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

Background & Aims: We applied advanced magnetic resonance imaging and Voxed based Morphometry analysis to assess brain tissue density in patients with cirrhosis.Methods: Forty eight patients with cirrhosis without overt hepatic encephalopathy (17 Child A, 13 Child B, and 18 Child C) and 51 healthy subjects were matched for age and sex. Seventeen patients had history of overt hepatic encephalopathy, eight of them had minimal hepatic encephalopathy at inclusion, 10 other patients had minimal hepatic encephalopathy at inclusion but without history of previous overt hepatic encephalopathy, and 21 patients had none of these features.Results: Patients with cirrhosis presented decreased brain density in many areas of the grey and white matter. The extension and size of the affected areas were greater in patients with alcoholic cirrhosis than in those with post-hepatitic cirrhosis and correlated directly with the degree of liver failure and cerebral dysfunction (as estimated by neuropsychological tests and the antecedent of overt hepatic encephalopathy). Twelve additional patients with cirrhosis who underwent liver transplantation were explored after a median time of 11 months (7-50 months) after liver transplant. At the time of liver transplantation, three patients belonged to class A of the Child-Pugh classification, five to class B and four to class C. Compared to healthy subjects, liver transplant patients showed areas of reduced brain density in both grey and white matter.Conclusions: These results indicate that loss of brain tissue density is common in cirrhosis, progresses during the course of the disease, is greater in patients with history of hepatic encephalopathy, and persists after liver transplantation. The significance, physiopathology, and clinical relevance of this abnormality cannot be ascertained from the current study. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Background and aims: To describe the clinical and neuropsychological features of a large group of cognitively intact persons subjected to brain high-resolution magnetic resonance (MR), to compare them with the general population, and to set norms for medial temporal atrophy and white matter lesions. Methods: Participants in the Italian Brain Normative Archive (IBNA) study were 483 consecutive volunteers undergoing MR for reasons unrelated to cognition (migraine or headache, visual and balance or auditory disturbances, paresthesias, and others) and showing no brain damage. Manual tracing of hippocampal and amygdalar volumes and visual rating of white matter lesions were made. The whole study group was stratified by age (≤60 and 60+ yrs) and by the reason for MR prescription. Results: In the whole group, mean age and education were 52.4±13.7 and 9.8±4.2 years, respectively, and the prevalence of women was 63%. Clinical, neuropsychological and morphometric features were similar in the stratified subgroups. Neuropsychological features were those expected for age and education based on Italian normative values. Hippocampal and amygdalar volumes were not associated with age, except for the right amygdala (B −0.159, 95% CI −0.28 to −0.03, p=0.016). Conclusions: Persons in the IBNA study had clinical and neuropsychological features consistent with that of the general population. Their brain morphometric features may be used as normative references for patients with suspected neurodegenerative disorders.

ABSTRACTBACKGROUND AND PURPOSE The Homeobox A1 (HOXA1) gene plays a critical role during development of the hindbrain in mice. Little is currently known about the relation between this gene and human brain development. The HOXA1 A218G polymorphism has been found to be associated with autism and larger head circumference in autistic patients. Similar effects were revealed also in healthy children but not in adult controls. The aim of this study was to investigate the role of the A218G polymorphism on the hindbrain structure of healthy adults. METHODS Healthy persons from two independent groups underwent 3‐dimensional high resolution magnetic resonance (MR) exam. Group A was made of 80 persons (27 G allele carriers and 53 non‐carriers) and Group B of 72 (26 carriers and 46 non‐carriers). Statistical parametric mapping 2 (SPM2) were used to perform voxel‐based analysis of the gray matter (GM) of the hindbrain in carriers and non. Significance threshold was set at .05 with small volume correction using a cerebellar mask. RESULTS In Group A, G carriers exhibited decreased GM volume in the superior posterior and anterior lobe of the cerebellum bilaterally. In Group B, decreased GM volume were found across the entire left cerebellar cortex. CONCLUSIONS These data suggest that the HOXA1 A218G polymorphism may affect cerebellar development in humans.

Purpose: To investigate the possible effect of the APOE epsilon 4 allele on age-related regional volume loss within the corpus callosum (CC) in healthy epsilon 4 allele carriers compared with noncarriers.Materials and Methods: A total of 211 subjects, ages 27 to 83 years, 51 epsilon 4 carriers and 160 noncarriers underwent T1-weighted MRI scan. All subjects had normal MRI scan and performed within normal range on a neuropsychological battery of tests. CC was segmented into seven functionally relevant regions using a previously published probabilistic map of the CC connectivity. We measured the volumes of the CC and its subregions. We used a regression model (with volumes as dependent and age as independent variables) and compared the slopes between carriers and noncarriers using an analysis of covariance model. We also carried out voxel-based-morphometry analysis to investigate the possible effect of the APOE epsilon 4 gene on the gray matter.Results: We found that the volume of the CC and all subregions decreased with increasing age in both groups. The slope was steeper in the APOE epsilon 4 carriers compared with-the noncarriers particularly in the prefrontal region (P = 0.02). No gray matter differences were observed between the two groups.Conclusion: APOE epsilon(4) polymorphism is associated with accelerated age-related volume loss in the prefrontal callosal tracts without gray matter loss. This result suggests the role of APOE epsilon(4) in the brain aging by primarily affecting white matter structures particularly in the frontal lobe.

The microtubule-associated protein Tau (MAPT) gene codes for the protein Tau that is involved in the pathogenesis of neurodegenerative diseases. Recent studies have detected an over-representation of the H1 haplotype of the MAPT gene in neurodegenerative disorders such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD) and Parkinson's disease (PD), whereas the H2 haplotype has been found to be related to familial FTD. We aimed to investigate the association between MAPT haplotype status and brain morphology in healthy adults. A total of 150 healthy subjects underwent 3D high-resolution magnetic resonance (MR). MR images were processed following an optimized protocol to perform the Voxel-based morphometry (VBM) comparisons of the gray matter (GM) in H1 carriers (n=141) in contrast to H2H2 homozygous (n=9), and H1H1 homozygous (n=85) in contrast to H2 carriers (n=65). The threshold for statistical significance was 0.005 uncorrected. Opposite comparisons were also carried out. The groups had similar demographic and cognitive features. Compared with H2H2, the H1 carriers showed up to 19% smaller GM volume in the head of the right caudate nucleus, in the right middle frontal gyrus, in the left insula and orbito-frontal cortex, and in the inferior temporal and inferior cerebellar lobes, bilaterally. Compared with all H2 carriers, H1H1 displayed lower GM in the same regions, but the effect was smaller (5%), possibly due to a dilution effect by H1 in the H2 carriers group. The data suggest that H1 haplotype is associated with a particular cerebral morphology that may increase the susceptibility of the healthy carriers to develop neurodegenerative diseases such as sporadic tauopathies.

The frequent polymorphism XbaI (A351G) in the estrogen receptor alpha (ERalpha) gene has been associated with some postmenopausal pathologies’ risk such as Alzheimer's disease (AD) or cognitive decline. In the present study, we explored whether the XbaI polymorphism leads to different gray matter volumes using voxel-based morphometry (VBM) on 20 magnetic resonance images of healthy postmenopausal women. Subjects carrying the less common XbaI/X allele were contrasted to non-carriers in groups well balanced by relevant confounding variables. The XbaI/X allele carriers displayed clusters ranging from 9 to 28% of tissue reductions in the cerebellar (cluster size, z, stereotactic coordinates: 16 mm3; 3.17; 14, −94, −38) and cerebral cortex, in particular in the occipital lobe (272 mm3; 3.76; −38,−68,−16), in the middle frontal gyrus (192 mm3; 3.71; 38, 12, 38) and in the middle temporal gyrus, while the opposite comparison was negative. The XbaI/X allele in ERalpha gene is associated to smaller gray matter volumes of the cerebral and cerebellar cortex. This allele might increase the susceptibility for senile neurodegenerative conditions, being associated to smaller cerebral reserve.

Background. White matter lesions (WMLs) may contribute to cognitive deficits in patients with mild cognitive impairment (MCI), but their pathogenesis is complex. Fluctuations of blood pressure (BP) over 24 hours and genetic predisposition to develop vascular damage have been implicated. Methods. In 63 MCI patients 65 years old or older, BP was measured both clinically and with ambulatory BP monitoring. Patients were classified in two groups: no/very mild (n = 34) and mild to severe (n = 29) WMLs, based on a visual scale on magnetic resonance (mean age 71.8 +/- 4.7 vs 74.6 +/- 5.1, and female gender 53% vs 66%, respectively). The volume of WMLs was measured by a semi-automatic method, separately for periventricular caps and rim, periventricular confluent, subcortical punctate, and subcortical confluent. Polymorphisms of cystatin C (CST3) and cholesterol 24-hydroxylase (CYP46) genes, putative risk factors for cerebrovascular disease, were determined. Results. The prevalence of cerebrovascular risk factors was similar in the two MCI groups of different WML severity, as well as clinic and ambulatory BP. In patients with mild to severe, but not in those with no/very mild WMLs, the volume of periventricular confluent WMLs increased with increasing daytime systolic BP (regression coefficient.47, 95% confidence interval [CI],.13 to.71 vs.02, 95% CI, -.32 to.36, p =.003 for the difference between slopes). The volume of other WML subtypes was not associated with ambulatory BP. Participants carrying both CST3*B and CYP46*T alleles were overrepresented in the MCI group with mild to severe WMLs (43% vs 17%, p.03). Conclusions. BP and gene putative risk factors for cerebrovascular disease are differentially associated with WMLs in two MCI groups of different WML severity. WMLs might develop for the convergence of innate with acquired factors.

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.

The MAPT gene codes for the protein tau, involved in the pathogenesis of neurodegenerative diseases. Recent studies have detected an over-representation of the H1 haplotype of the MAPT gene in neurodegenerative disorders such as progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia and Parkinson's disease, while the H2 haplotype has been found to be related to familial frontotemporal dementia. Studies investigating the role of these two haplotypes on the brain structure of healthy individuals are lacking. Aim of this study is to investigate the influence of the haplotypes of the MAPT gene on the cerebral structure of healthy adults. 150 healthy subjects underwent 3D high resolution MR. MR images were processed following an optimized protocol with SPM2 to perform a VBM comparison of the gray matter (GM) in H2H2 homozygous (n=9) contrasted to H2H1 heterozygous (n=56) and H1H1 homozygous persons (n=85) separately. The threshold for statistical significance was set at 0.005 uncorrected. Opposite comparisons were carried out for all experiments. The groups had similar age, sex, education and mini mental state exam. Compared to H2H2 carriers, the H1H1 (fig.1, red to yellow color bar, p<0.05 uncorrected for illustrative purpose) and H1H2 (fig.1, blue to green color bar) groups showed up to 15% smaller GM volume and dose effect in consistent regions: head of caudate nuclei, insula, inferior lobe of cerebellum, inferior temporal gyrus, and orbital frontal cortex. The opposite comparisons were negative. Replication of the analyses on ApoE ϵ3ϵ3 persons (n=103) were negative letting us to hypothesize a possible interaction between ϵ2/4 alleles and MAPT gene. The results suggest an influence of H1 genotypes on healthy brain structure: H1 carriers have smaller GM volume compared to H2H2 carriers in some cerebral regions, typically implicated in neurodegenerative conditions associated with the H1 haplotype.

Most violent crimes in Western societies are committed by a small group of men who display antisocial behavior from an early age that remains stable across the life-span. It is not known if these men display abnormal brain structure. We compared regional brain volumes of 26 persistently violent offenders with antisocial personality disorder and substance dependence and 25 healthy men using magnetic resonance imaging volumetry and voxel-based morphometry (VBM). The violent offenders, as compared with the healthy men, had markedly larger white matter volumes, bilaterally, in the occipital and parietal lobes, and in the left cerebellum, and larger grey matter volume in right cerebellum (effect sizes up to 1.24, P < 0.001). Among the offenders, volumes of these areas were not associated with psychopathy scores, substance abuse, psychotropic medication, or global IQ scores. By contrast, VBM analyses of grey matter revealed focal, symmetrical, bilateral areas of atrophy in the postcentral gyri, frontopolar cortex, and orbitofrontal cortex among the offenders as compared with the healthy men (z-scores as high as 5.06). Offenders with psychopathy showed the smallest volumes in these areas. The larger volumes in posterior brain areas may reflect atypical neurodevelopmental processes that underlie early-onset persistent antisocial and aggressive behavior.

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.

To assess the association of Medial Temporal lobe Atrophy (MTA) and White Matter Hyperintensities (WMHs) with gray matter perfusion in Mild Cognitive Impairment (MCI).

Aim: To describe the clinical and neuropsychological features of mild cognitive impairment (MCI) patients with medial temporal atrophy (MTA), white matter hyperintensities (WMH), both, and neither and to assess whether the rate of progression differs among groups. Methods: Ninety-five MCI patients were divided into 4 groups based on the presence of MTA and WMH: 29 were MTA– WMH–, 11 MTA– WMH+, 23 MTA+ WMH–, and 32 MTA+ WMH+. MCI patients were compared with 30 normal subjects. MTA and WMH were assessed with MR-based visual rating scales. Subjects underwent an extensive clinical and neuropsychological investigation. Fifty-six underwent follow-up evaluation. Results: MTA– WMH– had relatively good neuropsychological performance, little vascular and physical comorbidity. MTA– WMH+ performed poorly only on executive neuropsychological tests. MTA+ WMH– patients had poor neuropsychological performances (mainly on memory tests), high physical and vascular comorbidity. MTA+ WMH+ were impaired in neuropsychological performances, had a high number of physical diseases and severe vascular comorbidity. On follow-up, 25% of MTA+ WMH– and 32% of MTA+ WMH+ and none in MTA– WMH– and in MTA– WMH+ converted to dementia (p = 0.05, log rank test). Conclusion: Structural neuroimaging can identify subgroups of MCI patients with specific clinical and neuropsychological features.

Mild cognitive impairment (MCI) comprises an heterogeneous group of patients with a variety of clinical outcomes. Although amnestic MCI has often been considered as the pre-AD status, not all amnestic MCI patients progress to AD, as cognitive impairment can remain stable and MCI patients can even improve over time. Prediction of conversion to dementia is currently an issue of great theoretical interest and practical importance, as it would make it possible to implement strategies to prevent or delay dementia. Aim of this study was to find cerebral perfusion predictors of conversion to dementia in patients with amnestic MCI. 17 healthy subjects (age=69±3, 9 females), and 23 amnestic MCI patients (age=70±6, 10 females) underwent brain MR scan and 99mTc ECD SPECT. Amnestic MCI patients underwent a yearly follow-up, and we ascertained conversion to AD (converted to AD: N=9, age=69±3, 4 females; non-converted to dementia: N=14, age=71±8, 6 females). We processed SPECT images with SPM2 following an optimized protocol and performed a voxel-based statistical analysis comparing amnestic MCI patients converted to AD and non-converted to dementia vs controls, setting p-value at 0.001 uncorrected for multiple comparisons, setting the extent threshold at 100 voxels, using proportional scaling and entering age as a nuisance covariate. In comparison with normal controls, amnestic MCI patients who converted to AD showed hypoperfusion in the right parahippocampal gyrus and in the left inferior temporal and fusiform gyri (figure A), whereas amnestic MCI patients who did not convert to dementia showed hypoperfusion in the retrosplenial cortex, precuneus and occipital gyri, mainly on the left side (figure B). Parahippocampal and inferior temporal hypoperfusion in amnestic MCI patients appears as a predictor of conversion to AD; hypoperfusion in the retrosplenial cortex is involved in memory impairment but does not seem the key finding of convertion to dementia.

White matter lesions (WMLs) may contribute to cognitive deficit in patients with mild cognitive impairment (MCI), but little is known about pathogenesis. Fluctuations of blood pressure (BP) during the 24 hours and genetic predisposition to develop vascular damage have been implicated. The aim of this study is to investigate the association of 24-hours BP profile with WMLs in patients with MCI. In 63 MCI patients aged 65 and over, BP was measured both clinically and with ambulatory BP monitoring. Patients were divided into 34 with no/very mild and 29 with mild to severe WMLs based on a visual scale on magnetic resonance. The volume of WMLs was measured by a semi-automatic method, separately for periventricular caps and rim, periventricular confluent, subcortical punctuate, and subcortical confluent. Polymorphisms of cystatin C (CST3) and cholesterol 24-hydroxylase (CYP46) genes, putative risk factors for cerebrovascular disease, were determined. The prevalence of cerebrovascular risk factors was similar in the two groups, as well as clinic and ambulatory BP. In patients with mild to severe, but not in those with no/very mild WMLs, the total volume of WMLs increased with increasing daytime systolic BP (regression coefficient .34, 95% C.I. -.03 to .63 vs .01, 95% C.I. -.33 to .35, p=.01). This association was significant only for periventricular confluent WMLs. Subjects carrying both CST3*B and CYP46*T alleles were overrepresented in the MCI group with mild to severe WMLs (43% vs 17%, p .03). A subgroup of MCI patients with genetic predisposition are vulnerable to the effects of BP on the white matter, while others seem refractory.

We investigated the effect of apolipoprotein E (ApoE) on the whole brain in 51 individuals with mild cognitive impairment using voxel-based morphometry. Between cases heterozygous for the ApoE Ε4 (n = 15) and those who were ApoE Ε4 noncarriers (n = 28), only the right parahippocampal gyrus, with the entorhinal cortex included, reached the level of statistical significance. In cases homozygous for the Ε4 allele (n = 8) versus noncarriers, the greatest atrophy was located in the right amygdala followed by the right parahippocampal gyrus, the left amygdala and the left medial dorsal thalamic nucleus.

Memory complaints (MC) in the elderly may be an early symptom of Alzheimer's disease. However, the biological basis of MC in middle–aged individuals is poorly understood. Aim of this study is to investigate structural brain features of MC in healthy middle–aged adults. Sixty–nine cognitively intact subjects aged 60 years or younger were included in the present study. MC were investigated through a single question by asking about presence/absence of memory disturbances. Based on a yes/no answer, subjects were categorized into the two goups with (n=41; age:50±6; MMSE: 29.17±.95) and with no (n=28; age:48±6; MMSE: 29.32±.86) MC. All subjects underwent high resolution T1–weighted 3D magnetic resonance imaging. Images were processed with Statistical Parametric Map following an optimized protocol including normalization, segmentation into gray and white matter and cerebrospinal fluid, modulation, and smoothing. Fractional lobar volumes were computed and normalized to total intracranial volume. Gray matter volume in the temporal lobe was compared in subjects with and without MC with an ANCOVA model. Age, sex, and total intracranial volume were nuisance covariates and small volume correction at p<0.001 was achieved with a binary lobar mask including the temporal lobes. Subjects with and without MC did not differ for cognitive performance on any neuropsychological domain. Normalized temporal lobe volumes were significantly smaller in those with MC (right: 31.9±1.8 vs 33.3±2.2, p=0.005; left: 30.8±1.5 vs 32.0±2.2, p=0.008). Logistic regression analysis showed that subjects with MC had reduced temporal gray matter volume (odds ratio .80, 95% CI .69 to .94) also after adjustment for age, gender, education, and depressive symptoms. The reduction of gray matter was located in the left and right superior temporal gyrus (stereotactic coordinates ×, y, z [z score]: –50, 10, –10 [3.43] and 52, 14, –8 [3.16]) and in the right uncus (18, –2, –24 [3.19]) (figure 1). Brain structure in the temporal lobe of middle–aged adults with MC is different from those of adults with no MC. Follow–up studies should clarify whether these differences are normal inter–individual genetically–based features or pathological abnormalities that may predispose to the development of Alzheimer's disease.

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 Alzheimer's disease, the medial temporal structures and the temporoparietal junction.