1 LENITEM Laboratory of Epidemiology, Neuroimaging & Telemedicine IRCCS Centro S. Giovanni di Dio FBF, Brescia, Italy 2 Machine Vision Laboratory, Department of Mathemat ics and Computer Science, University of Udine, Udin e, Italy 3 Neuroradiology Unit, Hospital Città di Brescia, B rescia 4 Laboratory of Neuro Imaging, Department of Neurol ogy, UCLA School of Medicine, Los Angeles, CA, USA 5 Psychogeriatrics Ward – IRCCS Centro S. Giovanni di Dio FBF, Brescia, Italy 6 AFaR Associazione Fatebenefratelli per la Ricerca , Rome, Italy

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.

Alzheimer's disease (AD) is characterized by great clinical variability. The identification of measurable features, such as imaging markers, associated with genetic and non-genetic factors could thus be helpful for therapeutic development. Previous MRI studies suggest that the Apolipoprotein E (APOE) e4 allele has region-specific effects on brain atrophy in AD, and is associated with reduced temporal lobe volume [1], [2]. However less is known about its effect on the cortical mantle. Aim of this study was to compare APOE-related patterns of atrophy over the cortical mantle in AD patients. We studied AD patients carrying (e4+, n=15, age 72±10SD years) and not carrying (e4-, n=14, age 69±9) the e4 allele of APOE and compared them to 29 age-matched controls (age 70±9). Each subject underwent clinical evaluation, a neuropsychological battery, and high-resolution MRI. Regions of cortical gray matter (GM) loss were identified using the UCLA cortical pattern matching technique[3]. Patients who were e4+ and e4- had similar global cognitive deterioration (MMSE: 20±3 and 20±5, p=.862; t-test). Both patient groups showed diffuse cortical atrophy, sparing only the sensory and motor areas, the anterior cingulate and medial orbitofrontal cortex (p=.0001 for both e4+ vs controls and e4- vs controls, for the left and right hemisphere; permutation test [4]; Fig. 1, top panel). GM loss ranged between 15–20% in both e4+ and e4- groups (Fig. 1, bottom panel). Regions of greater atrophy in carriers than non-carriers mapped to the temporal lobes (Fig. 2, bottom panel), showing a trend for significance in the lateral lobe (p=.051 in the right hemisphere; permutation test with small volume correction; Fig. 2, top panel) and entorhinal cortex (p=.078 in the left hemisphere; Fig. 2, top panel). The opposite effect, mapping to the frontal and retrosplenial cortex (Fig. 2, bottom panel), was not significant (p>.138; Fig. 2, top panel). This study supports the hypothesis of greater vulnerability of the temporal regions in APOE e4 carriers. These results, if confirmed in larger samples, could aid in development of specific therapeutic treatments in preclinical Alzheimer disease.

Progressive atrophy in critical brain regions is one of the hallmarks of Alzheimer's disease (AD) and a candidate surrogate outcome in clinical trials of disease-modifying drugs. Aim of this study is to map the topography of acceleration-deceleration of cortical atrophy from health through incipient and mild to moderate AD. Twenty older healthy persons (OH, Mini Mental State Exam 29.1±1.0), 11 patients with incipient (iAD, 26.5±2.0), 15 with mild (miAD, 23.5±2.2), and 15 with moderate sporadic late-onset AD (moAD, 16.5±2.0) had high resolution 3D magnetic resonance (MR) imaging. Cortical pattern matching analysis was performed, allowing to map cortical atrophic changes with a precision of few mm. Maps of percent difference and statistical significance were computed between the following groups: iAD vs. OH, miAD vs. iAD, and moAD vs. miAD. Compared to OH, iAD featured cortical gray matter loss of 20–30% in the medial temporal, posterior cingulate, orbitofrontal cortices, and less widespread loss of 15–20% in the temporoparietal region. Compared to iAD, miAD featured widespread temporal, temporoparietal, dorsal parietal, and dorsal frontal gray matter loss of 30% and above, with less marked loss in the medial temporal (10–20%) and posterior cingulate regions (10–15%). Compared to miAD, moAD featured gray matter loss of 25–30% in the primary sensorimotor and visual cortices, loss in the temporal, parietal, and frontal regions being markedly lower (below 10%). These findings are preliminary to draw a 4-dimensional map (3 dimensions in space plus disease severity) of cortical involvement thatmight be the reference for therapeutic interventions aimed to modify disease progression.

Clinical observations have suggested that the neuropsychological profile of early and late onset forms of Alzheimer's disease (EOAD and LOAD) differ in that neocortical functions are more affected in the former and learning in the latter, suggesting that they might be different diseases. The aim of this study is to assess the brain structural basis of these observations, and test whether neocortical areas are more heavily affected in EOAD and medial temporal areas in LOAD. Fifteen patients with EOAD and 15 with LOAD (onset before and after age 65; Mini Mental State Examination 19.8, SD 4.0 and 20.7, SD 4.2) were assessed with a neuropsychological battery and high-resolution MRI together with 1:1 age- and sex-matched controls. Cortical atrophy was assessed with cortical pattern matching, and hippocampal atrophy with region-of-interest-based analysis. EOAD patients performed more poorly than LOAD on visuospatial, frontal-executive and learning tests. EOAD patients had the largest atrophy in the occipital [25% grey matter (GM) loss in the left and 24% in the right hemisphere] and parietal lobes (23% loss on both sides), while LOAD patients were remarkably atrophic in the hippocampus (21 and 22% loss). Hippocampal GM loss of EOAD (9 and 16% to the left and right) and occipital (12 and 14%) and parietal (13 and 12%) loss of LOAD patients were less marked. In EOAD, GM loss of 25% or more was mapped to large neocortical areas and affected all lobes, with relative sparing of primary sensory, motor, and visual cortex, and anterior cingulate and orbital cortex. In LOAD, GM loss was diffusely milder (below 15%); losses of 15-20% were confined to temporoparietal and retrosplenial cortex, and reached 25% in restricted areas of the medial temporal lobe and right superior temporal gyrus. These findings indicate that EOAD and LOAD differ in their typical topographic patterns of brain atrophy, suggesting different predisposing or aetiological factors.

Background and aims: Gender and age effect on brain morphology have been extensively investigated. However, the great variety in methods applied to morphology partly explain the conflicting results of linear patterns of tissue changes and lateral asymmetry in men and women. The aim of the present study was to assess the effect of age, gender and laterality on the volumes of gray matter (GM) and white matter (WM) in a large group of healthy adults by means of voxel-based morphometry. This technique, based on observer-independent algorithms, automatically segments the 3 types of tissue and computes the amount of tissue in each single voxel. Methods: Subjects were 229 healthy subjects of 40 years of age or older, who underwent magnetic resonance (MR) for reasons other than cognitive impairment. MR images were reoriented following the AC-PC line and, after removing the voxels below the cerebellum, were processed by Statistical Parametric Mapping (SPM99). GM and WM volumes were normalized for intracranial volume. Results: Women had more fractional GM and WM volumes than men. Age was negatively correlated with both fractional GM and WM, and a gender × age interaction effect was found for WM, men having greater WM loss with advancing age. Pairwise differences between left and right GM were negative (greater GM in right hemisphere) in men, and positive (greater GM in left hemisphere) in women (−0.56±4.2 vs 0.99±4.8; p=0.019). Conclusions: These results support side-specific accelerated WM loss in men, and may help our better understanding of changes in regional brain structures associated with pathological aging.

Estrogens are known to have protective effects on cognitive function in human, and on neurodegeneration in animal models. Data about neuroprotection on human age associated changes in vivo are lacking. To evaluate the potential effects of estrogen replacement therapy (ERT) on brain morphology in a sample of healthy postmenopausal women. Forty women underwent 3D high resolution MRI: 17 never treated (age 60.8±6.6), 16 with current ERT (age: 57.4±4.3), 7 with past ERT of the same duration (age 63±3.5). Voxel-based morphometry with SPM99 was used to compare women under past and current ERT to those never treated, with p<0.001 uncorrected. Non treated versus women with past treatment (fig 1) showed atrophy of the leftcerebellum {z, cluster size (peak coordinates): 3.74, 437 (-38, -72, -26)}, of bilateral temporal {right: 3.83, 142 (58, -44, 4), left: 3.58, 27 (-54, -8, 28)} and right orbitofrontal cortex {3.68, 123 (38, 42, 14)}. Non treated versus women with current treatment (fig 2) showed a similar pattern, but mainly limited to the right hemisphere: right orbitofrontal cortex {4.06, 178 (32, 38, -14)}, right lingual gyrus and cerebellum {4.02, 209 (44, -34, -20); (32, -34, -30)}, and extended to the occipital cortex {3.83, 159 (10, -98, 0)}. The use of ERT was associated with less regional brain atrophy, and the effect seems to be stronger in women with past treatment. The data support the view that ERT can protect against age-related neurodegeneration and cognitive decline.