Éva Csibri

Associative Learning, Acquired Equivalence, and Flexible Generalization of Knowledge in Mild Alzheimer Disease

BackgroundAcquired equivalence is a phenomenon in which prior training to treat 2 stimuli as equivalent increases generalization between them. Previous studies demonstrated that the hippocampal complex might play an important role in acquired equivalence associative learning. In this study, we tested the possibility that acquired equivalence learning is a sensitive marker of mild Alzheimer disease (AD). MethodsIn the associative learning test, antecedent stimuli were cartoon faces and consequent stimuli were different colored cartoon fishes. Each cartoon character had some pet fish and the task was to learn these face-fish associations using feedback provided after each decision. In the transfer phase, knowledge about face-fish pairs had to be generalized to new associations. ResultsAD patients exhibited mild impairments in the training phase, whereas they were profoundly impaired on the acquired equivalence test. Associative knowledge could not be transferred to a more flexible retrieval condition. ConclusionsThese results suggest that acquired equivalence learning is specifically impaired in early AD, which may indicate the pathology of the hippocampal complex.

Association between a Genetic Variant of the Alpha-7 Nicotinic Acetylcholine Receptor Subunit and Four Types of Dementia

We tested the hypothesis whether the partially duplicated variant of α7 nicotinic acetylcholine receptor subunit gene (CHRFAM7A) 2-bp deletion (–2 bp) polymorphism and apolipoprotein E (ApoE) ε4 allele confer susceptibility to Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), Pick’s disease (PiD) and vascular dementia (VD). The study included 175 AD, 35 DLB patients, 38 PiD, 96 VD and 175 healthy control (HC) probands. The CHRFAM7A genotype without the –2 bp allele was significantly over-represented in AD (p = 0.011), DLB (p = 0.001) and PiD (p < 0.0001) compared to HC, but there were no statistical differences in VD (p = 0.407) compared to HC. We confirmed again that the ApoE ε4 allele is a risk factor for dementias. The –2 bp polymorphism of CHRFAM7A can be implicated in AD, DLB and PiD. However, it is unlikely that it plays an important role in the pathogenesis of VD.

EEG network connectivity changes in mild cognitive impairment — Preliminary results

Resting state EEGs were compared between patients with amnestic subtype of mild cognitive impairment (aMCI) and matched elderly controls at two times over a one year period. The study aimed at investigating the role of functional connectivity between and within different brain regions in relation to the progression of cognitive deficit in MCI. The EEG was recorded in two sessions during eyes closed and eyes open resting conditions. Functional brain connectivity was investigated based on the measurement of phase synchronization in different frequency bands. Delta and theta synchronization characteristics indicated decreased level of local and large-scale connectivity in the patients within the frontal, between the frontal and temporal, and frontal and parietal brain areas which was more pronounced 1year later. As a consequence of opening the eyes connectivity in the alpha1 band within the parietal lobe decreased compared to the eyes closed condition but only in the control group. The lack of alpha1 band reactivity following eye opening could reliably differentiate patients from controls. Our preliminary results support the notion that the functional disconnection between distant brain areas is a characteristic feature of MCI, and may prove to be predictive in terms of the progression of this condition.

The Differentiation of Amnestic Type MCI from the Non-Amnestic Types by Structural MRI

Introduction: While amnestic mild cognitive impairment (aMCI) and non-amnestic mild cognitive impairment (naMCI) are theoretically different entities, only a few investigations studied the structural brain differences between these subtypes of mild cognitive impairment. The aim of the study was to find the structural differences between aMCI and naMCI, and to replicate previous findings on the differentiation between aMCI and healthy controls. Methods: Altogether 62 aMCI, naMCI, and healthy control subjects were included into the study based on the Petersen criteria. All patients underwent a routine brain MR examination, and a detailed neuropsychological examination. Results: The sizes of the hippocampus, the entorhinal cortex and the amygdala were decreased in aMCI relative to naMCI and to controls. Furthermore the cortical thickness of the entorhinal cortex, the fusiform gyrus, the precuneus and the isthmus of the cingulate gyrus were significantly decreased in aMCI relative to naMCI and healthy controls. The largest differences relative to controls were detected for the volume of the hippocampus (18% decrease vs. controls) and the cortical thickness (20% decrease vs. controls) of the entorhinal cortex: 1.6 and 1.4 in terms of Cohens d. Only the volume of the precuneus were decreased in the naMCI group (5% decrease) compared to the control subjects: 0.9 in terms of Cohens d. Significant between group differences were also found in the neuropsychological test results: a decreased anterograde, retrograde memory, and category fluency performance was detected in the aMCI group relative to controls and naMCI subjects. Subjects with naMCI showed decreased letter fluency relative to controls, while both MCI groups showed decreased executive functioning relative to controls as measured by the Trail Making test part B. Memory performance in the aMCI group and in the entire sample correlated with the thickness of the entorhinal cortex and with the volume of the amygdala. Conclusion: The amnestic mild cognitive impairment/non-amnestic mild cognitive impairment separation is not only theoretical but backed by structural imaging methods and neuropsychological tests. A better knowledge of the MCI subtypes can help to predict the direction of progression and create targeted prevention.

The nitric oxide synthase-3 codon 298 polymorphism is not associated with late-onset sporadic Alzheimer's dementia and Lewy body disease in a sample from Hungary.

An association study was performed between apolipoprotein E (apoE) polymorphism and the common structural polymorphism Glu/Asp at codon 298 of the nitric oxide synthase (NOS3) gene in late-onset sporadic Alzheimers dementia probands (LOAD), diffuse Lewy body dementia cases (DLBD) and controls in a Hungarian sample. The frequency of individuals who carried the apoE ϵ4 allele was significantly more common in both dementia groups (LOAD, 20%; DLBD, 27%; control, 8%; control versus DLBD, χ2=13.264, degrees of freedom=2, P<0.001; control versus LOAD, χ2=6.628, degrees of freedom=2, P<0.036). However, there were no significant differences in the NOS3 genotype and allele distributions between the LOAD, DLBD and control groups. The apoE status has been found to be independent from the NOS3 codon 298 polymorphism in the examined cohort. Despite the facts that NOS3 is associated with neuritic sprouting, and aberrant neuronal and glial expression of the same molecule has been found in neurodegenerative diseases, it is unlikely that the polymorphism Glu/Asp of the NOS3 gene is involved in the development of LOAD and DLBD.

What can DTI tell about early cognitive impairment? – Differentiation between MCI subtypes and healthy controls by diffusion tensor imaging

Mild cognitive impairment (MCI) gained a lot of interest recently, especially that the conversion rate to Alzheimer Disease (AD) in the amnestic subtype (aMCI) is higher than in the non-amnestic subtype (naMCI). We aimed to determine whether and how diffusion-weighted MRI (DWI) using the diffusion tensor model (DTI) can differentiate MCI subtypes from healthy subjects. High resolution 3D T1W and DWI images of patients (aMCI, n = 18; naMCI, n = 20; according to Petersen criteria) and controls (n = 27) were acquired at 3T and processed using ExploreDTI and SPM. Voxel-wise and region of interest (ROI) analyses of fractional anisotropy (FA) and mean diffusivity (MD) were performed with ANCOVA; MD was higher in aMCI compared to controls or naMCI in several grey and white matter (GM, WM) regions (especially in the temporal pole and the inferior temporal lobes), while FA was lower in WM ROI-s (e.g. left Cingulum). Moreover, significant correlations were identified between verbal fluency, visual and verbal memory performance and DTI metrics. Logistic regression showed that measuring FA of the crus of fornix along GM volumetry improves the discrimination of aMCI from naMCI. Additional information from DWI/DTI aids preclinical detection of AD and may help detecting early non-Alzheimer type dementia, too.

Decreased Event-Related Beta Synchronization During Memory Maintenance Marks Early Cognitive Decline in Mild Cognitive Impairment

Mild cognitive impairment (MCI) refers to a measurable deficit in cognition in the absence of dementia or impairment in activities of daily living. Working memory impairment is among the earliest signs of MCI. Oscillatory analysis of working memory might be a potential tool for identifying patients at increased risk of developing dementia. Our study aimed to assess the temporospatial pattern of spectral differences during working memory maintenance between MCI patients and healthy controls and to compare the sources of oscillatory activity between the two groups. Event-related spectral perturbation of 17 MCI patients and 21 healthy control participants was studied with 128-channel EEG during the Sternberg working memory task. Source localization was performed by using the eLORETA software. Among the participants, 13 MCI and 15 control participants underwent a structural brain MRI examination. Event-related synchronization (ERS) in the alpha and beta frequency band was significantly lower in MCI patients compared to healthy control participants during retention. Both study groups showed significant memory load-related enhancement in both frequency band. In the MCI group, source localization revealed significantly attenuated beta oscillatory activity in the inferior and middle temporal gyrus, in the fusiform gyrus, and in the cuneus. Beta ERS correlated significantly with the size of the hippocampus, entorhinal cortex, and parahippocampal gyrus. During the retention period, MCI is characterized by decreased alpha and beta ERS compared to controls indicating early impairment in neural networks serving working memory maintenance. The assessment of electrophysiological changes in the beta frequency range may provide a useful diagnostic tool for the early detection of cognitive impairment.

[Diabetes mellitus and Alzheimer's disease].

The incidence of Alzheimers disease and diabetes is increasing with age. Thus, in light of demographic change and aging societies, they are becoming a growing issue for public health. Further, there are linkages between the two diseases. In particular, risk assessment studies suggest that type 2 diabetes mellitus is a risk factor of Alzheimers disease. Hence, even though Alzheimers disease can only be influenced to a limited extent, optimal treatment of diabetes mellitus may have also a positive effect on Alzheimers disease. While the relationship between the two diseases is not yet completely clear, in addition to the known vascular effects of diabetes mellitus recent results shed light on central nervous system effects directly influencing the neurodegenerative process. Treatment of central insulin resistance, a phenomenon explored in recent years, may be a promising avenue, not only in addressing metabolic disorder, but also Alzheimers disease.