? and low tau), stage 1 (low A? and low tau), stage 2 (low A? and high tau), and suspected non-AD pathology (SNAP) (high A? and high tau). The data presented herein were collected between August 1995 and August 2014.An a priori cognitive composite score based on the following 4 tests previously shown to predict progression from normal cognition to symptom onset of mild cognitive impairment or dementia: Paired Associates immediate recall, Logical Memory delayed recall, Boston Naming, and Digit-Symbol Substitution. Linear mixed-effects models were used to compare the cognitive composite scores across the 4 groups over time, adjusting for baseline age, sex, education, and their interactions with time.Two hundred twenty-two cognitively normal participants were included in the analyses (mean follow-up, 11.0 years [range, 0-18.3 years] and mean baseline age, 56.9 years [range, 22.1-85.8 years]). Of these, 102 were stage 0, 46 were stage 1, 28 were stage 2, and 46 were SNAP. Individuals in stage 2 (low A? and high tau [or p-tau]) had lower baseline cognitive scores and a greater decline in the cognitive composite score relative to the other 3 groups (????-0.06 for all and P???.001 for the rate of decline for all). Individuals in stage 0, stage 1, and SNAP did not differ from one another in cognitive performance at baseline or over time (11.0 years) and showed practice-related improvement in performance. The APOE ?4 genotype was not associated with baseline cognitive composite score or the rate of change in the cognitive composite score.These results suggest that, to optimize observing a treatment effect, clinical trials enrolling cognitively normal individuals should selectively recruit participants with abnormal levels of both amyloid and tau (ie, stage 2) because this group would be expected to show the greatest cognitive decline over time if untreated.
| S-EPMC5173327 | biostudies-literature
Project description:OBJECTIVE:To investigate the relationship between cognitive reserve (CR) and clinical progression across the Alzheimer disease (AD) spectrum. METHODS:We selected 839 β-amyloid (Aβ)-positive participants with normal cognition (NC, n = 175), mild cognitive impairment (MCI, n = 437), or AD dementia (n = 227) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). CR was quantified using standardized residuals (W scores) from a (covariate-adjusted) linear regression with global cognition (13-item Alzheimer's Disease Assessment Scale-cognitive subscale) as an independent variable of interest, and either gray matter volumes or white matter hyperintensity volume as dependent variables. These W scores, reflecting whether an individual's degree of cerebral damage is lower or higher than clinically expected, were tested as predictors of diagnostic conversion (i.e., NC to MCI/AD dementia, or MCI to AD dementia) and longitudinal changes in memory (ADNI-MEM) and executive functions (ADNI-EF). RESULTS:The median follow-up period was 24 months (interquartile range 6-42). Corrected for age, sex, APOE4 status, and baseline cerebral damage, higher gray matter volume-based W scores (i.e., greater CR) were associated with a lower diagnostic conversion risk (hazard ratio [HR] 0.22, p < 0.001) and slower decline in memory (β = 0.48, p < 0.001) and executive function (β = 0.67, p < 0.001). Stratified by disease stage, we found similar results for NC (diagnostic conversion: HR 0.30, p = 0.038; ADNI-MEM: β = 0.52, p = 0.028; ADNI-EF: β = 0.42, p = 0.077) and MCI (diagnostic conversion: HR 0.21, p < 0.001; ADNI-MEM: β = 0.43, p = 0.003; ADNI-EF: β = 0.59, p < 0.001), but opposite findings (i.e., more rapid decline) for AD dementia (ADNI-MEM: β = -0.91, p = 0.002; ADNI-EF: β = -0.77, p = 0.081). CONCLUSIONS:Among Aβ-positive individuals, greater CR related to attenuated clinical progression in predementia stages of AD, but accelerated cognitive decline after the onset of dementia.
| S-EPMC6669930 | biostudies-literature
Project description:ObjectiveTo test whether higher global functional connectivity of the left frontal cortex (LFC) in Alzheimer disease (AD) is associated with more years of education (a proxy of cognitive reserve [CR]) and mitigates the association between AD-related fluorodeoxyglucose (FDG)-PET hypometabolism and episodic memory.MethodsForty-four amyloid-PET-positive patients with amnestic mild cognitive impairment (MCI-Aβ+) and 24 amyloid-PET-negative healthy controls (HC) were included. Voxel-based linear regression analyses were used to test the association between years of education and FDG-PET in MCI-Aβ+, controlled for episodic memory performance. Global LFC (gLFC) connectivity was computed through seed-based resting-state fMRI correlations between the LFC (seed) and each voxel in the gray matter. In linear regression analyses, education as a predictor of gLFC connectivity and the interaction of gLFC connectivity × FDG-PET hypometabolism on episodic memory were tested.ResultsFDG-PET metabolism in the precuneus was reduced in MCI-Aβ+ compared to HC (p = 0.028), with stronger reductions observed in MCI-Aβ+ with more years of education (p = 0.006). In MCI-Aβ+, higher gLFC connectivity was associated with more years of education (p = 0.021). At higher levels of gLFC connectivity, the association between precuneus FDG-PET hypometabolism and lower memory performance was attenuated (p = 0.027).ConclusionsHigher gLFC connectivity is a functional substrate of CR that helps to maintain episodic memory relatively well in the face of emerging FDG-PET hypometabolism in early-stage AD.
| S-EPMC5384837 | biostudies-literature
Project description:PurposeTo quantify the effect sizes of regional metabolic and morphometric measures in patients with preclinical and mild Alzheimer disease (AD) to aid in the identification of noninvasive biomarkers for the early detection of AD.Materials and methodsThe study was conducted with institutional review board approval and in compliance with HIPAA regulations. Written informed consent was obtained from each participant or participant's legal guardian. Fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and magnetic resonance (MR) imaging data were analyzed from 80 healthy control (HC) subjects, 68 individuals with AD, and 156 with amnestic mild cognitive impairment (MCI), 69 of whom had single-domain amnestic MCI. Regions of interest (ROIs) were derived after coregistering FDG PET and MR images by using high-throughput, subject-specific procedures. The Cohen d effect sizes were calculated for 42 predefined ROIs across the brain. Statistical comparison of the largest overall effect sizes for MR imaging and PET was performed. Metabolic effect sizes were determined with and without accounting for regional atrophy. Discriminative accuracy of ROIs showing the largest effect sizes were compared by calculating receiver operating characteristic curves.ResultsFor all disease groups, the hippocampus showed the largest morphometric effect size and the entorhinal cortex showed the largest metabolic effect size. In mild AD, the Cohen d effect size for hippocampal volume (1.92) was significantly larger (P < .05) than that for entorhinal metabolism (1.43). Regression of regional atrophy substantially reduced most metabolic effects. For all group comparisons, the areas under the receiver operating characteristic curves were significantly larger for hippocampal volume than for entorhinal metabolism.ConclusionThe current results show no evidence that FDG PET is more sensitive than MR imaging to the degeneration occurring in preclinical and mild AD, suggesting that an MR imaging finding may be a more practical clinical biomarker for early detection of AD.
| S-EPMC2923729 | biostudies-literature
Project description:There is strong epidemiologic evidence to suggest that older adults who maintain an active lifestyle in terms of social, mental, and physical engagement are protected to some degree against the onset of dementia. Such factors are said to contribute to cognitive reserve, which acts to compensate for the accumulation of amyloid and other brain pathologies. We present evidence that lifelong bilingualism is a further factor contributing to cognitive reserve.Data were collected from 211 consecutive patients diagnosed with probable Alzheimer disease (AD). Patients' age at onset of cognitive impairment was recorded, as was information on occupational history, education, and language history, including fluency in English and any other languages. Following this procedure, 102 patients were classified as bilingual and 109 as monolingual.We found that the bilingual patients had been diagnosed 4.3 years later and had reported the onset of symptoms 5.1 years later than the monolingual patients. The groups were equivalent on measures of cognitive and occupational level, there was no apparent effect of immigration status, and the monolingual patients had received more formal education. There were no gender differences.The present data confirm results from an earlier study, and thus we conclude that lifelong bilingualism confers protection against the onset of AD. The effect does not appear to be attributable to such possible confounding factors as education, occupational status, or immigration. Bilingualism thus appears to contribute to cognitive reserve, which acts to compensate for the effects of accumulated neuropathology.
| S-EPMC3033609 | biostudies-other
Project description:ObjectiveTo examine the utility of resting-state functional connectivity MRI (rs-fcMRI) measurements of network integrity as a predictor of future cognitive decline in preclinical Alzheimer disease (AD).MethodsA total of 237 clinically normal older adults (aged 63-90 years, Clinical Dementia Rating 0) underwent baseline β-amyloid (Aβ) imaging with Pittsburgh compound B PET and structural and rs-fcMRI. We identified 7 networks for analysis, including 4 cognitive networks (default, salience, dorsal attention, and frontoparietal control) and 3 noncognitive networks (primary visual, extrastriate visual, motor). Using linear and curvilinear mixed models, we used baseline connectivity in these networks to predict longitudinal changes in preclinical Alzheimer cognitive composite (PACC) performance, both alone and interacting with Aβ burden. Median neuropsychological follow-up was 3 years.ResultsBaseline connectivity in the default, salience, and control networks predicted longitudinal PACC decline, unlike connectivity in the dorsal attention and all noncognitive networks. Default, salience, and control network connectivity was also synergistic with Aβ burden in predicting decline, with combined higher Aβ and lower connectivity predicting the steepest curvilinear decline in PACC performance.ConclusionsIn clinically normal older adults, lower functional connectivity predicted more rapid decline in PACC scores over time, particularly when coupled with increased Aβ burden. Among examined networks, default, salience, and control networks were the strongest predictors of rate of change in PACC scores, with the inflection point of greatest decline beyond the fourth year of follow-up. These results suggest that rs-fcMRI may be a useful predictor of early, AD-related cognitive decline in clinical research settings.
| S-EPMC5496516 | biostudies-literature
Project description:ObjectiveWe compared the ability of arterial spin labeling (ASL), an MRI method that measures cerebral blood flow (CBF), to that of FDG-PET in distinguishing patients with Alzheimer disease (AD) from healthy, age-matched controls.MethodsFifteen patients with AD (mean age 72 ± 6 years, Mini-Mental State Examination score [MMSE] 20 ± 6) and 19 age-matched controls (mean age 68 ± 6 years, MMSE 29 ± 1) underwent structural MRI. Participants were injected with 5 mCi of FDG during pseudocontinuous ASL scan, which was followed by PET scanning. Statistical parametric mapping and regions of interest (ROI) analysis were used to compare the ability of the 2 modalities in distinguishing patients from controls. Similarity between the 2 modalities was further assessed with linear correlation maps of CBF and metabolism to neuropsychological test scores.ResultsGood agreement between hypoperfusion and hypometabolism patterns was observed, with overlap primarily in bilateral angular gyri and posterior cingulate. ROI results showed similar scales of functional deficit between patients and controls in both modalities. Both ASL and FDG-PET were able to distinguish neural networks associated with different neuropsychological tests with good overlap between modalities.ConclusionsOur voxel-wise results indicated that ASL-MRI provides largely overlapping information with FDG-PET. ROI analysis demonstrated that both modalities detected similar degrees of functional deficits in affected areas. Given its ease of acquisition and noninvasiveness, ASL-MRI may be an appealing alternative for AD studies.
| S-EPMC3235355 | biostudies-literature
Project description:ImportanceAlzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression.ObjectiveTo evaluate combinations of different plasma biomarkers for predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) individuals.Design, setting, and participantsThis prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention [WRAP]), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain Aβ pathology defined by cerebrospinal fluid (CSF) Aβ42/40 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible Aβ-positive and Aβ-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study; of those, 171 Aβ-positive participants were included in the main analyses.ExposuresBaseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma; CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort.Main outcomes and measuresThe primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination [MMSE] and the modified Preclinical Alzheimer Cognitive Composite [mPACC]) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E ε4 allele status, and baseline cognition. Multivariable models were compared based on model R2 coefficients and corrected Akaike information criterion.ResultsAmong 171 Aβ-positive CU participants included in the main analyses, 119 (mean [SD] age, 73.0 [5.4] years; 60.5% female) were from the BioFINDER-1 study, and 52 (mean [SD] age, 64.4 [4.6] years; 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R2 = 0.41) and the MMSE (model R2 = 0.34) and was superior to the covariates-only models (mPACC: R2 = 0.23; MMSE: R2 = 0.04; P < .001 for both comparisons). Results were validated in the WRAP cohort; for example, plasma P-tau217 was associated with mPACC slopes (R2 = 0.13 vs 0.01 in the covariates-only model; P = .01) and MMSE slopes (R2 = 0.29 vs 0.24 in the covariates-only model; P = .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time.Conclusions and relevanceIn this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.
| S-EPMC10087054 | biostudies-literature