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International audience; Spurred by availability of automatic segmentation software, in vivo MRI investigations of human hippocampal subfield volumes have proliferated in the recent years. However, a majority of these studies apply automatic segmentation to MRI scans with approximately 1 × 1 × 1 mm3 resolution, a resolution at which the internal structure of the hippocampus can rarely be visualized. Many of these studies have reported contradictory and often neurobiologically surprising results pertaining to the involvement of hippocampal subfields in normal brain function, aging, and disease. In this commentary, we first outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies, regardless of how images are segmented (i.e., manually or automatically). This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, we discuss the fact that automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images. For these reasons, we caution against using volumetric measurements of hippocampal subfields obtained from 1 × 1 × 1 mm3 images.

The brainstem controls sub-cortical and cortical activity and influences the processing of incoming information. The goal of this study was to characterize age related alterations of brainstem-brain interactions during different brain states detected by dynamic analysis of task-free fMRI. 79 young (20-40 years) and 51 older adults (55-80 years) were studied. Internal brainstem structures were segmented using a new multi-contrast segmentation approach. Brain and brainstem gray matter segmentations were warped onto a population template. The ICV-corrected Jacobian determinants were converted into z-score maps and the means from 420 cortical/subcortical/brainstem rois extracted. The fMRI was preprocessed in SPM12/Conn18 and the BOLD signal from 420 cortical/subcortical/brainstem rois extracted. A dynamic task-free analysis approach based on hierarchical cluster analysis was used to identify 15 brain states that were characterized using graph analysis (strength, diversity, modularity). Kruskal-Wallis tests and Spearman correlations were used for statistical analysis. One brain state (cluster 21) occurred more often in older adults (p=0.008). It was characterized by a lower mean modular strength and brainstem-cortical strength in older adults compared to younger adults. Global age related gray matter differences were positively correlated with brain state 21’s modular strength. Furthermore, brain state 21 duration was negatively correlated with working memory (r = -0.28, p=0.002). The findings suggest an age related weakening of the within and between network synchronization at the brainstem level during brain state 21 in older adults that negatively affects cortical and subcortical synchronization and working memory performance.

The brainstem is a site of early pathology in several neurodegenerative diseases. The overall goal of this project was (a) To develop a method to segment internal brainstem structures from MP2RAGE derived images. (b) To compare the segmentations at 3 and 7 T. (c) To investigate age effects on intensities and segmentations. MP2RAGE derived T1 weighted images (UNI) and T1 relaxation maps (T1map) were obtained from two public data sets (LEMON: 50 3 T data sets, ATAG: 46 7 T data sets). The UNI and T1map images were rescaled using a linear scaling procedure and a ratio (RATIO) image calculated. The brainstem was extracted and k-mean clustering used to identify six intensity clusters from the UNI, T1map and RATIO at 3 and 7 T. Nonlinear diffeomorphic mapping was used to warp the six intensity clusters in subject space into a common space to generate probabilistic group averages/priors that were used to inform the final probabilistic segmentations at the single subject level for each field strength. The six clusters corresponded to six brainstem tissue types (three gray matter clusters and two white matter clusters and one csf/tissue boundary cluster). The quantitative comparison of the 3 and 7 T probabilistic averages showed subtle differences that affected the localization of age-associated brainstem volume losses. The segmentation approach presented here identified the same brainstem gray and white matter structures at both field strengths. Further studies are necessary to investigate how resolution and field strength contribute to the subtle differences observed at the two field strengths.

Spurred by availability of automatic segmentation software, in vivo MRI investigations of human hippocampal subfield volumes have proliferated in the recent years. However, a majority of these studies apply automatic segmentation to MRI scans with approximately 1 × 1 × 1 mm3 resolution, a resolution at which the internal structure of the hippocampus can rarely be visualized. Many of these studies have reported contradictory and often neurobiologically surprising results pertaining to the involvement of hippocampal subfields in normal brain function, aging, and disease. In this commentary, we first outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies, regardless of how images are segmented (i.e., manually or automatically). This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, we discuss the fact that automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images. For these reasons, we caution against using volumetric measurements of hippocampal subfields obtained from 1 × 1 × 1 mm3 images., In this commentary, we outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies. This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images.

Objective Subfield-specific measurements provide superior information in the early stages of neurodegenerative diseases compared to global hippocampal measurements. The overall goal was to systematically compare the performance of five representative manual and automated T1 and T2 based subfield labeling techniques in a sub-set of the ADNI2 population. Methods The high resolution T2 weighted hippocampal images (T2-HighRes) and the corresponding T1 images from 106 ADNI2 subjects (41 controls, 57 MCI, 8 AD) were processed as follows. A. T1-based: 1. Freesurfer + Large-Diffeomorphic-Metric-Mapping in combination with shape analysis. 2. FreeSurfer 5.1 subfields using in-vivo atlas. B. T2-HighRes: 1. Model-based subfield segmentation using ex-vivo atlas (FreeSurfer 6.0). 2. T2-based automated multi-atlas segmentation combined with similarity-weighted voting (ASHS). 3. Manual subfield parcellation. Multiple regression analyses were used to calculate effect sizes (ES) for group, amyloid positivity in controls, and associations with cognitive/memory performance for each approach. Results Subfield volumetry was better than whole hippocampal volumetry for the detection of the mild atrophy differences between controls and MCI (ES: 0.27 vs 0.11). T2-HighRes approaches outperformed T1 approaches for the detection of early stage atrophy (ES: 0.27 vs.0.10), amyloid positivity (ES: 0.11 vs 0.04), and cognitive associations (ES: 0.22 vs 0.19). Conclusions T2-HighRes subfield approaches outperformed whole hippocampus and T1 subfield approaches. None of the different T2-HghRes methods tested had a clear advantage over the other methods. Each has strengths and weaknesses that need to be taken into account when deciding which one to use to get the best results from subfield volumetry., Highlights • Comparison of 4 automated and 1 manual subfield labeling technique in common data set. • Subfield labeling approaches perform better than whole hippocampal approaches. • High resolution T2 based approaches perform better than T1 based approaches. • Different high res T2 approaches have different strengths/weaknesses.

Gray matter (GM) atrophy associated with alcohol use disorders (AUD) affects predominantly the frontal lobes. Less is known how frontal lobe GM loss affects GM loss in other regions and how it influences drinking behavior or relapse after treatment. The profile similarity index (PSI) combined with graph analysis allows to assess how GM loss in one region affects GM loss in regions connected to it, ie, GM connectivity. The PSI was used to describe the pattern of GM connectivity in 21 light drinkers (LDs) and in 54 individuals with AUD (ALC) early in abstinence. Effects of abstinence and relapse were determined in a subgroup of 36 participants after 3 months. Compared with LD, GM losses within the extended brain reward system (eBRS) at 1-month abstinence were similar between abstainers (ABST) and relapsers (REL), but REL had also GM losses outside the eBRS. Lower GM connectivities in ventro-striatal/hypothalamic and dorsolateral prefrontal regions and thalami were present in both ABST and REL. Between-networks connectivity loss of the eBRS in ABST was confined to prefrontal regions. About 3 months later, the GM volume and connectivity losses had resolved in ABST, and insula connectivity was increased compared with LD. GM losses and GM connectivity losses in REL were unchanged. Overall, prolonged abstinence was associated with a normalization of within-eBRS connectivity and a reconnection of eBRS structures with other networks. The re-formation of structural connectivities within and across networks appears critical for cognitive-behavioral functioning related to the capacity to maintain abstinence after outpatient treatment.

Introduction Heterogeneity of segmentation protocols for medial temporal lobe regions and hippocampal subfields on in vivo magnetic resonance imaging hinders the ability to integrate findings across studies. We aim to develop a harmonized protocol based on expert consensus and histological evidence. Methods Our international working group, funded by the EU Joint Programme–Neurodegenerative Disease Research (JPND), is working toward the production of a reliable, validated, harmonized protocol for segmentation of medial temporal lobe regions. The working group uses a novel postmortem data set and online consensus procedures to ensure validity and facilitate adoption. Results This progress report describes the initial results and milestones that we have achieved to date, including the development of a draft protocol and results from the initial reliability tests and consensus procedures. Discussion A harmonized protocol will enable the standardization of segmentation methods across laboratories interested in medial temporal lobe research worldwide., Highlights • Harmonization of MRI-based segmentation of medial temporal regions is needed. • The Hippocampal Subfield Group includes >200 imaging and anatomy experts worldwide. • Reliable and valid protocol based on specialized histology data set in development. • A modified Delphi procedure is used to determine consensus on protocol rules. • Final protocol will provide subfield delineation in hippocampal body, head, and tail.

Post-traumatic stress disorder (PTSD) is a psychiatric illness with a highly polygenic architecture without large effect-size common single-nucleotide polymorphisms (SNPs). Thus, to capture a substantial portion of the genetic contribution, effects from many variants need to be aggregated. We investigated various aspects of one such approach that has been successfully applied to many traits, polygenic risk score (PRS) for PTSD. Theoretical analyses indicate the potential prediction ability of PRS. We used the latest summary statistics from the largest published genome-wide association study (GWAS) conducted by Psychiatric Genomics Consortium for PTSD (PGC-PTSD). We found that the PRS constructed for a cohort comprising veterans of recent wars (n = 244) explains a considerable proportion of PTSD onset (Nagelkerke R2 = 4.68%, P = 0.003) and severity (R2 = 4.35%, P = 0.0008) variances. However, the performance on an African ancestry sub-cohort was minimal. A PRS constructed with schizophrenia GWAS also explained a significant fraction of PTSD diagnosis variance (Nagelkerke R2 = 2.96%, P = 0.0175), confirming previously reported genetic correlation between the two psychiatric ailments. Overall, these findings demonstrate the important role polygenic analyses of PTSD will play in risk prediction models as well as in elucidating the biology of the disorder.

The advent of high-resolution magnetic resonance imaging (MRI) has enabled in vivo research in a variety of populations and diseases on the structure and function of hippocampal subfields and subdivisions of the parahippocampal gyrus. Because of the many extant and highly discrepant segmentation protocols, comparing results across studies is difficult. To overcome this barrier, the Hippocampal Subfields Group was formed as an international collaboration with the aim of developing a harmonized protocol for manual segmentation of hippocampal and parahippocampal subregions on high-resolution MRI. In this commentary we discuss the goals for this protocol and the associated key challenges involved in its development. These include differences among existing anatomical reference materials, striking the right balance between reliability of measurements and anatomical validity, and the development of a versatile protocol that can be adopted for the study of populations varying in age and health. The commentary outlines these key challenges, as well as the proposed solution of each, with concrete examples from our working plan. Finally, with two examples, we illustrate how the harmonized protocol, once completed, is expected to impact the field by producing measurements that are quantitatively comparable across labs and by facilitating the synthesis of findings across different studies. © 2016 Wiley Periodicals, Inc.

Background MR Imaging has shown atrophy in brainstem regions that were linked to autonomic dysfunction in epilepsy patients. The brainstem projects to and modulates the activation state of several wide-spread cortical/subcortical regions. The goal was to investigate 1. Impact of brainstem atrophy on gray matter connectivity of cortical/subcortical structures and autonomic control. 2. Impact on the modulation of cortical/subcortical functional connectivity. Methods 11 controls and 18 patients with non-lesional focal epilepsy (FE) underwent heart rate variability (HRV) measurements and a 3 T MRI (T1 in all subjects, task-free fMRI in 7 controls/ 12 FE). The brainstem was extracted, and atrophy assessed using deformation-based-morphometry. The age-corrected z-scores of the mean Jacobian determinants were extracted from 71 5x5x5 mm grids placed in brainstem regions associated with autonomic function. Cortical and non-brainstem subcortical gray matter atrophy was assessed with voxel-based-morphometry and mean age corrected z-scores of the modulated gray matter volumes extracted from 380 cortical/subcortical rois. The profile similarity index was used to characterize the impact of brainstem atrophy on gray matter connectivity. The fMRI was preprocessed in SPM12/Conn17 and the BOLD signal extracted from 398 ROIs (16 brainstem). A dynamic task-free analysis approach was used to identify activation states. Connectivity HRV relationship were assessed with Spearman rank correlations. Results HRV was negatively correlated with reduced brainstem right hippocampus/parahippocampus gray matter connectivity in controls (p, Highlights • Brainstem and cortical/subcortical gray matter (gm) connectivity is impaired in FE. • FE is associated with an abnormal brain activation state in the interictal state. • The severity of the gm impairment and of the abnormal brain state are correlated. • GM connectivity impairment and abnormal brain activity affect HRV.

Purpose Stereotactic radiosurgery (SRS) may be an alternative to anterior temporal lobectomy (ATL) for mesial temporal lobe epilepsy (MTLE). Visual field defects (VFD) occur in 9–100% of patients following open surgery for MTLE. Postoperative VFD after minimally invasive versus open surgery may differ. Methods This prospective trial randomized patients with unilateral hippocampal sclerosis and concordant video-EEG findings to SRS versus ATL. Humphries perimetry was obtained at 24 m after surgery. VFD ratios (VFDR = proportion of missing homonymous hemifield with 0 = no VFD, 0.5 = complete superior quadrantanopsia) quantified VFD. Regressions of VFDR were evaluated against treatment arm and covariates. MRI evaluated effects of volume changes on VFDR. The relationships of VFDR with seizure remission and driving status 3 years after surgery were evaluated. Results No patients reported visual changes or had abnormal bedside examinations, but 49 of 54 (91%) of patients experienced VFD on formal perimetry. Neither incidence nor severity of VFDR differed significantly by treatment arm. VFDR severity was not associated with seizure remission or driving status. Conclusion The nature of VFD was consistent with lesions of the optic radiations. Effective surgery (defined by seizure remission) of the mesial temporal lobe results in about a 90% incidence of typical VFD regardless of method.

Observations in witnessed Sudden Unexpected Death in Epilepsy (SUDEP) suggest that a fatal breakdown of the central autonomic control could play a major role in SUDEP. A previous MR study found volume losses in the mesencephalon in focal epilepsy that were more severe and extended into the lower brainstem in two patients who later died of SUDEP. The aims of this study were to demonstrate an association (1) between brainstem volume loss and impaired autonomic control (reduced heart rate variability [HRV]); (2) between brainstem damage and time to SUDEP in patients who later died of SUDEP. Two populations were studied: (1) Autonomic system function population (ASF, 18 patients with focal epilepsy, 11 controls) with HRV measurements and standardized 3 T MR exams. (2) SUDEP population (26 SUDEP epilepsy patients) with clinical MRI 1-10 years before SUDEP. Deformation-based morphometry of the brainstem was used to generate profile similarity maps from the resulting Jacobian determinant maps that were further characterized by graph analysis to identify regions with excessive expansion indicating significant volume loss or atrophy. The total number of regions with excessive expansion in ASF was negatively correlated with HRV (r = -.37, p = .03), excessive volume loss in periaqueductal gray/medulla oblongata autonomic nuclei explained most of the HRV associated variation (r/r2 = -.82/.67, p

Posttraumatic stress disorder (PTSD) is characterized by atrophy within the prefrontal-limbic network. Graph analysis was used to investigate to what degree atrophy in PTSD is associated with impaired structural connectivity within prefrontal limbic network (restricted) and how this affects the integration of the prefrontal limbic network with the rest of the brain (whole-brain). 85 male veterans (45 PTSD neg, 40 PTSD pos) underwent volumetric MRI on a 3T MR. Subfield volumes were obtained using a manual labeling scheme and cortical thickness measurements and subcortical volumes from FreeSurfer. Regression analysis was used to identify regions with volume loss. Graph analytical Toolbox (GAT) was used for graph-analysis. PTSD pos had a thinner rostral anterior cingulate and insular cortex but no hippocampal volume loss. PTSD was characterized by decreased nodal degree (orbitofrontal, anterior cingulate) and clustering coefficients (thalamus) but increased nodal betweenness (insula, orbitofrontal) and a reduced small world index in the whole brain analysis and by orbitofrontal and insular nodes with increased nodal degree, clustering coefficient and nodal betweenness in the restricted analysis. PTSD associated atrophy in the prefrontal-limbic network results in an increased structural connectivity within that network that negatively affected its integration with the rest of the brain.

ObjectiveAn increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1 − 3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol.MethodMRI scans of a single healthy adult human subject were acquired both at 3 T and 7 T. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement.ResultsThe differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail.ConclusionsThe combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies. published

Several psychiatric disorders, including major depressive disorder (MDD), are associated with increased blood markers of oxidative stress. The relevance of this to the oxidation-sensitive hippocampus (HC) is unknown. We investigated the relationship between peripheral oxidative stress markers and HC volume in unmedicated individuals with MDD (n=16) and healthy controls (n=19). To conserve power, our primary analysis was carried out in the combined group of subjects, and secondary analyses examined each group separately. Oxidative stress markers (oxidized glutathione (GSSG)) and antioxidants (reduced glutathione (GSH), glutathione peroxidase (Gpx), and Vitamin C) were assessed, and a "total net antioxidant score" was calculated. 4-T MRI estimated total HC volume and HC subfield (CA1, CA1-CA2 transition zone, subiculum and CA3/dentate gyrus [CA3&DG]) volumes. Across groups, the antioxidant score was significantly and positively correlated with total HC volume and CA3&DG subfield volume (normalized to total intracranial volume), adjusting for age and sex. Similar relationships were observed in each individual group but missed statistical significance, likely due to type II errors, with the exception of a significant correlation between the antioxidant score and CA3&DG volume in the MDD group. These preliminary data are consistent with oxidative stress being associated with smaller total HC and CA3&DG subfield volumes.

Objective To assess the effect of subsyndromal symptoms of depression (SSD) on ratings of disability for individuals with mild cognitive impairment (MCI). Methods Data from 405 MCI participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were analyzed. Participants were evaluated at baseline and at 6-month intervals over 2 years. Severity of depressive symptoms was rated utilizing the Geriatric Depression Scale. Disability was assessed utilizing the Functional Assessment Questionnaire (FAQ). Other clinical variables included white matter lesion (WML) and intracranial brain (ICV) volumes derived from magnetic resonance imaging, ratings of overall cognitive function (Alzheimer's Disease Assessment Scale, ADAS), and apolipoprotein E (ApoE) status. Demographic variables included age, education, and gender. Results SSD individuals had a lower volume of WML and higher frequency of ApoE ɛ4 alleles than nondepressed participants but the two groups did not differ with respect to other clinical or demographic variables. At baseline, SSD individuals were 1.77 times more likely to have poorer FAQ scores than individuals with no symptoms of depression after controlling for the effect of cognitive functioning, ICV, WML, and ApoE status. The presence of SSD at baseline was not associated with a poorer course of disability outcomes, cognitive functioning, or conversion to dementia over 24 months. Conclusions SSD demonstrated a significant impact on disability for MCI individuals, who are also at high risk for functional limitations related to neurodegenerative disease. Therefore, the treatment of SSD may represent a significant avenue to reduce the burden of disability in this vulnerable patient population.

Structural imaging studies investigating the relationship between hippocampal volume (HCV) and peripheral measures of glucocorticoids (GCs) have produced conflicting results in both normal populations and in individuals with MDD, raising the possibility of other modulating factors. In preclinical studies, dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS; together abbreviated, DHEA(S)) have been shown to antagonize the actions of GCs on the central nervous system. Therefore, considering the relationship of HCV to both of these hormones simultaneously may be important, although it has rarely been done in human populations. Using high-resolution magnetic resonance imaging (MRI), the present pilot study examined the relationship between morning serum cortisol, DHEA(S), and HCV in nineteen normal controls and eighteen unmedicated subjects with Major Depressive Disorder (MDD). Serum cortisol and DHEA(S) were not significantly correlated with HCV across all subjects (cortisol: r = −0.165, p = 0.33; DHEA: r = 0.164, p = 0.35; DHEAS: r = 0.211, p = 0.22, respectively). However, the ratios of cortisol/DHEA(S) were significantly negatively correlated with HCV in combined group (Cortisol/DHEA: r = −0.461, p = 0.005; Cortisol/DHEAS: r = −0.363, p = 0.03). Significant or near-significant correlations were found between some hormonal measurements and HCV in the MDDs alone (DHEA: r = 0.482, p = 0.059; DHEAS: r = 0.507, p = 0.045; cort/DHEA: r = −0.589, p = 0.02; cort/DHEAS: r = −0.424 p = 0.10), but not in the controls alone (DHEA: r = 0.070, p = 0.79; DHEAS: r = 0.077, p = 0.77; cort/DHEA: r = −0.427, p = 0.09; cort/DHEAS: r = −0.331, p = 0.19). However, Group (MDDs vs controls) did not have a significant effect on the relationship between cortisol, DHEA(S), and their ratios with HCV (p > 0.475 in all analyses). Although the exact relationship between serum and central steroid concentrations as well as their effects on the human hippocampus remains not known, these preliminary results suggest that the ratio of cortisol to DHEA(S), compared to serum cortisol alone, may convey additional information about “net steroid activity” with relation to HCV.

Autopsy studies of Alzheimer's disease (AD) have found that neurofibrillary tangle (NFT) pathology of the medial temporal lobe (MTL) demonstrates selective topography with relatively stereotyped subregional involvement at early disease stages, prompting interest in more granular measurement of these structures with in vivo magnetic resonance imaging. We applied a novel, automated method for measurement of hippocampal subfields and extrahippocampal MTL cortical regions. The cohort included cognitively normal (CN) adults (n = 86), early mild cognitive impairment (n = 43), late MCI (n = 22), and mild AD (n = 40) patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI). For pseudolongitudinal analysis of the continuum from preclinical to mild AD dementia, the groups were further divided according to amyloid status based on positron emission tomography. Specific subregions associated with the early NFT pathology of AD were more sensitive to preclinical and early prodromal AD than whole hippocampal volume while more diffuse involvement was found in later stages. In particular, BA35, the first region associated with NFT deposition, was the only region to discriminate preclinical AD from amyloid negative cognitively normal adults ("normal aging"). In general, patterns of atrophy in the pseudolongitudinal analysis largely recapitulated Braak staging of NFTs within the MTL.

OBJECTIVES: To investigate the association between cognitive decline and cortical atrophy in individuals with mild cognitive impairment (MCI) and chronic subsyndromal symptoms of depression (SSD) over a four-year period. DESIGN: Prospective cohort study. SETTING: Multicenter, clinic-based. PARTICIPANTS: Within the Alzheimer’s Disease Neuroimaging Initiative repository, the Neuropsychiatric Inventory was used to identify MCI individuals with stable endorsement (SSD group N=32) or no endorsement (non-SSD group N=69) of depressive symptoms across timepoints. MEASUREMENTS: Repeated measures of cognitive outcomes, cortical atrophy, and their associations were evaluated with mixed effects models adjusting for age, education, gender, and APOE genotype. RESULTS: The SSD group demonstrated accelerated decline on measures of global cognition (Alzheimer’s Disease Assessment Scale (df=421, t=2.242, p=0.025), memory (Wechsler Memory Scale-Revised Logical Memory II (df=244, t=−2.525, p=0.011), information processing speed (Trail Making Test Parts A (df=421, t=2.376, p=0.018) and B (df=421, t=2.533, p=0.012)), and semantic fluency (Category Fluency (df=424, t=−2.418, p=0.016), as well as accelerated frontal lobe (df=341, t=−2.648, p=0.008) and anterior cingulate (df=341, t=−3.786, p

Memory impairment is one of the most prominent cognitive deficits in temporal lobe epilepsy (TLE). The overall goal of this study was to explore the contribution of cortical and hippocampal (subfield) damage to impairment of auditory immediate recall (AIMrecall), auditory delayed recall (ADMrecall), and auditory delayed recognition (ADMrecog) of the Wechsler Memory Scale III (WMS-III) in TLE with (TLE-MTS) and without hippocampal sclerosis (TLE-no). It was hypothesized that volume loss in different subfields determines memory impairment in TLE-MTS and temporal neocortical thinning in TLE-no.T1 whole brain and T2-weighted hippocampal magnetic resonance imaging and WMS-III were acquired in 22 controls, 18 TLE-MTS, and 25 TLE-no. Hippocampal subfields were determined on the T2 image. Free surfer was used to obtain cortical thickness averages of temporal, frontal, and parietal cortical regions of interest (ROI). MANOVA and stepwise regression analysis were used to identify hippocampal subfields and cortical ROI significantly contributing to AIMrecall, ADMrecall, and ADMrecog.In TLE-MTS, AIMrecall was associated with cornu ammonis 3 (CA3) and dentate (CA3DG) and pars opercularis, ADMrecall with CA1 and pars triangularis, and ADMrecog with CA1. In TLE-no, AIMrecall was associated with CA3DG and fusiform gyrus (FUSI), and ADMrecall and ADMrecog were associated with FUSI.The study provided the evidence for different structural correlates of the verbal memory impairment in TLE-MTS and TLE-no. In TLE-MTS, the memory impairment was mainly associated by subfield-specific hippocampal and inferior frontal cortical damage. In TLE-no, the impairment was associated by mesial-temporal cortical and to a lesser degree hippocampal damage.

Posttraumatic stress disorder (PTSD) accounts for a substantial proportion of casualties among surviving soldiers of the Iraq and Afghanistan wars. Currently, the assessment of PTSD is based exclusively on symptoms, making it difficult to obtain an accurate diagnosis. This study aimed to find potential imaging markers for PTSD using structural, perfusion, and diffusion magnetic resonance imaging (MRI) together. Seventeen male veterans with PTSD (45 ± 14 years old) and 15 age-matched male veterans without PTSD had measurements of regional cerebral blood flow (rCBF) using arterial spin labeling (ASL) perfusion MRI. A slightly larger group had also measurements of white matter integrity using diffusion tensor imaging (DTI) with computations of regional fractional anisotropy (FA). The same subjects also had structural MRI of the hippocampal subfields as reported recently (W. Zhen et al. Arch Gen Psych 2010;67(3):296–303). On ASL-MRI, subjects with PTSD had increased rCBF in primarily right parietal and superior temporal cortices. On DTI, subjects with PTSD had FA reduction in white matter regions of the prefrontal lobe, including areas near the anterior cingulate cortex and prefrontal cortex as well as in the posterior angular gyrus. In conclusion, PTSD is associated with a systematic pattern of physiological and structural abnormalities in predominantly frontal lobe and limbic brain regions. Structural, perfusion, and diffusion MRI together may provide a signature for a PTSD marker.

We sought to determine whether there are structural and metabolic changes in the brains of older adults with cognitive complaints yet who do not meet MCI criteria (i.e., preMCI). We compared the volumes of regional lobar gray matter (GM) and medial temporal lobe structures, including the hippocampus, entorhinal cortex (ERC), fusiform and parahippocampal gyri, and metabolite ratios from the posterior cingulate in individuals who had a Clinical Demetia Rating (CDR) of 0.5, but who did not meet MCI criteria (preMCI, N = 17), patients with mild cognitive impairment (MCI, N = 13), and cognitively normal controls (N = 18). Controls had more ERC, fusiform, and frontal gray matter volume than preMCI and MCI subjects and greater parahippocampal volume and more posterior cingulate N-acetylaspartate (NAA)/myoinosotil (mI) than MCI. There were no significant differences between MCI and preMCI subjects on any of these measures. These findings suggest there are neurodegenerative changes in the brains of older adults who have cognitive complaints severe enough to qualify for CDR = 0.5 yet show no deficits on formal neuropsychological testing. The results further support the hypothesis that detection of individuals with very mild forms of Alzheimer's disease (AD) may be facilitated by use of the CDR, which emphasizes changes in cognition over time within individuals rather than comparison with group norms.

Depressed mood is a frequent co-morbidity of dementia suggesting that they might share a common neuropathological substrate. Gray matter (GM) atrophy and white matter lesions (WML) have been described in both conditions. Our aims were to determine the relationship of GM and WML with cognition and depressed mood in the same population. Structural brain images were obtained from 42 controls, 20 Alzheimer's disease (AD) patients and 32 subjects with cognitive impairment/dementia due to subcortical cerebrovascular disease (vascCIND/IVD). Images were segmented to obtain lobar GM, white matter and WML volumes. Lobar WML had a negative effect on GM in all lobes in controls, on frontal, parietal and occipital GM in AD and on frontal GM in vascCIND/IVD. Frontal, temporal and hippocampal GM were associated with cognitive functions and frontal WML load with depressed mood. Cognitive function is associated with GM atrophy and depressed mood is associated with frontal WML. This indicates that although both often occur together, depressed mood and cognitive impairment have different pathological correlates.

Temporal lobe epilepsy (TLE) is the most common form of partial epilepsy. Based on imaging and histopathologic findings, two types of nonlesional TLE are distinguished: TLE with mesiotemporal lobe sclerosis (TLE-MTS) characterized by an atrophied hippocampus with signal abnormalities on magnetic resonance imaging (MRI) and severe neuronal loss on histologic examination (TLE-MTS, about 60–70%), and TLE with normal-appearing hippocampus on MRI and no or only mild hippocampal neuronal loss on histologic examination (TLE-no, about 30–40%). Depth electroencephalography (EEG) recordings (Vossler et al., 2004) and neuroimaging (Carne et al., 2007, Mueller et al., 2007a) suggest that in TLE-MTS seizures arise from a circumscribed region in the mesiotemporal region/hippocampus as opposed to TLE-no, wherein they arise from a more widespread, less well-defined region in inferolateral temporal lobe. In both conditions, seizures are not restricted to the hippocampus and/or temporal lobe, but can also spread to other brain regions and cause structural and metabolic abnormalities similar to those in the focus (Jutila et al., 2001; Moran et al., 2001; Keller et al., 2004). A structure of particular interest in this regard is the thalamus, in which bilateral volume loss and/or uni- or bilateral hypometabolism have consistently been described in TLE-MTS (Juhasz et al., 1999; Mueller et al., 2006, 2007a; Gong et al., 2008; Labate et al., 2008; Seidenberg et al., 2008). The thalamus not only receives massive neuronal projections from temporal limbic regions but has also widespread reciprocal connections to subcortical structures and other cortical regions. Because of its unique role as gateway between brain structures, it has been suggested that the thalamus might play an active role in seizure propagation to other brain regions (Margerison & Corsellis, 1966; Lothman & Collins, 1981; Cassidy & Gale, 1998; Rosenberg et al., 2006; Guye et al., 2006; Bertram et al., 2008; Sloan & Bertram, 2008). Seizure spread beyond the thalamus could cause neuronal loss due to deafferentation or local excitotoxic effects and thus contribute to the widespread extratemporal structural abnormalities observed in TLE. To our knowledge the relationship between thalamic volume losses and structural changes in extratemporal brain regions in TLE has not been studied systematically. The overall aim of this study was to further investigate how volume losses in the epileptogenic focus (TLE-MTS, hippocampus; TLE-no, cortical: thickness of the inferior temporal gyrus), ipsilateral thalamus, and extrafocal cortical structures relate to each other using the FreeSurfer software package (version 3.05; https://surfer.nmr.mgh.harvard.edu) to assess cortical thickness and deformation-based morphometry to identify regions of thalamic volume loss. Specifically, the following hypotheses were tested: (1) In TLE-MTS, thalamic volume loss is most prominent in the anterior thalamic and lateral dorsal nucleus, that is, nuclei receiving direct projections from CA1, the only hippocampal subfield with direct connections to the thalamus (Herkenham, 1978; Cenquizca & Swanson, 2006). Volume/neuronal loss there leads to loss of thalamocortical projections and thus to cortical thinning in the corresponding temporal and extratemporal projection areas. (2) Based on the assumption that the focus in TLE-no is located in the inferolateral temporal lobe, the medial pulvinar, which receives projections from this area, will show the most prominent volume loss. The distribution of extrafocal cortical thinning corresponds to cortical projection areas of the pulvinar.

Fluid attenuated inversion recovery (FLAIR) and diffusion tensor imaging (DTI) techniques have been widely used to evaluate white matter (WM) alterations associated with aging, dementia and cerebral vascular disease. The relationship between FLAIR detected WM lesions (WML) and DTI detected WM integrity changes, however, remains unclear. To investigate this association, voxelwise correlations between 4 Tesla DTI and FLAIR images from elderly subjects were performed by relating WML volume and intensity in FLAIR to fractional anisotropy (FA) and mean diffusivity (MD) in DTI. Significant DTI–FLAIR correlations were found in regions overlapping with the WML of moderate intensities in FLAIR. No significant correlations were detected in periventricular regions where the FLAIR intensities are particularly high. The findings are consistent with a transitional model for WM degeneration from normal WM to cerebrospinal fluid (CSF). The results show that the correlation between DTI and FLAIR disappears when the FLAIR intensity of WML reaches its maximum at a certain lesion severity, and that the correlations may remerge with reversed signs when the lesion severity is further increased. These results suggest that the different stages of WM degeneration in elderly subjects can be better characterized by regional DTI–FLAIR correlations than single modality alone.

High-resolution magnetic resonance imaging (MRI) at 4 Tesla depicts details of the internal structure of the hippocampus not visible at 1.5 Tesla, and so allows for in vivo parcellation of different hippocampal subfields. The aim of this study was to test if distinct subfield atrophy patterns can be detected in temporal lobe epilepsy (TLE) with mesial temporal sclerosis (TLE-MTS) and without (TLE-no) hippocampal sclerosis.High-resolution T(2)-weighted hippocampal images were acquired in 34 controls: 15 TLE-MTS and 18 TLE-no. Entorhinal cortex (ERC), subiculum (SUB), CA1, CA2, and CA3, and dentate (CA3DG) volumes were determined using a manual parcellation scheme.TLE-MTS had significantly smaller ipsilateral CA1, CA2, CA3DG, and total hippocampal volume than controls or TLE-no. Mean ipsilateral CA1 and CA3DG z-scores were significantly lower than ipsilateral CA2, ERC, and SUB z-scores. There were no significant differences between the various subfield or hippocampal z-scores on either the ipsi- or the contralateral side in TLE-no. Using a z-scoreor=-2.0 to identify severe volume loss, the following atrophy patterns were found in TLE-MTS: CA1 atrophy, CA3DG atrophy, CA1 and CA3DG atrophy, and global hippocampal atrophy. Significant subfield atrophy was found in three TLE-no: contralateral SUB atrophy, bilateral CA3DG atrophy, and ipsilateral ERC and SUB atrophy.Using a manual parcellation scheme on 4 Tesla high-resolution MRI, we found the characteristic ipsilateral CA1 and CA3DG atrophy described in TLE-MTS. Seventeen percent of the TLE-no had subfield atrophy despite normal total hippocampal volume. These findings indicate that high-resolution MRI and subfield volumetry provide superior information compared to standard hippocampal volumetry.

Histopathological studies and animal models suggest that different physiological and pathophysiological processes exert different subfield specific effects on the hippocampus. High-resolution images at 4T depict details of the internal structure of the hippocampus allowing for in vivo volumetry of hippocampal subfields. The aims of this study were (1) to determine patterns of hippocampal subfield volume loss due to normal aging and Apo e4 carrier state, (2) to determine subfield specific volume losses due to preclinical (MCI) and clinical Alzheimer’s disease (AD) and their modification due to age and Apo e4 carrier state. One hundred fifty seven subjects (119 cognitively healthy elderly controls, 20 MCI and 18 AD) were studied with a high resolution T2 weighted imaging sequence obtained at 4T aimed at the hippocampus. Apo e4 carrier state was known in 95 subjects (66 controls, 14 MCI, 15 AD). Subiculum (SUB), CA1, CA1–CA2 transition zone (CA1–2 transition), CA3- dentate gyrus (CA3&DG) were manually marked. Multiple linear regression analysis was used to test for effects of age, Apo e4 carrier state and effects of MCI and AD on different hippocampal subfields. Age had a significant negative effect on CA1 and CA3&DG volumes in controls (P < 0.05). AD had significantly smaller volumes of SUB, CA1, CA1–2 transition, and MCI had smaller CA1–2 transition volumes than controls (P < 0.05). Apo e4 carrier state was associated with volume loss in CA3&DG compared to non-Apo e4 carriers in healthy controls and AD. Based on these findings, we conclude that subfield volumetry provides regional selective information that allows to distinguish between different normal and pathological processes affecting the hippocampus and thus for an improved differential diagnosis of neurodegenerative diseases affecting the hippocampus.

MRI at high magnetic fields (>3.0 T) is complicated by strong inhomogeneous radio-frequency fields, sometimes termed the “bias field”. These lead to non-biological intensity non-uniformities across the image. They can complicate further image analysis such as registration and tissue segmentation. Existing methods for intensity uniformity restoration have been optimized for 1.5 T, but they are less effective for 3.0 T MRI, and not at all satisfactory for higher fields. Also, many of the existing restoration algorithms require a brain template or use a prior atlas, which can restrict their practicalities. In this study an effective intensity uniformity restoration algorithm has been developed based on non-parametric statistics of high order local intensity co-occurrences. These statistics are restored with a non-stationary Wiener filter. The algorithm also assumes a smooth non-uniformity and is stable. It does not require a prior atlas and is robust to variations in anatomy. In geriatric brain imaging it is robust to variations such as enlarged ventricles and low contrast to noise ratio. The co-occurrence statistics improve robustness to whole head images with pronounced non-uniformities present in high field acquisitions. Its significantly improved performance and lower time requirements have been demonstrated by comparing it to the very commonly used N3 algorithm on BrainWeb MR simulator images as well as on real 4 T human head images.

Background Details of the internal hippocampal structure visible at 4 T allow for in vivo volumetry of subfields. The aims of this study were: 1. To determine if Apo e4 has subfield specific effects in controls. 2. To study the influence of Apo e4 on hippocampal subfields in AD. Methods 81 subjects (66 controls, mean age 60.8 ± 13.6, range: 28–85 years), and 15 AD (mean age 67.5 ± 9.3) were studied. Entorhinal cortex, subiculum, CA1, CA1–CA2 transition zone, CA3–4 and dentate gyrus (CA3&DG) and total hippocampal volume were determined using a manual marking strategy. Results Significant effects for Apo e4 on the CA3&DG were found in the total control population ( p = 0.042) and in older controls (61–85 years) ( p = 0.036) but not in younger (28–60 years) controls. Significant effects for Apo e4 ( p = 0.0035) on CA3&DG were also found in a subgroup of older subjects and AD subjects. AD with Apo e4 had smaller CA3&DG than AD without Apo e4 ( p = 0.027). Conclusions These findings suggest that Apo e4 exerts a regionally selective effect on CA3&DG in normal aging and AD.

Mesial temporal lobe epilepsy (TLE) is characterized by stereotyped origination and spread pattern of epileptogenic activity, which is reflected in stereotyped topographic distribution of neuronal atrophy on magnetic resonance imaging (MRI). Both epileptogenic activity and atrophy spread appear to follow white matter connections. We model the networked spread of activity and atrophy in TLE from first principles via two simple first order network diffusion models. Atrophy distribution is modeled as a simple consequence of the propagation of epileptogenic activity in one model, and as a progressive degenerative process in the other. We show that the network models closely reproduce the regional volumetric gray matter atrophy distribution of two epilepsy cohorts: 29 TLE subjects with medial temporal sclerosis (TLE-MTS), and 50 TLE subjects with normal appearance on MRI (TLE-no). Statistical validation at the group level suggests high correlation with measured atrophy (R = 0.586 for TLE-MTS, R = 0.283 for TLE-no). We conclude that atrophy spread model out-performs the hyperactivity spread model. These results pave the way for future clinical application of the proposed model on individual patients, including estimating future spread of atrophy, identification of seizure onset zones and surgical planning., Author Summary Medial temporal lobe epilepsy is the most common form of focal epilepsy. In this work we investigate two models describing the dynamics of epilepsy. In the first model the extrahippocampal spread of seizure activity is primarily responsible for the apparent topographic distribution of atrophy. The second hypothesis is that loss of hippocampal neurons leads to remote deafferentation followed by gradual and progressive neuronal loss in connected regions. Impoverishment of hippocampal connections can lead to reduced complexity of remote circuitry. The purpose of this work is to develop network theoretic models of regional atrophy dynamics resulting from each of the above hypotheses, and to statistically determine which model is a better descriptor of the spatial patterning of real TLE atrophy. Both models are based on simple graph theoretic models of influence spread as a network diffusion process, enacted on the brains structural connectivity network.

Objective Investigate the association of chronic depressive symptomatology (chrDS) with cortical atrophy rates and conversion to Alzheimer dementia (AD) over 3 years in mild cognitive impairment (MCI). Methods In a multicenter, clinic-based study, MCI elderly participants were selected from the Alzheimer's Disease Neuroimaging Initiative repository, based on availability of both serial structural magnetic resonance imaging and chrDS endorsed on three depression-related items from the Neuropsychiatric Inventory Questionnaire (chrDS N = 32 or no depressive symptoms N = 62) throughout follow-up. Clinical and laboratory investigations were performed every 6 months during the first 2 years and yearly thereafter (median follow-up: 3 years; interquartile range: 1.5–4.0 years). Cortical atrophy rates in 16 predefined frontotemporoparietal regions affected in major depression and AD and the rate of incident AD at follow-up. Results ChrDS in a single domain amnestic MCI sample were associated with accelerated cortical atrophy in the frontal lobe and anterior cingulate but not with atrophy rates in temporomedial or other AD-affected regions. During follow-up, 38 participants (42.7%) developed AD. Participants with chrDS had 60% shorter conversion time to AD than those without depressive symptoms. This association remained significant in survival models adjusted for temporomedial atrophy rates and showed the same trend in models adjusted for frontal cortical atrophy rate, which all increased the risk of AD. Conclusion Our results suggest that chrDS associated with progressive atrophy of frontal regions may represent an additional risk factor for conversion to dementia in MCI as opposite to representing typical prodromal AD symptomatology.

Introduction Alzheimer's Disease Neuroimaging Initiative (ADNI) is now in its 10th year. The primary objective of the magnetic resonance imaging (MRI) core of ADNI has been to improve methods for clinical trials in Alzheimer's disease (AD) and related disorders. Methods We review the contributions of the MRI core from present and past cycles of ADNI (ADNI-1, -Grand Opportunity and -2). We also review plans for the future-ADNI-3. Results Contributions of the MRI core include creating standardized acquisition protocols and quality control methods; examining the effect of technical features of image acquisition and analysis on outcome metrics; deriving sample size estimates for future trials based on those outcomes; and piloting the potential utility of MR perfusion, diffusion, and functional connectivity measures in multicenter clinical trials. Discussion Over the past decade the MRI core of ADNI has fulfilled its mandate of improving methods for clinical trials in AD and will continue to do so in the future.

The medial temporal lobe is implicated as a key brain region involved in the pathogenesis of Alzheimer's disease (AD) and consequent memory loss. Tau tangle aggregation in this region may develop concurrently with cortical Aβ deposition in preclinical AD, but the pathological relationship between tau and Aβ remains unclear. We used task-free fMRI with a focus on the medical temporal lobe, together with Aβ PET imaging, in cognitively normal elderly human participants. We found that cortical Aβ load was related to disrupted intrinsic functional connectivity of the perirhinal cortex, which is typically the first brain region affected by tauopathies in AD. There was no concurrent association of cortical Aβ load with cognitive performance or brain atrophy. These findings suggest that dysfunction in the medial temporal lobe may represent a very early sign of preclinical AD and may predict future memory loss.

Neurodegeneration refers to a large clinically and pathologically heterogeneous disease entity associated with slowly progressive neuronal loss in different anatomical and functional systems of the brain. Neurodegenerative diseases often affect cognition, e.g. Alzheimer's disease (AD), dementia with Lewy bodies and vascular dementia, or different aspects of the motor system, e.g., amyotrophic lateral sclerosis, Parkinson's disease and ataxic disorders. Owing to increasing knowledge about the mechanisms leading to neurodegeneration, the development of treatments able to modify the neurodegenerative process becomes possible for the first time. Currently, clinical outcome measures are used to assess the efficacy of such treatments. However, most clinical outcome measures have a low test-retest reliability and thus considerable measurement variance. Therefore, large patient populations and long observation times are needed to detect treatment effects. Furthermore, clinical outcome measures cannot distinguish between symptomatic and disease-modifying treatment effects. Therefore, alternative biomarkers including neuroimaging may take on a more important role in this process. Because MR scanners are widely available and allow for non-invasive detection and quantification of changes in brain structure and metabolism, there is increasing interest in the use of MRI/MRS to monitor objectively treatment effects in clinical trials of neurodegenerative diseases. Particularly volumetric MRI has been used to measure atrophy rates in treatment trials of AD because the relationship between atrophic changes and neuron loss is well established and correlates well with clinical measures. More research is needed to determine the value of other MR modalities, i.e. diffusion, perfusion and functional MRI and MR spectroscopy, for clinical trials with neuroprotective drugs.

Cortical malformations (CMs) are increasingly recognized as the epileptogenic substrate in patients with medically refractory neocortical epilepsy (NE). The aim of this study was to test the hypotheses that: 1. CMs are metabolically heterogeneous. 2. The structurally normal appearing perilesional zone is characterized by similar metabolic abnormalities as the CM.Magnetic resonance spectroscopic imaging (MRSI) in combination with tissue segmentation was performed on eight patients with NE and CMs and 19 age matched controls. In controls, NAA, Cr, Cho,NAA/Cr and NAA/Cho of all voxels of a given lobe were expressed as a function of white matter content and thresholds for pathological values determined by calculating the 95% prediction intervals. These thresholds were used to identify metabolically abnormal voxels within the CM and in the perilesional zone.30% of all voxels in the CMs were abnormal, most frequently because of decreases of NAA or increases of Cho. Abnormal voxels tended to form metabolically heterogeneous clusters interspersed in metabolically normal regions. Furthermore, 15% of all voxels in the perilesional zone were abnormal, the most frequent being decreases of NAA and Cr.In CMs metabolically normal regions are interspersed with metabolically heterogeneous abnormal regions. Metabolic abnormalities in the perilesional zone share several characteristics of CMs and might therefore represent areas with microscopic malformations and/or intrinsic epileptogenicity.

Summary: Purpose: The aim of this study was to evaluate the usefulness of multislice magnetic resonance spectroscopic imaging (MRSI) in combination with tissue segmentation for the identification of the epileptogenic focus in neocortical epilepsy (NE). Methods: Twenty patients with NE (10 with MRI-visible malformations, 10 with normal MRI) and 19 controls were studied. In controls, N-acetylaspartate NAA/Cr and NAA/Cho of all voxels of a given lobe were expressed as a function of white matter, and thresholds were determined by calculating the 95% prediction intervals (PIs) for NAA/Cr and NAA/Cho. Voxels with NAA/Cr or NAA/Cho values less than the 95% PI were defined as “pathological.” Z-scores were calculated. Depending on the magnitude of those z-scores, we used two different methods (score-localization or forced-localization) to identify in a given subject the lobe with the highest percentage of pathological voxels, which was supposed to represent the epileptogenic lobe. Results: MRSI correctly identified the lobe containing the epileptogenic focus as defined by EEG in 65% of the NE patients. MRSI localization of the focus was correct in 70% of the patients with an MRI-visible malformation and in 60% of the patients with normal MRI. Of the patients, 15% had metabolically abnormal brain regions outside the epileptogenic lobe, and 35% of the patients had evidence for secondary hippocampal damage. Conclusions: MRSI may be helpful for the identification of the epileptogenic focus in NE patients, even in NE with normal MRI.

Purpose: Long echo time (TE) spectroscopy reliably identifies the epileptogenic hippocampus in mesial temporal lobe epilepsy. Short-TE spectroscopy gives additional metabolic information but may have more artifacts. The aim of this study was to test (a) lateralization of the seizure focus by short-TE spectroscopy, and (b) value of myoinositol (MI) in the identification of the epileptogenic hippocampus. Methods: Twenty-four patients with temporal lobe epilepsy: 16 with mesial temporal sclerosis (TLE-MTS), eight patients with normal magnetic resonance imaging (MRI; TLE-No), and 16 controls were studied with hippocampal 2D short-TE magnetic resonance spectroscopic imaging (MRSI). Results: In TLE-MTS, the ipsilateral N-acetylaspartate (NAA) was decreased compared with contralateral (p = 0.03) or controls (p = 0.007). Additionally, the ipsilateral MI was decreased compared with controls (p = 0.012). TLE-No values showed no side differences and were not different from controls. Abnormalities in the anterior hippocampus correctly lateralized the epileptogenic hippocampus in less than or equal to82% of TLE-MTS and in less than or equal to80% of the TLE-No. Conclusions: The accuracy of short-TE MRSI at 1.5 T for focus lateralization in mTLE is comparable to that of long-TE MRSI. MI might be helpful for focus lateralization, but more information about the factors influencing the MI concentration is needed.

The American Epilepsy Society (AES) annual meeting took place in Washington DC in December 2017. In an expert interview, Susanne Mueller discusses the results of a validation study she presented at the meeting, which investigated brainstem changes in focal epilepsy and sudden unexplained death in epilepsy (SUDEP).1

© 2015 Elsevier Ireland Ltd. Accelerated cell aging, indexed in peripheral leukocytes by telomere shortness and in peripheral blood mononuclear cells (PBMCs) by telomerase activity, has been reported in several studies of major depressive disorder (MDD). However, the relevance of these peripheral measures for brain indices that are presumably more directly related to MDD pathophysiology is unknown. In this study, we explored the relationship between PBMC telomerase activity and leukocyte telomere length and magnetic resonance imaging-estimated hippocampal volume in un-medicated depressed individuals and healthy controls. We predicted that, to the extent peripheral and central telomerase activity are directly related, PBMC telomerase activity would be positively correlated with hippocampal volume, perhaps due to hippocampal telomerase-associated neurogenesis, neuroprotection or neurotrophic facilitation, and that this effect would be clearer in individuals with increased PBMC telomerase activity, as previously reported in un-medicated MDD. We did not have specific hypotheses regarding the relationship between leukocyte telomere length and hippocampal volume, due to conflicting reports in the published literature. We found, in 25 un-medicated MDD subjects, that PBMC telomerase activity was significantly positively correlated with hippocampal volume; this relationship was not observed in 18 healthy controls. Leukocyte telomere length was not significantly related to hippocampal volume in either group (19 unmedicated MDD subjects and 17 healthy controls). Although the nature of the relationship between peripheral telomerase activity and telomere length and the hippocampus is unclear, these preliminary data are consistent with the possibility that PBMC telomerase activity indexes, and may provide a novel window into, hippocampal neuroprotection and/or neurogenesis in MDD.

Summary: Purpose: Structural and metabolic abnormalities in the hippocampal region in medial temporal lobe epilepsy (mTLE) are well described; less is known about extrahippocampal changes. This study was designed to characterize extrahippocampal metabolic abnormalities in mTLE with magnetic resonance spectroscopy in combination with tissue segmentation and volumetry of gray and white matter. Methods: Multislice magnetic resonance spectroscopic imaging (1H-MRSI) in combination with tissue segmentation was performed on 16 patients with mTLE and 12 age-matched healthy volunteers. The data were analyzed by using a regression-analysis model that estimated the metabolite concentrations in 100% cortical gray and 100% white matter in the frontal lobe and nonfrontal brain. The segmented image was used to calculate the fraction of gray and white matter in these regions. Results: mTLE had significantly lower N-acetyl aspartate (NAA) in ipsi- and contralateral frontal gray (p = 0.03) and in ipsi- and contralateral nonfrontal white matter (p = 0.008) compared with controls. Although there were no associated volumetric deficits in frontal gray and white matter, ipsilateral nonfrontal gray matter (p = 0.003) was significantly smaller than that in controls. Conclusions: mTLE is associated with extrahippocampal metabolic abnormalities and volumetric deficits, but these do not necessarily affect the same regions.