OBJECTIVES:We set to investigate the possible role of genes and environment in developing Alzheimer's disease (AD) in monozygotic twin pairs discordant for AD.METHODS:Three pairs of twins discordant for AD, who were enrolled in the Finnish Twin Cohort, were used in the study and compared with 13 controls. Gray matter changes were assessed with magnetic resonance images using voxel-based morphometry with statistical parametric mapping.RESULTS:In the affected twins, the peaks of volume loss were located bilaterally in the temporal (including the hippocampus), the frontal, and the parietal lobes, while in the unaffected siblings, the peaks were located in the frontal gyri and in the parietal lobule. Thus, in the unaffected twins, the pattern of volume loss overlaps with the neocortical but not with the medial temporal areas.DISCUSSION:These findings suggest that genetic factors more largely control neocortical regions, whereas environmental factors more strongly affect medial temporal regions.

Aim of this study was to find cerebral perfusion correlates of conversion to dementia in patients with amnestic MCI.

Hepatic encephalopathy in cirrhosis is usually reversible after treatment and is considered a functional brain disorder.However, histopathological data and studies using CT to measure brain volume suggest that patients may develop structural abnormalities consistent with atrophy and degenerative changes in brain cells.Nevertheless, the presence, location and intensity of parenchymal brain changes in cirrhosis and its possible correlation with disease severity has not been specifically investigated.We applied brain magnetic resonance imaging (MRI) techniques used in the assessment of brain atrophy in patients with neurodegenerative disorders (i.e.Alzheimer's disease) to patients with cirrhosis.A brain MRI was performed in 60 patients with cirrhosis in different stages of the disease (19 Child A, 17 Child B, and 24 Child C) and 51 age and sexmatched healthy controls.Images were analyzed using Sienax, a method that quantifies brain volume, and voxel-based morphometry (VBM), a method that allows assessment of focal atrophy in brain regions.Overall, patients with cirrhosis had significantly lower total brain volume as well as both grey and white matter volumes compared to healthy subjects (Total brain volume: 1206&72 vs1273f65, p iO.OO1).Consistent with these findings, the use of VBM identified areas of reduced grey and white matter density, which occurred predominantly in frontal and occipital lobes and cingulated gyrus.These changes were more important in patients with alcoholic cirrhosis, but occurred in patients with hepatitis C cirrhosis as well, and correlated with disease severity, as assessed by Child-Pugh score, and hepatic encephalopathy.In conclusion, the use of advanced MRI techniques reveals the existence of areas of reduced brain density in patients with cirrhosis that correlate with etiology, disease severity and hepatic encephalopathy.These findings might be relevant to the understanding of the effects of cirrhosis on brain function.

Objectives Sex steroid hormones are implicated in the cognitive processes of the adult brain. Among studies reporting a positive effect of estrogen replacement therapy (ERT) on cognition, the most consistent evidence is that it enhances verbal memory and visuospatial functions. In the present study we investigated the effect of ERT on cognition and on brain morphology in healthy postmenopausal women, taking into account the distinction in current and past ERT users. Methods Participants were postmenopausal nondemented women recruited from the community: ERT users were 40 (23 current users, 17 past users), while never users were 43. Forty of recruited subjects gave consent to undergo 3D high resolution MRI (16 current users, 7 past users and 17 never users). Participants underwent MMSE and a battery of neuropsychological tests measuring memory, language, intelligence, attention and visuo-spatial abilities. Results The past users group outperformed the never users in four tests: Token test, WCST categories, attentional matrices and Rey's delayed list; the current users group outperformed the never users in the Rey's list test. ERT users had greater grey matter volumes mainly in the cerebellum, but an increase was observed also in the parietal and occipital cortex. Conclusions ERT use appears to improve linguistic, attentive and planning abilities. Interestingly, the beneficial effects on cognition were detected mainly in the past users subgroup. Here we propose that the trophic effect of estrogens on cerebellum might account for the observed improvement in cognition.

White matter hyperintensities (WMHs) are a common finding in normal elderly persons. We studied the biological damage associated with WMHs by assessing the correspondence between WMH location and regional gray matter loss.Voxel–based morphometry of the gray matter was carried out with statistical parametric mapping on high resolution MR images.Neurologically intact persons with mainly anterior (frontal>parieto–occipital; N = 39) and mainly posterior WMHs (parieto– occipital>frontal; N = 14) were compared with a group devoid of WMHs (N = 80). Subjects with mainly frontal WMHs had bilateral frontal (medial, superior, and inferior gyri) atrophy in gray matter, while subjects with mainly posterior WMHs had more diffuse atrophy, involving mainly the frontal but also the right insular region. Our findings suggest that frontal WMHs are associated with frontal gray matter damage while parietooccipital WMHs seem to have a weaker and more diffuse impact on gray matter.

R. Rossi*, M. Boccardi*, F. Sabattoli*, S. Galluzzi*, C. Testa***, M. Bonetti***, A. Beltramello****, A. Orlandini*****, A. Falini******, E. Piovan****, G. Minonzio*******, G.B. Frisoni********* * Laboratorio of Epidemiologia, Neuroimaging and Telemedicina, IRCCS San Giovanni di Dio-FBF; Brescia, Italy ** Laboratorio Machine Vision, Departimento di Matematica e scienze informatiche, Università di Udine; Udine, Italy *** Servizio di Neuroradiologia, Istituto Clinico Città di Brescia; Brescia, Italy **** Servizio di Neuroradiologia, Ospedale Maggiore Borgo Trento; Verona, Italy ***** Servizio di Neuroradiologia, Istituto Ospedaliero Poliambulanza; Brescia, Italy ****** Servizio di Neuroradiologia, Istituto Scientifico Universitario San Raffaele; Milano, Italy ******* Servizio di Neuroradiologia, Ospedale di Circolo e Fondazione Macchi/Università; Italy ******** AFaR Associazione Fatebenefratelli per la Ricerca; Roma, Italy

BACKGROUND:The diagnosis of mild cognitive impairment (MCI) is clinically unhelpful, as many patients with MCI develop dementia but many do not.OBJECTIVE:To identify clinical instruments easily applicable in the clinical routine that might be useful to predict progression to dementia in patients with MCI assessed in the outpatient facility of a memory clinic.PARTICIPANTS AND METHODS:52 dementia-free patients (mean (standard deviation) age 70 (6) years; 56% women) with MCI, and 65 healthy controls (age 69 (6) years; 54% women) underwent brain magnetic resonance scan with standardised visual assessment of medial temporal atrophy (MTA) and subcortical cerebrovascular lesions (SVLs). Follow-up assessment occurred 15.4 (SD 3.4) months after baseline to detect incident dementia and improvement, defined as normal neuropsychological performance on follow-up.RESULTS:Patients were classified into three groups according to the presence of memory disturbance only (MCI Mem), other neuropsychological deficits (MCI Oth) or both (MCI Mem+). MCI Mem and Mem+ showed MTA more frequently (31% and 47% v 5% and 14% of controls and MCI Oth, p<0.001). 11 patients developed dementia (annual rate 16.5%) and 7 improved on follow-up. The only independent predictor of progression was MTA (odds ratio (OR) 7.1, 95% confidence interval (CI) 1.4 to 35.0), whereas predictors of improvement were the absence of memory impairment (OR 18.5, 95% CI 2.0 to 171.3) and normal MRI scan (OR 10.0, 95% CI 1.7 to 60.2).CONCLUSION:Neuropsychological patterns identify groups of patients with MCI showing specific clinical features and risk of progression to dementia. MTA clinically rated with a visual scale is the most relevant predictor of progression and improvement.

M. Boccardi*, R. Ghidoni**, S. Govoni***, C. Testa*****, M. Bonetti*****, A. Beltramello******, A. Orlandini*******, A. Falini********, E. Piovan******, G. Minonzio*********, L. Benussi**, G. Binetti**, G.B. Frisoni*********** * LENITEM, (Laboratory of Epidemiology, Neuroimaging and Telemedicine) IRCCS San Giovanni di Dio-FBF; Brescia, Italy; ** NeuroBioGen Lab-Memory Clinic, IRCCS San Giovanni di Dio-FBF; Brescia, Italy; *** Department of Experimental and Applied Pharmacology, University of Pavia; Pavia, Italy; **** Machine Vision Laboratory, Department of Mathematics and Computer Science, University of Udine; Udine, Italy; ***** Servizio di Neuroradiologia, Istituto Clinico Città di Brescia; Brescia, Italy; ****** Servizio di Neuroradiologia, Ospedale Maggiore; Verona, Italy; ******* Servizio di Diagnostica per Immagini, Istituto Ospedaliero Fondazione Poliambulanza; Brescia, Italy; ******** Servizio di Neuroradiologia, Istituto Scientifico Universitario San Raffaele; Milano, Italy; ********* Servizio di Neuroradiologia, Ospedale di Circolo e Fondazione Macchi/Università degli Studi di Insubria; Varese, Italy; ********** AFaR (Associazione Fatebenefratelli per la Ricerca); Roma, Italy”

OBJECTIVE:To examine the brain structural correlates of age at onset in patients with Alzheimer's disease. METHODS:We studied nine patients with early onset (age < or =65 years), nine with late onset (age > 65) Alzheimer's disease (EOAD and LOAD, respectively) of mild-moderate severity, and 26 controls who were stratified into younger (YC, age < or =65, n = 9) and older (OC, age > 65, n = 17) subjects. The patients were closely matched for clinical severity: 3/2/3/1 patients had clinical dementia rating of 0.5/1/2/3, respectively, in both the groups. High resolution magnetic resonance images of the brain of the EOAD and YC groups and the LOAD and OC groups were compared on a voxel by voxel basis with statistical parametric mapping to detect areas specifically atrophic. RESULTS:The patients with EOAD showed greater neocortical atrophy at the temporoparietal junction while the patients with LOAD showed greater hippocampal atrophy. The results could not be accounted for by the apolipoprotein E genotype. CONCLUSIONS:Since genetic factors are believed to play a relevant pathogenetic role in EOAD and environmental factors in LOAD, genetic and environmental factors may differentially predispose the neocortical and limbic areas to the development of Alzheimer's neuropathology.

Background: Mild cognitive impairment (MCI) is the most widely used concept in classifying cognitive impairment in the elderly who do not fulfil the criteria for dementia. MCI is considered to confer an increased risk of progressing to dementia and most often Alzheimer's disease ( AD). Various approaches such as imaging of the brain have been applied to predict the conversion of MCI to dementia. A number of volumetric magnetic resonance imaging (MRI) studies have detected atrophy of the medial temporal lobe in subjects with MCI, but for the other cerebral regions the results have been inconsistent.Objective: To study the pattern of brain atrophy in MCI.Methods: Thirty two controls and 51 individuals with MCI deriving from population based cohorts were studied by MRI using voxel based morphometry. The threshold of t maps was set at p<0.001.Results: Individuals with MCI had significant unilateral atrophy in the medial temporal lobe on the right side. Less extensive atrophy was found elsewhere-for example, in the temporal lobe, left superior parietal lobule, left anterior cingulate gyrus, and bilaterally in the thalami.Conclusions: The MRI findings in MCI resemble those seen in early AD.

PURPOSE:To compare the accuracy of voxel-based morphometry (VBM) and region of interest (ROI)-based hippocampal volumetry to detect medial temporal lobe atrophy in Alzheimer's disease (AD).MATERIALS AND METHODS:A total of 27 AD patients (age 74 +/- 9 years; 22 women; Mini-Mental State Exam [MMSE] 21 +/- 4) and 25 controls (age 70 +/- 8; 16 women; MMSE 29 +/- 1) were studied. Accuracy of VBM to detect gray matter loss in those seven AD patients and 11 controls with similar ROI-based hippocampal measures and of ROI-based volumetry to detect gray matter loss in those four AD patients and five controls with similar VBM-based hippocampal measures was assessed. VBM was performed with statistical parametric mapping (SPM99).RESULTS:The area under the curve was 0.96 (95% C.I., 0.92-1.00) for VBM, 0.89 (95% C.I., 0.80-0.98) for ROI-based hippocampal measures, and 0.99 (95% C.I., 0.96-1.00) for both. In subjects with similar ROI-based hippocampal measures, VBM detected atrophy in AD patients at P < 0.0001, while in subjects with similar VBM-based hippocampal measure, volumetry was not significant (P = 0.11). Both measures independently contributed to discrimination (P = 0.004 and P = 0.032) in a logistic regression model.CONCLUSION:These results indicate that VBM is more accurate, but the combination of both methods provides the highest accuracy for detection of hippocampal atrophy in AD.

To investigate the difference in the morphologic expression of frontotemporal dementia (FTD) and Alzheimer's disease (AD) in patients carrying and not carrying the ϵ4 allele of APOE, MR images of 26 controls, 18 AD patients (11 carrying the ϵ4 allele, seven non-carriers), and eight FTD (two carriers, six non-carriers) were compared using voxel by voxel analysis. Greater atrophy was found in the disease-specific regions of the ϵ4 carriers vs the non-carriers at P<0.05 corrected: medial temporal atrophy was greater in the AD carrying the ϵ4 allele, right ventral striatal atrophy in the FTD carrying the allele. The non-carriers did not have atrophic regions compared to the carriers. The ϵ4 allele of the APOE might modulate the expression of degenerative dementias by enhancing the specific effects of neurodegenerative diseases on the brain.

Objectives: Subcortical ischemic vascular disease (SIVD) is frequently associated with cognitive impairment. Rating scales to grade cerebrovascular disease are available, but their sensitivity to the clinical features of mild SIVD is unclear. The aim of the study is to devise and validate a computed tomography (CT)-based visual rating scale sensitive to SIVD in patients with mild cognitive deterioration. Methods: Subjects were 122 consecutive outpatients of a memory clinic (mean age ± SD 77 ± 8 years, 71% females, mean ± SD score of mental state exam 22 ± 3, 61% with clinical dementia rating of 0.5 and 39% of 1). Diffuse leukoaraiosis, fuzzy and patchy lesions, and lacunes were assessed on ordinary CT films and weights were computed based on clinical indicators of SIVD. A continuous score and an ordinal class (0–3) with higher values indicating higher vascular damage were derived. Results: Intraclass correlation coefficients for intra- and interrater reliability of the subcortical vascular score and class ranged from 0.84 to 0.88. Convergent validity versus the scale of Wahlund et al. was good (Spearman’s correlation coefficient between 0.53 and 0.73, p < 0.0005). Known-group validity was assessed versus clinical diagnoses of degenerative (mild cognitive impairment determined by Petersen et al. and NINCDS-ADRDA probable Alzheimer’s disease; n = 58), mixed (possible Alzheimer’s disease with cerebrovascular disease; n = 21), and vascular cognitive impairment (criteria of Erkinjuntti et al. for subcortical vascular dementia and cognitive impairment; n = 43). Patients with degenerative cognitive impairment were more often in the lower subcortical vascular classes (43% in class 0, 43% in class 1, 14% in class 2, and 0% in class 3), while patients with mixed (0, 24, 24, and 52%) and vascular cognitive impairment were in increasingly higher subcortical vascular classes (0, 12, 35, 53%; p < 0.00005). Criterion-related validity was assessed versus clinical indicators of cerebrovascular disease. Hypertension, platelet aggregation inhibitor use, balance, gait, and bradykinesia increased linearly with increasing subcortical vascular class (p for trend <0.02). Conclusions: This rating scale is valid and sensitive to capture different degrees of SIVD associated with mild cognitive deterioration.

We describe an Italian pedigree with hereditary dementia associated with a novel T122R mutation in the presenilin-2 gene (PSEN2). The clinical history, symptom presentation, and structural neuroimaging were consistent with an atypical form of dementia. Disease expression varied within family members. One in a pair of mutated monozygotic twins had evident signs of disease, whereas the other did not, even if her functional neuroimaging investigations, cerebrospinal fluid levels of Abeta1-42, and Tau protein were able to provide markers for future disease development. These observations suggest the importance of still unknown biological and perhaps environmental factors in the disease determination.

Objectives: To test the applicability of an automated method of magnetic resonance image analysis (voxel based morphometry) to detect presence and severity of regional grey matter density reduction—a proxy of atrophy—in Alzheimer's disease. Methods: Twenty nine probable Alzheimer's patients and 26 non-demented controls (mini-mental state examinations mean (SD) 21 (4) and 29 (1)) underwent high resolution 3D brain magnetic resonance imaging. Spatial normalisation to a stereotactic template, segmentation into grey matter, white matter, and cerebrospinal fluid, and smoothing of the grey matter were carried out based on statistical parametric mapping (SPM99) algorithms. Analyses were carried out: (a) contrasting all Alzheimer's patients with all controls (p<0.05 corrected for multiple comparisons); (b) contrasting the three Alzheimer's patients with mini-mental state of 26 and higher with all controls (p<0.0001 uncorrected); and (c) correlating grey matter density with mini-mental state score within the Alzheimer's group (p<0.0001 uncorrected). Results: When all Alzheimer's patients were compared with controls, the largest atrophic regions corresponded to the right and left hippocampal/amygdalar complex. All parts of the hippocampus (head, body, and tail) were affected. More localised atrophic regions were in the temporal and cingulate gyri, precuneus, insular cortex, caudate nucleus, and frontal cortex. When the mildest Alzheimer's patients were contrasted with controls, the hippocampal/amygdalar complex were again found significantly atrophic bilaterally. The mini-mental state score correlated with grey matter density reduction in the temporal and posterior cingulate gyri, and precuneus, mainly to the right. Conclusions: Voxel based morphometry with statistical parametric mapping is sensitive to regional grey matter density reduction in mild Alzheimer's disease.

Crude and corrected amygdaloid volumes were computed from magnetic resonance scans in ten patients with frontotemporal dementia (FTD), 25 patients with Alzheimer's disease (AD) and 27 controls. Amygdaloid atrophy was present in FTD (P<0.005) compared to controls, and a trend for increasing atrophy from controls, through FTD to AD (P for trend <0.00005) showed that FTD amygdaloid volumes were intermediate between controls and AD. Behavioral and Klüver–Bucy-like symptoms, characteristic of FTD, cannot be explained by amygdaloid atrophy alone.

We present a CT-based visual rating scale sensitive to subcortical cerebrovascular disease (sCVD) in patients with cognitive impairment.