Maarit Lehtovirta

Hippocampal volumes in Alzheimer's disease, Parkinson's disease with and without dementia, and in vascular dementia An MRI study

Hippocampal atrophy detected by volumetric MRI is a sensitive feature of early Alzheimers disease (AD), but there are no studies evaluating hippocampal atrophy by MR volumetry in other dementing diseases. We therefore compared hippocampal volumes in a total of 113 subjects: 50 patients with mild to moderate AD, 9 patients with vascular dementia (VaD), 12 patients with idiopathic Parkinsons disease (PD) without dementia, 8 patients with PD and dementia (PDD), and 34 elderly control subjects. Thin, coronal, contiguous images were obtained by a 1.5-T MR imager. All patient groups had significantly smaller volumes of the hippocampus compared with the control group. In the PDD group, the absolute volumes were even smaller than in the AD group. In the PD group, the volumes were diminished to a lesser but significant extent. The volumes in the VaD group varied: of nine patients, two had no atrophy, three had unilateral, and four had bilateral atrophy. We postulate that hippocampal atrophy does not seem to be a specific phenomenon of dementia in AD but also occurs in VaD and PDD, and even in PD when no dementia is present. However, coexistence of AD pathology in our PD and VaD patients cannot be ruled out. Further studies with access to neuropathologic data are needed.

MRI of the Hippocampus in Alzheimer’s Disease: Sensitivity, Specificity, and Analysis of the Incorrectly Classified Subjects

In this study, magnetic resonance imaging (MRI) of the hippocampus for the diagnosis of early Alzheimers disease (AD) is evaluated. We measured hippocampal volumes and the area of the medial hippocampus with a 1.5 T MR imager in 160 subjects: 55 patients with probable AD according to the NINCDS-ADRDA criteria, 43 subjects fulfilling the NIMH criteria of age-associated memory impairment (AAMI), 42 cognitively normal elderly controls, and 20 controls younger than 50 years. Three methods for normalization were compared. The hippocampi were atrophied in the AD patients, but not in the AAMI subjects or the elderly controls. There was no significant correlation between hippocampal volumes and age in the nondemented subjects. The discrimination based on volumetry resulted in an overall correct classification of 92% of AD patients vs. nondemented elderly subjects, whereas discrimination based on hippocampal area was less accurate, producing a correct classification in 80% of the subjects. We conclude that the hippocampus as assessed by MRI volumetry is atrophied early in AD, and spared by aging or AAMI. A brief critical review of previous studies is in concordance with the presented data: all the previous studies that have used volumetry, have similarly ended up with a good classification, whereas simpler or subjective measurements, subject to various sources of bias, have produced most variable results.

Volumes of the Entorhinal and Perirhinal Cortices in Alzheimer’s Disease

We measured the volumes of the entorhinal, perirhinal, and temporopolar cortices on magnetic resonance images by using a recently designed histology-based protocol in 30 patients with early Alzheimers disease (AD) and 32 healthy control subjects. Compared to the controls, all of these cortical regions were significantly atrophied in AD patients (p < 0.0001). However, the entorhinal cortex was the most severely involved brain region studied, with 40% volume loss, and this region provided the highest discriminative accuracy (92%) in separating patients with AD from healthy control subjects. Importantly, the entorhinal volume loss was evident already in mild AD. In addition, the volume of the entorhinal cortex was not dependent on age, but it did correlate significantly with the severity of the disease. Because it assesses the major site of initial neuropathological changes in AD, magnetic resonance imaging volumetric measurement of the entorhinal cortex can offer a tool for distinguishing AD patients even in the very early stages of the disease from healthy aged subjects.

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)

Clinical and neuropsychological characteristics in familial and sporadic Alzheimer's disease: Relation to apolipoprotein E polymorphism

Alzheimers disease (AD) is a heterogeneous entity presenting as sporadic and familial disease.In familial AD, there is evidence for genetic linkage to a yet undefined gene on chromosome 14 in early-onset pedigrees and on chromosome 19 in late-onset pedigrees. In a few early-onset kindreds, there were mutations in the amyloid precursor gene on chromosome 21. There is an increased frequency of apolipoprotein E (ApoE) epsilon 4 allele in patients with late-onset AD. We studied the clinical presentation and profile of cognitive deficits in 58 AD patients at the early stage of the disease. We divided the AD patients into subgroups of sporadic late-onset (SLO) (more than equals to 65 years), familial late-onset (FLO) (more than equals to 65 years), sporadic early-onset (SEO) (less than 65 years), and familial early-onset (FEO) (less than 65 years) patients and into three subgroups according to their ApoE genotype zero epsilon 4, one epsilon 4, and two epsilon 4 alleles. The AD subgroups did not differ in the global clinical severity of dementia or the duration of the disease. SLO, FLO, SEO, and FEO subgroups did not differ in clinical characteristics such as occurrence of rigidity, hypokinesia, tremor, myoclonus, hallucinations, delusions, or epileptic seizures nor in the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions. The epsilon 4 allele frequency was 0.43 for all AD patients and did not differ across subgroups divided according to the familial aggregation and age of onset. Patients with two epsilon 4 alleles had earlier age at onset of dementia than those with no epsilon 4 allele (63 plus minus 9 versus 68 plus minus 9 years), but otherwise the clinical symptoms and signs were not related to the ApoE genotype. However, the AD patients with two epsilon 4 alleles had lowest scores on memory tests and differed significantly from those with one or zero epsilon 4 allele in the delayed list learning (p less than 0.05) and from those with zero epsilon 4 allele in the immediate and delayed story recall. In contrast, verbal functions were better preserved in two epsilon 4 patients than in those with other ApoE genotypes. This study failed to confirm the earlier reports of severe aphasia, agnosia, and apraxia in familial AD patients, but the clinical phenotype was similar irrespective to the familial aggregation. However, AD patients with two epsilon 4 alleles are characterized by more severe memory loss and earlier age of onset than those without the epsilon 4 allele. NEUROLOGY 1996;46: 413-419

The level of cerebrospinal fluid tau correlates with neurofibrillary tangles in Alzheimer's disease

WE measured tau concentrations in cerebrospinal fluid (CSF) samples taken during the lifetime of 43 patients with Alzheimers disease (AD) and correlated these values with neurofibrillary tangle (NFT) scores as well as glial fibrillary acidic protein (GFAP) expression as a marker of astrocytosis in the brain post-mortem. The CSF tau values showed a positive correlation with neocortical NFT scores (r = 0.44, p < 0.005), while GFAP immmunoreactivity did not correlate with CSF tau. This study reveals a high variation in CSF tau values in patients with neuropathologically confirmed AD (range 194–1539 pg/ml) and indicates that high CSF tau values in the late phase of Alzheimers disease predict severe neurodegeneration as evidenced by increased NFT scores.

Subgroups of Alzheimer's disease based on cerebrospinal fluid molecular markers.

Alzheimers disease, the most common cause of dementia, is multifactorial and heterogeneous; its diagnosis remains probable. We postulated that more than one disease mechanism yielded Alzheimers histopathology, and that subgroups of the disease might be identified by the cerebrospinal fluid (CSF) levels of proteins associated with senile (neuritic) plaques and neurofibrillary tangles. We immunoassayed levels of tau, ubiquitin, and Aβ1‐42 in retrospectively collected CSF samples of 468 clinically diagnosed Alzheimers disease patients (N = 353) or non‐Alzheimers subjects (N = 115). Latent profile analysis assigned each subject to a cluster based on the levels of these molecular markers. Alzheimers disease was subdivided into at least five subgroups based on CSF levels of Aβ1‐42, tau, and ubiquitin; each subgroup presented a different clinical profile. These subgroups, which can be identified by CSF analysis, might benefit differently from different therapeutic drugs. Ann Neurol 2005;58:748–757

SPECT and MRI analysis in Alzheimer's disease: relation to apolipoprotein E epsilon 4 allele.

OBJECTIVES--The epsilon 4 allele of apolipoprotein E (ApoE) is a risk factor for late onset Alzheimers disease. ApoE is present in senile plaques, neurofibrillary tangles, and cerebrovascular amyloid, and it is implicated in synaptogenesis. The effect of ApoE polymorphism on the volumes of hippocampus, amygdala, and frontal lobe was studied. The hypothesis was that the patients with Alzheimers disease carrying the epsilon 4 allele have more pronounced atrophy. The relation of ApoE and cerebral blood flow on cortical areas was also assessed. METHODS--Fifty eight patients with Alzheimers disease at the early stage of the disease and 34 control subjects were studied. Patients with Alzheimers disease were divided into subgroups according to the number of the epsilon 4 alleles. Volumes were measured by MRI and regional cerebral blood flow ratios referred to the cerebellum were examined by 99mTc-HMPAO SPECT. ApoE genotypes were determined by digestion of ApoE polymerase chain reaction products with the restriction enzyme Hha1. RESULTS--patients with Alzheimers disease had smaller volumes of hippocampi and amygdala compared with control subjects, and the patients with Alzheimers disease homozygous for the epsilon 4 allele had the most prominent volume loss in the medial temporal lobe structures. The frontal lobe volumes did not differ significantly. All patients with Alzheimers disease had bilateral temporoparietal hypoperfusion and the subgroups with one or no epsilon 4 alleles also had frontal hypoperfusion compared with control subjects. The occipital perfusion ratios tended to decrease with increasing number of epsilon 4 alleles. CONCLUSIONS--Patients with Alzheimers disease homozygous for the epsilon 4 allele seem to have severe damage in the medial temporal lobe structures early in the disease process and differ from the patients with Alzheimers disease with one or no epsilon 4 alleles.

Hippocampus in Alzheimer’s disease: a 3-year follow-up MRI study

BACKGROUND Due to the progressive nature of Alzheimers disease (AD), it has been proposed that serial imaging studies tracking the course of progression might improve the diagnostic accuracy of AD. METHODS Longitudinal changes in hippocampal volumes were evaluated using magnetic resonance imaging (MRI) over a period of 3 years in 27 AD patients and 8 control subjects. RESULTS A statistically nonsignificant trend towards accelerated volume loss in the AD group compared to control subjects was observed. During the study period, the average shrinkage of the hippocampal volume ranged from -2.2% to -5.8% in control subjects, and from -2.3% to -15.6% in AD patients. CONCLUSIONS The observed changes at an individual level were small, and within the accuracy range of the measurements. Therefore, serial MRI of the hippocampus did not offer any advantage over a single MRI to support the diagnosis of AD in this study sample.

Major decrease in the volume of the entorhinal cortex in patients with Alzheimer’s disease carrying the apolipoprotein E ε4 allele

OBJECTIVE Recent evidence indicates that the apolipoprotein E (ApoE) ε4 allele is a risk factor for developing Alzheimer’s disease. It has also been proposed that it is associated with increased counts of amyloid plaques and neurofibrillary tangles that in turn are neuropathological hallmarks initially appearing in the medial temporal lobe structures in Alzheimer’s disease. In this study, the effect of the ApoE ε4 allele on the volume of the entorhinal cortex was evaluated in vivo. METHODS The volume of the entorhinal cortex was measured on MR images using a recently designed histology based protocol in 16 patients with Alzheimer’s disease with ApoE ε4 (mean age 70.4 (SD 9.9)), 11 patients with Alzheimer’s disease without ApoE ε4 (mean age 69.1 (SD7.1)), and in 31 healthy age and sex matched normal controls (72.2 (SD 3.9)). The patients met the NINCDS-ADRDA criteria for probable Alzheimer’s disease and were in mild to moderate stages of the disease. MRI was performed with a 1.5 Tesla Magnetom and a 3D technique permitting the reconstruction of 2.0 mm thick contiguous slices perpendicular to the axis of the anterior-posterior commissure. RESULTS The patients with Alzheimer’s disease without the ApoE ε4 allele had atrophy in the entorhinal cortex, the volume was reduced by 27 % compared with control subjects. However, the most prominent shrinkage (45%) in the entorhinal cortex was seen in patients with Alzheimer’s disease with the ApoE ε4 allele (p=0.0001). The effect of ε4 on the entorhinal cortex volume was especially prominent in female patients with Alzheimer’s disease compared to male patients with Alzheimer’s disease (p=0.014). Additionally, patients with the ApoE ε4 allele had inferior performance in verbal and visual memory functions than those without the allele CONCLUSIONS Volumetric MRI measurements disclose that ApoE ε4 is associated with the degree of atrophy in the entorhinal cortex in early Alzheimer’s disease, this effect being especially prominent in female patients with Alzheimer’s disease.