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Vascular risk and FDDNP-PET influence cognitive performance.

ABSTRACT: The relationship of cerebrovascular risk and Alzheimer's disease (AD) pathology to cognition in pre-dementia has been extensively investigated and is well-established. Cerebrovascular risk can be measured using a Framingham Stroke Risk Profile (FSRP) score, while positron emission tomography (PET) scans with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) measure AD neuropathology (i.e., amyloid-? plaques and tau tangles). Here we report results of 75 healthy non-demented subjects (mean age, 63 years) who underwent neuropsychological testing, physical assessments, and FDDNP-PET scans. Controlling for AD family history, education, and APOE4 status in a general linear model, higher FSRP risk and global FDDNP-PET binding were each associated with poorer cognitive functioning. The interaction of FSRP and global FDDNP-PET binding was not significant in the model, indicating that stroke risk and plaque and tangle burden each contributed to worse cognitive performance. Within our healthy volunteers, age, blood pressure, and antihypertensive medication use were vascular risks that contributed significantly to the above findings. These findings suggest that even mild cerebrovascular risk may influence the extent of cognitive dysfunction in pre-dementia, along with amyloid-? and tau burden.

SUBMITTER: Merrill DA

PROVIDER: S-EPMC3874398 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Vascular risk and FDDNP-PET influence cognitive performance.

Merrill David A DA Siddarth Prabha P Kepe Vladimir V Raja Pushpa V PV Saito Nathan N Ercoli Linda M LM Miller Karen J KJ Lavretsky Helen H Bookheimer Susan Y SY Barrio Jorge R JR Small Gary W GW

Journal of Alzheimer's disease : JAD 20130101 1

The relationship of cerebrovascular risk and Alzheimer's disease (AD) pathology to cognition in pre-dementia has been extensively investigated and is well-established. Cerebrovascular risk can be measured using a Framingham Stroke Risk Profile (FSRP) score, while positron emission tomography (PET) scans with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) measure AD neuropathology (i.e., amyloid-β plaques and tau tangles). Here we report results of 75 hea ...[more]

PMID: 23380994

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Project description:ObjectivesWhile global measures of cardiovascular (CV) risk are used to guide prevention and treatment decisions, these estimates fail to account for the considerable interindividual variability in pre-clinical risk status. This study investigated heterogeneity in CV risk factor profiles and its association with demographic, genetic, and cognitive variables.MethodsA latent profile analysis was applied to data from 727 recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Women were cognitively healthy, within three years of their last menstrual period, and free of current or past CV disease. Education level, apolipoprotein E ?4 allele (APOE4), ethnicity, and age were modeled as predictors of latent class membership. The association between class membership, characterizing CV risk profiles, and performance on five cognitive factors was examined. A supervised random forest algorithm with a 10-fold cross-validation estimator was used to test accuracy of CV risk classification.ResultsThe best-fitting model generated two distinct phenotypic classes of CV risk 62% of women were "low-risk" and 38% "high-risk". Women classified as low-risk outperformed high-risk women on language and mental flexibility tasks (p?=?0.008) and a global measure of cognition (p?=?0.029). Women with a college degree or above were more likely to be in the low-risk class (OR?=?1.595, p?=?0.044). Older age and a Hispanic ethnicity increased the probability of being at high-risk (OR?=?1.140, p?=?0.002; OR?=?2.622, p?=?0.012; respectively). The prevalence rate of APOE-?4 was higher in the high-risk class compared with rates in the low-risk class.ConclusionAmong recently menopausal women, significant heterogeneity in CV risk is associated with education level, age, ethnicity, and genetic indicators. The model-based latent classes were also associated with cognitive function. These differences may point to phenotypes for CV disease risk. Evaluating the evolution of phenotypes could in turn clarify preclinical disease, and screening and preventive strategies. ClinicalTrials.gov NCT00154180.

Project description:BackgroundThe translocase of outer mitochondrial membrane 40 (TOMM40), which lies in linkage disequilibrium with the apolipoprotein E (APOE) gene, has been implicated in Alzheimer's disease (AD). TOMM40 influences AD pathology through mitochondrial neurotoxicity, and the medial temporal lobe (MTL) is the most likely brain region for identifying early manifestations of AD-related morphology changes. While early reports indicated that the longer length poly-T allele of TOMM40 increases risk for AD, these findings have not been consistently replicated in further studies. We examined the effect of TOMM40 and APOE on regional brain positron emission tomography (PET) 2-(1-{6-[(2 [F18]fluoroethyl) (methyl) amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) binding values in MTL.MethodsA total of 73 non-demented older adults (42 females; mean age: 62.9(10.9) completed genotyping for both APOE and TOMM40 and received FDDNP-PET scans. For TOMM40, the lengths of the poly-T sequence were classified as short (14-20 repeats; S), long (21-29 repeats, L) or very long (>29 repeats, VL). Using general linear models, we examined medial temporal lobe FDDNP binding and cognitive functioning between TOMM40 and APOE-4 groups, with age, sex, and education as covariates.ResultsData from 30 individuals with APOE-4 and L TOMM40 poly-T length, 11 non E4 TOMM40 S/S, 14 non E4 TOMM40 S/VL and 13 non E4 TOMM40 VL/VL were analyzed. Medial temporal FDDNP binding differed significantly between TOMM40/APOE groups (F(3,62) = 3.3,p = .03). Participants with TOMM40 S/S exhibited significantly lower binding compared to TOMM40 S/VL and APOE-4 carriers. We did not find a significant relationship between TOMM40 poly-T lengths/APOE risk groups and cognitive functioning.ConclusionsThis is the first report to demonstrate a significant association between longer TOMM40 poly-T lengths and higher medial temporal plaque and tangle burden in non-demented older adults. Identifying biomarkers that are risk factors for AD will enhance our ability to identify subjects likely to benefit from novel AD treatments.

Project description:Background and purpose: The aggregation of vascular risk factors (VRFs) can aggravate cognitive impairment in stroke-free patients. Metabolites in serum and cerebrospinal fluid (CSF) may irreversibly reflect early functional deterioration. This study evaluated small-molecule metabolites (<1,000 Da) in the serum and CSF of patients with different degrees of cerebrovascular burden and investigated the correlation between metabolism and cognitive performance associated with VRFs. Methods: The subjects were divided into a low-risk group (10-year stroke risk ≤ 5%), a middle-risk group (10-year stroke risk >5% and <15%), and a high-risk group (10 years stroke risk ≥ 15%) according to the Framingham stroke risk profile (FSRP) score, which was used to quantify VRFs. We assess the cognitive function of the participants. We semiquantitatively quantified the small molecules using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The correlation between the small molecules and cognitive function, along with VRFs, was investigated to identify key small molecules and possible underlying metabolic pathways. Results: When the FSRP scores increased, the cognitive performances of the subjects decreased, specifically the performance regarding the tasks of immediate memory, delayed recall, and executive function. Seven metabolites (2-aminobutyric acid, Asp Asp Ser, Asp Thr Arg, Ile Cys Arg, 1-methyluric acid, 3-tert-butyladipic acid, and 5α-dihydrotestosterone glucuronide) in serum and three metabolites [Asp His, 13-HOTrE(r), and 2,5-di-tert-Butylhydroquinone] in CSF were significantly increased, and one metabolite (arachidonoyl PAF C-16) in serum was significantly decreased in high-risk group subjects. Among these metabolites, 1-methyluric acid, 3-tert-butyladipic, acid and Ile Cys Arg in serum and 13-HOTrE(r), 2,5-di-tert-butylhydroquinone, and Asp His in CSF were found to be negatively related with cognitive performance in the high-risk group. Arachidonoyl PAF C-16 in serum was found to be associated with better cognitive performance. Caffeine metabolism and the tricarboxylic acid cycle (TCA cycle) were identified as key pathways. Conclusions: 1-Methyluric acid, 3-tert-butyladipic acid, arachidonoyl PAF C-16, and Ile Cys Arg in serum and 13-HOTrE(r), 2,5-di-tert-butylhydroquinone, and Asp His in CSF were identified as potential biomarkers of vascular cognitive impairment (VCI) at the early stage. Caffeine metabolism and the TCA cycle may play important roles in the pathophysiology of VRF-associated cognitive impairment.

Project description:Head movement during a PET scan (especially a dynamic scan) can affect both the qualitative and the quantitative aspects of an image, making it difficult to accurately interpret the results. The primary objective of this study was to develop a retrospective image-based movement correction (MC) method and evaluate its implementation on dynamic 2-(1-{6-[(2-(18)F-fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ((18)F-FDDNP) PET images of cognitively intact controls and patients with Alzheimer's disease (AD).Dynamic (18)F-FDDNP PET images, used for in vivo imaging of beta-amyloid plaques and neurofibrillary tangles, were obtained from 12 AD patients and 9 age-matched controls. For each study, a transmission scan was first acquired for attenuation correction. An accurate retrospective MC method that corrected for transmission-emission and emission-emission misalignments was applied to all studies. No restriction was assumed for zero movement between the transmission scan and the first emission scan. Logan analysis, with the cerebellum as the reference region, was used to estimate various regional distribution volume ratio (DVR) values in the brain before and after MC. Discriminant analysis was used to build a predictive model for group membership, using data with and without MC.MC improved the image quality and quantitative values in (18)F-FDDNP PET images. In this subject population, no significant difference in DVR value was observed in the medial temporal (MTL) region of controls and patients with AD before MC. However, after MC, significant differences in DVR values in the frontal, parietal, posterior cingulate, MTL, lateral temporal (LTL), and global regions were seen between the 2 groups (P < 0.05). In controls and patients with AD, the variability of regional DVR values (as measured by the coefficient of variation) decreased on average by more than 18% after MC. Mean DVR separation between controls and patients with AD was higher in frontal, MTL, LTL, and global regions after MC. Group classification by discriminant analysis based on (18)F-FDDNP DVR values was markedly improved after MC.The streamlined and easy-to-use MC method presented in this work significantly improves the image quality and the measured tracer kinetics of (18)F-FDDNP PET images. The proposed MC method has the potential to be applied to PET studies on patients having other disorders (e.g., Down syndrome and Parkinson's disease) and to brain PET scans with other molecular imaging probes.

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Vascular risk and FDDNP-PET influence cognitive performance.

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Vascular risk and FDDNP-PET influence cognitive performance.

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