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1.  Mapping creatinine and cystatin C related white matter brain deficits in the elderly 
Neurobiology of aging  2012;34(4):1221-1230.
Poor kidney function is associated with increased risk of cognitive decline and generalized brain atrophy. Chronic kidney disease impairs glomerular filtration rate (eGFR), and this deterioration is indicated by elevated blood levels of kidney biomarkers such as creatinine (SCr) and cystatin C (CysC). Here we hypothesized that impaired renal function would be associated with brain deficits in regions vulnerable to neurodegeneration.
Using tensor-based morphometry, we related patterns of brain volumetric differences to SCr, CysC levels, and eGFR in a large cohort of 738 (mean age: 75.5±6·8 years; 438 men/300 women) elderly Caucasian subjects scanned as part of the Alzheimer’s Disease Neuroimaging Initiative.
Elevated kidney biomarkers were associated with volume deficits in the white matter region of the brain. All the three renal parameters in our study showed significant associations consistently with a region that corresponds with the anterior limb of internal capsule, bilaterally.
This is the first study to report a marked profile of structural alterations in the brain associated with elevated kidney biomarkers; helping us explain the cognitive deficits.
PMCID: PMC3603573  PMID: 23182131
creatinine; cystatin C; GFR; kidney function; brain volumes; brain structure; brain atrophy; neuroimaging; cognitive deficits
2.  Ventricular atrophy and its clinical correlates in the imaging cohort from the ADCS MCI Donepezil/Vitamin E study 
We analyzed the baseline and 3-year T1-weighted magnetic resonance imaging data of 110 amnestic mild cognitive impairment (MCI) participants with minimal hippocampal atrophy at baseline from the Alzheimer’s Disease Cooperative Study group (ADCS) MCI Donepezil/Vitamin E trial. 46 subjects converted to AD (MCIc) while 64 remained stable (MCInc). We used the radial distance technique to examine the differences in lateral ventricle shape and size between MCIc and MCInc and the associations between ventricular enlargement and cognitive decline.
MCIc group had significantly larger frontal and right body/occipital horns relative to MCInc at baseline and significantly larger bilateral frontal, body/occipital and left temporal horns at follow-up. Global cognitive decline measured with ADAScog and MMSE and decline in activities of daily living (ADL) were associated with posterior lateral ventricle enlargement. Decline in ADAScog and ADL were associated with left temporal and decline in MMSE with right temporal horn enlargement. After correction for baseline hippocampal volume decline in ADL showed a significant association with right frontal horn enlargement. Executive decline was associated with right frontal and left temporal horn enlargement.
PMCID: PMC3662002  PMID: 23694947
Alzheimer’s disease; AD; mild cognitive impairment; MCI; imaging; MRI; brain atrophy; ventricular enlargement
3.  Quantitative analysis of structural neuroimaging of mesial temporal lobe epilepsy 
Imaging in medicine  2013;5(3):10.2217/iim.13.28.
Mesial temporal lobe epilepsy (MTLE) is the most common of the surgically remediable drug-resistant epilepsies. MRI is the primary diagnostic tool to detect anatomical abnormalities and, when combined with EEG, can more accurately identify an epileptogenic lesion, which is often hippocampal sclerosis in cases of MTLE. As structural imaging technology has advanced the surgical treatment of MTLE and other lesional epilepsies, so too have the analysis techniques that are used to measure different structural attributes of the brain. These techniques, which are reviewed here and have been used chiefly in basic research of epilepsy and in studies of MTLE, have identified different types and the extent of anatomical abnormalities that can extend beyond the affected hippocampus. These results suggest that structural imaging and sophisticated imaging analysis could provide important information to identify networks capable of generating spontaneous seizures and ultimately help guide surgical therapy that improves postsurgical seizure-freedom outcomes.
PMCID: PMC3847906  PMID: 24319498
drug-resistant epilepsy; DTI; mesial temporal lobe epilepsy; morphometry; MRI; quantitative neuroimaging
4.  Three-dimensional mapping of hippocampal and amygdalar structure in euthymic adults with bipolar disorder not treated with lithium 
Psychiatry research  2012;211(3):195-201.
Structural neuroimaging studies of the amygdala and hippocampus in bipolar disorder have been largely inconsistent. This may be due in part to differences in the proportion of subjects taking lithium or experiencing an acute mood state, as both factors have recently been shown to influence gray matter structure. To avoid these problems, we evaluated euthymic subjects not currently taking lithium. Thirty-two subjects with bipolar type I disorder and 32 healthy subjects were scanned using magnetic resonance imaging. Subcortical regions were manually traced, and converted to three-dimensional meshes to evaluate the main effect of bipolar illness on radial distance. Statistical analyses found no evidence for a main effect of bipolar illness in either region, although exploratory analyses found a significant age by diagnosis interaction in the right amygdala, as well as positive associations between radial distance of the left amygdala and both prior hospitalizations for mania and current medication status. These findings suggest that, when not treated with lithium or in an acute mood state, patients with bipolar disorder exhibit no structural abnormalities of the amygdala or hippocampus. Future studies, nevertheless, that further elucidate the impact of age, course of illness, and medication on amygdala structure in bipolar disorder are warranted.
PMCID: PMC3594485  PMID: 23149020
mood disorder; magnetic resonance imaging; hippocampus; amygdala; lithium; bipolar disorder
5.  NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis 
Science translational medicine  2013;5(178):178ra40.
The early events leading to the development of rheumatoid arthritis (RA) remain unclear but formation of autoantibodies to citrullinated antigens (ACPA) is considered a key pathogenic phenomenon. Neutrophils isolated from patients with various autoimmune diseases display enhanced extracellular trap formation (NETs), a phenomenon that externalizes autoantigens and immunostimulatory molecules. We investigated whether aberrant NETosis occurs in RA, determined its triggers and examined its deleterious inflammatory consequences. Enhanced NETosis was observed in circulating and synovial fluid RA neutrophils, compared to neutrophils from healthy controls and from patients with osteoarthritis. Further, netting neutrophils infiltrated RA synovial tissue, rheumatoid nodules and skin. NETosis correlated with ACPA presence and levels and with systemic inflammatory markers. RA sera and immunoglobulin fractions from RA patients with high levels of ACPA and/or rheumatoid factor significantly enhanced NETosis, and the NETs induced by these autoantibodies displayed distinct protein content. During NETosis, neutrophils externalized citrullinated autoantigens implicated in RA pathogenesis, whereas anti-citrullinated vimentin antibodies potently induced NET formation. The inflammatory cytokines IL-17A and TNF-α induced NETosis in RA neutrophils. In turn, NETs significantly augmented inflammatory responses in RA and OA synovial fibroblasts, including induction of IL-6, IL-8, chemokines and adhesion molecules. These observations implicate accelerated NETosis in RA pathogenesis, through externalization of citrullinated autoantigens and immunostimulatory molecules that may promote aberrant adaptive and innate immune responses in the joint and in the periphery, and perpetuate pathogenic mechanisms in this disease.
PMCID: PMC3727661  PMID: 23536012
6.  Regional Differences in White Matter Breakdown Between Frontotemporal Dementia and Early-Onset Alzheimer's Disease1 
White matter abnormalities have been associated with both behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD).
Using MRI diffusion tensor imaging (DTI) measures, we compared white matter integrity between patients with bvFTD and those with early-onset AD and correlated these biomarkers with behavioral symptoms involving emotional blunting.
We studied 8 bvFTD and 12 AD patients as well as 12 demographically-matched healthy controls (NCs). Using four DTI metrics (fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity), we assessed the frontal lobes (FWM) and genu of the corpus callosum (GWM), which are vulnerable late-myelinating regions, and a contrasting early-myelinating region (splenium of the corpus callosum). The Scale of Emotional Blunting Scale (SEB) was used to assess emotional functioning of the study participants.
Compared to AD patients and NCs, the bvFTD subjects exhibited significantly worse FWM and GWM integrity on all four DTI metrics sensitive to myelin and axonal integrity. In contrast, AD patients showed a numerical trend toward worse splenium of the corpus callosum integrity than bvFTD and NC groups. Significant associations between SEB ratings and GWM DTI measures were demonstrated in the combined bvFTD and AD sample. When examined separately, these relationships remained robust for the bvFTD group but not the AD group.
The regional DTI alterations suggest that FTD and AD are each associated with a characteristic distribution of white matter degradation. White matter breakdown in late-myelinating regions was associated with symptoms of emotional blunting, particularly within the bvFTD group.
PMCID: PMC3947877  PMID: 24150110
Alzheimer's disease; behavioral variant; diffusion tensor imaging; early onset; frontotemporal dementia; magnetic resonance imaging; myelin; white matter
7.  Atypical nucleus accumbens morphology in psychopathy: another limbic piece in the puzzle 
Psychopathy has been associated with increased putamen and striatum volumes. The nucleus accumbens –a key structure in reversal learning, less effective in psychopathy –has not yet received specific attention. Moreover, basal ganglia morphology has never been explored. We examined the morphology of the caudate, putamen and accumbens, manually segmented from magnetic resonance images of 26 offenders (age: 32.5±8.4) with medium-high psychopathy (mean PCL-R=30±5) and 25 healthy controls (age: 34.6±10.8). Local differences were statistically modeled using a surface-based radial distance mapping method (p<0.05; multiple comparisons correction through permutation tests). In psychopathy, the caudate and putamen had normal global volume, but different morphology, significant after correction for multiple comparisons, for the right dorsal putamen (permutation test: p=0.02). The volume of the nucleus accumbens was 13% smaller in psychopathy (p corrected for multiple comparisons <0.006). The atypical morphology consisted of predominant anterior hypotrophy bilaterally (10–30%). Caudate and putamen local morphology displayed negative correlation with the lifestyle factor of the PCL-R (permutation test: p=0.05 and 0.03). From these data, psychopathy appears to be associated with an atypical striatal morphology, with highly significant global and local differences of the accumbens. This is, consistent with the clinical syndrome and with theories of limbic involvement.
PMCID: PMC3603572  PMID: 23399314
psychopathy; neuroimaging; basal ganglia; nucleus accumbens; MRI; ASPD
ParkWest is a large Norwegian multicenter study of newly diagnosed drug-naïve subjects with Parkinson’s disease (PD). Cognitively normal PD subjects (PDCN) and PD subjects with mild cognitive impairment (PDMCI) from this cohort have significant hippocampal atrophy and ventricular enlargement compared to normal controls. Here we aimed to investigate whether the same structural changes are associated with CSF levels of Aβ38, Aβ40, Aβ42, total tau and phosphorylated tau.
We performed 3D radial distance analyses of the hippocampi and lateral ventricles using the MRI data from ParkWest subjects who provided CSF at baseline. Our sample consisted of 73 PDCN and 18 PDMCI subjects.
We found significant associations between the levels of all three CSF Aβ analytes and t-tau and lateral ventricular enlargement in the pooled sample. In the PDCN sample all three amyloid analytesshowed significant associations with the radial distance of the occipital and frontal horns of the lateral ventricles. CSF Aβ38 and Aβ42 showed negative associations with enlargement in occipital and frontal horns of the lateral ventricles in the pooled sample, and a negative association with the occipital horns in PDMCI.
CSF Aβ levels in early PD correlate with ventricular enlargement, previously associated with PDD. CSF and MRI markers may therefore help identify PD patients at high risk for developing cognitive decline and dementia in the course of their illness. Contrary to Alzheimer’s disease, we found no associations between CSF t-tau and p-tau and hippocampal atrophy.
PMCID: PMC3608817  PMID: 23408705
Parkinson disease; Mild Cognitive Impairment; Magnetic Resonance Imaging; Cerebrospinal Fluid; Hippocampus; Lateral Ventricles
9.  Connectomics Sheds New Light on Alzheimer's Disease 
Biological psychiatry  2013;73(5):390-392.
PMCID: PMC3661406  PMID: 23399468
10.  Regionally Specific Increased Volume of the Amygdala in Williams Syndrome. Evidence From Surface-based Modeling 
Human brain mapping  2012;35(3):866-874.
Williams syndrome (WS) is a condition caused by a contiguous deletion of approximately 26–28 genes from chromosome 7, and is characterized by abnormal social and emotional processing and abnormal structure and function of the amygdala. Prior studies show that the amygdala is relatively enlarged in WS, but very little is known regarding the regional specificity of increased amygdalar volume in this condition. Here we investigated the regional specificity of structural alterations of the amygdala in WS, compared to a typically developing (TD) control group. We acquired high resolution brain MRI data from 79 participants (39 WS, 40 TD) and used a surface-based analytical modeling approach. The WS group exhibited several areas of increased radial expansion of the amygdalar surface and no areas of decreased radial expansion of the amygdalar surface compared to TD controls. The areas found to exhibit particularly increased radial expansion in WS included the bilateral posterior cortical nucleus, lateral nucleus, and the central nucleus. This greater regional and anatomical specificity of altered amygdala structure in WS contributes to a model relating genetic risk in WS to the development of key brain regions for social and emotional functioning.
PMCID: PMC3751984  PMID: 23152007
Williams syndrome; genetics; amygdala; shape
11.  White matter microstructure in body dysmorphic disorder and its clinical correlates 
Psychiatry research  2013;211(2):132-140.
Body dysmorphic disorder (BDD) is characterized by an often-delusional preoccupation with misperceived defects of appearance, causing significant distress and disability. Although previous studies have found functional abnormalities in visual processing, frontostriatal, and limbic systems, no study to date has investigated the microstructure of white matter connecting these systems in BDD. Fourteen medication-free BDD participants and 16 healthy controls were scanned using diffusion-weighted MRI. We utilized probabilistic tractography to reconstruct tracts of interest, and tract-based spatial statistics to investigate whole brain white matter. To estimate white matter microstructure we used fractional anisotropy (FA), mean diffusivity (MD), and linear and planar anisotropy (cl and cp). We correlated diffusion measures with clinical measures of symptom severity and poor insight/delusionality. Poor insight negatively correlated with FA and cl and positively correlated with MD in the inferior longitudinal fasciculus (ILF) and the forceps major (FM). FA and cl were lower in the ILF and IFOF and higher in the FM in the BDD group, but differences were nonsignificant. This is the first diffusion-weighted MR investigation of white matter in BDD. Results suggest a relationship between impairments in insight, a clinically important phenotype, and fiber disorganization in tracts connecting visual with emotion/memory processing systems.
PMCID: PMC3570702  PMID: 23375265
diffusion tensor imaging; probabilistic tractography; high angular resolution diffusion imaging; inferior longitudinal fasciculus; inferior fronto-occipital fasciculus; forceps major
12.  Impaired default network functional connectivity in autosomal dominant Alzheimer disease 
Neurology  2013;81(8):736-744.
To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network.
Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO).
We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO.
Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease.
PMCID: PMC3776464  PMID: 23884042
13.  Sentrin/SUMO Specific Proteases as Novel Tissue-Selective Modulators of Vitamin D Receptor-Mediated Signaling 
PLoS ONE  2014;9(2):e89506.
Vitamin D receptor (VDR) is a substrate for modification with small ubiquitin-like modifier (SUMO). To further assess the role of reversible SUMOylation within the vitamin D hormonal response, we evaluated the effects of sentrin/SUMO-specific proteases (SENPs) that can function to remove small ubiquitin-like modifier (SUMO) from target proteins upon the activities of VDR and related receptors. We report that SENP1 and SENP2 strikingly potentiate ligand-mediated transactivation of VDR and also its heterodimeric partner, retinoid X receptor (RXRα) with depletion of cellular SENP1 significantly diminishing the hormonal responsiveness of the endogenous vitamin D target gene CYP24A1. We find that SENP-directed modulation of VDR activity is cell line-dependent, achieving potent modulatory effects in Caco-2 and HEK-293 cells, while in MCF-7 cells the vitamin D signal is unaffected by any tested SENP. In support of their function as novel modulators of the vitamin D hormonal pathway we demonstrate that both SENP1 and SENP2 can interact with VDR and reverse its modification with SUMO2. In a preliminary analysis we identify lysine 91, a residue known to be critical for formation and DNA binding of the VDR-RXR heterodimer, as a minor SUMO acceptor site within VDR. In combination, our results support a repressor function for SUMOylation of VDR and reveal SENPs as a novel class of VDR/RXR co-regulatory protein that significantly modulate the vitamin D response and which could also have important impact upon the functionality of both RXR-containing homo and heterodimers.
PMCID: PMC3930751  PMID: 24586832
14.  A Systematic Review of Biomarkers for Disease Progression in Alzheimer's Disease 
PLoS ONE  2014;9(2):e88854.
Using surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true slowing of the neurodegenerative process. A systematic review was undertaken to determine what biomarkers for disease progression in Alzheimer's disease exist and how well they perform.
MEDLINE and Embase (1950–2011) were searched using five search strategies. Abstracts were assessed to identify papers meriting review in full. Studies of participants with probable Alzheimer's disease diagnosed by formal criteria were included. We made no restriction on age, disease duration, or drug treatment. We only included studies with a longitudinal design, in which the putative biomarker and clinical measure were both measured at least twice, as this is the only appropriate study design to use when developing a disease progression biomarker. We included studies which attempted to draw associations between the changes over time in the biomarker used to investigate disease progression and a clinical measure of disease progression.
Fifty-nine studies were finally included. The commonest biomarker modality examined was brain MRI (17/59, 29% of included studies). Median follow-up in included studies was only 1.0 (IQR 0.8–1.7) year and most studies only measured the putative biomarker and clinical measure twice. Included studies were generally of poor quality with small numbers of participants (median 31 (IQR 17 to 64)), applied excessively restrictive study entry criteria, had flawed methodologies and conducted overly simplistic statistical analyses without adjusting for confounding factors.
We found insufficient evidence to recommend the use of any biomarker as an outcome measure for disease progression in Alzheimer's disease trials. However, further investigation into the efficacy of using MRI measurements of ventricular volume and whole brain volume appeared to be merited. A provisional ‘roadmap’ to improve the quality of future disease progression biomarker studies is presented.
PMCID: PMC3928315  PMID: 24558437
15.  Genetic effects on the cerebellar role in working memory: Same brain, different genes? 
NeuroImage  2013;86:392-403.
Over the past several years, evidence has accumulated showing that the cerebellum plays a significant role in cognitive function. Here we show, in a large genetically informative twin sample (n = 430; aged 16–30 years), that the cerebellum is strongly, and reliably (n = 30 rescans), activated during an n-back working memory task, particularly lobules I–IV, VIIa Crus I and II, IX and the vermis. Monozygotic twin correlations for cerebellar activation were generally much larger than dizygotic twin correlations, consistent with genetic influences. Structural equation models showed that up to 65% of the variance in cerebellar activation during working memory is genetic (averaging 34% across significant voxels), most prominently in the lobules VI, and VIIa Crus I, with the remaining variance explained by unique/unshared environmental factors. Heritability estimates for brain activation in the cerebellum agree with those found for working memory activation in the cerebral cortex, even though cerebellar cyto-architecture differs substantially. Phenotypic correlations between BOLD percent signal change in cerebrum and cerebellum were low, and bivariate modeling indicated that genetic influences on the cerebellum are at least partly specific to the cerebellum. Activation on the voxel-level correlated very weakly with cerebellar gray matter volume, suggesting specific genetic influences on the BOLD signal. Heritable signals identified here should facilitate discovery of genetic polymorphisms influencing cerebellar function through genome-wide association studies, to elucidate the genetic liability to brain disorders affecting the cerebellum.
PMCID: PMC3925745  PMID: 24128737
Cerebellum; Heritability; Genetics; Functional MRI; Working memory; Twin study
16.  Unbiased tensor-based morphometry: Improved robustness and sample size estimates for Alzheimer’s disease clinical trials 
NeuroImage  2012;66:648-661.
Various neuroimaging measures are being evaluated for tracking Alzheimer’s disease (AD) progression in therapeutic trials, including measures of structural brain change based on repeated scanning of patients with magnetic resonance imaging (MRI). Methods to compute brain change must be robust to scan quality. Biases may arise if any scans are thrown out, as this can lead to the true changes being overestimated or underestimated. Here we analyzed the full MRI dataset from the first phase of Alzheimer’s Disease Neuroimaging Initiative (ADNI-1) from the first phase of Alzheimer’s Disease Neuroimaging Initiative (ADNI-1) and assessed several sources of bias that can arise when tracking brain changes with structural brain imaging methods, as part of a pipeline for tensor-based morphometry (TBM). In all healthy subjects who completed MRI scanning at screening, 6, 12, and 24 months, brain atrophy was essentially linear with no detectable bias in longitudinal measures. In power analyses for clinical trials based on these change measures, only 39 AD patients and 95 mild cognitive impairment (MCI) subjects were needed for a 24-month trial to detect a 25% reduction in the average rate of change using a two-sided test (α=0.05, power=80%). Further sample size reductions were achieved by stratifying the data into Apolipoprotein E (ApoE) ε4 carriers versus non-carriers. We show how selective data exclusion affects sample size estimates, motivating an objective comparison of different analysis techniques based on statistical power and robustness. TBM is an unbiased, robust, high-throughput imaging surrogate marker for large, multi-site neuroimaging studies and clinical trials of AD and MCI.
PMCID: PMC3785376  PMID: 23153970
Alzheimer’s disease; Mild cognitive impairment; Aging; ADNI; Tensor-based morphometry; Drug trial
17.  Influence of chronic exercise on carotid atherosclerosis in marathon runners 
BMJ Open  2014;4(2):e004498.
The effect of habitual, high-intensity exercise training on the progression of atherosclerosis is unclear. We assessed indices of vascular health (central systolic blood pressure (SBP) and arterial stiffness as well as carotid intima-medial thickness (cIMT)) in addition to cardiovascular risk factors of trained runners versus their untrained spouses or partners to evaluate the impact of exercise on the development of carotid atherosclerosis.
field study at Boston Marathon.
42 qualifiers (mean age±SD: 46±13 years, 21 women) for the 2012 Boston Marathon and their sedentary domestic controls (46±12 years, n=21 women).
We measured medical and running history, vital signs, anthropometrics, blood lipids, C reactive protein (CRP), 10 years Framingham risk, central arterial stiffness and SBP and cIMT.
Multiple cardiovascular risk factors, including CRP, non-high-density lipoprotein cholesterol, triglycerides, heart rate, body weight and body mass index (all p<0.05), were reduced in the runners. The left and right cIMT, as well as central SBP, were not different between the two groups (all p>0.31) and were associated with age (all r≥0.41; p<0.01) and Framingham risk score (all r≥0.44; p<0.01) independent of exercise group (all p>0.08 for interactions). The amplification of the central pressure waveform (augmentation pressure at heart rate 75 bpm) was also not different between the two groups (p=0.07) but was related to age (p<0.01) and group (p=0.02) in a multiple linear regression model.
Habitual endurance exercise improves the cardiovascular risk profile, but does not reduce the magnitude of carotid atherosclerosis associated with age and cardiovascular risk factors.
PMCID: PMC3927935  PMID: 24531453
Sports Medicine
18.  Relation of Callosal Structure to Cognitive Abilities in Temporal Lobe Epilepsy 
The main objective of this paper is to analyze the influence of mesial temporal lobe epilepsy (mTLE) on the morphology of the corpus callosum (CC) and its relation to cognitive abilities. More specifically, we investigated correlations between intellectual abilities and callosal morphology, while additionally exploring the modulating impact of (a) side of seizure onset (b) age of disease onset. For this reason a large representative sample of patients with hippocampal sclerosis (n = 79; 35 males; 44 females; age: 18–63 years) with disease onset ranging from 0 to 50 years of age, and consisting of 46 left and 33 right mTLE-patients was recruited. Intelligence was measured using the Wechsler-Adult Intelligence Scale Revised. To get localizations of correlations with high anatomic precision, callosal morphology was examined using computational mesh-based modeling methods, applied to anatomical brain MRI scans. Intellectual performance was positively associated with callosal thickness in anterior and midcallosal callosal regions, with anterior parts being slightly more affected by age of disease onset and side of seizure onset than posterior parts. Earlier age at onset of epilepsy was associated with lower thickness in anterior and midcallosal regions. In addition, laterality of seizure onset had a significant influence on anterior CC morphology, with left hemispheric origin having stronger effects. We found that in mTLE, anterior and midcallosal CC morphology are related to cognitive performance. The findings support recent findings of detrimental effects of early onset mTLE on anterior brain regions and of a distinct effect particularly of left mTLE on frontal lobe functioning and structure. The causal nature of the relationship remains an open question, i.e., whether CC morphology impacts IQ development or whether IQ development impacts CC morphology, or both.
PMCID: PMC3920113  PMID: 24575078
MRI; temporal lobe epilepsy; corpus callosum; full-scale IQ; intelligence; Wechsler-adult intelligence scale revised
19.  The protein arginine deiminases (PADs): Structure, Function, Inhibition, and Disease 
Biopolymers  2013;99(2):155-163.
The post translational modification of histones has significant effects on overall chromatin function. One such modification is citrullination, which is catalyzed by the protein arginine deiminases (PADs), a unique family of enzymes that catalyzes the hydrolysis of peptidyl-arginine to form peptidyl-citrulline on histones, fibrinogen, and other biologically relevant proteins. Overexpression and/or increased PAD activity is observed in several diseases, including rheumatoid arthritis, Alzheimer’s disease, multiple sclerosis, lupus, Parkinson’s disease, and cancer. This review discusses the important structural and mechanistic characteristics of the PADs, as well as recent investigations into the role of the PADs in increasing disease severity in RA and colitis and the importance of PAD activity in mediating neutrophil extracellular trap (NET) formation through chromatin decondensation. Lastly, efforts to develop PAD inhibitors with excellent potency, selectivity and in vivo efficacy are discussed, highlighting the most promising inhibitors.
PMCID: PMC3507426  PMID: 23175390
20.  Magnetic Resonance Field Strength Effects on Diffusion Measures and Brain Connectivity Networks 
Brain Connectivity  2013;3(1):72-86.
The quest to map brain connectivity is being pursued worldwide using diffusion imaging, among other techniques. Even so, we know little about how brain connectivity measures depend on the magnetic field strength of the scanner. To investigate this, we scanned 10 healthy subjects at 7 and 3 tesla—using 128-gradient high-angular resolution diffusion imaging. For each subject and scan, whole-brain tractography was used to estimate connectivity between 113 cortical and subcortical regions. We examined how scanner field strength affects (i) the signal-to-noise ratio (SNR) of the non-diffusion-sensitized reference images (b0); (ii) diffusion tensor imaging (DTI)-derived fractional anisotropy (FA), mean, radial, and axial diffusivity (MD/RD/AD), in atlas-defined regions; (iii) whole-brain tractography; (iv) the 113×113 brain connectivity maps; and (v) five commonly used network topology measures. We also assessed effects of the multi-channel reconstruction methods (sum-of-squares, SOS, at 7T; adaptive recombine, AC, at 3T). At 7T with SOS, the b0 images had 18.3% higher SNR than with 3T-AC. FA was similar for most regions of interest (ROIs) derived from an online DTI atlas (ICBM81), but higher at 7T in the cerebral peduncle and internal capsule. MD, AD, and RD were lower at 7T for most ROIs. The apparent fiber density between some subcortical regions was greater at 7T-SOS than 3T-AC, with a consistent connection pattern overall. Suggesting the need for caution, the recovered brain network was apparently more efficient at 7T, which cannot be biologically true as the same subjects were assessed. Care is needed when comparing network measures across studies, and when interpreting apparently discrepant findings.
PMCID: PMC3621300  PMID: 23205551
brain network analysis; DTI; fractional anisotropy; graph theory; high-field MRI; high angular resolution diffusion imaging (HARDI); signal-to-noise ratio; tractography
21.  Regional brain volume differences in symptomatic and presymptomatic carriers of familial Alzheimer’s disease mutations 
Mutations in the presenilin (PSEN1, PSEN2) and amyloid precursor protein (APP) genes cause familial Alzheimer’s disease (FAD) in a nearly fully penetrant, autosomal dominant manner, providing a unique opportunity to study presymptomatic individuals who can be predicted to develop Alzheimer’s disease (AD) with essentially 100% certainty. Using tensor-based morphometry (TBM), we examined brain volume differences between presymptomatic and symptomatic FAD mutation carriers and non-carrier (NC) relatives.
Twenty-five mutation carriers and 10 NC relatives underwent brain MRI and clinical assessment. Four mutation carriers had dementia (MUT-Dem), 12 had amnestic mild cognitive impairment (MUT-aMCI) and nine were cognitively normal (MUT-Norm). TBM brain volume maps of MUT-Norm, MUT-aMCI and MUT-Dem subjects were compared to NC subjects.
MUT-Norm subjects exhibited significantly smaller volumes in the thalamus, caudate and putamen. MUT-aMCI subjects had smaller volumes in the thalamus, splenium and pons, but not in the caudate or putamen. MUT-Dem subjects demonstrated smaller volumes in temporal, parietal and left frontal regions. As non-demented carriers approached the expected age of dementia diagnosis, this was associated with larger ventricular and caudate volumes and a trend towards smaller temporal lobe volume.
Cognitively intact FAD mutation carriers had lower thalamic, caudate and putamen volumes, and we found preliminary evidence for increasing caudate size during the predementia stage. These regions may be affected earliest during prodromal stages of FAD, while cortical atrophy may occur in later stages, when carriers show cognitive deficits. Further studies of this population will help us understand the progression of neurobiological changes in AD.
PMCID: PMC3779052  PMID: 23085935
22.  Brain putamen volume changes in newly-diagnosed patients with obstructive sleep apnea 
NeuroImage : Clinical  2014;4:383-391.
Obstructive sleep apnea (OSA) is accompanied by cognitive, motor, autonomic, learning, and affective abnormalities. The putamen serves several of these functions, especially motor and autonomic behaviors, but whether global and specific sub-regions of that structure are damaged is unclear. We assessed global and regional putamen volumes in 43 recently-diagnosed, treatment-naïve OSA (age, 46.4 ± 8.8 years; 31 male) and 61 control subjects (47.6 ± 8.8 years; 39 male) using high-resolution T1-weighted images collected with a 3.0-Tesla MRI scanner. Global putamen volumes were calculated, and group differences evaluated with independent samples t-tests, as well as with analysis of covariance (covariates; age, gender, and total intracranial volume). Regional differences between groups were visualized with 3D surface morphometry-based group ratio maps. OSA subjects showed significantly higher global putamen volumes, relative to controls. Regional analyses showed putamen areas with increased and decreased tissue volumes in OSA relative to control subjects, including increases in caudal, mid-dorsal, mid-ventral portions, and ventral regions, while areas with decreased volumes appeared in rostral, mid-dorsal, medial-caudal, and mid-ventral sites. Global putamen volumes were significantly higher in the OSA subjects, but local sites showed both higher and lower volumes. The appearance of localized volume alterations points to differential hypoxic or perfusion action on glia and other tissues within the structure, and may reflect a stage in progression of injury in these newly-diagnosed patients toward the overall volume loss found in patients with chronic OSA. The regional changes may underlie some of the specific deficits in motor, autonomic, and neuropsychologic functions in OSA.
•Global and regional putamen volumes were examined in newly-diagnosed OSA.•Global volumes are higher, but subareas showed increases and decreases.•The volume increases suggest transient tissue swelling from hypoxic action.•Altered sites likely contribute to motor and other functional deficits in OSA.
PMCID: PMC3930100  PMID: 24567910
OSA, Obstructive sleep apnea; 3D, Three dimensional; MRI, Magnetic resonance imaging; AHI, Apnea–hypopnea index; ESS, Epworth Sleepiness Scale; PSQI, Pittsburgh Sleep Quality Index; BDI-II, Beck Depression Inventory II; BAI, Beck Anxiety Inventory; PD, Proton density; MNI, Montreal Neurological Institute; CSF, Cerebrospinal fluid; TIV, Total intracranial volume; MPRAGE, Magnetization prepared rapid acquisition gradient-echo; TR, Repetition time; TE, Echo time; FA, Flip angle; FOV, Field of view; GRAPPA, Generalized autocalibrating partially parallel acquisition; Magnetic resonance imaging; Cognition; 3D surface morphometry; Basal ganglia; Intermittent hypoxia; Autonomic; Motor
23.  Predicting the Risk of Suicide by Analyzing the Text of Clinical Notes 
PLoS ONE  2014;9(1):e85733.
We developed linguistics-driven prediction models to estimate the risk of suicide. These models were generated from unstructured clinical notes taken from a national sample of U.S. Veterans Administration (VA) medical records. We created three matched cohorts: veterans who committed suicide, veterans who used mental health services and did not commit suicide, and veterans who did not use mental health services and did not commit suicide during the observation period (n = 70 in each group). From the clinical notes, we generated datasets of single keywords and multi-word phrases, and constructed prediction models using a machine-learning algorithm based on a genetic programming framework. The resulting inference accuracy was consistently 65% or more. Our data therefore suggests that computerized text analytics can be applied to unstructured medical records to estimate the risk of suicide. The resulting system could allow clinicians to potentially screen seemingly healthy patients at the primary care level, and to continuously evaluate the suicide risk among psychiatric patients.
PMCID: PMC3904866  PMID: 24489669
24.  Fat-mass-related hormone, plasma leptin, predicts brain volumes in the elderly 
Neuroreport  2013;24(2):58-62.
Leptin, a hormone produced by body fat tissue, acts on hypothalamic receptors in the brain to regulate appetite and energy expenditure, and on neurons in the arcuate nucleus to signal that a individual has had enough to eat. Leptin enters the central nervous system at levels that depend on a individual’s body fat. Obese people, on average, show greater brain atrophy in old age, so it is valuable to know whether brain atrophy relates to leptin levels, which can be targeted by interventions. We therefore determined how plasma leptin levels, and BMI, relate to brain structure, and whether leptin levels might account for BMI’s effect on the brain. We measured regional brain volumes using tensor-based morphometry, in MRI scans of 517 elderly individuals with plasma leptin measured (mean: 13.3±0.6 ng/ml; mean age: 75.2±7.3 years; 321 men/196 women). We related plasma leptin levels to brain volumes at every location in the brain after adjusting for age, sex, and diagnosis and, later, also BMI. Plasma leptin levels were significantly higher (a) in women than men, and (b) in obese versus overweight, normal or underweight individuals. People with higher leptin levels showed deficits in frontal, parietal, temporal and occipital lobes, brainstem, and the cerebellum, irrespective of age, sex, or diagnosis. These associations persisted after controlling for BMI. Greater brain atrophy may occur in people with central leptin insufficiency, a marker of obesity. Therapeutic manipulation of leptin may be a promising direction for slowing brain decline.
PMCID: PMC3635486  PMID: 23238164
Alzheimer’s disease; BMI; brain structure; leptin; MRI; obesity
The collection of brain images from populations of subjects who have been genotyped with genome-wide scans makes it feasible to search for genetic effects on the brain. Even so, multivariate methods are sorely needed that can search both images and the genome for relationships, making use of the correlation structure of both datasets. Here we investigate the use of sparse canonical correlation analysis (CCA) to home in on sets of genetic variants that explain variance in a set of images. We extend recent work on penalized matrix decomposition to account for the correlations in both datasets. Such methods show promise in imaging genetics as they exploit the natural covariance in the datasets. They also avoid an astronomically heavy statistical correction for searching the whole genome and the entire image for promising associations.
PMCID: PMC3892670  PMID: 24443689
Diffusion tensor imaging; Genome wide association; Canonical correlation analysis; sparsity; lasso

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