Faculty Bibliography
Searched for:
person:deleom01
Total Results:
414
Alzheimer's disease markers, hypertension, and gray matter damage in normal elderly
It is not well known whether Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers are associated with brain damage in cognitively normal elderly. The combined influence of CSF biomarkers and hypertension (HTN) on the gray matter (GM) is also not well described. One hundred fifteen cognitively healthy subjects (mean age 62.6 +/- 9.5%, 62% women) received clinical assessment, a high resolution magnetic resonance imaging (MRI), and a lumbar puncture. The CSF levels of total tau (t-tau), hyperphosphorylated tau (p-tau(231)), amyloid beta (Abeta42/Abeta40), p-tau(231)/Abeta42, and t-tau/Abeta42 were dichotomized as 'high' and 'low' based on accepted cut off values. Statistical parametric mapping was used to examine MRI scans for regional GM density, studied as a function of the CSF markers, HTN, and combination of both. Global and medial temporal lobe (MTL) GM was also assessed. Voxel based morphometry revealed that higher t-tau was associated with lower GM density in the precunei. Subjects with higher p-tau(231) and p-tau(231)/Abeta42 had less GM in temporal lobes. Low Abeta42/Abeta40 was related to less GM in the thalami, caudate, and midbrain. Subjects with hypertension showed more GM atrophy in the cerebellum, occipital, and frontal regions. Simultaneous presence of elevated CSF AD biomarkers and HTN was associated with more GM atrophy than either marker individually, but no interaction effects were identified. In conclusion, in normal elderly CSF tau markers were associated predominantly with lower GM estimates in structures typically affected early in the AD process. In this presymptomatic stage when no cognitive impairment is present, AD biomarkers and HTN have additive effects on gray matter damage
PMCID:3179821
PMID: 21530003
ISSN: 1558-1497
CID: 140516
Alternative normalization methods demonstrate widespread cortical hypometabolism in untreated de novo Parkinson's disease
AIM: Previous positron emission tomography (PET) [18F]fluorodeoxyglucose ([18F]FDG) studies in Parkinson's disease (PD) demonstrated that moderate to late stage patients display widespread cortical hypometabolism, whereas early stage PD patients exhibit little or no cortical changes. However, recent studies suggested that conventional data normalization procedures may not always be valid, and demonstrated that alternative normalization strategies better allow detection of low magnitude changes. We hypothesized that these alternative normalization procedures would disclose more widespread metabolic alterations in de novo PD. METHODS: [18F]FDG PET scans of 26 untreated de novo PD patients (Hoehn & Yahr stage I-II) and 21 age-matched controls were compared using voxel-based analysis. Normalization was performed using gray matter (GM), white matter (WM) reference regions and Yakushev normalization. RESULTS: Compared to GM normalization, WM and Yakushev normalization procedures disclosed much larger cortical regions of relative hypometabolism in the PD group with extensive involvement of frontal and parieto-temporal-occipital cortices, and several subcortical structures. Furthermore, in the WM and Yakushev normalized analyses, stage II patients displayed more prominent cortical hypometabolism than did stage I patients. CONCLUSION: The use of alternative normalization procedures, other than GM, suggests that much more extensive cortical hypometabolism is present in untreated de novo PD patients than hitherto reported. The finding may have implications for our understanding of the basic pathophysiology of early-stage PD.
PMCID:3846292
PMID: 22695340
ISSN: 1824-4785
CID: 177232
Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2012:109(10):3985-90.DOI: 10.1073/pnas.1105829109
Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans
Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 x 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 x 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5' UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.
PMCID:3309762
PMID: 22343285
ISSN: 0027-8424
CID: 179987
Ordering of Alzheimer disease biomarkers
PMID: 22410455
ISSN: 0003-9942
CID: 161188
Surgery and Brain Atrophy in Cognitively Normal Elderly Subjects and Subjects Diagnosed with Mild Cognitive Impairment
BACKGROUND:: Structural magnetic resonance imaging is used to longitudinally monitor the progression of Alzheimer disease from its presymptomatic to symptomatic phases. Using magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative, we tested the hypothesis that surgery would impact brain parameters associated with progression of dementia. METHODS:: Brain images from the neuroimaging initiative database were used to study normal volunteer subjects and patients with mild cognitive impairment for the age group 55 to 90 inclusive. We compared changes in regional brain anatomy for three visits that defined two intervisit intervals for a surgical cohort (n = 41) and a propensity matched nonsurgical control cohort (n = 123). The first interval for the surgical cohort contained the surgical date. Regional brain volumes were determined with Freesurfer and quantitatively described with J-image software (University of California at San Francisco, San Francisco, California). Statistical analysis used Repeated Measures ANCOVA (SPSS, v.18.0; Chicago, IL). RESULTS:: We found that surgical patients, during the first follow-up interval (5-9 months), but not subsequently, had increased rates of atrophy for cortical gray matter and hippocampus, and lateral ventricle enlargement, as compared with nonsurgical controls. A composite score of five cognitive tests during this interval showed reduced performance for surgical patients with mild cognitive impairment. CONCLUSIONS:: Elderly subjects after surgery experienced an increased rate of brain atrophy during the initial evaluation interval, a time associated with enhanced risk for postoperative cognitive dysfunction. Although there was no difference in atrophy rate by diagnosis, subjects with mild cognitive impairment suffered greater subsequent cognitive effects.
PMCID:3418798
PMID: 22293721
ISSN: 0003-3022
CID: 161579
Maternal age affects brain metabolism in adult children of mothers affected by Alzheimer's disease
Cognitively normal (NL) individuals with a maternal history of late-onset Alzheimer's disease (MH) show reduced brain glucose metabolism on FDG-PET as compared to those with a paternal history (PH) and those with negative family history (NH) of Alzheimer's disease (AD). This FDG-PET study investigates whether metabolic deficits in NL MH are associated with advancing maternal age at birth. Ninety-six NL individuals with FDG-PET were examined, including 36 MH, 24 PH, and 36 NH. Regional-to-whole brain gray matter standardized FDG uptake value ratios were examined for associations with parental age across groups using automated regions-of-interest and statistical parametric mapping. Groups were comparable for clinical and neuropsychological measures. Brain metabolism in AD-vulnerable regions was lower in MH compared to NH and PH, and negatively correlated with maternal age at birth only in MH. There were no associations between paternal age and metabolism in any group. Evidence for a maternally inherited, maternal age-related mechanism provides further insight on risk factors and genetic transmission in late-onset AD
PMCID:3155000
PMID: 21514691
ISSN: 1558-1497
CID: 140517
Age and diagnostic performance of Alzheimer disease CSF biomarkers
OBJECTIVES: Core CSF changes in Alzheimer disease (AD) are decreased amyloid beta(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly. METHODS: We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43-89 years) and 304 controls (67, 44-91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43-89 years) followed for at least 2 years, or until dementia diagnosis. RESULTS: The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages. CONCLUSION: Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.
PMCID:3280049
PMID: 22302554
ISSN: 0028-3878
CID: 160262
Postoperative Cognitive Decline in the Elderly: Cognitive Impairment vs. Normals [Meeting Abstract]
ISI:000303574200082
ISSN: 1385-4046
CID: 950032
7 tesla mr susceptibility-contrast microscopy imaging of amyloid pathologyand the hippocampus in Alzheimer's disease [Meeting Abstract]
Background: Due to well-known markedly increased susceptibility contrast at ultra-high-field MR, this work is using 7T MR susceptibiltyweighted imaging (SWI) to better identify the histopathologic correlate of amyloid plaques containing iron and otherwise invisible subhippocampal structures of human post-mortem brain in patients with Alzheimer's disease. Methods: Post-mortem brain specimens of the frontal lobe and hippocampus were obtained from 8 patients (mean age 71.266.2 years) with clinically diagnosed AD and 6 age-matched healthy controls (72.4 66.6 years) without AD. Coronal 1w3 cm thick brain slices were preserved and fixed in 2% agar or formalin for this study. Imaging was performed on a 7.0T MR. A 24- element phased array head coil was used. High resolution 3D SWI was obtained with isotropic voxel size 150w320I=m. For imaging optimization to better visualize amyloid plaques, we varied TR, TE, bandwidth and flip angle from 30-100ms, 12-36ms, 60-140Hz/pixel and 10-40-; respectively. Results: Compared to controls, 7T SWI revealed a largely increased number of hypointense foci inADbrain samples along the cortical mantle of the frontal and entorhinal cortex due to enhanced susceptibility effects and superb signal. Figure 1 shows amyloid plaques identified with histologic slice (A) and in post-processed SWI image of the frontal cortex of an AD patient (B) as compared to a healthy control (C). The average phase value in the cortex region of AD data (2296 6 72) is significantly higher than that of control data (2032 6 64), which indicates higher iron amount in AD samples. In addition, 7T SWI also provides high resolution images for subregional hippocampal structures including CA1 CA2 CA3 subiculum, and dentate gyrus with significant atrophy of these structures in AD patients. Conclusions: Our findings suggest that SWI with optimization at ultra-high-field strength MR (i.e. 7T) has exhibited the capability to detect diminutive susceptibility contrast associated with iron deposition and otherwise invisible fine hippocampal structures with near histopathologic resolution. Therefore, SWI has great potential for direct detection and quantification of amyloid plaques in live human brain, and may become feasible in vivo in the near future
EMBASE:70860987
ISSN: 1552-5260
CID: 178074
A comparison of methods for deriving normative scores for evaluating cognitive impairment [Meeting Abstract]
ORIGINAL:0007564
ISSN: 1552-5260
CID: 174415
