Cristina Geroldi

Resting state fMRI in Alzheimer's disease: beyond the default mode network

Using resting state (RS) functional magnetic resonance imaging (fMRI), the connectivity patterns of the default mode (DMN), frontoparietal, executive, and salience networks were explored in 13 Alzheimers disease (AD) patients, 12 amnestic mild cognitive impairment (aMCI) patients, and 13 healthy controls. Compared with controls and aMCI, AD was associated with opposing connectivity effects in the DMN (decreased) and frontal networks (enhanced). The only RS abnormality found in aMCI patients compared with controls was a precuneus connectivity reduction in the DMN. RS fMRI group differences were only partly related to gray matter atrophy. In AD patients, the mean executive network connectivity was positively associated with frontal-executive and language neuropsychological scores. These results suggest that AD is associated with an alteration of large-scale functional brain networks, which extends well beyond the DMN. In AD, the limited resources of the DMN may be paralleled, in an attempt to maintain cognitive efficiency, by an increased prefrontal connectivity. A medial parietal RS fMRI signal change seems to be present since the early phase of AD.

Hippocampal and entorhinal cortex atrophy in frontotemporal dementia and Alzheimer’s disease

Objective: To describe atrophic changes of the hippocampus and entorhinal cortex in frontotemporal dementia (FTD) and compare them with those of AD. Background: The medial temporal lobe shows atrophic changes early in the course of AD, but whether these changes are specific to AD or occur in other degenerative dementias, and to what extent, is unclear. Methods: The authors measured the volumes of the left and right hippocampus and entorhinal cortex from MR images (1.5 T, 2-mm–thick slices) in 12 patients with FTD, 30 with AD, and 30 elderly control subjects. Results: In FTD patients, the left and right hippocampus (16% and 21% tissue loss) and the entorhinal cortex (28% and 27% loss) were more atrophic than the control subjects. Atrophy of the hippocampus in FTD was less severe than in AD, but atrophy of the entorhinal cortex was equally severe. Greater hippocampal and entorhinal cortex atrophy was present in the most severe patients in both groups (as high as a 49% tissue loss). The sensitivity of the hippocampus and the entorhinal cortex to discriminate FTD patients from control subjects was low (49% and 52%, respectively; specificity set at 90%), whereas hippocampal volumes could better differentiate AD patients from control subjects (80% sensitivity). Conclusions: At variance with AD, detectable in vivo atrophy of the hippocampus might not be an early event in FTD. Differential patterns of atrophy might help in the diagnostic process of the degenerative dementias.

White Matter Damage in Alzheimer Disease and Its Relationship to Gray Matter Atrophy

PURPOSE To explore the regional patterns of white matter (WM) tract damage in (a) patients with probable Alzheimer disease (AD) and (b) patients with amnestic mild cognitive impairment (aMCI) and at least one abnormal biomarker and to investigate whether WM damage is related to gray matter (GM) atrophy. MATERIALS AND METHODS This study was approved by the institutional review board, and written informed consent was obtained from each participant. Twenty-three patients with AD, 15 patients with aMCI, and 15 healthy control subjects underwent diffusion tensor magnetic resonance imaging. WM tract damage was investigated by using tract-based spatial statistics, and GM atrophy was measured by using voxel-based morphometry. RESULTS Compared with control subjects, patients with AD had an increase in mean diffusivity in all major WM tracts studied, including the limbic, cortico-cortical, interhemispheric, and corticospinal tracts. Conversely, fractional anisotropy decreased only in the parahippocampal tract, fornix, and small, inferior parietal regions. In addition, patients with AD showed a widespread increase in axial and radial diffusivity compared with control subjects. Patients with aMCI showed an increase in axial diffusivity only in tracts projecting to the frontal cortex and splenium of the corpus callosum. Significant and anatomically congruent correlations between WM changes and regional GM atrophy were found in patients with AD. Conversely, damage to most WM tracts in patients with aMCI did not correlate with GM atrophy. CONCLUSION In AD, the observed patterns of WM abnormalities may reflect the advanced phase of a secondary degenerative process and an association, especially in the early phases of the disease, with primary WM tract damage over and above GM abnormalities.

Contrasting Results Between Caregiver's Report and Direct Assessment of Activities of Daily Living in Patients Affected by Mild and Very Mild Dementia: The Contribution of the Caregiver's Personal Characteristics

OBJECTIVE: To determine the level of agreement between the primary caregivers report on patient activities of daily living (ADLs) and ADLs assessed directly in a sample of patients affected by very mild and mild dementia and to assess whether this agreement is influenced by the caregivers depressive symptoms and burden.

Mild cognitive impairment with subcortical vascular features

Abstract.Objectives: To identify non-demented individuals with cognitive impairment due to a cerebrovascular etiology among those coming to observation of a memory clinic and to describe their clinical features and outcome. Methods: Patients were enrolled in a prospective study on early cognitive impairment carried out in a Memory Clinic. Mild cognitive impairment of the vascular type (MCI-V) was defined based on modified criteria for subcortical vascular dementia (SVD) by Erkinjuntti and colleagues. Twenty-nine patients with MCI-V (age 78 ± 7, Mini Mental State Exam (MMSE) 24 ± 3) were compared with 14 with mild cognitive impairment of degenerative etiology (MCI) based on the Mayo Clinic criteria (age 72 ± 9, MMSE 25 ± 2), and to 21 patients with frank SVD (age 80 ± 6, MMSE 21 ± 3). Patients were followed over time for 32 ± 8 months. Results: MCI-V patients had a neuropsychological profile characterized by poor performance on frontal tests (Wisconsin card sorting and word fluency) and neurological features of parkinsonism without tremor (impairment of balance and gait). Of those followed for at least 40 months, 50 % of patients with MCI-V and SVD had died, while all MCI patients were still alive (P = 0.03). Of those alive, 68 % of the MCI-V, 52 % of the SVD, and 17 % of the MCI patients had reached one of the following outcomes at 40 months: nursing home placement, functional loss, and cognitive deterioration (P = 0.02). Conclusions: Patients with MCI-V have a distinctive clinical picture and can be identified in a clinical setting. Because of the high frequency of adverse outcomes, very early preventive measures need to be devised.

MRI-Based Automated Computer Classification of Probable AD Versus Normal Controls

Automated computer classification (ACC) techniques are needed to facilitate physicians diagnosis of complex diseases in individual patients. We provide an example of ACC using computational techniques within the context of cross-sectional analysis of magnetic resonance images (MRI) in neurodegenerative diseases, namely Alzheimers dementia (AD). In this paper, the accuracy of our ACC methodology is assessed when presented with real life, imperfect data, i.e., cohorts of MRI with varying acquisition parameters and imaging quality. The comparative methodology uses the Jacobian determinants derived from dense deformation fields and scaled grey-level intensity from a selected volume of interest centered on the medial temporal lobe. The ACC performance is assessed in a series of leave-one-out experiments aimed at separating 75 probable AD and 75 age-matched normal controls. The resulting accuracy is 92% using a support vector machine classifier based on least squares optimization. Finally, it is shown in the Appendix that determinants and scaled grey-level intensity are appreciably more robust to varying parameters in validation studies using simulated data, when compared to raw intensities or grey/white matter volumes. The ability of cross-sectional MRI at detecting probable AD with high accuracy could have profound implications in the management of suspected AD candidates.

APOE-ε4 is associated with less frontal and more medial temporal lobe atrophy in AD

Objective: To test the hypothesis that the ε4 allele of APOE is associated with a region-specific pattern of brain atrophy in AD. Methods: Volumes of the hippocampi, entorhinal cortices, and anterior temporal and frontal lobes were measured in 28 mild to moderate AD patients and 30 controls using MRI. Within the AD group, 14 patients were noncarriers (−/−), 9 were heterozygous (ε4/−), and 5 were homozygous (ε4/4) for the ε4 allele. Dementia severity was similar across the three AD groups. Results: Smaller volumes were found with increasing dose of the ε4 allele in the hippocampus, entorhinal cortex, and anterior temporal lobes in AD patients. When compared with controls, the volume loss in the right and left temporal regions ranged from −15.3 to −22.7% in the −/− AD group, from −26.2 to −36.0% in the ε4/− group, and from −24.0 to −48.0% in the ε4/4 group (p < 0.0005). In contrast, larger volumes were found in the frontal lobes with increasing ε4 gene dose. When compared with controls, volume differences of the right frontal lobe were −11.8% in the −/− AD group, −8.5 in the ε4/− group, and −1.4% in the ε4/4 group (p = 0.03). Conclusions: We found smaller volumes in the temporal lobe regions but larger volumes in the frontal lobes with increasing APOE-ε4 gene dose in AD patients. These data suggest a region-specific biological effect of the ε4 allele in the brains of AD patients.

Assessment of White Matter Tract Damage in Mild Cognitive Impairment and Alzheimer's Disease

Diffusion tensor MRI‐based tractography was used to investigate white matter (WM) changes in the major limbic (i.e., fornix and cingulum) and cortico‐cortical association pathways [i.e., the uncinate fasciculus, the inferior fronto‐occipital fasciculus, the inferior longitudinal fasciculus (ILF), the superior longitudinal fasciculus, and the corpus callosum] in 25 Alzheimers disease (AD) patients, 19 amnestic mild cognitive impairment (aMCI) patients, and 15 healthy controls (HC). Mean diffusivity (MD), fractional anisotropy (FA), as well as axial (DA) and radial (DR) diffusivities were measured for each tract, using an atlas‐based tractography approach. The association of WM tract integrity with hippocampal volume was also assessed. MD values were significantly different among groups in all WM tracts (P values ranging from 0.002 to 0.03), except in the fornix (P = 0.06) and the inferior fronto‐occipital fasciculus (P = 0.09). Conversely, FA was significantly different among groups in the fornix only (P = 0.02). DA values were significantly different among groups in all WM tracts (P values ranging from 0.001 to 0.01), except in the fornix (P = 0.13) and the cingulum (P = 0.29). Significantly different DR values among groups were found in the fornix (P = 0.02) and the ILF (P = 0.01). In the fornix and cingulum, DR was significantly more increased than DA in both patient groups compared to HC. No difference in DA versus DR was found in cortico‐cortical WM tracts. DA values in the fornix were significantly correlated with the hippocampal volume. This study demonstrates a different pattern of WM involvement in the limbic and cortico‐cortical association pathways in aMCI and AD patients. Hum Brain Mapp, 2010.

Hippocampal volume and cortical sources of EEG alpha rhythms in mild cognitive impairment and Alzheimer disease

Atrophy of hippocampus and alteration of resting eyes-closed electroencephalographic (EEG) rhythms represent important features of mild cognitive impairment (MCI) and Alzheimers disease (AD). Here we evaluated linear and non-linear aspects of the relationship between these features in the continuum along MCI and AD conditions, as a reflection of neurodegenerative processes. Eyes-closed resting EEG data were recorded in 60 healthy elderly (Nold), 88 MCI, and 35 Alzheimers disease (AD) patients. Hippocampal volume was measured in magnetic resonance imaging of the MCI and AD subjects. Based on the normalized hippocampal volume, selected MCI subjects could be divided into two demographically paired sub-groups: those with larger hippocampal volume (MCI +h; N=40; mini mental state evaluation - MMSE - score=27.5+/-0.26 SE) and those with smaller hippocampal volume (MCI -h; N=40; h; MMSE=26.5+/-0.34 SE); the normalized hippocampal volume was statistically greater in the MCI +h than in the MCI -h and AD subjects (p<0.0001). 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. Results showed that the power of occipital, parietal, and temporal alpha 1 sources was maximum in MCI +h, intermediate in MCI -h, and low in AD patients. Furthermore, the power of these sources was linearly and non-linearly correlated with the normalized hippocampal volume. These 3 EEG sources were given as input for evaluating correlations (linear, exponential, logarithmic and power) with hippocampal volume. When subjects were considered as a unique group, there was a significant linear correlation of hippocampal volume with the magnitude of alpha 1 sources in the parietal, occipital and temporal areas. In general, the EEG sources showing significant linear correlation with hippocampal volume also supported a non-linear correlation with hippocampal volume strongly for the logarithmic one. The present results suggest that progressive atrophy of hippocampus correlates with decreased cortical alpha power, as estimated by using LORETA source modeling, in the continuum along MCI and AD conditions.

Medial temporal atrophy but not memory deficit predicts progression to dementia in patients with mild cognitive impairment

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.