Cortical brain volume abnormalities associated with few or multiple neuropsychiatric symptoms in Alzheimer's disease.

New research on assessing neuropsychiatric manifestations of Alzheimer´s Disease (AD) involves grouping neuropsychiatric symptoms into syndromes. Yet this approach is limited by high inter-subject variability in neuropsychiatric symptoms and a relatively low degree of concordance across studies attempting to cluster neuropsychiatric symptoms into syndromes. An alternative strategy that involves dichotomizing AD subjects into those with few versus multiple neuropsychiatric symptoms is both consonant with real-world clinical practice and can contribute to understanding neurobiological underpinnings of neuropsychiatric symptoms in AD patients. The aim of this study was to address whether the number of neuropsychiatric symptoms (i.e., presence of few [≤2] versus multiple [≥3] symptoms) in AD would be associated with degree of significant gray matter (GM) volume loss. Of particular interest was volume loss in brain regions involved in memory, emotional processing and salience brain networks, including the prefrontal, lateral temporal and parietal cortices, anterior cingulate gyrus, temporo-limbic structures and insula. We recruited 19 AD patients and 13 healthy controls, which underwent an MRI and neuropsychiatric assessment. Regional brain volumes were determined using voxel-based morphometry and other advanced imaging processing methods. Our results indicated the presence of different patterns of GM atrophy in the two AD subgroups relative to healthy controls. AD patients with multiple neuropsychiatric manifestations showed more evident GM atrophy in the left superior temporal gyrus and insula as compared with healthy controls. In contrast, AD subjects with few neuropsychiatric symptoms displayed more GM atrophy in prefrontal regions, as well as in the dorsal anterior cingulate ad post-central gyri, as compared with healthy controls. Our findings suggest that the presence of multiple neuropsychiatric symptoms is more related to the degree of atrophy in specific brain networks rather than dependent on the global severity of widespread neurodegenerative brain changes.

APOE ε4 associated with preserved executive function performance and maintenance of temporal and cingulate brain volumes in younger adults.

The APOE ε4 allele is associated with cognitive deficits and brain atrophy in older adults, but studies in younger adults are mixed. We examined APOE genotype effects on cognition and brain structure in younger adults and whether genotype effects differed by age and with presence of depression. 157 adults (32 % ε4 carriers, 46 % depressed) between 20 and 50 years of age completed neuropsychological testing, 131 of which also completed 3 T cranial MRI. We did not observe a direct effect of APOE genotype on cognitive performance or structural MRI measures. A significant genotype by age interaction was observed for executive function, where age had less of an effect on executive function in ε4 carriers. Similar interactions were observed for the entorhinal cortex, rostral and caudal anterior cingulate cortex and parahippocampal gyrus, where the effect of age on regional volumes was reduced in ε4 carriers. There were no significant interactions between APOE genotype and depression diagnosis. The ε4 allele benefits younger adults by allowing them to maintain executive function performance and volumes of cingulate and temporal cortex regions with aging, at least through age fifty years.

Posterior structural brain volumes differ in maltreated youth with and without chronic posttraumatic stress disorder.

Magnetic resonance imaging studies of maltreated children with posttraumatic stress disorder (PTSD) suggest that maltreatment-related PTSD is associated with adverse brain development. Maltreated youth resilient to chronic PTSD were not previously investigated and may elucidate neuromechanisms of the stress diathesis that leads to resilience to chronic PTSD. In this cross-sectional study, anatomical volumetric and corpus callosum diffusion tensor imaging measures were examined using magnetic resonance imaging in maltreated youth with chronic PTSD (N = 38), without PTSD (N = 35), and nonmaltreated participants (n = 59). Groups were sociodemographically similar. Participants underwent assessments for strict inclusion/exclusion criteria and psychopathology. Maltreated youth with PTSD were psychobiologically different from maltreated youth without PTSD and nonmaltreated controls. Maltreated youth with PTSD had smaller posterior cerebral and cerebellar gray matter volumes than did maltreated youth without PTSD and nonmaltreated participants. Cerebral and cerebellar gray matter volumes inversely correlated with PTSD symptoms. Posterior corpus callosum microstructure in pediatric maltreatment-related PTSD differed compared to maltreated youth without PTSD and controls. The group differences remained significant when controlling for psychopathology, numbers of Axis I disorders, and trauma load. Alterations of these posterior brain structures may result from a shared trauma-related mechanism or an inherent vulnerability that mediates the pathway from chronic PTSD to comorbidity.

Hippocampal Malrotation Is Associated With Prolonged Febrile Seizures: Results of the FEBSTAT Study.

OBJECTIVE: Hippocampal malrotation is characterized by incomplete hippocampal inversion with a rounded shape and blurred internal architecture. There is still debate about whether hippocampal malrotation has pathologic significance. We present findings from the Consequences of Prolonged Febrile Seizures in Childhood (FEBSTAT) study on the frequency of and risk factors for hippocampal malrotation. SUBJECTS AND METHODS: FEBSTAT is a prospective multicenter study investigating the consequences of febrile status epilepticus in childhood. MRI studies of 226 patients with febrile status epilepticus were analyzed visually by two board-certified neuroradiologists blinded to clinical details and were compared with MRI studies of 96 subjects with first simple febrile seizure. Quantitative analysis of hippocampal volume was performed by two independent observers. RESULTS: Hippocampal malrotation was present in 20 of 226 (8.8%) patients with febrile status epilepticus compared with two of 96 (2.1%) control subjects (odds ratio [OR], 4.56; 95% CI, 1.05-19.92). Hippocampal malrotation was exclusively left-sided in 18 of 22 (81.8%) patients and bilateral in the remaining four patients (18.2%). There was no case of exclusively right-sided hippocampal malrotation. Hippocampal malrotation was more common in boys than in girls (OR, 6.1; 95% CI, 1.7-21.5). On quantitative volumetric MRI analysis, the left hippocampal volume was smaller in patients with hippocampal malrotation than in control subjects with simple febrile seizure (p = 0.004), and the right-to-left hippocampal volume ratio was higher in the hippocampal malrotation group than in the simple febrile seizure group (p < 0.001). CONCLUSION: Hippocampal malrotation is a developmental malformation that predominantly affects the left hippocampus in male patients and is more frequently found in children with prolonged febrile status epilepticus than in control subjects. These data provide further evidence that hippocampal malrotation represents a pathologic error in brain development rather than a normal variant.

Widespread white matter but focal gray matter alterations in depressed individuals with thoughts of death.

BACKGROUND: Past work demonstrates that depressed individuals with suicidal thoughts or behaviors exhibit specific neuroanatomical alterations. This may represent a distinct phenotype characterized by specific findings on neuroimaging, but it is unclear if these findings extend to individuals with milder thoughts of death. We examined this question in outpatients with recurrent Major Depressive Disorder not receiving antidepressant treatment. METHODS: We examined 165 subjects: 53 depressed without thoughts of death, 21 depressed with thoughts of death, and 91 healthy comparison subjects. Participants completed 3T cranial MRI, including anatomical and diffusion tensor imaging acquisitions. Automated methods measured regional gray matter volumes in addition to cortical thickness. White matter analyses examined diffusion measures within specific fiber tracts and included voxelwise comparisons. RESULTS: After adjustment for multiple comparisons, the depressed group with thoughts of death did not exhibit differences in regional gray matter volume, but did exhibit reduced cortical thickness in frontoparietal regions and the insula. This depressed group with thoughts of death also exhibited widespread white matter differences in fractional anisotropy and radial diffusivity. These differences were observed primarily in posterior parietal white matter regions and central white matter tracts adjacent to the basal ganglia and thalamus. CONCLUSIONS: Mild thoughts of death are associated with structural alterations in regions of the salience network, default mode network, and thalamocortical circuits. Further work is needed to understand the pathological basis of these findings.

Association of gene variants of the renin-angiotensin system with accelerated hippocampal volume loss and cognitive decline in old age.

OBJECTIVE: Genetic factors confer risk for neuropsychiatric phenotypes, but the polygenic etiology of these phenotypes makes identification of genetic culprits challenging. An approach to this challenge is to examine the effects of genetic variation on relevant endophenotypes, such as hippocampal volume loss. A smaller hippocampus is associated with gene variants of the renin-angiotensin system (RAS), a system implicated in vascular disease. However, no studies to date have investigated longitudinally the effects of genetic variation of RAS on the hippocampus. METHOD: The authors examined the effects of polymorphisms of AGTR1, the gene encoding angiotensin-II type 1 receptor of RAS, on longitudinal hippocampal volumes of older adults. In all, 138 older adults (age ≥60 years) were followed for an average of about 4 years. The participants underwent repeated structural MRI and comprehensive neurocognitive testing, and they were genotyped for four AGTR1 single-nucleotide polymorphisms (SNPs) with low pairwise linkage disequilibrium values and apolipoprotein E (APOE) genotype. RESULTS: Genetic variants at three AGTR1 SNPs (rs2638363, rs1492103, and rs2675511) were independently associated with accelerated hippocampal volume loss over the 4-year follow-up period in the right but not left hemisphere. Intriguingly, these AGTR1 risk alleles also predicted worse episodic memory performance but were not related to other cognitive measures. Two risk variants (rs2638363 and rs12721331) interacted with the APOE4 allele to accelerate right hippocampal volume loss. CONCLUSIONS: Risk genetic variants of the RAS may accelerate memory decline in older adults, an effect that may be conferred by accelerated hippocampal volume loss. Molecules involved in this system may hold promise as early therapeutic targets for late-life neuropsychiatric disorders.

Comprehensive population-averaged arterial input function for dynamic contrast-enhanced vmagnetic resonance imaging of head and neck cancer.

PURPOSE: To generate a population-averaged arterial input function (PA-AIF) for quantitative analysis of dynamic contrast-enhanced MRI data in head and neck cancer patients. METHODS AND MATERIALS: Twenty patients underwent dynamic contrast-enhanced MRI during concurrent chemoradiation therapy. Imaging consisted of 2 baseline scans 1 week apart (B1/B2) and 1 scan after 1 week of chemoradiation therapy (Wk1). Regions of interest (ROIs) in the right and left carotid arteries were drawn on coronal images. Plasma concentration curves of all ROIs were averaged and fit to a biexponential decay function to obtain the final PA-AIF (AvgAll). Right-sided and left-sided ROI plasma concentration curves were averaged separately to obtain side-specific AIFs (AvgRight/AvgLeft). Regions of interest were divided by time point to obtain time-point-specific AIFs (AvgB1/AvgB2/AvgWk1). The vascular transfer constant (Ktrans) and the fractional extravascular, extracellular space volume (Ve) for primaries and nodes were calculated using the AvgAll AIF, the appropriate side-specific AIF, and the appropriate time-point-specific AIF. Median Ktrans and Ve values derived from AvgAll were compared with those obtained from the side-specific and time-point-specific AIFs. The effect of using individual AIFs was also investigated. RESULTS: The plasma parameters for AvgAll were a1,2 = 27.11/17.65 kg/L, m1,2 = 11.75/0.21 min(-1). The coefficients of repeatability (CRs) for AvgAll versus AvgLeft were 0.04 min(-1) for Ktrans and 0.02 for Ve. For AvgAll versus AvgRight, the CRs were 0.08 min(-1) for Ktrans and 0.02 for Ve. When AvgAll was compared with AvgB1/AvgB2/AvgWk1, the CRs were slightly higher: 0.32/0.19/0.78 min(-1), respectively, for Ktrans; and 0.07/0.08/0.09 for Ve. Use of a PA-AIF was not significantly different from use of individual AIFs. CONCLUSION: A PA-AIF for head and neck cancer was generated that accounts for differences in right carotid artery versus left carotid artery, day-to-day fluctuations, and early treatment-induced changes. The small CRs obtained for Ktrans and Ve indicate that side-specific AIFs are not necessary. However, a time-point-specific AIF may improve pharmacokinetic accuracy.

Cingulum bundle white matter lesions influence antidepressant response in late-life depression: a pilot study.

BACKGROUND: Late-life depression is associated with white matter hyperintense lesions (WMLs) occurring in specific fiber tracts. In this study, we sought to determine if greater WML severity in the cingulum bundle or uncinate fasciculus was associated with poor short-term antidepressant response. METHODS: Eleven depressed elders completed a baseline cranial 3T MRI and received antidepressant treatment following a medication algorithm. MRIs were analyzed to measure the fraction of each fiber tract׳s volume occupied by WMLs. Statistical analyses examined the effect of dichotomized fiber tract WML severity on three- and six-month depression severity after controlling for age and baseline depression severity. RESULTS: Greater WML severity in the left hemispheric cingulum bundle adjacent to the hippocampus was associated with greater post-treatment depression severity at three- (F1,7=6.42, p=0.0390) and six-month assessments (F1,5=9.62, p=0.0268). Other fiber tract WML measures were not significantly associated with outcomes. LIMITATIONS: The study had a small sample size and analyses were limited to only a priori fiber tracts. CONCLUSIONS: This pilot study supports the hypothesis that focal damage to the cingulum bundle may contribute to poor short-term antidepressant response. These findings warrant further investigation with a larger, more definitive study.

Application of variable threshold intensity to segmentation for white matter hyperintensities in fluid attenuated inversion recovery magnetic resonance images.

INTRODUCTION: White matter hyperintensities (WMHs) are regions of abnormally high intensity on T2-weighted or fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). Accurate and reproducible automatic segmentation of WMHs is important since WMHs are often seen in the elderly and are associated with various geriatric and psychiatric disorders. METHODS: We developed a fully automated monospectral segmentation method for WMHs using FLAIR MRIs. Through this method, we introduce an optimal threshold intensity (I O ) for segmenting WMHs, which varies with WMHs volume (V WMH), and we establish the I O -V WMH relationship. RESULTS: Our method showed accurate validations in volumetric and spatial agreements of automatically segmented WMHs compared with manually segmented WMHs for 32 confirmatory images. Bland-Altman values of volumetric agreement were 0.96 ± 8.311 ml (bias and 95 % confidence interval), and the similarity index of spatial agreement was 0.762 ± 0.127 (mean ± standard deviation). Furthermore, similar validation accuracies were obtained in the images acquired from different scanners. CONCLUSIONS: The proposed segmentation method uses only FLAIR MRIs, has the potential to be accurate with images obtained from different scanners, and can be implemented with a fully automated procedure. In our study, validation results were obtained with FLAIR MRIs from only two scanner types. The design of the method may allow its use in large multicenter studies with correct efficiency.

Hippocampus atrophy and the longitudinal course of late-life depression.

OBJECTIVES: Smaller hippocampal volumes are observed in depression but it remains unclear how antidepressant response and persistent depression relate to changes in hippocampal volume. We examined the longitudinal relationship between hippocampal atrophy and course of late-life depression. SETTING: Academic medical center. PARTICIPANTS: Depressed and never-depressed cognitively intact subjects age 60 years or older. MEASUREMENTS: Depression severity was measured every three months with the Montgomery-Asberg Depression Rating Scale (MADRS). Participants also completed cranial 1.5-T magnetic resonance imaging every 2 years. We compared 2-year change in hippocampal volume based on remission status, then in expanded analyses examined how hippocampal volumes predicted MADRS score. RESULTS: In analyses of 92 depressed and 70 never-depressed subjects, over 2 years the cohort whose depression never remitted exhibited greater hippocampal atrophy than the never-depressed cohort. In expanded analyses of a broader sample of 152 depressed elders, depression severity was significantly predicted by a hippocampus × time interaction where smaller hippocampus volumes over time were associated with greater depression severity. CONCLUSIONS: Hippocampal atrophy is associated with greater and persistent depression severity. Neuropathological studies are needed to determine if this atrophy is related to the toxic effects of persistent depression or related to underlying Alzheimer disease.

Hippocampal sclerosis after febrile status epilepticus: the FEBSTAT study.

OBJECTIVE: Whether febrile status epilepticus (FSE) produces hippocampal sclerosis (HS) and temporal lobe epilepsy (TLE) has long been debated. Our objective is to determine whether FSE produces acute hippocampal injury that evolves to HS. METHODS: FEBSTAT and 2 affiliated studies prospectively recruited 226 children aged 1 month to 6 years with FSE and controls with simple febrile seizures. All had acute magnetic resonance imaging (MRI), and follow-up MRI was obtained approximately 1 year later in the majority. Visual interpretation by 2 neuroradiologists informed only of subject age was augmented by hippocampal volumetrics, analysis of the intrahippocampal distribution of T2 signal, and apparent diffusion coefficients. RESULTS: Hippocampal T2 hyperintensity, maximum in Sommer's sector, occurred acutely after FSE in 22 of 226 children in association with increased volume. Follow-up MRI obtained on 14 of the 22 with acute T2 hyperintensity showed HS in 10 and reduced hippocampal volume in 12. In contrast, follow-up of 116 children without acute hyperintensity showed abnormal T2 signal in only 1 (following another episode of FSE). Furthermore, compared to controls with simple febrile seizures, FSE subjects with normal acute MRI had abnormally low right to left hippocampal volume ratios, smaller hippocampi initially, and reduced hippocampal growth. INTERPRETATION: Hippocampal T2 hyperintensity after FSE represents acute injury often evolving to a radiological appearance of HS after 1 year. Furthermore, impaired growth of normal-appearing hippocampi after FSE suggests subtle injury even in the absence of T2 hyperintensity. Longer follow-up is needed to determine the relationship of these findings to TLE.

Risk factors for febrile status epilepticus: a case-control study.

OBJECTIVE: To identify risk factors for developing a first febrile status epilepticus (FSE) among children with a first febrile seizure (FS). STUDY DESIGN: Cases were children with a first FS that was FSE drawn from the Consequences of Prolonged Febrile Seizures in Childhood and Columbia cohorts. Controls were children with a first simple FS and separately, children with a first complex FS that was not FSE. Identical questionnaires were administered to family members of the 3 cohorts. Magnetic resonance imaging protocol and readings were consistent across cohorts, and seizure phenomenology was assessed by the same physicians. Risk factors were analyzed using logistic regression. RESULTS: Compared with children with simple FS, FSE was associated with younger age, lower temperature, longer duration (1-24 hours) of recognized temperature before FS, female sex, structural temporal lobe abnormalities, and first-degree family history of FS. Compared with children with other complex FS, FSE was associated with low temperature and longer duration (1-24 hours) of temperature recognition before FS. Risk factors for complex FS that was not FSE were similar in magnitude to those for FSE but only younger age was significant. CONCLUSIONS: Among children with a first FS, FSE appears to be due to a combination of lower seizure threshold (younger age and lower temperatures) and impaired regulation of seizure duration. Clinicians evaluating FS should be aware of these factors as many episodes of FSE go unnoticed. Further work is needed to develop strategies to prevent FSE.

Perfluoropropane gas as a magnetic resonance lung imaging contrast agent in humans.

BACKGROUND: Fluorine-enhanced MRI is a relatively inexpensive and straightforward technique that facilitates regional assessments of pulmonary ventilation. In this report, we assess its suitability through the use of perfluoropropane (PFP) in a cohort of human subjects with normal lungs and subjects with lung disease. METHODS: Twenty-eight subjects between the ages of 18 and 71 years were recruited for imaging and were classified based on spirometry findings and medical history. Imaging was carried out on a Siemens TIM Trio 3T MRI scanner using two-dimensional, gradient echo, fast low-angle shot and three-dimensional gradient echo, volumetric, interpolated, breath-hold examination sequences for proton localizers and PFP functional scans, respectively. Respiratory waveforms and physiologic signals of interest were monitored throughout the imaging sessions. A region-growing algorithm was applied to the proton localizers to define the lung field of view for analysis of the PFP scans. RESULTS: All subjects tolerated the gas mixture well with no adverse side effects. Images of healthy lungs demonstrated a homogeneous distribution of the gas with sufficient signal-to-noise ratios, while lung images from asthmatic and emphysematous lungs demonstrated increased heterogeneity and ventilation defects. CONCLUSIONS: Fluorine-enhanced MRI using a normoxic PFP gas mixture is a well-tolerated, radiation-free technique for regionally assessing pulmonary ventilation. The inherent physical characteristics and applicability of the gaseous agent within a magnetic resonance setting facilitated a clear differentiation between normal and diseased lungs.

Negative life stress and longitudinal hippocampal volume changes in older adults with and without depression.

Major depressive disorder is associated with smaller hippocampal volumes but the mechanisms underlying this relationship are unclear. To examine the effect of environmental influences, we examined the relationship between self-reported stressors and two-year change in hippocampal volume. Seventy elderly nondepressed subjects and eighty-nine elderly depressed subjects were followed for two years. The number of negative stressful life events (nSLE), perceived stress levels, and cranial MRI were obtained at baseline and at the two-year assessment. For secondary analyses, subjects provided blood for 5-HTTLPR polymorphism genotyping. After controlling for covariates including presence or absence of depression, greater numbers of baseline nSLEs were significantly associated with greater baseline hippocampal volumes bilaterally. Greater numbers of baseline nSLEs were also associated with reduction in hippocampal volume over two years in the right but not the left hemisphere. Neither perceived stress levels nor changes in stress measures were significantly associated with hippocampal volume measures. However, in secondary analyses, we found that increases in perceived stress over time was associated with volume reduction of the left hippocampus, but only in 5-HTTLPR L/L homozygotes. Our findings suggest different short- and long-term effects of negative life stressors on hippocampal volumes in older adults. These effects appear independent on the presence or absence of depression. Furthermore, these effects may be moderated by genetic polymorphisms in key neurotransmitter systems. These novel findings have important implications for understanding environmental influences on brain aging.

A comparison of radial keyhole strategies for high spatial and temporal resolution 4D contrast-enhanced MRI in small animal tumor models.

PURPOSE: Dynamic contrast-enhanced (DCE) MRI has been widely used as a quantitative imaging method for monitoring tumor response to therapy. The simultaneous challenges of increasing temporal and spatial resolution in a setting where the signal from the much smaller voxel is weaker have made this MR technique difficult to implement in small-animal imaging. Existing protocols employed in preclinical DCE-MRI acquire a limited number of slices resulting in potentially lost information in the third dimension. This study describes and compares a family of four-dimensional (3D spatial + time), projection acquisition, radial keyhole-sampling strategies that support high spatial and temporal resolution. METHODS: The 4D method is based on a RF-spoiled, steady-state, gradient-recalled sequence with minimal echo time. An interleaved 3D radial trajectory with a quasi-uniform distribution of points in k-space was used for sampling temporally resolved datasets. These volumes were reconstructed with three different k-space filters encompassing a range of possible radial keyhole strategies. The effect of k-space filtering on spatial and temporal resolution was studied in a 5 mM CuSO(4) phantom consisting of a meshgrid with 350-µm spacing and in 12 tumors from three cell lines (HT-29, LoVo, MX-1) and a primary mouse sarcoma model (three tumors∕group). The time-to-peak signal intensity was used to assess the effect of the reconstruction filters on temporal resolution. As a measure of heterogeneity in the third dimension, the authors analyzed the spatial distribution of the rate of transport (K(trans)) of the contrast agent across the endothelium barrier for several different types of tumors. RESULTS: Four-dimensional radial keyhole imaging does not degrade the system spatial resolution. Phantom studies indicate there is a maximum 40% decrease in signal-to-noise ratio as compared to a fully sampled dataset. T1 measurements obtained with the interleaved radial technique do not differ significantly from those made with a conventional Cartesian spin-echo sequence. A bin-by-bin comparison of the distribution of the time-to-peak parameter shows that 4D radial keyhole reconstruction does not cause significant temporal blurring when a temporal resolution of 9.9 s is used for the subsamples of the keyhole data. In vivo studies reveal substantial tumor heterogeneity in the third spatial dimension that may be missed with lower resolution imaging protocols. CONCLUSIONS: Volumetric keyhole imaging with projection acquisition provides a means to increase spatiotemporal resolution and coverage over that provided by existing 2D Cartesian protocols. Furthermore, there is no difference in temporal resolution between the higher spatial resolution keyhole reconstruction and the undersampled projection data. The technique allows one to measure complex heterogeneity of kinetic parameters with isotropic, microscopic spatial resolution.

Fiber tract-specific white matter lesion severity Findings in late-life depression and by AGTR1 A1166C genotype.

Past work demonstrated that late-life depression is associated with greater severity of ischemic cerebral hyperintense white matter lesions, particularly frontal lesions. However, these lesions are also associated with other neuropsychiatric deficits, so these clinical relationships may depend on which fiber tracts are damaged. We examined the ratio of lesion to nonlesioned white matter tissue within multiple fiber tracts between depressed and nondepressed elders. We also sought to determine if the AGTR1 A1166C and BDNF Val66Met polymorphisms contributed to vulnerability to lesion development in discrete tracts. The 3T structural MR images and blood samples for genetic analyses were acquired on 54 depressed and 37 nondepressed elders. Lesion maps were created through an automated tissue segmentation process and applied to a probabilistic white matter fiber tract atlas allowing for identification of the fraction of the tract occupied by lesion. The depressed cohort exhibited a significantly greater lesion ratio only in the left upper cingulum near the cingulate gyrus (F((1,86)) = 4.62, P = 0.0344), supporting past work implicating cingulate dysfunction in the pathogenesis of depression. In the 62 Caucasian subjects with genetic data, AGTR1 C1166 carriers exhibited greater lesion ratios across multiple tracts including the anterior thalamic radiation and inferior fronto-occipital fasciculus. In contrast, BDNF Met allele carriers exhibited greater lesion ratios only in the frontal corpus callosum. Although these findings did not survive correction for multiple comparisons, this study supports our hypothesis and provides preliminary evidence that genetic differences related to vascular disease may increase lesion vulnerability differentially across fiber tracts.

Bipolar disorder, brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and brain morphology.

In this study of the effect of bipolar status and presence of BDNF Val66Met polymorphism on differences in regional brain volumes, we hypothesized based on previous studies that 1) bipolar subjects will have smaller regional brain volumes than healthy controls; 2) BDNF Met66 allele carriers within the same population are likely to have smaller regional brain volumes as compared to Val66 homozygyotes. In our Caucasian sample of 166 bipolar subjects and 64 gender-matched healthy controls, we found significant decreases in total (p = 0.005) and regional gray matter volumes in bipolar patients compared to healthy controls, more pronounced in the inferior and posterior parts of the brain, together with a concomitant increase in total CSF (p = 0.012) particularly in the lateral ventricles (p = 0.023). However, there was no difference in white matter volumes noted by other studies. Furthermore we did not find significant differences in other brain regions that have been reported by other authors. Nor did we find a significant effect of BDNF on these measurements.

Trajectories of early brain volume development in fragile X syndrome and autism.

OBJECTIVE: To examine patterns of early brain growth in young children with fragile X syndrome (FXS) compared with a comparison group (controls) and a group with idiopathic autism. METHOD: The study included 53 boys 18 to 42 months of age with FXS, 68 boys with idiopathic autism (autism spectrum disorder), and a comparison group of 50 typically developing and developmentally delayed controls. Structural brain volumes were examined using magnetic resonance imaging across two time points, at 2 to 3 and again at 4 to 5 years of age, and total brain volumes and regional (lobar) tissue volumes were examined. In addition, a selected group of subcortical structures implicated in the behavioral features of FXS (e.g., basal ganglia, hippocampus, amygdala) was studied. RESULTS: Children with FXS had larger global brain volumes compared with controls but were not different than children with idiopathic autism, and the rate of brain growth from 2 to 5 years of age paralleled that seen in controls. In contrast to children with idiopathic autism who had generalized cortical lobe enlargement, children with FXS showed specific enlargement in the temporal lobe white matter, cerebellar gray matter, and caudate nucleus, but a significantly smaller amygdala. CONCLUSIONS: This structural longitudinal magnetic resonance imaging study of preschoolers with FXS observed generalized brain overgrowth in children with FXS compared with controls, evident at age 2 and maintained across ages 4 to 5. In addition, different patterns of brain growth that distinguished boys with FXS from boys with idiopathic autism were found.

MRI abnormalities following febrile status epilepticus in children: the FEBSTAT study.

OBJECTIVE: The FEBSTAT study is a prospective study that seeks to determine the acute and long-term consequences of febrile status epilepticus (FSE) in childhood. METHODS: From 2003 to 2010, 199 children age 1 month to 5 years presenting with FSE (>30 minutes) were enrolled in FEBSTAT within 72 hours of the FSE episode. Of these, 191 had imaging with emphasis on the hippocampus. All MRIs were reviewed by 2 neuroradiologists blinded to clinical details. A group of 96 children with first simple FS who were imaged using a similar protocol served as controls. RESULTS: A total of 22 (11.5%) children had definitely abnormal (n = 17) or equivocal (n = 5) increased T2 signal in the hippocampus following FSE compared with none in the control group (p < 0.0001). Developmental abnormalities of the hippocampus were more common in the FSE group (n = 20, 10.5%) than in controls (n = 2, 2.1%) (p = 0.0097) with hippocampal malrotation being the most common (15 cases and 2 controls). Extrahippocampal imaging abnormalities were present in 15.7% of the FSE group and 15.6% of the controls. However, extrahippocampal imaging abnormalities of the temporal lobe were more common in the FSE group (7.9%) than in controls (1.0%) (p = 0.015). CONCLUSIONS: This prospective study demonstrates that children with FSE are at risk for acute hippocampal injury and that a substantial number also have abnormalities in hippocampal development. Follow-up studies are in progress to determine the long-term outcomes in these children.

Thermal dose fractionation affects tumour physiological response.

PURPOSE: It is unknown whether a thermal dose should be administered using a few large fractions with higher temperatures or a larger number of fractions with lower temperatures. To evaluate this we assessed the effect of administering the same total thermal dose, approximately 30 CEM43T(90), in one versus three to four fractions per week, over 5 weeks. MATERIALS AND METHODS: Canine sarcomas were randomised to receive one of the hyperthermia fractionation schemes along with fractionated radiotherapy. Tumour response was based on changes in tumour volume, oxygenation, water diffusion quantified using MRI, and a panel of histological and immunohistochemical end points. RESULTS: There was a greater reduction in tumour volume and water diffusion at the end of therapy in tumours receiving one hyperthermia fraction per week. There was a weak but significant association between improved tumour oxygenation 24 h after the first hyperthermia treatment and extent of volume reduction at the end of therapy. Finally, the direction of change of HIF-1α and CA-IX immunoreactivity after the first hyperthermia fraction was similar and there was an inverse relationship between temperature and the direction of change of CA-IX. There were no significant changes in interstitial fluid pressure, VEGF, vWF, apoptosis or necrosis as a function of treatment group or temperature. CONCLUSIONS: We did not identify an advantage to a three to four per week hyperthermia prescription, and response data pointed to a one per week prescription being superior.