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1.  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.
doi:10.1016/j.neurobiolaging.2013.04.006
PMCID: PMC3706494  PMID: 23643484
aging; magnetic resonance imaging; longitudinal; trajectory; atrophy; amygdala; cerebral cortex; hippocampus; thalamus; white matter
2.  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.
doi:10.1523/JNEUROSCI.5506-12.2013
PMCID: PMC4050197  PMID: 23658162
3.  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.
doi:10.1093/cercor/bhp279
PMCID: PMC3025722  PMID: 20051356
aging; amyloid; cerebral cortex; CSF biomarkers; MRI
4.  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.
doi:10.1037/a0018827
PMCID: PMC3068612  PMID: 20230119
aging; atrophy; cerebral cortex; hippocampus; cognition
5.  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.
doi:10.1093/cercor/bhn232
PMCID: PMC2733683  PMID: 19150922
aging; cortex; frontal lobes; morphometry; MRI
6.  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.
doi:10.1523/JNEUROSCI.3785-09.2010
PMCID: PMC2828879  PMID: 20147537
Alzheimer's disease; Magnetoencephalography; ABeta-peptide; Phosphorylation; Hippocampus; Cerebral cortex; Entorhinal cortex; Parahippocampal cortex
7.  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.
doi:10.1523/JNEUROSCI.3252-09.2009
PMCID: PMC2827793  PMID: 19955375
MRI; aging; longitudinal; ADNI; cerebral cortex; hippocampus
8.  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.
doi:10.1523/JNEUROSCI.0115-09.2009
PMCID: PMC2782778  PMID: 19587284
MRI; aging; sex; cerebral cortex; hippocampus; FreeSurfer
9.  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.
doi:10.1016/j.neurobiolaging.2009.05.013
PMCID: PMC4040218  PMID: 19570593
MRI morphometry; Age; Cortex; White matter; Cerebellum; Ventricles; Hippocampus; Amygdala; Thalamus; Basal ganglia
10.  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.
doi:10.1016/j.neuroimage.2009.05.084
PMCID: PMC2828679  PMID: 19501655
11.  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.
doi:10.1371/journal.pone.0047739
PMCID: PMC3474753  PMID: 23082203
12.  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.
doi:10.1002/ana.22509
PMCID: PMC3368003  PMID: 22002658
13.  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.
doi:10.1371/journal.pone.0042325
PMCID: PMC3410919  PMID: 22876315
14.  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.
doi:10.1002/hbm.20799
PMCID: PMC3367885  PMID: 19603409
HARDI; spherical deconvolution; q-space; Q-ball; crossing fibers; fiber tracks; tracktography; linear model; spherical harmonics
15.  Medial Temporal Lobe Function and Structure in Mild Cognitive Impairment 
Annals of neurology  2004;56(1):27-35.
Functional magnetic resonance imaging (fMRI) was used to study memory-associated activation of medial temporal lobe (MTL) regions in 32 nondemented elderly individuals with mild cognitive impairment (MCI). Subjects performed a visual encoding task during fMRI scanning and were tested for recognition of stimuli afterward. MTL regions of interest were identified from each individual’s structural MRI, and activation was quantified within each region. Greater extent of activation within the hippocampal formation and parahippocampal gyrus (PHG) was correlated with better memory performance. There was, however, a paradoxical relationship between extent of activation and clinical status at both baseline and follow-up evaluations. Subjects with greater clinical impairment, based on the Clinical Dementia Rating Sum of Boxes, recruited a larger extent of the right PHG during encoding, even after accounting for atrophy. Moreover, those who subsequently declined over the 2.5 years of clinical follow-up (44% of the subjects) activated a significantly greater extent of the right PHG during encoding, despite equivalent memory performance. We hypothesize that increased activation in MTL regions reflects a compensatory response to accumulating AD pathology and may serve as a marker for impending clinical decline.
doi:10.1002/ana.20163
PMCID: PMC4335689  PMID: 15236399
16.  CETP polymorphisms associate with brain structure, atrophy rate, and Alzheimer’s disease risk in an APOE-dependent manner 
Brain imaging and behavior  2012;6(1):16-26.
Two alleles in cholesteryl ester transfer protein (CETP) gene polymorphisms have been disputably linked to enhanced cognition and decreased risk of Alzheimer’s disease (AD): the V and A alleles of I405V and C-629A. This study investigates whether these polymorphisms affect brain structure in 188 elderly controls and 318 AD or mild cognitive impairment (MCI) subjects from the Alzheimer’s Disease Neuroimaging Initiative cohort. Nominally signficant associations were dependent on APOE ε4 carrier status. In APOE ε4 carriers, the V and A alleles, both of which decrease CETP and increase HDL, associated with greater baseline cortical thickness and less 12-month atrophy in the medial temporal lobe. Conversely, in APOE ε4 non-carriers, the I allele, which increases CETP and decreases HDL, associated with greater baseline thickness, less atrophy and lower risk of dementia. These results suggest CETP may contribute to the genetic variability of brain structure and dementia susceptibility in an APOE-dependent manner.
doi:10.1007/s11682-011-9137-0
PMCID: PMC4305449  PMID: 21892657
Imaging genetics; Quantitative neuroimaging; CETP; Alzheimer’s disease; Dementia; APOE
17.  Boosting the Power of Schizophrenia Genetics by Leveraging New Statistical Tools 
Schizophrenia Bulletin  2013;40(1):13-17.
Genome-wide association studies (GWAS) have identified a large number of gene variants associated with schizophrenia, but these variants explain only a small portion of the heritability. It is becoming increasingly clear that schizophrenia is influenced by many genes, most of which have effects too small to be identified using traditional GWAS statistical methods. By applying recently developed Empirical Bayes statistical approaches, we have demonstrated that functional genic elements show differential contribution to phenotypic variance, with some elements (regulatory regions and exons) showing strong enrichment for association with schizophrenia. Applying related methods, we also showed abundant genetic overlap (pleiotropy) between schizophrenia and other phenotypes, including bipolar disorder, cardiovascular disease risk factors, and multiple sclerosis. We estimated the number of gene variants with effects in schizophrenia and bipolar disorder to be approximately 1.2%. By applying our novel statistical framework, we dramatically improved gene discovery and detected a large number of new gene loci associated with schizophrenia that have not yet been identified with standard GWAS methods. Utilizing independent schizophrenia substudies, we showed that these new loci have high replication rates in de novo samples, indicating that they likely represent true schizophrenia risk genes. The new statistical tools provide a powerful approach for uncovering more of the missing heritability of schizophrenia and other complex disorders. In conclusion, the highly polygenic architecture of schizophrenia strongly suggests the utility of research approaches that recognize schizophrenia neuropathology as a complex dynamic system, with many small gene effects integrated in functional networks.
doi:10.1093/schbul/sbt168
PMCID: PMC3885310  PMID: 24319118
GWAS; polygenicity; pleiotropy; empirical Bayes approach; molecular genetics
18.  Genome-Wide Association Study of Shared Components of Reading Disability and Language Impairment 
Genes, brain, and behavior  2013;12(8):792-801.
Written and verbal language are neurobehavioral traits vital to the development of communication skills. Unfortunately, disorders involving these traits—specifically reading disability (RD) and language impairment (LI)—are common and prevent affected individuals from developing adequate communication skills, leaving them at risk for adverse academic, socioeconomic, and psychiatric outcomes. Both RD and LI are complex traits that frequently co-occur, leading us to hypothesize that these disorders share genetic etiologies. To test this, we performed a genome wide association study on individuals affected with both RD and LI in the Avon Longitudinal Study of Parents and Children. The strongest associations were seen with markers in ZNF385D (OR=1.81, p=5.45 × 10−7) and COL4A2 (OR=1.71, p=7.59×10−7). Markers within NDST4 showed the strongest associations with LI individually (OR=1.827, p=1.40×10−7). We replicated association of ZNF385D using receptive vocabulary measures in the Pediatric Imaging Neurocognitive Genetics study (p=0.00245). We then used diffusion tensor imaging fiber tract volume data on 16 fiber tracts to examine the implications of replicated markers. ZNF385D was a predictor of overall fiber tract volumes in both hemispheres, as well as global brain volume. Here, we present evidence for ZNF385D as a candidate gene for RD and LI. The implication of transcription factor ZNF385D in RD and LI underscores the importance of transcriptional regulation in the development of higher order neurocognitive traits. Further study is necessary to discern target genes of ZNF385D and how it functions within neural development of fluent language.
doi:10.1111/gbb.12085
PMCID: PMC3904347  PMID: 24024963
ALSPAC; Language Impairment; Reading Disability; Dyslexia GWAS; ZNF385D; PING
19.  The Challenge of Connecting the Dots in the B.R.A.I.N 
Neuron  2013;80(2):10.1016/j.neuron.2013.09.008.
The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has focused scientific attention on the necessary tools to understand the human brain and mind. Here, we outline our collective vision for what we can achieve within a decade with properly targeted efforts, and discuss likely technological deliverables and neuroscience progress.
doi:10.1016/j.neuron.2013.09.008
PMCID: PMC3864648  PMID: 24139032
20.  Independence of Early Speech Processing from Word Meaning 
Cerebral Cortex (New York, NY)  2012;23(10):2370-2379.
We combined magnetoencephalography (MEG) with magnetic resonance imaging and electrocorticography to separate in anatomy and latency 2 fundamental stages underlying speech comprehension. The first acoustic-phonetic stage is selective for words relative to control stimuli individually matched on acoustic properties. It begins ∼60 ms after stimulus onset and is localized to middle superior temporal cortex. It was replicated in another experiment, but is strongly dissociated from the response to tones in the same subjects. Within the same task, semantic priming of the same words by a related picture modulates cortical processing in a broader network, but this does not begin until ∼217 ms. The earlier onset of acoustic-phonetic processing compared with lexico-semantic modulation was significant in each individual subject. The MEG source estimates were confirmed with intracranial local field potential and high gamma power responses acquired in 2 additional subjects performing the same task. These recordings further identified sites within superior temporal cortex that responded only to the acoustic-phonetic contrast at short latencies, or the lexico-semantic at long. The independence of the early acoustic-phonetic response from semantic context suggests a limited role for lexical feedback in early speech perception.
doi:10.1093/cercor/bhs228
PMCID: PMC3767959  PMID: 22875868
ECoG; MEG; N400; speech processing
21.  Longitudinal Restriction Spectrum Imaging is Resistant to Pseudoresponse in Patients with High-Grade Gliomas treated with Bevacizumab 
Background and Purpose
Antiangiogenic therapies, such as bevacizumab, decrease contrast enhancement and FLAIR hyperintensity (FLAIR-HI) in patients with high-grade gliomas in a manner that may not correlate with actual tumor response. This study evaluated the ability of an advanced DWI technique, restriction spectrum imaging (RSI), to improve conspicuity within regions of restricted diffusion (RD) compared to ADC in patients treated with bevacizumab, and to demonstrate that unlike ADC, RSI is less affected by bevacizumab-induced reductions in FLAIR-HI.
Materials and Methods
RSI cellularity maps (RSI-CMs) and DWI were available for 12 patients with recurrent high-grade gliomas at baseline and following initiation of bevacizumab. VOIs were drawn for regions of RD, surrounding FLAIR-HI, and normal appearing white matter (NAWM), and intensity values within regions of RD and FLAIR-HI were normalized to NAWM. Normalized values were compared between RSI-CMs and ADC at baseline and on-treatment using repeated measures (RM) ANOVA.
Results
All patients exhibited decreases in contrast enhancement and FLAIR-HI following treatment. Normalized intensity values were higher on RSI-CMs compared to ADC in regions of RD, whereas intensity values were higher on ADC compared to RSI-CMs in regions of FLAIR-HI. Bevacizumab-induced decreases in FLAIR-HI had a greater effect on ADC than on the RSI-CMs, with the relative sensitivity of ADC to changes in FLAIR-HI being over 20 times higher than that on RSI-CMs.
Conclusion
RSI is less influenced by reductions in FLAIR-HI compared to ADC, which may confer an advantage of RSI over ADC for interpreting tumor response on imaging following antiangiogenic therapy.
doi:10.3174/ajnr.A3506
PMCID: PMC3925350  PMID: 23578667
22.  Improved conspicuity and delineation of high-grade primary and metastatic brain tumors using “restriction spectrum imaging”: Quantitative comparison with high b-value DWI and ADC 
Background and Purpose
Restriction spectrum imaging (RSI) is a sensitive DWI technique for probing separable water diffusion compartments in tissues. Here, we evaluate RSI tumor cellularity maps (RSI-CM) derived from the spherically-restricted water compartment for improved tumor conspicuity and delineation from non-tumor tissue and reduced sensitivity to edema compared with high b-value DWI and ADC.
Materials and Methods
RSI was performed in 10 pre-surgical patients: 4 with glioblastoma, 3 with primary CNS lymphoma, and 3 with metastatic brain tumors. Multi-directional DWI data was collected at b = 500, 1500, and 4000 sec/mm2. Quantification of tumor conspicuity (TC), edema conspicuity (EC), and relative sensitivity to edema (RSE) for RSI-CM, DWI at b = 4000 (DWI-4000), and ADC were compared in manually drawn VOIs. Receiver operating characteristic (ROC) curves were used to evaluate the sensitivity and specificity of each method for delineating tumor from NAWM.
Results
Significant TC was seen with both RSI-CM and DWI-4000, but not ADC. Significant EC was seen with ADC, but not RSI-CM or DWI-4000. Significantly greater TC was seen with RSI-CM compared with DWI-4000. Significantly reduced RSE was seen with RSI-CM compared with both DWI-4000 and ADC. Greater sensitivity and specificity for delineating tumor from NAWM was seen with RSI-CM (AUC = .91) compared with both DWI-4000 (AUC = .77) and ADC (AUC = .66).
Conclusion
RSI-CM offers improved conspicuity and delineation of high-grade primary and metastatic brain tumors and reduced sensitivity to edema compared with high b-value DWI and ADC.
doi:10.3174/ajnr.A3327
PMCID: PMC4146398  PMID: 23139079
23.  The role of clusterin in amyloid-β associated neurodegeneration 
JAMA neurology  2014;71(2):180-187.
Importance
Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer's disease (AD) neurodegeneration. However, the precise role of clusterin in AD pathogenesis is still not well understood.
Objective
To elucidate the relationship between clusterin, amyloid-β (Aβ), p-tau, and rate of brain atrophy over time among non-demented older individuals.
Design
A longitudinal cohort of cognitively normal older participants (HC) and individuals with mild cognitive impairment (MCI) assessed with baseline lumbar puncture and longitudinal structural MRI.
Setting
Research centers across the United States and Canada.
Participants
We examined 241 non-demented older individuals (91 participants with a Clinical Dementia Rating (CDR) of 0 and 150 individuals with a CDR of 0.5).
Main Outcome Measures
Using linear mixed effects models, we investigated interactions between CSF clusterin, CSF Aβ1-42 and CSF p-tau181p on atrophy rate of the entorhinal cortex and hippocampus.
Results
Across all participants, we found a significant interaction between CSF clusterin and CSF Aβ1-42 on entorhinal cortex atrophy rate, but not on hippocampal atrophy rate. CSF clusterin was associated with entorhinal cortex atrophy rate among CSF Aβ1-42 positive individuals, but not among CSF Aβ1-42 negative individuals. In secondary analyses, we found significant interactions between CSF Aβ1-42 and CSF clusterin and CSF Aβ1-42 and CSF p-tau181p on entorhinal cortex atrophy rate. We found similar results in subgroup analyses within the MCI and HC cohorts.
Conclusions and Relevance
In non-demented older individuals, Aβ-associated volume loss occurs in the presence of elevated clusterin. The effect of clusterin on Aβ-associated brain atrophy is not confounded or explained by p-tau. These findings implicate a potentially important role for clusterin in the earliest stages of the AD neurodegenerative process and suggest independent effects of clusterin and p-tau on Aβ-associated volume loss.
doi:10.1001/jamaneurol.2013.4560
PMCID: PMC4118752  PMID: 24378367
24.  APOE ε4 does not modulate amyloid-β associated neurodegeneration in preclinical Alzheimer’s disease 
Background and Purpose
Among cognitively normal older individuals, the relationship between the two hallmark proteins of Alzheimer’s disease (AD), amyloid-β (Aβ) and tau, the ε4 allele of apolipoprotein E (APOE ε4), and neurodegeneration is not well understood.
Materials and Methods
We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. Within the same linear mixed effects model, we concurrently investigated main and interactive effects between APOE ε4 genotype and CSF Aβ1-42, CSF phospo-tau (p-tau181p) and CSF Aβ1-42, and APOE ε4 genotype and CSF p-tau181p on entorhinal cortex atrophy rate. We also examined the relationship between APOE ε4, CSF p-tau181p, and CSF Aβ1-42 on atrophy rate of other AD-vulnerable neuroanatomic regions.
Results
The full model with main and interactive effects demonstrated a significant interaction only between CSF p-tau181p and CSF Aβ1-42 on entorhinal cortex atrophy rate indicating elevated atrophy over time in individuals with increased CSF p-tau181p and decreased CSF Aβ1-42. APOE ε4 genotype was significantly and specifically associated with CSF Aβ1-42. However, the interaction between APOE ε4 genotype and either CSF Aβ1-42 or CSF p-tau181p on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions.
Conclusions
Based upon our findings and building upon prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD where APOE ε4 primarily influences Alzheimer’s pathology via Aβ-related mechanisms and in turn, Aβ-associated neurodegeneration occurs only in the presence of phospho-tau.
doi:10.3174/ajnr.A3267
PMCID: PMC4041629  PMID: 22976236
preclinical AD; neurodegeneration; p-tau; amyloid-β; APOE
25.  Recovery of White Matter Tracts in Regions of Peritumoral FLAIR Hyperintensity using Restriction Spectrum Imaging 
Background
DTI is being increasingly used for visualizing critical white matter tracts adjacent to brain tumors prior to neurosurgical resection. However, brain tumors, particularly high-grade gliomas, are typically surrounded by regions of FLAIR hyperintensity (FLAIR-HI) that include edema, which increase isotropic diffusion, degrading the ability of standard DTI to uncover orientation estimates within these regions.
Purpose
We introduce a new technique, RSI, which overcomes this limitation by removing the spherical, fast diffusion component introduced by edema, providing better analysis of white matter architecture.
Methods
Ten patients with high-grade gliomas surrounded by FLAIR-HI that at least partially resolved on follow-up imaging were included. All patients underwent RSI and DTI at baseline (FLAIR-HI present) and at follow-up (FLAIR-HI partially resolved). FA values obtained with RSI and DTI were compared within regions of FLAIR-HI and NAWM at both time points.
Results
RSI showed higher FA in regions of FLAIR-HI and NAWM relative to DTI, reflecting RSIs ability to specifically measure the slow, restricted volume fraction in regions of edema and NAWM. Furthermore, a method by time interaction revealed that FA estimates increased when the FLAIR-HI resolved using standard DTI, but remained stable with RSI. Tractography performed within the region of FLAIR-HI revealed the superior ability of RSI to track fibers through severe edema relative to standard DTI.
Conclusion
RSI improves the quantification and visualization of white matter tracts in regions of peritumoral FLAIR-HI associated with edema relative to standard DTI, and may provide a valuable tool for neurosurgical planning.
doi:10.3174/ajnr.A3372
PMCID: PMC3928241  PMID: 23275591

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