Mikko P. Laakso

Magnetic resonance imaging of the entorhinal cortex and hippocampus in mild cognitive impairment and Alzheimer’s disease

OBJECTIVES To explore volume changes of the entorhinal cortex (ERC) and hippocampus in mild cognitive impairment (MCI) and Alzheimers disease (AD) compared with normal cognition (NC); to determine the powers of the ERC and the hippocampus for discrimination between these groups. METHODS This study included 40 subjects with NC, 36 patients with MCI, and 29 patients with AD. Volumes of the ERC and hippocampus were manually measured based on coronal T1 weighted MR images. Global cerebral changes were assessed using semiautomatic image segmentation. RESULTS Both ERC and hippocampal volumes were reduced in MCI (ERC 13%, hippocampus 11%, p<0.05) and AD (ERC 39%, hippocampus 27%, p<0.01) compared with NC. Furthermore, AD showed greater volume losses in the ERC than in the hippocampus (p<0.01). In addition, AD and MCI also had cortical grey matter loss (p< 0.01) and ventricular enlargement (p<0.01) when compared with NC. There was a significant correlation between ERC and hippocampal volumes in MCI and AD (both p<0.001), but not in NC. Using ERC and hippocampus together improved discrimination between AD and CN but did not improve discrimination between MCI and NC. The ERC was better than the hippocampus for distinguishing MCI from AD. In addition, loss of cortical grey matter significantly contributed to the hippocampus for discriminating MCI and AD from NC. CONCLUSIONS Volume reductions in the ERC and hippocampus may be early signs of AD pathology that can be measured using MRI.

Volumes of hippocampus, amygdala and frontal lobes in the MRI-based diagnosis of early Alzheimer's disease: Correlation with memory functions

SummaryWe studied the usefulness of measuring volumes of the hippocampus, amygdala and frontal lobes with coronal magnetic resonance imaging (MRI) scans in the diagnosis of early Alzheimers disease (AD). We examined 32 patients diagnosed according to the NINCDS-ADRDA criteria of probable AD and 16 age-matched healthy cognitively normal controls. The AD patients had mild dementia with a mean score of 22.8 in the Mini-Mental Status Examination (MMSE). We used a 1.5T magnetic resonance imager and normalized the volumes for brain area. The AD patients had significantly smaller volumes of the right and the left hippocampus (−38%) (ANOVA, p<0.001) and the left frontal lobe (−16%, p<0.05) compared to controls. The reductions in volumes of the right frontal lobe (−13%), the right amygdala (−14%) or the left amygdala (−18%) were not statistically significant. In the discriminant function analysis which included the volumes of the hippocampus, amygdala, and the frontal lobes and age, the volumes of the left and right hippocampus, the left and right frontal lobe, and the right amygdala entered the model and we could correctly classify 92% of the subjects into AD and control groups (Chi-square 42.6, df 5, p<0.0001). By using the volumes of the hippocampus, the frontal lobes or the amygdala on their alone, the correct classification was achieved in 88%, 65% and 58% of the subjects, respectively. In addition, in AD patients the volumes of the left hippocampus correlated significantly with the MMSE score and with immediate and delayed verbal memory; the smaller the volume the more impaired was their performance. Our data indicate that measurements of volumes of the hippocampus might be useful in diagnosis of early 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.

Volumes of hippocampus, amygdala and frontal lobe in Alzheimer patients with different apolipoprotein E genotypes

An increased frequency of apolipoprotein E E4 allele has been reported in patients with late onset Alzheimers disease. Apolipoprotein E participates in the transport of cholesterol and other lipids and interferes with the growth and regeneration of both peripheral and central nervous system tissues during development and after injury. Apolipoprotein E is also implicated in synaptogenesis. Apolipoprotein E isoforms differ in binding to amyloid-beta-protein and tau protein in vitro. Here, we wanted to study the effect of apolipoprotein E genotype on the magnitude of damage in the hippocampus, where a marked synapse loss exists in Alzheimers disease. We measured by magnetic resonance imaging the volumes of the hippocampus, amygdala, and frontal lobes in the three Alzheimer subgroups: patients with 2, 1 or 0 E4 alleles. We also investigated the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions of these Alzheimer subgroups. All Alzheimer patients were at early stage of the disease. We found that Alzheimer patients with E4/4 genotype (N = 5) had smaller volumes of the hippocampus and the amygdala than those with E3/4 (N = 9) and those with E3/3 or E2/3 (N = 12). The difference was significant for the right hippocampus (-54% of control) and the right amygdala (-37% of control). The volumes of the frontal lobes were similar across the Alzheimer subgroups. The patients with E4/4 also showed lowest scores on delayed memory tests and differed from E3/3, 3/2 patients in the list learning test (< 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of subcortical ischemic vascular dementia and AD on entorhinal cortex and hippocampus.

Objective To determine the effects of subcortical ischemic vascular dementia (SIVD) and AD on entorhinal cortex (ERC) and hippocampus. Methods Thirty-eight cognitively normal subjects, 18 patients with SIVD, and 22 patients with AD were included. Volumes of ERC and hippocampus were manually measured based on MRI. Global cerebral changes of cortical gray matter, subcortical gray matter, white matter, sulcal CSF, ventricular CSF (vCSF), and white matter signal hyperintensities (WMSH) were assessed. Results Patients with SIVD had 21.7% (p < 0.01) smaller ERC and 18.2% (p < 0.01) smaller hippocampi than cognitively normal subjects and 24.4% (p < 0.01) larger ERC and 11.1% (p < 0.05) larger hippocampi than patients with AD. In addition, patients with SIVD had less cortical gray matter and white matter and more vCSF and WMSH (all p < 0.01) than cognitively normal subjects and more vCSF and WMSH (p < 0.01) than patients with AD. The volumes of ERC and hippocampus were positively correlated to similar extents (p < 0.01) in SIVD and AD. Cortical gray matter loss was positively correlated (p < 0.01) with hippocampal atrophy, but not with ERC atrophy, in SIVD and AD. Hippocampal volume alone could classify 82% of patients with SIVD from cognitively normal subjects and 63% of patients with SIVD from subjects with AD. Adding global cerebral changes to hippocampus substantially improved the classification to 96% between patients with SIVD and cognitively normal subjects and 83% between subjects with SIVD and those with AD, whereas adding ERC change to hippocampus did not significantly improve the discrimination. Conclusions The entorhinal cortex and hippocampus are less affected by subcortical ischemic vascular dementia than by AD.

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.

Apolipoprotein E genotype and hippocampal asymmetry in Alzheimer's disease: a volumetric MRI study

Asymmetry of brain structures is common to many species and is even present in utero. Some developmental, pathological, and dementing diseases are associated with alterations in normal anatomical asymmetries. Anatomical asymmetries, however, have been only superficially studied in Alzheimers disease. Recent evidence indicates that the allele ε4 of the apolipoprotein E (ApoE), a well known risk factor for Alzheimers disease, might play a part in determining some brain morphological changes both in normal carriers and in patients with Alzheimers disease. This study evaluated the effect of the ApoE genotype on hippocampal asymmetry in patients with Alzheimers disease carrying 0, 1, and 2 copies of the allele. Volumetric right-left differences of the hippocampi were computed in 28 right handed patients with Alzheimers disease (14 -/-, 9 ε4/-, and 5 ε4/4) and 30 controls without detectable cognitive deficit. In controls, the right hippocampus was larger than the left, whereas in patients with Alzheimers disease this asymmetry was progressively reduced with increasing gene dose of the ε4 allele, and the asymmetry was reversed in the ε4/4 Alzheimers disease group. The mean right-left volume differences were: 1.2, 0.7, 0.2, and -1.0 in controls, -/-, ε4/-, and ε4/4 patients, respectively (sex adjusted p for trend=0.017). The data indicate a dose dependent effect of the ApoE ε4 allele on hippocampal volume asymmetry in Alzheimers disease.

MRI of amygdala fails to diagnose early Alzheimer's disease.

We evaluated the ability of MRI of the amygdala to diagnose early Alzheimers disease (AD). The volume of the amygdala was measured in 54 patients with probable AD, 38 subjects with age-associated memory impairment (AAMI), 34 cognitively normal elderly controls (OC) and 20 young controls (YC). The amygdala was atrophied in all the elderly study groups with atrophy being strongest in the AD group (p < 0.0001). The OC and AAMI groups differed from the YC group (p < 0.05) but not from each other. There was a major overlap between the study groups. The volumes also correlated with age (p < 0.0001) and gender (p < 0.001). A correct classification was achieved in 74% of AD patients and the non-demented elderly subjects. Thus, MRI of amygdala fails to diagnose AD accurately.

Hippocampal atrophy, acute THA treatment and memory in Alzheimer's disease.

We designed the present study to investigate the hypothesis that progression of hippocampal pathology may decrease the therapeutic effects of anti-cholinesterase drug, tetrahydroaminoacridine, on memory functioning in Alzheimers disease (AD) patients. Memory, visuoconstructive, executive and vigilance functions were assessed after administration of placebo (p.o.; two placebo sessions) and tetrahydroaminoacridine (one session for 25 and 75 mg, p.o.). Eight patients performed better on list learning test during tetrahydroaminoacridine 75 mg than after placebo or tetrahydroaminoacridine 25 mg. The responders performed during baseline examination better than the non-responders in executive and some declarative memory functions, and had higher MMSE scores than the non-responders. The responders had larger left and right hippocampi than the non-responders. The hippocampal volume correlated with list learning performance. The results suggest that severe hippocampal atrophy may block memory improving effect of an anticholinesterase drug, tetrahydroaminoacridine.

Decreased brain creatine levels in elderly apolipoprotein E ε4 carriers

Summary. Apolipoprotein E (ApoE) genotype has been shown to influence results in neuroimaging studies using a number of various imaging modalities. No in vivo data exists on whether or not there are ApoE-related changes observable by proton magnetic resonance spectroscopy (MRS). In this study we measured absolute peak areas of proton MR spectra obtained from the occipital cortex in 22 non-demented elderly with (n = 8) or without (n = 14) the ApoE ε4 allele. No statistically significant differences were found in levels of N-acetyl aspartate, myo-inositol, or choline containing compounds between the groups. Instead, compared with the non-carriers, the levels of creatine were significantly lower in the ε4 carriers, suggesting increased metabolic demands in the brain of the ε4 carriers. The levels of creatine also correlated significantly with age and performance on the Mini-Mental State Examination test in the ε4 carriers, but not in the non-carriers. These findings may be of significant clinical interest as potential indicator of incipient AD, and also from therapeutical point of view given the potential neuroprotective effects of creatine.