7T MP2RAGE for cortical myelin segmentation: Impact of aging.

BACKGROUND: Myelin and iron are major contributors to the cortical MR signal. The aim of this study was to investigate 1. Can MP2RAGE-derived contrasts at 7T in combination with k-means clustering be used to distinguish between heavily and sparsely myelinated layers in cortical gray matter (GM)? 2. Does this approach provide meaningful biological information? METHODS: The following contrasts were generated from the 7T MP2RAGE images from 45 healthy controls (age: 19-75, f/m = 23/22) from the ATAG data repository: 1. T1 weighted image (UNI). 2. T1 relaxation image (T1map). 3. INVC/T1map ratio (RATIO). K-means clustering identified 6 clusters/tissue maps (csf, csf/gm-transition, wm, wm/gm transition, heavily myelinated cortical GM (dGM), sparsely myelinated cortical GM (sGM)). These tissue maps were then processed with SPM/DARTEL (volume-based analyses) and Freesurfer (surface-based analyses) and dGM and sGM volume/thickness of young adults (n = 27, 19-27 years) compared to those of older adults (n = 18, 42-75 years) at p<0.001 uncorrected. RESULTS: The resulting maps showed good agreement with histological maps in the literature. Volume- and surface analyses found age-related dGM loss/thinning in the mid-posterior cingulate and parahippocampal/entorhinal gyrus and age-related sGM losses in lateral, mesial and orbitofrontal frontal, insular cortex and superior temporal gyrus. CONCLUSION: The MP2RAGE derived UNI, T1map and RATIO contrasts can be used to identify dGM and sGM. Considering the close relationship between cortical myelo- and cytoarchitecture, the findings reported here indicate that this new technique might provide new insights into the nature of cortical GM loss in physiological and pathological conditions.

Traumatic Brain Injury and Post-Traumatic Stress Disorder and Their Influence on Development and Pattern of Alzheimer's Disease Pathology in Later Life.

Background: Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are potential risk factors for the development of dementia including Alzheimer's disease (AD) in later life. The findings of studies investigating this question are inconsistent though. Objective: To investigate if these inconsistencies are caused by the existence of subgroups with different vulnerability for AD pathology and if these subgroups are characterized by atypical tau load/atrophy pattern. Methods: The MRI and PET data of 89 subjects with or without previous TBI and/or PTSD from the DoD ADNI database were used to calculate an age-corrected gray matter tau mismatch metric (ageN-T mismatch-score and matrix) for each subject. This metric provides a measure to what degree regional tau accumulation drives regional gray matter atrophy (matrix) and can be used to calculate a summary score (score) reflecting the severity of AD pathology in an individual. Results: The ageN-T mismatch summary score was positively correlated with whole brain beta-amyloid load and general cognitive function but not with PTSD or TBI severity. Hierarchical cluster analysis identified five different spatial patterns of tau-gray matter interactions. These clusters reflected the different stages of the typical AD tau progression pattern. None was exclusively associated with PTSD and/or TBI. Conclusions: These findings suggest that a) although subsets of patients with PTSD and/or TBI develop AD-pathology, a history of TBI or PTSD alone or both is not associated with a significantly higher risk to develop AD pathology in later life. b) remote TBI or PTSD do not modify the typical AD pathology distribution pattern.

Mapping internal brainstem structures using T1 and T2 weighted 3T images.

Background: Many neurodegenerative diseases affect the brainstem and often do so in an early stage. The overall goal of this project was (a) to develop a method to segment internal brainstem structures from T1 and T2 weighted sequences by taking advantage of the superior myelin contrast of the T1/T2 ratio image (RATIO) and (b) to test if this approach provides biological meaningful information by investigating the effects of aging on different brainstem gray matter structures. Methods: 675 T1 and T2 weighted images were obtained from the Human Connectome Project Aging. The intensities of the T1 and T2 images were re-scaled and RATIO images calculated. The brainstem was isolated and k-means clustering used to identify five intensity clusters. Non-linear diffeomorphic mapping was used to warp the five 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. The five clusters corresponded to five brainstem tissue types (two gray matters, two mixed gray/white, and 1 csf/tissue partial volume). Results: These cluster maps were used to calculate Jacobian determinant maps and the mean Jacobians of 48 brainstem gray matter structures extracted. Significant linear or quadratic age effects were found for all but five structures. Conclusions: These findings suggest that it is possible to obtain a biologically meaningful segmentation of internal brainstem structures from T1 and T2 weighted sequences using a fully automated segmentation procedure.

Hippocampal subfield volumetry from structural isotropic 1 mm3 MRI scans: A note of caution.

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 gray matter structural connectome and its relationship to alcohol relapse: Reconnecting for recovery.

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.

Effect of Combat Exposure and Posttraumatic Stress Disorder on Telomere Length and Amygdala Volume.

BACKGROUND: Traumatic stress can adversely affect physical and mental health through neurobiological stress response systems. We examined the effects of trauma exposure and posttraumatic stress disorder (PTSD) on telomere length, a biomarker of cellular aging, and volume of the amygdala, a key structure of stress regulation, in combat-exposed veterans. In addition, the relationships of psychopathological symptoms and autonomic function with telomere length and amygdala volume were examined. METHODS: Male combat veterans were categorized as having PTSD diagnosis (n = 102) or no lifetime PTSD diagnosis (n = 111) based on the Clinician-Administered PTSD Scale. Subjects were assessed for stress-related psychopathology, trauma severity, autonomic function, and amygdala volumes by magnetic resonance imaging. RESULTS: A significant interaction was found between trauma severity and PTSD status for telomere length and amygdala volume after adjusting for multiple confounders. Subjects with PTSD showed shorter telomere length and larger amygdala volume than those without PTSD among veterans exposed to high trauma, while there was no significant group difference in these parameters among those exposed to low trauma. Among veterans exposed to high trauma, greater telomere shortening was significantly correlated with greater norepinephrine, and larger amygdala volume was correlated with more severe psychological symptoms and higher heart rates. CONCLUSIONS: These data suggest that the intensity of the index trauma event plays an important role in interacting with PTSD symptomatology and autonomic activity in predicting telomere length and amygdala volume. These results highlight the importance of trauma severity and PTSD status in predicting certain biological outcomes.

Mapping internal brainstem structures using MP2RAGE derived T1 weighted and T1 relaxation images at 3 and 7 T.

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.

Brainstem atrophy in focal epilepsy destabilizes brainstem-brain interactions: Preliminary findings.

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 < .05, FDR) and reduced brainstem to right parietal cortex, lingual gyrus, left hippocampus/amygdala, parahippocampus, temporal pole, and bilateral anterior thalamus connectivity in FE (p < .05, FDR). Dynamic task-free fMRI analysis identified 22 states. The strength of the functional brainstem/cortical connectivity of state 15 was negatively associated with HRV (r = -0.5, p = .03) and positively with decreased brainstem-cortical (0.49, p = .03) gray matter connectivity. CONCLUSION: The findings of this small pilot study suggest that impaired brainstem-cortex gray matter connectivity in FE negatively affects the brainstem's ability to control cortical activation.

Progress update from the hippocampal subfields group.

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.

Amyloid causes intermittent network disruptions in cognitively intact older subjects.

Recent findings in AD models but also human patients suggest that amyloid can cause intermittent neuronal hyperactivity. The overall goal of this study was to use dynamic fMRI analysis combined with graph analysis to a) characterize the graph analytical signature of two types of intermittent hyperactivity (spike-like (spike) and hypersynchronus-like (synchron)) in simulated data and b) to attempt to identify one of these signatures in task-free fMRIs of cognitively intact subjects (CN) with or without increased brain amyloid. The toolbox simtb was used to generate 33 data sets with 2 short spike events, 33 with 2 synchron and 33 baseline data sets. A combination of sliding windows, hierarchical cluster analysis and graph analysis was used to characterize the spike and the synchron signature. Florbetapir-F18 PET and task-free 3 T fMRI was acquired in 49 CN (age = 70.7 ± 6.4). Processing the real data with the same approach as the simulated data identified phases whose graph analytical signature resembled that of the synchron signature in the simulated data. The duration of these phases was positively correlated with amyloid load (r = 0.42, p < 0.05) and negatively with memory performance (r = -0.43, p < 0.05). In conclusion, amyloid positivity is associated with intermittent hyperactivity that is caused by short phases of hypersynchronous activity. The negative association with memory performance suggests that these disturbances have the potential to interfere with cognitive processes and could lead to cognitive impairment if they become more frequent or more severe with increasing amyloid deposition.

Brainstem network disruption: A pathway to sudden unexplained death in epilepsy?

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 < .001). The total number of regions with excessive expansion in SUDEP was negatively correlated with time to SUDEP (r = -.39, p = .03), excessive volume loss in the raphe/medulla oblongata at the obex level explained most of the variation of the time between MRI to SUDEP (r/r2 = -.60/.35,p = .001). Epilepsy is associated with brainstem atrophy that impairs autonomic control and can increase the risk for SUDEP if it expands into the mesencephalon.

Systematic comparison of different techniques to measure hippocampal subfield volumes in ADNI2.

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.

Posttraumatic stress disorder, symptoms, and white matter abnormalities among combat-exposed veterans.

Posttraumatic stress disorder (PTSD) is associated with abnormalities in functional connectivity of a specific cortico-limbic network; however, less is known about white matter abnormalities providing structural connections for this network. This study investigated whether the diagnosis and symptoms of PTSD are associated with alterations in fractional anisotropy (FA), an index reflecting white matter organization, across six, a priori-defined tracts. White matter FA was quantified by diffusion tensor imaging using 3 T-MRI among 57 male, combat-exposed veterans with no history of moderate to severe head injuries or current alcohol dependence: 31 met criteria for PTSD and 26 were demographically comparable, combat-exposed controls without PTSD. Clinician-administered and self-report questionnaires assessed PTSD severity, dissociation, and mood. PTSD + veterans had significantly higher FA than exposed controls in the superior fronto-occipital fasciculus (SFOF) and borderline higher FA in the anterior corona radiata (ACR) and cingulum (CGC), controlling for age and neurovascular comorbidities. When lifetime alcohol use disorders was included, only the association of PTSD with SFOF-FA remained significant. Among PTSD + veterans, higher SFOF-FA was associated with greater mood disturbance, dissociative symptoms, and re-experiencing, while lower FA of the uncinate fasciculus (UF) was associated with greater mood disturbance symptoms. Compared to combat-exposed controls without PTSD, veterans with PTSD exhibited higher white matter FA in the SFOF, and a similar tendency in the ACR and CGC, tracts involved in conflict-processing and spatial attention. Prior alcohol use might explain the associations of PTSD with ACR-FA and CGC-FA but not the association with SFOF-FA.

Quantitative surface analysis of combined MRI and PET enhances detection of focal cortical dysplasias.

OBJECTIVE: Focal cortical dysplasias (FCDs) often cause pharmacoresistant epilepsy, and surgical resection can lead to seizure-freedom. Magnetic resonance imaging (MRI) and positron emission tomography (PET) play complementary roles in FCD identification/localization; nevertheless, many FCDs are small or subtle, and difficult to find on routine radiological inspection. We aimed to automatically detect subtle or visually-unidentifiable FCDs by building a classifier based on an optimized cortical surface sampling of combined MRI and PET features. METHODS: Cortical surfaces of 28 patients with histopathologically-proven FCDs were extracted. Morphology and intensity-based features characterizing FCD lesions were calculated vertex-wise on each cortical surface, and fed to a 2-step (Support Vector Machine and patch-based) classifier. Classifier performance was assessed compared to manual lesion labels. RESULTS: Our classifier using combined feature selections from MRI and PET outperformed both quantitative MRI and multimodal visual analysis in FCD detection (93% vs 82% vs 68%). No false positives were identified in the controls, whereas 3.4% of the vertices outside FCD lesions were also classified to be lesional ("extralesional clusters"). Patients with type I or IIa FCDs displayed a higher prevalence of extralesional clusters at an intermediate distance to the FCD lesions compared to type IIb FCDs (p < 0.05). The former had a correspondingly lower chance of positive surgical outcome (71% vs 91%). CONCLUSIONS: Machine learning with multimodal feature sampling can improve FCD detection. The spread of extralesional clusters characterize different FCD subtypes, and may represent structurally or functionally abnormal tissue on a microscopic scale, with implications for surgical outcomes.

Cortical Atrophy is Associated with Accelerated Cognitive Decline in Mild Cognitive Impairment with Subsyndromal Depression.

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 4-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 individuals with MCI and stable endorsement (SSD group N = 32) or no endorsement (non-SSD group N = 69) of depressive symptoms across time points. MEASUREMENTS: Repeated measures of cognitive outcomes, cortical atrophy, and their associations were evaluated with mixed effects models adjusting for age, education, sex, and APOE genotype. RESULTS: The SSD group demonstrated accelerated decline on measures of global cognition (Alzheimer 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 < 0.001) atrophy. No group differences were observed for rate of decline on measures of attention, learning, and confrontation naming or for rate of atrophy in any other regions. Accelerated frontal lobe and anterior cingulate atrophy was associated with cognitive decline on measures of global cognition, information processing speed, and semantic fluency (all p < 0.05), but not memory. CONCLUSIONS: Individuals with chronic SSD may represent an MCI subgroup that is highly vulnerable to accelerated cognitive decline, an effect that may be governed by frontal lobe and anterior cingulate atrophy.

MRI-negative temporal lobe epilepsy-What do we know?

Temporal lobe epilepsy (TLE) is the most common focal epilepsy in adults. TLE has a high chance of becoming medically refractory, and as such, is frequently considered for further evaluation and surgical intervention. Up to 30% of TLE cases, however, can have normal ("nonlesional" or negative) magnetic resonance imaging (MRI) results, which complicates the presurgical workup and has been associated with worse surgical outcomes. Helped by contributions from advanced imaging techniques and electrical source localization, the number of surgeries performed on MRI-negative TLE has increased over the last decade. Thereby new epidemiologic, clinical, electrophysiologic, neuropathologic, and surgical data of MRI-negative TLE has emerged, showing characteristics that are distinct from those of lesional TLE. This review article summarizes what we know today about MRI-negative TLE, and discusses the comprehensive assessment of patients with MRI-negative TLE in a structured and systematic approach. It also includes a concise description of the most recent developments in structural and functional imaging, and highlights postprocessing imaging techniques that have been shown to add localization value in MRI-negative epilepsies. We evaluate surgical outcomes of MRI-negative TLE, identify prognostic makers of postoperative seizure freedom, and discuss strategies for optimizing the selection of surgical candidates in this group.

Amyloid Associated Intermittent Network Disruptions in Cognitively Intact Older Subjects: Structural Connectivity Matters.

Observations in animal models suggest that amyloid can cause network hypersynchrony in the early preclinical phase of Alzheimer's disease (AD). The aim of this study was (a) to obtain evidence of paroxysmal hypersynchrony in cognitively intact subjects (CN) with increased brain amyloid load from task-free fMRI exams using a dynamic analysis approach, (b) to investigate if and how hypersynchrony interferes with memory performance, and (c) to describe its relationship with gray and white matter connectivity. Florbetapir-F18 PET and task-free 3T functional and structural MRI were acquired in 47 CN (age = 70.6 ± 6.6), 17 were amyloid pos (florbetapir SUVR >1.11). A parcellation scheme encompassing 382 regions of interest was used to extract regional gray matter volumes, FA-weighted fiber tracts and regional BOLD signals. Graph analysis was used to characterize the gray matter atrophy profile and the white matter connectivity of each subject. The fMRI data was processed using a combination of sliding windows, graph and hierarchical cluster analysis. Each activity cluster was characterized by identifying strength dispersion (difference between pos and neg strength) their maximal and minimal pos and neg strength rois and by investigating their distribution and association with memory performance and gray and white matter connectivity using spearman rank correlations (FDR p < 0.05). The cluster analysis identified eight different activity clusters. Cluster 8 was characterized by the largest strength dispersion indicating hypersynchrony. Its duration/subject was positively correlated with amyloid load (r = 0.42, p = 0.03) and negatively with memory performance (CVLT delayed recall r = -0.39 p = 0.04). The assessment of the regional strength distribution indicated a functional disconnection between mesial temporal structures and the rest of the brain. White matter connectivity was increased in left lateral and mesial temporal lobe and was positively correlated with strength dispersion in the cross-modality analysis suggesting that it enables widespread hypersynchrony. In contrast, precuneus, gray matter connectivity was decreased in the right fusiform gyrus and negatively correlated with high degrees of strength dispersion suggesting that progressing gray matter atrophy could prevent the generation of paroxysmal hypersynchrony in later stages of the disease.

Medial temporal lobe subregional morphometry using high resolution MRI in Alzheimer's disease.

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.

A harmonized segmentation protocol for hippocampal and parahippocampal subregions: Why do we need one and what are the key goals?

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.

Cortisol/DHEA ratio and hippocampal volume: A pilot study in major depression and healthy controls.

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=-0.424p=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.