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1.  What is normal in normal aging? Effects of Aging, Amyloid and Alzheimer’s Disease on the Cerebral Cortex and the Hippocampus 
Progress in neurobiology  2014;117:20-40.
What can be expected in normal aging, and where does normal aging stop and pathological neurodegeneration begin? With the slow progression of age-related dementias such as Alzheimer’s Disease (AD), it is difficult to distinguish age-related changes from effects of undetected disease. We review recent research on changes of the cerebral cortex and the hippocampus in aging and the borders between normal aging and AD. We argue that prominent cortical reductions are evident in fronto-temporal regions in elderly even with low probability of AD, including regions overlapping the default mode network. Importantly, these regions show high levels of amyloid deposition in AD, and are both structurally and functionally vulnerable early in the disease. This normalcy-pathology homology is critical to understand, since aging itself is the major risk factor for sporadic AD. Thus, rather than necessarily reflecting early signs of disease, these changes may be part of normal aging, and may inform on why the aging brain is so much more susceptible to AD than is the younger brain. We suggest that regions characterized by a high degree of life-long plasticity are vulnerable to detrimental effects of normal aging, and that this age-vulnerability renders them more susceptible to additional, pathological AD-related changes. We conclude that it will be difficult to understand AD without understanding why it preferably affects older brains, and that we need a model that accounts for age-related changes in AD-vulnerable regions independently of AD-pathology.
PMCID: PMC4343307  PMID: 24548606
normal aging; Alzheimer’s disease (AD); default mode network (DMN); cerebral cortex; hippocampus; amyloid
2.  Accelerating Cortical Thinning: Unique to Dementia or Universal in Aging? 
Cerebral Cortex (New York, NY)  2012;24(4):919-934.
Does accelerated cortical atrophy in aging, especially in areas vulnerable to early Alzheimer's disease (AD), unequivocally signify neurodegenerative disease or can it be part of normal aging? We addressed this in 3 ways. First, age trajectories of cortical thickness were delineated cross-sectionally (n = 1100) and longitudinally (n = 207). Second, effects of undetected AD on the age trajectories were simulated by mixing the sample with a sample of patients with very mild to moderate AD. Third, atrophy in AD-vulnerable regions was examined in older adults with very low probability of incipient AD based on 2-year neuropsychological stability, CSF Aβ1-42 levels, and apolipoprotein ɛ4 negativity. Steady decline was seen in most regions, but accelerated cortical thinning in entorhinal cortex was observed across groups. Very low-risk older adults had longitudinal entorhinal atrophy rates similar to other healthy older adults, and this atrophy was predictive of memory change. While steady decline in cortical thickness is the norm in aging, acceleration in AD-prone regions does not uniquely signify neurodegenerative illness but can be part of healthy aging. The relationship between the entorhinal changes and changes in memory performance suggests that non-AD mechanisms in AD-prone areas may still be causative for cognitive reductions.
PMCID: PMC3948495  PMID: 23236213
aging; Alzheimer's disease; atrophy; cortical thickness; magnetic resonance imaging
3.  Critical ages in the life-course of the adult brain: nonlinear subcortical aging 
Neurobiology of aging  2013;34(10):2239-2247.
Age-related changes in brain structure result from a complex interplay between various neurobiological processes, which may contribute to more complex trajectories than can be described by simple linear or quadratic models. We used a non-parametric smoothing spline approach to delineate cross-sectionally estimated age-trajectories of the volume of 17 neuroanatomical structures in 1100 healthy adults (18–94 years). Accelerated estimated decline in advanced age characterized some structures, e.g. hippocampus, but was not the norm. For most areas, one or two critical ages were identified, characterized by changes in the estimated rate of change. One year follow up data from 142 healthy older adults (60–91 years) confirmed the existence of estimated change from the cross-sectional analyses for all areas except one (caudate). The cross-sectional and the longitudinal analyses agreed well on the rank order of age effects on specific brain structures (Spearman’s ρ = .91). The main conclusions are that most brain structures do not follow a simple path throughout adult life, and that accelerated decline in high age is not the norm of healthy brain aging.
PMCID: PMC3706494  PMID: 23643484
aging; magnetic resonance imaging; longitudinal; trajectory; atrophy; amygdala; cerebral cortex; hippocampus; thalamus; white matter
4.  Brain Changes in Older Adults at Very Low Risk for Alzheimer's Disease 
The Journal of Neuroscience  2013;33(19):8237-8242.
Alzheimer's disease (AD) has a slow onset, so it is challenging to distinguish brain changes in healthy elderly persons from incipient AD. One-year brain changes with a distinct frontotemporal pattern have been shown in older adults. However, it is not clear to what extent these changes may have been affected by undetected, early AD. To address this, we estimated 1-year atrophy by magnetic resonance imaging (MRI) in 132 healthy elderly persons who had remained free of diagnosed mild cognitive impairment or AD for at least 3 years. We found significant volumetric reductions throughout the brain. The sample was further divided into low-risk groups based on clinical, biomarker, genetic, or cognitive criteria. Although sample sizes varied, significant reductions were observed in all groups, with rates and topographical distribution of atrophy comparable to that of the full sample. Volume reductions were especially pronounced in the default mode network, closely matching the previously described frontotemporal pattern of changes in healthy aging. Atrophy in the hippocampus predicted change in memory, with no additional default mode network contributions. In conclusion, reductions in regional brain volumes can be detected over the course of 1 year even in older adults who are unlikely to be in a presymptomatic stage of AD.
PMCID: PMC4050197  PMID: 23658162
5.  Brain Atrophy in Healthy Aging Is Related to CSF Levels of Aβ1-42 
Cerebral Cortex (New York, NY)  2010;20(9):2069-2079.
Reduced levels of β-amyloid1-42 (Aβ1-42) and increased levels of tau proteins in the cerebrospinal fluid (CSF) are found in Alzheimer’s disease (AD), likely reflecting Aβ deposition in plaques and neuronal and axonal damage. It is not known whether these biomarkers are associated with brain atrophy also in healthy aging. We tested the relationship between CSF levels of Aβ1-42 and tau (total tau and tau phosphorylated at threonine 181) proteins and 1-year brain atrophy in 71 cognitively normal elderly individuals. Results showed that under a certain threshold value, levels of Aβ1-42 correlated highly with 1-year change in a wide range of brain areas. The strongest relationships were not found in the regions most vulnerable early in AD. Above the threshold level, Aβ1-42 was not related to brain changes, but significant volume reductions as well as ventricular expansion were still seen. It is concluded that Aβ1-42 correlates with brain atrophy and ventricular expansion in a subgroup of cognitively normal elderly individuals but that reductions independent of CSF levels of Aβ1-42 is common. Further research and follow-up examinations over several years are needed to test whether degenerative pathology will eventually develop in the group of cognitively normal elderly individuals with low levels of Aβ1-42.
PMCID: PMC3025722  PMID: 20051356
aging; amyloid; cerebral cortex; CSF biomarkers; MRI
6.  Cortical Gray Matter Atrophy in Healthy Aging Cannot Be Explained by Undetected Incipient Cognitive Disorders: A Comment on Burgmans et al. (2009) 
Neuropsychology  2010;24(2):258-266.
Burgmans, van Boxtel, Vuurman, et al. (2009) published an interesting study titled “The Prevalence of Cortical Gray Matter Atrophy May Be Overestimated in the Healthy Aging Brain” on how subclinical cognitive disorders may affect correlations between age and cortical volume. Correlations between cortical gray matter volume and age were found in 30 elderly with cognitive decline after 6 years, but not in 28 elderly without cognitive decline. This study is important, and demonstrates that preclinical cognitive disorders may affect cortical brain volumes before being detectable by neuropsychological tests. However, we are not convinced by the conclusions: “… gray matter atrophy … is to a lesser extent associated with the healthy aging process, but more likely with brain processes underlying significant cognitive decline” (p. 547) and “… cortical gray matter atrophy in the aging brain may be overestimated in a large number of studies on healthy aging” (p. 547). We analyzed the cross-sectional MR data (n = 1,037) as well as longitudinal data from a sample of very well-screened elderly followed by cognitive testing for 2 years. In the cross-sectional data, the correlations between age and brain volumes were generally not much reduced when the upper age limit was lowered. This would not be expected if age-related incipient cognitive disorders caused the correlations given that the incidence of cognitive decline increased with age. Longitudinally, 1-year atrophy was identified in all tested regions. It is likely that cortical brain atrophy is manifested in cognitively normal elderly without subclinical cognitive disorders.
PMCID: PMC3068612  PMID: 20230119
aging; atrophy; cerebral cortex; hippocampus; cognition
7.  High Consistency of Regional Cortical Thinning in Aging across Multiple Samples 
Cerebral Cortex (New York, NY)  2009;19(9):2001-2012.
Cross-sectional magnetic resonance imaging (MRI) studies of cortical thickness and volume have shown age effects on large areas, but there are substantial discrepancies across studies regarding the localization and magnitude of effects. These discrepancies hinder understanding of effects of aging on brain morphometry, and limit the potential usefulness of MR in research on healthy and pathological age-related brain changes. The present study was undertaken to overcome this problem by assessing the consistency of age effects on cortical thickness across 6 different samples with a total of 883 participants. A surface-based segmentation procedure (FreeSurfer) was used to calculate cortical thickness continuously across the brain surface. The results showed consistent age effects across samples in the superior, middle, and inferior frontal gyri, superior and middle temporal gyri, precuneus, inferior and superior parietal cortices, fusiform and lingual gyri, and the temporo-parietal junction. The strongest effects were seen in the superior and inferior frontal gyri, as well as superior parts of the temporal lobe. The inferior temporal lobe and anterior cingulate cortices were relatively less affected by age. The results are discussed in relation to leading theories of cognitive aging.
PMCID: PMC2733683  PMID: 19150922
aging; cortex; frontal lobes; morphometry; MRI
8.  CSF biomarkers in prediction of cerebral and clinical change in Mild Cognitive Impairment and Alzheimer's Disease 
Brain atrophy and altered CSF-levels of amyloid beta (Aβ42) and the microtubule-associated protein tau are potent biomarkers of Alzheimer's Disease (AD) related pathology. However, the relationship between CSF biomarkers and brain morphometry is poorly understood. Thus, we addressed the following questions: (1) Can CSF biomarker levels explain the morphometric differences between normal controls (NC) and patients with mild cognitive impairment (MCI) or AD? (2) How are CSF biomarkers related to atrophy across the brain? (3) How closely are CSF biomarkers and morphometry related to clinical change (CDR sum of boxes [CDR-sb])? 370 participants (105 NC/ 175 MCI/ 90 AD) from the Alzheimer's Disease Neuroimaging Initiative were studied, of whom 309 were followed for one and 176 for two years. Analyses were performed across the entire cortical surface, as well as for 30 cortical and subcortical regions of interest (ROIs). Results showed that CSF biomarker levels could not account for group differences in brain morphometry at baseline but that CSF biomarker levels showed moderate relationships to longitudinal atrophy rates in numerous brain areas, not restricted to medial temporal structures. Baseline morphometry was at least as predictive of atrophy as were CSF biomarkers. Even MCI patients with levels of Aβ42 comparable to controls and of p-tau lower than controls showed more atrophy than the controls. Morphometry predicted change in CDR-sb better than did CSF biomarkers. These results indicate that morphometric changes in MCI and AD are not secondary to CSF biomarker changes, and that the two types of biomarkers yield complementary information.
PMCID: PMC2828879  PMID: 20147537
Alzheimer's disease; Magnetoencephalography; ABeta-peptide; Phosphorylation; Hippocampus; Cerebral cortex; Entorhinal cortex; Parahippocampal cortex
9.  One year brain atrophy evident in healthy aging 
An accurate description of changes in the brain in healthy aging is needed to understand the basis of age-related changes in cognitive function. Cross-sectional magnetic resonance imaging (MRI) studies suggest thinning of the cerebral cortex, volumetric reductions of most subcortical structures and ventricular expansion. However, there is a paucity of detailed longitudinal studies to support the cross-sectional findings. In the present study, 142 healthy elderly participants (60–91 years) were followed with repeated MRI, and were compared to 122 patients with mild to moderate Alzheimer's disease (AD). Volume changes were measured across the entire cortex and in 48 regions of interest (ROIs). Cortical reductions in the healthy elderly were extensive after only one year, especially evident in temporal and prefrontal cortex where annual decline was about 0.5%. All subcortical and ventricular regions except caudate nucleus and the 4th ventricle changed significantly over one year. Some of the atrophy occurred in areas vulnerable to AD, while other changes were observed in areas less characteristic of the disease in early stages. This suggests that the changes are not primarily driven by degenerative processes associated with AD, although it is likely that preclinical changes associated with AD are superposed on changes due to normal aging in some subjects, especially in the temporal lobes. Finally, atrophy was found to accelerate with increasing age, and this was especially prominent in areas vulnerable to AD. Thus, it is possible that the accelerating atrophy with increasing age is due to preclinical AD.
PMCID: PMC2827793  PMID: 19955375
MRI; aging; longitudinal; ADNI; cerebral cortex; hippocampus
10.  Minute effects of sex on the aging brain: a multi-sample MRI-study of healthy aging and Alzheimer’s disease 
Age is associated with substantial macro-structural brain changes. While some recent magnetic resonance imaging (MRI) studies have reported larger age-effects in men than women, others find no sex differences. As brain morphometry is a potentially important tool in diagnosis and monitoring of age-related neurological diseases, e.g. Alzheimer’s disease (AD), it is important to know whether sex influences brain aging. We analyzed cross-sectional MR scans from 1143 healthy participants from seven subsamples provided by four independent research groups. In addition, 96 patients with mild AD were included. Estimates of cortical thickness continuously across the brain surface, as well as volume of 17 subcortical structures, were obtained by use of automated segmentation tools (FreeSurfer). In the healthy participants, no differences in aging slopes between women and men were found in any part of the cortex. Pallidum corrected for intracranial volume showed slightly higher age correlations for men. The analyses were repeated in each of the seven sub-samples, and the lack of age × sex interactions was largely replicated. Analyses of the AD sample showed no interactions between sex and age for any brain region. It is concluded that sex has negligible effects on the age-slope of brain volumes both in healthy participants and in AD.
PMCID: PMC2782778  PMID: 19587284
MRI; aging; sex; cerebral cortex; hippocampus; FreeSurfer
11.  Consistent neuroanatomical age-related volume differences across multiple samples 
Neurobiology of aging  2009;32(5):916-932.
Magnetic Resonance Imaging (MRI) is the principal method for studying structural age-related brain changes in vivo. However, previous research has yielded inconsistent results, precluding understanding of structural changes of the aging brain. This inconsistency is due to methodological differences and/or different aging patterns across samples. To overcome these problems, we tested age effects on 17 different neuroanatomical structures and total brain volume across five samples, of which one was split to further investigate consistency (883 participants). Widespread age-related volume differences were seen consistently across samples. In four of the five samples, all structures, except the brain stem, showed age-related volume differences. The strongest and most consistent effects were found for cerebral cortex, pallidum, putamen and accumbens volume. Total brain volume, cerebral white matter, caudate, hippocampus and the ventricles consistently showed non-linear age functions. Healthy aging appears associated with more widespread and consistent age-related neuroanatomical volume differences than previously believed.
PMCID: PMC4040218  PMID: 19570593
MRI morphometry; Age; Cortex; White matter; Cerebellum; Ventricles; Hippocampus; Amygdala; Thalamus; Basal ganglia
12.  Increased sensitivity to effects of normal aging and Alzheimer’s disease on cortical thickness by adjustment for local variability in gray/white contrast: A multi-sample MRI study 
NeuroImage  2009;47(4):1545-1557.
MRI-based estimates of cerebral morphometric properties, e.g. cortical thickness, are pivotal to studies of normal and pathological brain changes. These measures are based on automated or manual segmentation procedures, which utilize the tissue contrast between gray and white matter on T1-weighted MR images. Tissue contrast is unlikely to remain a constant property across groups of different age and health. An important question is therefore how the sensitivity of cortical thickness estimates is influenced by variability in WM/GM contrast. The effect of adjusting for variability in WM/GM contrast on age sensitivity of cortical thickness was tested in 1,189 healthy subjects from six different samples, enabling evaluation of consistency of effects within and between sites and scanners. Further, the influence of Alzheimer’s disease (AD) diagnosis on cortical thickness with and without correction for contrast was tested in an additional sample of 96 patients. In healthy controls, regional increases in the sensitivity of the cortical thickness measure to age were found after correcting for contrast. Across samples, the strongest effects were observed in frontal, lateral temporal and parietal areas. Controlling for contrast variability also increased the cortical thickness estimates’ sensitivity to AD, thus replicating the finding in an independent clinical sample. The results showed increased sensitivity of cortical estimates to AD in areas earlier reported to be compromised in AD, including medial temporal, inferior and superior parietal regions. In sum, the findings indicate that adjusting for contrast can increase the sensitivity of MR morphometry to variables of interest.
PMCID: PMC2828679  PMID: 19501655
13.  Identifying common genetic variants in blood pressure due to polygenic pleiotropy with associated phenotypes 
Hypertension  2014;63(4):819-826.
Blood pressure is a critical determinant of cardiovascular morbidity and mortality. It is affected by environmental factors, but has a strong heritable component. Despite recent large genome-wide association studies, few genetic risk factors for blood pressure have been identified. Epidemiological studies suggest associations between blood pressure and several diseases and traits, which may partly arise from a shared genetic basis (genetic pleiotropy). Using genome-wide association studies summary statistics and a genetic pleiotropy-informed conditional False Discovery Rate method, we systematically investigated genetic overlap between systolic blood pressure and 12 co-morbid traits and diseases. We found significant ‘enrichment’ of single nucleotide polymorphisms associated with systolic blood pressure as a function of their association with body mass index, low density lipoprotein, waist hip ratio, schizophrenia, bone mineral density, type 1 diabetes and celiac disease. In contrast, the magnitude of enrichment due to shared polygenic effects was smaller with the other phenotypes (triglycerides, high density lipoproteins, type 2 diabetes, rheumatoid arthritis, and height). Applying the conditional False Discovery Rate method to the enriched phenotypes, we identified 62 loci associated with systolic blood pressure (False Discovery Rate < 0.01), including 42 novel loci. The observed polygenic overlap between systolic blood pressure and several related disorders indicates that the epidemiological associations are not mediated solely via lifestyle factors, but also reflect an etiological relation that warrants further investigation. The new gene loci identified implicate novel genetic mechanisms related to lipid biology and the immune system in systolic blood pressure.
PMCID: PMC3984909  PMID: 24396023
Genome-wide association study; genetic pleiotropy; systolic blood pressure; comorbid disorders
14.  Enrichment and Stratification for Predementia Alzheimer Disease Clinical Trials 
PLoS ONE  2012;7(10):e47739.
The tau and amyloid pathobiological processes underlying Alzheimer disease (AD) progresses slowly over periods of decades before clinical manifestation as mild cognitive impairment (MCI), then more rapidly to dementia, and eventually to end-stage organ failure. The failure of clinical trials of candidate disease modifying therapies to slow disease progression in patients already diagnosed with early AD has led to increased interest in exploring the possibility of early intervention and prevention trials, targeting MCI and cognitively healthy (HC) populations. Here, we stratify MCI individuals based on cerebrospinal fluid (CSF) biomarkers and structural atrophy risk factors for the disease. We also stratify HC individuals into risk groups on the basis of CSF biomarkers for the two hallmark AD pathologies. Results show that the broad category of MCI can be decomposed into subsets of individuals with significantly different average regional atrophy rates. By thus selectively identifying individuals, combinations of these biomarkers and risk factors could enable significant reductions in sample size requirements for clinical trials of investigational AD-modifying therapies, and provide stratification mechanisms to more finely assess response to therapy. Power is sufficiently high that detecting efficacy in MCI cohorts should not be a limiting factor in AD therapeutics research. In contrast, we show that sample size estimates for clinical trials aimed at the preclinical stage of the disorder (HCs with evidence of AD pathology) are prohibitively large. Longer natural history studies are needed to inform design of trials aimed at the presymptomatic stage.
PMCID: PMC3474753  PMID: 23082203
15.  Amyloid-β associated volume loss occurs only in the presence of phospho-tau 
Annals of Neurology  2011;70(4):657-661.
The relationship between neurodegeneration and the two hallmark proteins of Alzheimer's disease, amyloid-β (Aβ) and tau, is still unclear. Here, we examined 286 non-demented participants (107 cognitively normal older adults and 179 memory impaired individuals) who underwent longitudinal MR imaging and lumbar puncture. Using mixed effects models, we investigated the relationship between longitudinal entorhinal cortex atrophy, CSF p-tau181p and CSF Aβ1-42. We found a significant relationship between elevated entorhinal cortex atrophy and decreased CSF Aβ1-42 only with elevated CSF p-tau181p. Our findings indicate that Aβ-associated volume loss occurs only in the presence of phospho-tauin humans at risk for dementia.
PMCID: PMC3368003  PMID: 22002658
16.  Rates of Decline in Alzheimer Disease Decrease with Age 
PLoS ONE  2012;7(8):e42325.
Age is the strongest risk factor for sporadic Alzheimer disease (AD), yet the effects of age on rates of clinical decline and brain atrophy in AD have been largely unexplored. Here, we examined longitudinal rates of change as a function of baseline age for measures of clinical decline and structural MRI-based regional brain atrophy, in cohorts of AD, mild cognitive impairment (MCI), and cognitively healthy (HC) individuals aged 65 to 90 years (total n = 723). The effect of age was modeled using mixed effects linear regression. There was pronounced reduction in rates of clinical decline and atrophy with age for AD and MCI individuals, whereas HCs showed increased rates of clinical decline and atrophy with age. This resulted in convergence in rates of change for HCs and patients with advancing age for several measures. Baseline cerebrospinal fluid densities of AD-relevant proteins, Aβ1–42, tau, and phospho-tau181p (ptau), showed a similar pattern of convergence with advanced age across cohorts, particularly for ptau. In contrast, baseline clinical measures did not differ by age, indicating uniformity of clinical severity at baseline. These results imply that the phenotypic expression of AD is relatively mild in individuals older than approximately 85 years, and this may affect the ability to distinguish AD from normal aging in the very old. Our findings show that inclusion of older individuals in clinical trials will substantially reduce the power to detect disease-modifying therapeutic effects, leading to dramatic increases in required clinical trial sample sizes with age of study sample.
PMCID: PMC3410919  PMID: 22876315
17.  Optimal Diffusion MRI Acquisition for Fiber orientation Density Estimation: An Analytic Approach 
Human Brain Mapping  2009;30(11):3696-3703.
An important challenge in the design of diffusion MRI experiments is how to optimize statistical efficiency, i.e., the accuracy with which parameters can be estimated from the diffusion data in a given amount of imaging time. In model-based spherical deconvolution analysis, the quantity of interest is the fiber orientation density (FOD). Here, we demonstrate how the spherical harmonics (SH) can be used to form an explicit analytic expression for the efficiency of the minimum variance (maximally efficient) linear unbiased estimator of the FOD. Using this expression, we calculate optimal b-values for maximum FOD estimation efficiency with SH expansion orders of L = 2, 4, 6, and 8 to be approximately b = 1500, 3000, 4600, and 6200 s/mm2, respectively. However, the arrangement of diffusion directions and scanner-specific hardware limitations also play a role in determining the realizable efficiency of the FOD estimator that can be achieved in practice. We show how some commonly used methods for selecting diffusion directions are sometimes inefficient, and propose a new method for selecting diffusion directions in MRI based on maximizing the statistical efficiency. We further demonstrate how scanner-specific hardware limitations generally lead to optimal b-values that are slightly lower than the ideal b-values. In summary, the analytic expression for the statistical efficiency of the unbiased FOD estimator provides important insight into the fundamental tradeoff between angular resolution, b-value, and FOD estimation accuracy.
PMCID: PMC3367885  PMID: 19603409
HARDI; spherical deconvolution; q-space; Q-ball; crossing fibers; fiber tracks; tracktography; linear model; spherical harmonics
18.  Shared common variants in prostate cancer and blood lipids 
Background: Epidemiological and clinical studies suggest comorbidity between prostate cancer (PCA) and cardiovascular disease (CVD) risk factors. However, the relationship between these two phenotypes is still not well understood. Here we sought to identify shared genetic loci between PCA and CVD risk factors.
Methods: We applied a genetic epidemiology method based on conjunction false discovery rate (FDR) that combines summary statistics from different genome-wide association studies (GWAS), and allows identification of genetic overlap between two phenotypes. We evaluated summary statistics from large, multi-centre GWA studies of PCA (n = 50 000) and CVD risk factors (n = 200 000) [triglycerides (TG), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, systolic blood pressure, body mass index, waist-hip ratio and type 2 diabetes (T2D)]. Enrichment of single nucleotide polymorphisms (SNPs) associated with PCA and CVD risk factors was assessed with conditional quantile-quantile plots and the Anderson-Darling test. Moreover, we pinpointed shared loci using conjunction FDR.
Results: We found the strongest enrichment of P-values in PCA was conditional on LDL and conditional on TG. In contrast, we found only weak enrichment conditional on HDL or conditional on the other traits investigated. Conjunction FDR identified altogether 17 loci; 10 loci were associated with PCA and LDL, 3 loci were associated with PCA and TG and additionally 4 loci were associated with PCA, LDL and TG jointly (conjunction FDR < 0.01). For T2D, we detected one locus adjacent to HNF1B.
Conclusions: We found polygenic overlap between PCA predisposition and blood lipids, in particular LDL and TG, and identified 17 pleiotropic gene loci between PCA and LDL, and PCA and TG, respectively. These findings provide novel pathobiological insights and may have implications for trials using targeting lipid-lowering agents in a prevention or cancer setting.
PMCID: PMC4121563  PMID: 24786909
Prostate cancer; blood lipids; cholesterol; type 2 diabetes; genetic epidemiology; pleiotropy
19.  Covariate-modulated local false discovery rate for genome-wide association studies 
Bioinformatics  2014;30(15):2098-2104.
Motivation: Genome-wide association studies (GWAS) have largely failed to identify most of the genetic basis of highly heritable diseases and complex traits. Recent work has suggested this could be because many genetic variants, each with individually small effects, compose their genetic architecture, limiting the power of GWAS, given currently obtainable sample sizes. In this scenario, Bonferroni-derived thresholds are severely underpowered to detect the vast majority of associations. Local false discovery rate (fdr) methods provide more power to detect non-null associations, but implicit assumptions about the exchangeability of single nucleotide polymorphisms (SNPs) limit their ability to discover non-null loci.
Methods: We propose a novel covariate-modulated local false discovery rate (cmfdr) that incorporates prior information about gene element–based functional annotations of SNPs, so that SNPs from categories enriched for non-null associations have a lower fdr for a given value of a test statistic than SNPs in unenriched categories. This readjustment of fdr based on functional annotations is achieved empirically by fitting a covariate-modulated parametric two-group mixture model. The proposed cmfdr methodology is applied to a large Crohn’s disease GWAS.
Results: Use of cmfdr dramatically improves power, e.g. increasing the number of loci declared significant at the 0.05 fdr level by a factor of 5.4. We also demonstrate that SNPs were declared significant using cmfdr compared with usual fdr replicate in much higher numbers, while maintaining similar replication rates for a given fdr cutoff in de novo samples, using the eight Crohn’s disease substudies as independent training and test datasets.
Availability an implementation:
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC4103587  PMID: 24711653
20.  Shape Abnormalities of Subcortical and Ventricular Structures in Mild Cognitive Impairment and Alzheimer’s Disease: Detecting, Quantifying, and Predicting 
Human brain mapping  2014;35(8):3701-3725.
This article assesses the feasibility of using shape information to detect and quantify the subcortical and ventricular structural changes in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) patients. We first demonstrate structural shape abnormalities in MCI and AD as compared with healthy controls (HC). Exploring the development to AD, we then divide the MCI participants into two subgroups based on longitudinal clinical information: (1) MCI patients who remained stable; (2) MCI patients who converted to AD over time. We focus on seven structures (amygdala, hippocampus, thalamus, caudate, putamen, globus pallidus, and lateral ventricles) in 754 MR scans (210 HC, 369 MCI of which 151 converted to AD over time, and 175 AD). The hippocampus and amygdala were further subsegmented based on high field 0.8 mm isotropic 7.0T scans for finer exploration. For MCI and AD, prominent ventricular expansions were detected and we found that these patients had strongest hippocampal atrophy occurring at CA1 and strongest amygdala atrophy at the basolateral complex. Mild atrophy in basal ganglia structures was also detected in MCI and AD. Stronger atrophy in the amygdala and hippocampus, and greater expansion in ventricles was observed in MCI converters, relative to those MCI who remained stable. Furthermore, we performed principal component analysis on a linear shape space of each structure. A subsequent linear discriminant analysis on the principal component values of hippocampus, amygdala, and ventricle leads to correct classification of 88% HC subjects and 86% AD subjects.
PMCID: PMC4474087  PMID: 24443091
Alzheimer’s disease; mild cognitive impairment; subcortical structures; lateral ventricles; high field; subsegmentations; shape abnormality; large deformation diffeomorphic metric mapping
21.  Brain Volume Reductions in Adolescent Heavy Drinkers 
Brain abnormalities in adolescent heavy drinkers may result from alcohol exposure, or stem from pre-existing neural features.
This longitudinal morphometric study investigated 40 healthy adolescents, ages 12–17 at study entry, half of whom (n=20) initiated heavy drinking over the 3 year follow-up. Both assessments included high-resolution magnetic resonance imaging. FreeSurfer was used to segment brain volumes, which were measured longitudinally using the newly developed QUARC tool.
At baseline, participants who later transitioned into heavy drinking showed smaller left cingulate, pars triangularis, and rostral anterior cingulate volume, and less right cerebellar white matter volumes (p<.05), compared to continuous non-using teens. Over time, participants who initiated heavy drinking showed significantly greater volume reduction in the left ventral diencephalon, left inferior and middle temporal gyrus, and left caudate and brain stem, compared to substance-naïve youth (p<.05).
Findings suggest preexisting volume differences in frontal brain regions in future drinkers and greater brain volume reduction in subcortical and temporal regions after alcohol use was initiated. This is consistent with literature showing pre-existing cognitive deficits on tasks recruited by frontal regions, as well as post-drinking consequences on brain regions involved in language and spatial tasks.
PMCID: PMC4061267  PMID: 24632141
adolescence; alcohol abuse; brain development; neuroimaging; magnetic resonance imaging
22.  Age-related Changes in Tissue Signal Properties Within Cortical Areas Important for Word Understanding in 12- to 19-Month-Old Infants 
Cerebral Cortex (New York, NY)  2013;24(7):1948-1955.
Recently, our laboratory has shown that the neural mechanisms for encoding lexico-semantic information in adults operate functionally by 12–18 months of age within left frontotemporal cortices (Travis et al., 2011. Spatiotemporal neural dynamics of word understanding in 12- to 18-month-old-infants. Cereb Cortex. 8:1832–1839). However, there is minimal knowledge of the structural changes that occur within these and other cortical regions important for language development. To identify regional structural changes taking place during this important period in infant development, we examined age-related changes in tissue signal properties of gray matter (GM) and white matter (WM) intensity and contrast. T1-weighted surface-based measures were acquired from 12- to 19-month-old infants and analyzed using a general linear model. Significant age effects were observed for GM and WM intensity and contrast within bilateral inferior lateral and anterovental temporal regions, dorsomedial frontal, and superior parietal cortices. Region of interest (ROI) analyses revealed that GM and WM intensity and contrast significantly increased with age within the same left lateral temporal regions shown to generate lexico-semantic activity in infants and adults. These findings suggest that neurophysiological processes supporting linguistic and cognitive behaviors may develop before cellular and structural maturation is complete within associative cortices. These results have important implications for understanding the neurobiological mechanisms relating structural to functional brain development.
PMCID: PMC4051897  PMID: 23448869
brain development; infants; language, structural MRI
23.  Large arteriolar component of oxygen delivery implies safe margin of oxygen supply to cerebral tissue 
Nature communications  2014;5:5734.
What is the organization of cerebral microvascular oxygenation and morphology that allows adequate tissue oxygenation at different activity levels? We address this question in the mouse cerebral cortex using microscopic imaging of intravascular O2 partial pressure and blood flow combined with numerical modeling. Here we show that parenchymal arterioles are responsible for 50% of the extracted O2 at baseline activity and the majority of the remaining O2 exchange takes place within the first few capillary branches. Most capillaries release little O2 at baseline acting as an O2 reserve that is recruited during increased neuronal activity or decreased blood flow. Our results challenge the common perception that capillaries are the major site of O2 delivery to cerebral tissue. The understanding of oxygenation distribution along arterio-capillary paths may have profound implications for the interpretation of BOLD fMRI signal and for evaluating microvascular O2 delivery capacity to support cerebral tissue in disease.
PMCID: PMC4260810  PMID: 25483924
25.  APOE interacts with age to modify rate of decline in cognitive and brain changes in Alzheimer’s disease 
To determine (1) whether age-standardized cognitive declines and brain morphometric change differ between Young-Old (YOAD) and Very-Old (VOAD) patients with Alzheimer’s disease (AD) and (2) whether apolipoprotein E (APOE) genotype modifies these neuropsychological and morphometric changes.
Baseline and 12-month follow up neuropsychological and morphometric measures were examined for healthy control and AD individuals. The two AD groups were further divided into subgroups on the basis of the presence of at least one APOE ε4 allele.
The YOAD showed more severe deficits andsteeper declines in cognition than the VOAD. Moreover, the presence of an APOE ε4 allele had a more deleterious effect on the YOAD than the VOAD on cognition and brain structure both cross-sectionally and longitudinally.
Results underscore the importance of integrating an individual’s age and genetic susceptibility—and their interaction—when examining neuropsychological and neuroimaging changes in the early stages of Alzheimer’s disease.
PMCID: PMC3815680  PMID: 23896613
Alzheimer’s disease; APOE genotype; cognition; morphometry; MRI; longitudinal

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