Marina Boccardi

Quantitative comparison of 21 protocols for labeling hippocampal subfields and parahippocampal subregions in in vivo MRI: Towards a harmonized segmentation protocol

OBJECTIVE An 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. METHOD MRI 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. RESULTS The 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. CONCLUSIONS The 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.

Frontotemporal dementia as a neural system disease

Some brain structures atrophic in frontotemporal dementia (FTD) belong to the rostral limbic system (RLS), that regulates context-dependent behaviors after evaluation of the motivational content of stimuli. The clinical manifestations of FTD are consistent with its impairment. Aim of this study was to assess whole brain morphology in FTD using magnetic resonance imaging (MRI) and voxel-based morphometry with statistic parametric mapping (SPM99) to test the hypothesis that the RLS might be specifically targeted by FTD. Nine FTD patients and 26 healthy controls underwent high resolution 3D MRI. SPM99 performed (a) spatial normalization to a customized template, (b) segmentation, (c) smoothing, (d) voxel-by-voxel comparison of gray matter between cases and controls. P was set at 0.05 corrected for multiple comparisons. All but one regions of the RLS (the periaqueductal gray) were atrophic in FTD. At P<0.001 uncorrected also the periaqueductal gray was atrophic. Atrophy outside the RLS was confined to a few voxels in the frontal and temporal gyri. FTD might be a neural-system disease where the RLS is predominantly damaged.

The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: Evidence of validity

An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance.

The MRI pattern of frontal and temporal brain atrophy in fronto-temporal dementia

OBJECTIVE To compare patterns of brain atrophy in fronto-temporal dementia (FTD) and Alzheimers disease (AD) since atrophy in individual areas may not be sufficiently specific as diagnostic marker. METHODS Frontal, temporal and hippocampal atrophy was measured from MRI of 10 FTD patients, 27 AD, and 27 controls. Corrected atrophy and asymmetry were computed (W-scores). RESULTS FTD had mild atrophy in the hippocampus (average W-score=-1.3), severe in the frontal (W-score=-2.4) and very severe in the temporal lobes (W-score=-2.9). AD had moderate atrophy in the hippocampus and temporal lobes (W-score=-1.8 and -1.9, respectively), and very mild frontal atrophy (W-score=-0.9). Atrophy was more asymmetrical in FTD (left more atrophic) than in AD patients, particularly in the temporal lobes. A discriminant function including the asymmetry values of frontal and temporal regions could separate FTD from AD with 90% sensitivity and 93% specificity. CONCLUSIONS FTD is characterized by a specific pattern of atrophy, more useful than atrophy of single regions in the differential diagnosis.

Alexithymia in healthy women: A brain morphology study

BACKGROUND Alexithymia relates to difficulty recognizing and describing own feelings. Recent literature shows that specific structures process emotions. Aim of this study was to investigate whether alexithymia is associated with a specific cerebral morphology of candidate structures in healthy adults. METHODS Fifty-four female volunteers were enrolled in the study and the 20-item Toronto Alexithymia Scale (TAS-20) was self-administered. Gray matter (GM) volume was assessed with an optimized voxel-based morphometry (VBM) protocol on high-resolution 3D magnetic resonance images. The following three experiments were carried out: 1) contrast between the 14 volunteers with TAS-20 scores > or = 61 (alexithymic) and the 30 with scores < 51 (non-alexithymic), 2) correlation of TAS-20 scores on the whole sample and 3) contrast between the 14 alexithymic and 14 non-alexithymic matched by age. The significant threshold for VBM comparisons and correlation was set at p<0.005 uncorrected. RESULTS The alexithymic group showed smaller GM volume in the anterior cingulate cortex (cluster size: 735 voxel no.; z=3.26; stereotaxic coordinates: -12, 22, 30) and middle temporal gyrus (256; 3.21; -60, 2, -20). Of specific biological relevance, smaller clusters were located in the anterior insula, orbitofrontal cortex and superior temporal sulcus. The opposite comparison was negative. The correlation analysis confirmed the pattern of results mainly in the left hemisphere. CONCLUSIONS Our findings suggest that the ability to process emotional aspects of the self correlates with morphology of a specific set of cerebral structures known to be involved in decision making and self awareness and rich in neurons subserving social competence.

Delphi definition of the EADC-ADNI harmonized protocol for hippocampal segmentation on magnetic resonance

This study aimed to have international experts converge on a harmonized definition of whole hippocampus boundaries and segmentation procedures, to define standard operating procedures for magnetic resonance (MR)‐based manual hippocampal segmentation.

Effects of hormone therapy on brain morphology of healthy postmenopausal women : a Voxel-based morphometry study

Objective: Estrogens are known to be protective in age-associated cognitive changes in humans and in neurodegeneration in animal models. The aim of this study was to evaluate the potential effects of estrogen therapy (ET) on human gray matter volume in vivo. Design: Forty healthy postmenopausal women underwent three-dimensional high-resolution magnetic resonance imaging: 17 were never treated, 16 were currently receiving ET, and 7 had had ET in the past. Voxel-based morphometry (VBM) with SPM2 was used, according to an optimized protocol, to compare women under past and current ET to those never treated. Significance threshold was set at P = 0.01, corrected by false discovery rate. Results: Voxel-based morphometry indicated that estrogen use was associated with greater gray matter volumes in the whole group of treated women, which included the cerebellum (cluster size, Z coordinates: 5,527; 5.15; −14 −54 −10), the amygdaloid-hippocampal complex (left: 19; 3.55; −22 −4 −18; right: 45; 3.61; 16 −6 −16), and extended to the frontal, temporal, parietal, and occipital neocortex. The comparison current ET versus past ET use showed that women who underwent treatment in the past had greater volumes of gray matter compared to women under current treatment. Conclusions: ET might slow down age-related gray matter loss in postmenopausal women. The structures that exhibited greater volume in association with ET included the cerebellar and cerebral cortices and, typically involved in Alzheimers disease, the medial temporal structures and the temporoparietal junction.

Abnormal hippocampal shape in offenders with psychopathy

Posterior hippocampal volumes correlate negatively with the severity of psychopathy, but local morphological features are unknown. The aim of this study was to investigate hippocampal morphology in habitually violent offenders having psychopathy. Manual tracings of hippocampi from magnetic resonance images of 26 offenders (age: 32.5 ± 8.4), with different degrees of psychopathy (12 high, 14 medium psychopathy based on the Psychopathy Checklist Revised), and 25 healthy controls (age: 34.6 ± 10.8) were used for statistical modelling of local changes with a surface‐based radial distance mapping method. Both offenders and controls had similar hippocampal volume and asymmetry ratios. Local analysis showed that the high psychopathy group had a significant depression along the longitudinal hippocampal axis, on both the dorsal and ventral aspects, when compared with the healthy controls and the medium psychopathy group. The opposite comparison revealed abnormal enlargement of the lateral borders in both the right and left hippocampi of both high and medium psychopathy groups versus controls, throughout CA1, CA2‐3 and the subicular regions. These enlargement and reduction effects survived statistical correction for multiple comparisons in the main contrast (26 offenders vs. 25 controls) and in most subgroup comparisons. A statistical check excluded a possible confounding effect from amphetamine and polysubstance abuse. These results indicate that habitually violent offenders exhibit a specific abnormal hippocampal morphology, in the absence of total gray matter volume changes, that may relate to different autonomic modulation and abnormal fear‐conditioning. Hum Brain Mapp, 2010.

Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers

The diagnosis of Alzheimers disease can be improved by the use of biological measures. Biomarkers of functional impairment, neuronal loss, and protein deposition that can be assessed by neuroimaging (ie, MRI and PET) or CSF analysis are increasingly being used to diagnose Alzheimers disease in research studies and specialist clinical settings. However, the validation of the clinical usefulness of these biomarkers is incomplete, and that is hampering reimbursement for these tests by health insurance providers, their widespread clinical implementation, and improvements in quality of health care. We have developed a strategic five-phase roadmap to foster the clinical validation of biomarkers in Alzheimers disease, adapted from the approach for cancer biomarkers. Sufficient evidence of analytical validity (phase 1 of a structured framework adapted from oncology) is available for all biomarkers, but their clinical validity (phases 2 and 3) and clinical utility (phases 4 and 5) are incomplete. To complete these phases, research priorities include the standardisation of the readout of these assays and thresholds for normality, the evaluation of their performance in detecting early disease, the development of diagnostic algorithms comprising combinations of biomarkers, and the development of clinical guidelines for the use of biomarkers in qualified memory clinics.

White-matter lesions along the cholinergic tracts are related to cortical sources of EEG rhythms in amnesic mild cognitive impairment.

Does impairment of cholinergic systems represent an important factor in the development of amnesic mild cognitive impairment (aMCI), as a preclinical stage of Alzheimers disease (AD)? Here we tested the hypothesis that electroencephalographic (EEG) rhythms, known to be modulated by the cholinergic system, may be particularly affected in aMCI patients with lesions along the cholinergic white‐matter tracts. Eyes‐closed resting EEG data were recorded in 28 healthy elderly (Nold) and 57 aMCI patients. Lesions along the cholinergic white‐matter tracts were detected with fluid‐attenuated inversion recovery sequences on magnetic resonance imaging. The estimation of the cholinergic lesion was performed with a validated semi‐automatic algorithm pipeline after registration to a stereotactic template, image integration with stereotactic masks of the cholinergic tracts, and normalization to intracranial volume. The aMCI patients were divided into two groups of high (MCI Ch+; N = 29; MMSE = 26.2) and low cholinergic damage (MCI Ch−; N = 28; MMSE = 26.6). EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–10.5 Hz), alpha 2 (10.5–13 Hz), beta 1 (13–20 Hz), and beta 2 (20–30 Hz). Cortical EEG generators were estimated by LORETA software. As main results, (i) power of occipital, parietal, temporal, and limbic alpha 1 sources was maximum in Nold, intermediate in MCI Ch−, and low in MCI Ch+ patients; (ii) the same trend was true in theta sources. These results are consistent with the hypothesis that damage to the cholinergic system is associated with alterations of EEG sources in aMCI subjects. Hum Brain Mapp 2009.