Bipolar disorder is characterized by extreme mood swings, including both manic and depressive episodes commonly accompanied by psychosis. Many imaging studies have investigated white matter changes in bipolar illness, and the results have suggested abnormal intra- and inter-hemispheric white matter structures, particularly in the fronto-limbic and callosal systems. However, some inconsistency remains in the literature, and no study to-date has utilized brain network analysis using graph theory. Here, we acquired 64-direction diffusion weighted imaging (DWI) on 25 euthymic bipolar I subjects and 25 gender/age matched healthy subjects. White matter integrity measures were computed and compared in 50 white matter ROIs. The results indicated impaired integrity in the corpus callosum. Guided by this, we constructed whole brain structural connectivity networks using graph theory. We devised brain network metrics (inter-hemispheric path length and efficiency) to further probe inter-hemispheric integration, and demonstrated relatively preserved intra-hemispheric but significantly impaired inter-hemispheric integration in our bipolar subjects.
bipolar disorder; diffusion imaging; tractography; brain network analysis
The presence of noise in High Angular Resolution Diffusion Imaging (HARDI) data of the brain can limit the accuracy with which fiber pathways of the brain can be extracted. In this work, we present a variational model to denoise HARDI data corrupted by Rician noise. Numerical experiments are performed on three types of data: 2D synthetic data, 3D diffusion-weighted Magnetic Resonance Imaging (DW-MRI) data of a hardware phantom containing synthetic fibers, and 3D real HARDI brain data. Experiments show that our model is effective for denoising HARDI-type data while preserving important aspects of the fiber pathways such as fractional anisotropy and the orientation distribution functions.
Investigators are interested in determining whether lifetime behavioral traits and specific mood states experienced close to death affect brain gene and protein expression as assessed in post-mortem human brains. Major obstacles to conducting this type of research are the uncertain reliability of the post-mortem psychiatric diagnoses and clinical information because of the retrospective nature of the information. In this study, we addressed the concordance of clinical information obtained through an informant compared with information obtained through a clinician interview of the subject. To test this, we measured both lifetime and within the week psychiatric symptoms of subjects (n=20) and an informant, their next-of-kin (n=20) who were asked identical questions. We found Diagnostic and Statistical Manual (DSM)-IV axis 1 diagnoses by Mini-International Neuropsychiatric Interview proportion of positive agreement for major depression was 0.97, bipolar disorder was 0.81, whereas proportion of negative agreement was 0.97 for schizophrenia. Symptom scale intra-class correlation coefficients and 95% confidence interval were: Bipolar Inventory of Signs and Symptoms=0.59 (0.23, 0.81), Brief Psychiatric Rating Scale=0.58 (0.19, 0.81), Hamilton Depression Rating Scale=0.44 (0.03, 0.72), Montgomery Asberg Depression Rating Scale=0.44 (0.03, 0.72), Young Mania Rating Scale=0.61 (0.30, 0.82), Barratt Impulsiveness Score=0.36 (−0.11, 0.70) and Childhood Trauma Questionnaire=0.48 (−0.15, 0.83). We show that DSM-IV diagnoses; lifetime impulsivity severity, childhood trauma score and symptom scores were significantly consistent between the subjects and their informants. These data suggest, with some limitations, that both retrospective and informant obtained information can provide useful clinical information in post-mortem research.
BISS; HAM-D; informant interview; MADRS; next-of-kin interview; post-mortem; psychological autopsy
Significant deficiencies in understanding of xenospecific immunity have impeded the success of preclinical trials in xenoislet transplantation. While galactose-α1,3-galactose, the gal epitope, has emerged as the principal target of rejection in pig-to-primate models of solid organ transplant, the importance of gal-specific immunity in islet xenotransplant models has yet to be clearly demonstrated. Here we directly compare the immunogenicity, survival and function of neonatal porcine islets (NPIs) from gal-expressing wild-type (WT) or gal-deficient galactosyl transferase knock-out (GTKO) donors. Paired diabetic rhesus macaques were transplanted with either WT (n=5) or GTKO (n=5) NPIs. Recipient blood glucose, transaminase, and serum xenoantibody levels were used to monitor response to transplant. Four of 5 GTKO versus 1 of 5 WT recipients achieved insulin-independent normoglycemia; transplantation of WT islets resulted in significantly greater transaminitis. WT NPIs were more susceptible to antibody and complement binding and destruction in vitro. Our results confirm that gal is an important variable in xenoislet transplantation. GTKO NPI recipients have improved rates of normoglycemia, likely due to decreased susceptibility of xenografts to innate immunity mediated by complement and preformed xenoantibody. Therefore, the use of GTKO donors is an important step towards improved consistency and interpretability of results in future xenoislet studies.
Xenotransplantation; costimulation blockade; porcine islets; transgenic pigs; innate immunity; Gal knockout
Juvenile myoclonic epilepsy (JME) is characterized by myoclonic jerks of the upper limbs, often triggered by cognitive stressors. Here we aim to reconcile this particular seizure phenotype with the known frontal lobe type neuropsychological profile, photosensitivity, hyperexcitable motor cortex, and recent advanced imaging studies that identified abnormal functional connectivity of the motor cortex and supplementary motor area (SMA).
We acquired fMRI and diffusion tensor imaging (DTI) in a cohort of 29 patients with JME and 28 healthy control subjects. We used fMRI to determine functional connectivity and DTI-based region parcellation and voxel-wise comparison of probabilistic tractography data to assess the structural connectivity profiles of the mesial frontal lobe.
Patients with JME showed alterations of mesial frontal connectivity with increased structural connectivity between the prefrontal cognitive cortex and motor cortex. We found a positive correlation between DTI and fMRI-based measures of structural and functional connectivity: the greater the structural connectivity between these 2 regions, the greater the observed functional connectivity of corresponding areas. Furthermore, connectivity was reduced between prefrontal and frontopolar regions and increased between the occipital cortex and the SMA.
The observed alterations in microstructural connectivity of the mesial frontal region may represent the anatomic basis for cognitive triggering of motor seizures in JME. Changes in the mesial frontal connectivity profile provide an explanatory framework for several other clinical observations in JME and may be the link between seizure semiology, neurophysiology, neuropsychology, and imaging findings in JME.
Screening mammography results in the increased detection of indolent tumors. We hypothesized that screen and symptom-detected tumors would show genotypic differences as copy number imbalances (CNIs) that in part explain differences in the clinical behavior between screen and symptom-detected breast tumors.
We evaluated 850 women aged ≥ 40 diagnosed with stage I–II breast cancer at the MD Anderson Cancer Center between 1985 to 2000 with information available on method of tumor detection (screen versus symptoms). CNIs in screen and symptom-detected tumors were identified using high-density molecular inversion probe arrays. Cox proportional modeling was used to estimate the effect of method of tumor detection on disease-free survival after adjusting for age, stage and the CNIs.
The majority of tumors were symptom-detected (n=603) compared to screen-detected (n=247). Copy number gains in chromosomes 2p, 3q, 8q, 11p and 20q were associated with method of breast cancer detection (p<0.00001). We estimated that 32% and 63% of the survival advantage of screen-detection was accounted for by age, stage, nuclear grade and Ki67 in women aged 50–70 and aged 40–87, respectively. In each age category, an additional 20% of the survival advantage was accounted for by CNIs associated with method of detection.
Specific CNIs differ between screen and symptom-detected tumors and explain part of the survival advantage associated with screen-detected tumors. Measurement of tumor genotype has the potential to improve discrimination between indolent and aggressive screen-detected tumors and aid patient and physician decision making about use of surgical and adjuvant treatments.
Neuroimaging research implicates the hippocampus in the aetiology of major depressive disorder (MDD). Imaging genetics studies have investigated the influence of the serotonin transporter-linked polymorphic region (5HTTLPR) and brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on the hippocampus in healthy individuals and patients with depression (MDD). However, conflicting results have led to inconclusive evidence about the effect of 5HTTLPR or BDNF on hippocampal volume (HCV). We hypothesized that analysis methods based on three-dimensional (3D) hippocampal shape mapping could offer improved sensitivity to clarify these effects. Magnetic resonance imaging data were collected in parallel samples of 111 healthy individuals and 84 MDD patients. Manual hippocampal segmentation was conducted and the resulting data used to investigate the influence of 5HTTLPR and BDNF Val66Met genotypes on HCV and 3D shape within each sample. Hippocampal volume normalized by intracranial volume (ICV) showed no significant difference between 5HTTLPR S allele carriers and L/L homozygotes or between BDNF Met allele carriers and Val/Val homozygotes in the group of healthy individuals. Moreover, there was no significant difference in normalized HCV between 5HTTLPR diallelic and triallelic classifications or between the BDNF Val66Met genotypes in MDD patients, although there was a relationship between BDNF Val66Met and ICV. Shape analysis detected dispersed between-group differences, but these effects did not survive multiple testing correction. In this study, there was no evidence of a genetic effect for 5HTTLPR or BDNF Val66Met on hippocampal morphology in either healthy individuals or MDD patients despite the relatively large sample sizes and sensitive methodology.
BDNF; 5HTTLPR; hippocampus; major depressive disorder; MRI; shape mapping
The majority of studies relating amyloid pathology with brain volumes have been cross-sectional. Apolipoprotein E4 (APOE4), a genetic risk factor for Alzheimer’s disease (AD), is also associated with hippocampal volume loss. No studies have considered the effects of amyloid pathology and APOE4 together on longitudinal volume loss.
We evaluated whether an abnormal level of cerebrospinal fluid beta-amyloid (CSF Aβ) and APOE4 carrier status were independently associated with greater hippocampal volume loss over 1 year. We then assessed whether APOE4 status and CSF Aβ acted synergistically, testing the significance of an interaction term in the regression analysis. We included 297 participants: 77 cognitively normal (NC), 144 with mild cognitive impairment (MCI), and 76 with AD.
An abnormal CSF Aβ level was found to be associated with greater hippocampal volume loss over 1 year in each group. APOE4 was associated with hippocampal volume loss only in the NC and MCI groups. APOE4 carriers with abnormal CSF Aβ in the MCI group acted synergistically to produce disproportionately greater volume loss than noncarriers.
Baseline CSF Aβ predicts progression of hippocampal volume loss. APOE4 carrier status amplifies the degree of neurodegeneration in MCI. Understanding the effect of interactions between genetic risk and amyloid pathology will be important in clinical trials and our understanding of the disease process.
apolipoprotein E4; hippocampal atrophy; beta-amyloid; biomarker; MRI
We previously reported that children in the UKALL XI ALL trial with HLA-DP 1 and -DP 3 supertypes had significantly worse event-free survival (EFS) than children with other DP supertypes. As DP 1 and DP 3 share two of four key antigen-binding amino-acid polymorphisms (aspartic acid84–lysine69), we asked whether Asp84-Lys69 or Asp84 alone were independent prognostic indicators in childhood acute lymphoblastic leukemia (ALL). We analysed EFS in 798 UKALL XI patients, stratified by Asp84-Lys69 vs non-Asp84-Lys69, for a median follow-up of 12.5 years. Asp84-Lys69 was associated with a significantly worse EFS than non-Asp84-Lys69 (5-year EFS: Asp84-Lys69: 58.8% (95% CI (confidence of interval): 52.7–64.9%); non-Asp84-Lys69: 67.3% (63.4–71.2%); 2P=0.007). Post-relapse EFS was 10% less in Asp84-Lys69 than non-Asp84-Lys69 patients. EFS was significantly worse (P=0.03) and post-relapse EFS marginally worse (P=0.06) in patients with Asp84 compared with Gly84. These results suggest that Asp84-Lys69 predicted adverse EFS in the context of UKALL XI because of Asp84, and may have influenced post-relapse EFS. We speculate that this may be due to the recruitment of Asp84-Lys69-restricted regulatory T cells in the context of this regimen, leading to the re-emergence of residual disease. However, functional and molecular studies of the prognostic value of this and other HLA molecular signatures in other childhood ALL trials are needed.
childhood ALL; HLA-DP supertype; DP molecular signature; event-free survival; relapse
Histologic studies show that the amygdala is affected by Alzheimer disease (AD) pathology, and its medial aspect is the most involved. We aimed to assess in vivo local structural differences in the amygdala of patients with AD using high-field MRI.
A total of 19 patients with AD (mean age 76, SD 6 years, mean Mini-Mental State Examination score [MMSE] 13, SD 4) and 19 healthy elderly controls (age 74, SD 5, MMSE 29, SD 1) were enrolled. The radial atrophy mapping technique was used to reconstruct the 3-dimensional surface of the amygdala. Maps of surface tissue loss in patients with AD vs controls were computed and statistically tested with permutation tests thresholded at p < 0.05, to correct for multiple comparisons. A digital atlas of the amygdalar nuclei was used to infer which nuclei were involved.
Both amygdalar volumes were significantly smaller in patients with AD (right 1,508 mm3, SD 418; left 1,646, SD 419) than controls (right 2,129 mm3, SD 316; left 2,077, SD 376; p < 0.002). In the dorsomedial part, significant local tissue loss (20%–30%) was mapped in the medial and central nuclei. Ventrally, the lateral nucleus (La) and the basolateral ventral medial nucleus (BLVM) were also involved (20%–30% loss).
We found in vivo local structural differences in the amygdala of patients with AD. The nuclei involved have known connections to the hippocampus (BLVM, La) and olfactory system (medial nucleus) and with cholinergic pathways (central nucleus). This pattern is consistent with the known pathophysiology of neural systems affected by AD.
Reduced mismatch negativity (MMN) in response to auditory change is a well-established finding in schizophrenia and has been shown to be correlated with impaired daily functioning, rather than with hallmark signs and symptoms of the disorder. In this study, we investigated (1) whether the relationship between reduced MMN and impaired daily functioning is mediated by cortical volume loss in temporal and frontal brain regions in schizophrenia and (2) whether this relationship varies with the type of auditory deviant generating MMN. MMN in response to duration, frequency, and intensity deviants was recorded from 18 schizophrenia subjects and 18 pairwise age- and gender-matched healthy subjects. Patients’ levels of global functioning were rated on the Social and Occupational Functioning Assessment Scale. High-resolution structural magnetic resonance scans were acquired to generate average cerebral cortex and temporal lobe models using cortical pattern matching. This technique allows accurate statistical comparison and averaging of cortical measures across subjects, despite wide variations in gyral patterns. MMN amplitude was reduced in schizophrenia patients and correlated with their impaired day-to-day function level. Only in patients, bilateral gray matter reduction in Heschl's gyrus, as well as motor and executive regions of the frontal cortex, correlated with reduced MMN amplitude in response to frequency deviants, while reduced gray matter in right Heschl's gyrus also correlated with reduced MMN to duration deviants. Our findings further support the importance of MMN reduction in schizophrenia by linking frontotemporal cerebral gray matter pathology to an automatically generated event-related potential index of daily functioning.
magnetic resonance imaging; cortical pattern matching; mismatch negativity; event-related potential; sociooccupational functioning; auditory; temporal lobes; frontal lobes; Heschl's gyrus
Temporal lobe epilepsy (TLE) is typically associated with long-term memory dysfunction. The frontal lobes support high-level cognition comprising executive skills and working memory that is vital for daily life functioning. Deficits in these functions have been increasingly reported in TLE. Evidence from both the neuropsychological and neuroimaging literature suggests both executive function and working memory are compromised in the presence of TLE. In relation to executive impairment, particular focus has been paid to set shifting as measured by the Wisconsin Card Sorting Task. Other discrete executive functions such as decision-making and theory of mind also appear vulnerable but have received little attention. With regard to working memory, the medial temporal lobe structures appear have a more critical role, but with emerging evidence of hippocampal dependent and independent processes. The relative role of underlying pathology and seizure spread is likely to have considerable bearing upon the cognitive phenotype and trajectory in TLE. The identification of the nature of frontal lobe dysfunction in TLE thus has important clinical implications for prognosis and surgical management. Longitudinal neuropsychological and neuroimaging studies assessing frontal lobe function in TLE patients pre- and postoperatively will improve our understanding further.
Temporal lobe epilepsy; Cognition; Working memory; Executive function; Neuroimaging
We analyzed the degree of genetic control over intersubject variability in the microstructure of cerebral white matter (WM) using diffusion tensor imaging (DTI). We performed heritability, genetic correlation and quantitative trait loci (QTL) analyses for the whole-brain and 10 major cerebral WM tracts. Average measurements for fractional anisotropy (FA), radial (L⊥) and axial (L||) diffusivities served as quantitative traits. These analyses were done in 467 healthy individuals (182 males/285 females; average age 47.9±13.5 years; age range:19–85 years), recruited from randomly-ascertained pedigrees of extended families. Significant heritability was observed for FA (h2=.52±.11;p=10−7) and L⊥(h2=.37±.14; p=0.001), while L|| measurements were not significantly heritable (h2=.09±.12; p=.20). Genetic correlation analysis indicated that the FA and L⊥ shared 46% of the genetic variance. Tract-wise analysis revealed a regionally diverse pattern of genetic control, which was unrelated to ontogenic factors, such as tract-wise age-of-peak FA values and rates of age-related change in FA. QTL analysis indicated linkages for whole-brain average FA (LOD=2.36) at the marker D15S816on chromosome 15q25, and for L⊥(LOD=2.24) near the marker D3S1754 on the chromosome 3q27. These sites have been reported to have significant co-inheritance with two psychiatric disorders (major depression and obsessive-compulsive disorder) in which patients show characteristic alterations in cerebral WM. Our findings suggest that the microstructure of cerebral white matter is under a strong genetic control and further studies in healthy as well as patients with brain-related illnesses are imperative to identify the genes that may influence cerebral white matter.
white matter; diffusion tensor imaging; DTI; heritability; linkage
Physical activity (PA) has been hypothesized to spare gray matter volume in late adulthood, but longitudinal data testing an association has been lacking. Here we tested whether PA would be associated with greater gray matter volume after a 9-year follow-up, a threshold could be identified for the amount of walking necessary to spare gray matter volume, and greater gray matter volume associated with PA would be associated with a reduced risk for cognitive impairment 13 years after the PA evaluation.
In 299 adults (mean age 78 years) from the Cardiovascular Health Cognition Study, we examined the association between gray matter volume, PA, and cognitive impairment. Physical activity was quantified as the number of blocks walked over 1 week. High-resolution brain scans were acquired 9 years after the PA assessment on cognitively normal adults. White matter hyperintensities, ventricular grade, and other health variables at baseline were used as covariates. Clinical adjudication for cognitive impairment occurred 13 years after baseline.
Walking amounts ranged from 0 to 300 blocks (mean 56.3; SD 69.7). Greater PA predicted greater volumes of frontal, occipital, entorhinal, and hippocampal regions 9 years later. Walking 72 blocks was necessary to detect increased gray matter volume but walking more than 72 blocks did not spare additional volume. Greater gray matter volume with PA reduced the risk for cognitive impairment 2-fold.
Greater amounts of walking are associated with greater gray matter volume, which is in turn associated with a reduced risk of cognitive impairment.
= modified Mini-Mental State Examination;
= Cardiovascular Health Study Cognition Study;
= Digit Symbol Substitution Test;
= gray matter;
= mild cognitive impairment;
= odds ratio;
= physical activity;
= Statistical Parametric Mapping;
= total intracranial volume;
= voxel-based morphometry;
= white matter.
The aim of this study was to determine if there were focal cortical abnormalities in juvenile myoclonic epilepsy (JME) using neuropsychological investigations and MRI.
Twenty-eight patients with JME and a large sample of healthy controls were assessed using a series of neuropsychological tests as well as structural and diffusion tensor MRI (DTI). DTI measures assessed fractional anisotropy (FA) within a white matter skeleton.
Neuropsychological testing indicated subtle dysfunctions in verbal fluency, comprehension, and expression, as well as nonverbal memory and mental flexibility. Utilizing whole-brain voxel-based morphometry for gray matter MRI data and tract-based spatial statistics for white matter diffusion MRI data, we found reductions in gray matter volume (GMV) in the supplementary motor area and posterior cingulate cortex and reductions in FA in underlying white matter of the corpus callosum. Supplementary motor area FA predicted scores in word naming tasks and expression scores. Posterior cingulate cortex GMV and FA predicted cognitive inhibition scores on the mental flexibility task.
The neuropsychological, structural, and tractography results implicate mesial frontal cortex, especially the supplementary motor area, and posterior cingulate cortex in JME.
Interactions between prevalent late-life medical conditions and expansion of the cerebral ventricles are not well understood. Thirty elderly subjects received three magnetic resonance (MR) scans each, in 1997–1999, 2002–2004, and 2003–2005. A linear expansion model of MR-measured lateral ventricle volume was estimated for each subject by fitting a line to a plot of their 1997–1999 and 2002–2004 volumes as a function of time. Acceleration in ventricular expansion was defined as the deviation between the 2003–2005 volumes measured from MR and the 2003–2005 volumes predicted by the linear expansion model. Ventricular acceleration was analyzed in a multivariate model with age, race, history of heart disease, diabetes, and hypertension as fixed effects. Ventricular acceleration was significantly higher in non-whites, diabetics, and those without heart disease (p < 0.05). Ventricular acceleration was higher in subjects with a history of hypertension, but the difference was not statistically significant (p = 0.08). Acceleration of ventricular expansion in the elderly may be related to demographic and cardiovascular factors.
Magnetic resonance imaging; Lateral ventricles; Aging; Diabetes; Heart disease
In this article, we review recent mathematical models and computational methods for the processing of diffusion Magnetic Resonance Images, including state-of-the-art reconstruction of diffusion models, cerebral white matter connectivity analysis, and segmentation techniques. We focus on Diffusion Tensor Images (DTI) and Q-Ball Images (QBI).
diffusion MRI; Diffusion Tensor Imaging (DTI); High Angular Resolution Diffusion Imaging (HARDI); Q-Ball Imaging (QBI); Orientation Distribution Function (ODF); Spherical Harmonics (SH); Funk-Radon Transform (FRT); sub-voxel fiber configurations; tractography; manifold learning; N-cuts; stratification; segmentation; non-uniform complexity
Image registration is a key step in a great variety of biomedical imaging applications. It provides the ability to geometrically align one dataset with another, and is a prerequisite for all imaging applications that compare datasets across subjects, imaging modalities, or across time. Registration algorithms also enable the pooling and comparison of experimental findings across laboratories, the construction of population-based brain atlases, and the creation of systems to detect group patterns in structural and functional imaging data. We review the major types of registration approaches used in brain imaging today. We focus on their conceptual basis, the underlying mathematics, and their strengths and weaknesses in different contexts. We describe the major goals of registration, including data fusion, quantification of change, automated image segmentation and labeling, shape measurement, and pathology detection. We indicate that registration algorithms have great potential when used in conjunction with a digital brain atlas, which acts as a reference system in which brain images can be compared for statistical analysis. The resulting armory of registration approaches is fundamental to medical image analysis, and in a brain mapping context provides a means to elucidate clinical, demographic, or functional trends in the anatomy or physiology of the brain.
Brain mapping; Image registration; Brain atlas
The authors used surface-based anatomic mapping to detect features of hippocampal anatomy that correlated with surgical outcomes in patients undergoing surgery for mesial temporal lobe epilepsy with hippocampal sclerosis. Compared with a seizure-free group, hippocampal profiles for the non–seizure-free group had greater diffuse ipsilateral atrophy and more region-specific contralateral atrophy in the anterior, lateral hippocampus. These atrophic regions may indicate areas of increased epileptogenicity, contributing to poorer surgical outcomes.
Diffusion weighted magnetic resonance imaging is a powerful tool that can be employed to study white matter microstructure by examining the 3D displacement profile of water molecules in brain tissue. By applying diffusion-sensitized gradients along a minimum of six directions, second-order tensors (represented by three-by-three positive definite matrices) can be computed to model dominant diffusion processes. However, conventional DTI is not sufficient to resolve more complicated white matter configurations, e.g., crossing fiber tracts. Recently, a number of high-angular resolution schemes with more than six gradient directions have been employed to address this issue. In this article, we introduce the tensor distribution function (TDF), a probability function defined on the space of symmetric positive definite matrices. Using the calculus of variations, we solve the TDF that optimally describes the observed data. Here, fiber crossing is modeled as an ensemble of Gaussian diffusion processes with weights specified by the TDF. Once this optimal TDF is determined, the orientation distribution function (ODF) can easily be computed by analytic integration of the resulting displacement probability function. Moreover, a tensor orientation distribution function (TOD) may also be derived from the TDF, allowing for the estimation of principal fiber directions and their corresponding eigenvalues.
diffusion MRI; diffusion tensor imaging; high angular resolution diffusion imaging
C-reactive protein (CRP) is a marker for systemic inflammation and increased cardiovascular disease risk. Regular exercise may decrease CRP. ApoE has three common genotype variants: E2/3, 3/3, and 3/4 that modulate lipid metabolism and may have other metabolic physiologic roles, including some evidence that the genotype affects CRP levels. We assessed fasting serum CRP in 117(M=51, F=66) healthy adults who volunteered for a 6 month aerobic exercise program. Both pre and post-training measurements were available in 71 (M=31, F=40) subjects. At baseline and follow-up, numbers of subjects in the 3 groups were approximately equal: 2/3, n = 33 and 20; 3/3, n = 41 and 26; and 3/4, n = 43 and 25.
At baseline, CRP levels differed by APOE genotype: means ± sd were 2.84 ± 2.18, 2.59 ± 2.34, and 1.90 ± 2.13 mg/L for E2/3, 3/3, and 3/4 subjects, respectively (3/4 vs. 2/3, p<0.05). In women, CRP was higher than men (3.14 ± 2.49 vs. 2.12 ± 2.13 mg/L, p<0.006). Exercise failed to affect CRP in the entire cohort (2.68 ± 2.38 vs 2.52 ± 2.48 mg/L), or in any APOE genotype group, and the APOE genotype effect observed at baseline persisted after training.
In a largely white study cohort CRP is higher in Apo E 3/3 than in 3/4 subjects and in women compared to men, but remains unchanged by 6 months of standard aerobic exercise training of the volume and higher intensity promoted by national organizations to reduce cardiovascular disease risk. How APOE genotype affects CRP is not known.
APOE; C-reactive protein; aerobic exercise; gender
Our objective was to investigate whether asymptomatic carriers of apolipoprotein E ε4 [APOE-4] demonstrate pathological differences and atrophy in medial temporal lobe (MTL) sub-regions. We measured cortical thickness and volume in MTL sub-regions (hippocampal CA fields 1, 2 and 3; dentate gyrus; entorhinal cortex; subiculum; perirhinal cortex; parahippocampal cortex; and fusiform gyrus) using a high-resolution in-plane (.4×.4mm) MRI sequence in 30 cognitively normal volunteers (14 APOE–4 carriers, 16 non-carriers, mean age 57 years). A cortical unfolding procedure maximized visibility of this convoluted cortex, providing cortical ribbon thickness measures throughout individual subregions of the hippocampus and surrounding cortex. APOE–4 carriers had reduced cortical thickness compared with non-carriers in entorhinal cortex (ERC) and the subiculum (Sub), but not in the main hippocampal body or perirhinal cortex. Average cortical thickness was 14.8% lower (p=1.0e−6) for ERC and 12.6% lower (p=6.8e−5) for Sub in APOE-4 carriers. Standard volumetric measures of the same regions showed similar, but non-significant trends. Cognitively intact carriers of APOE-4 show regionally specific thinning of the cortical ribbon compared to APOE-3 carriers; cortical thickness may be a more sensitive measure of pathological differences in genetic risk subjects than standard volumetry.
Asthma is a complex polygenic disease in which gene–environment interactions are important. The gene encoding tumour necrosis factor alpha (TNFα) is one of several candidate loci for asthma pathogenesis and is highly polymorphic. A number of studies have investigated the polymorphism of TNFα‐308 gene promoter (substitution G→A, designated as TNF1 and TNF2) in relation to asthma susceptibility in different populations. However, the results of individual studies have been inconsistent.
To address the inconsistent findings in studies of the association of the polymorphism of TNFα‐308 gene promoter with susceptibility to asthma, a systematic review was undertaken of the published data and a meta‐analysis was performed. The MEDLINE database was searched for case‐control studies published in English language journals from 1966 to October 2005. Data were extracted using standardised forms and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.
Fifteen eligible studies, comprising 2409 patients with asthma and 3266 controls, were included in the meta‐analysis. Using the random effects model, the pooled result showed that the TNF2 allele is associated with overall susceptibility to asthma (OR 1.37, 95% CI 1.02 to 1.84, p = 0.04). The ORs for asthma susceptibility in TNF2 homozygote individuals were significantly increased at 2.01 (95% CI 1.26 to 3.20, p = 0.009) and 1.51 (95% CI 1.02 to 2.22, p = 0.041) compared with TNF1 homozygotes and TNF2/1 heterozygotes, respectively. In addition, the pooled OR for asthma risk in TNF2/1 heterozygotes was also significantly higher than that in TNF1/1 homozygotes (OR 1.47, 95% CI 1.01 to 2.13, p = 0.045).
The TNF2 allele confers a significant risk for developing asthma. A large scale case‐control study is needed to clarify the functional effect of the polymorphism of the TNFα gene in the pathogenesis of asthma.
asthma; genetics; tumour necrosis factor; polymorphism; meta‐analysis
Hippocampal volume change over time, measured with MRI, has huge potential as a marker for Alzheimer's disease. The objectives of this study were: (i) to test if constant and accelerated hippocampal loss can be detected in Alzheimer's disease, mild cognitive impairment and normal ageing over short periods, e.g. 6–12 months, with MRI in the large multicentre setting of the Alzheimer's Disease Neuroimaging Initiative (ADNI); (ii) to determine the extent to which the polymorphism of the apolipoprotein E (ApoE) gene modulates hippocampal change; and (iii) to determine if rates of hippocampal loss correlate with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, such as the β-amyloid (Aβ1–42) and tau proteins (tau). The MRI multicentre study included 112 cognitive normal elderly individuals, 226 mild cognitive impairment and 96 Alzheimer's disease patients who all had at least three successive MRI scans, involving 47 different imaging centres. The mild cognitive impairment and Alzheimer's disease groups showed hippocampal volume loss over 6 months and accelerated loss over 1 year. Moreover, increased rates of hippocampal loss were associated with presence of the ApoE allele ɛ4 gene in Alzheimer's disease and lower CSF Aβ1–42 in mild cognitive impairment, irrespective of ApoE genotype, whereas relations with tau were only trends. The power to measure hippocampal change was improved by exploiting correlations statistically between successive MRI observations. The demonstration of considerable hippocampal loss in mild cognitive impairment and Alzheimer's disease patients over only 6 months and accelerated loss over 12 months illustrates the power of MRI to track morphological brain changes over time in a large multisite setting. Furthermore, the relations between faster hippocampal loss in the presence of ApoE allele ɛ4 and decreased CSF Aβ1–42 supports the concept that increased hippocampal loss is an indicator of Alzheimer's disease pathology and a potential marker for the efficacy of therapeutic interventions in Alzheimer's disease.
MRI; mild cognitive impairment; ageing; human brain mapping; hippocampus