Agnès Michon

Working memory load-related electroencephalographic parameters can differentiate progressive from stable mild cognitive impairment

Recent studies described several changes of endogenous event-related potentials (ERP) and brain rhythm synchronization during memory activation in patients with Alzheimers disease (AD). To examine whether memory-related EEG parameters may predict cognitive decline in mild cognitive impairment (MCI), we assessed P200 and N200 latencies as well as beta event-related synchronization (ERS) in 16 elderly controls (EC), 29 MCI cases and 10 patients with AD during the successful performance of a pure attentional detection task as compared with a highly working memory demanding two-back task. At 1 year follow-up, 16 MCI patients showed progressive cognitive decline (PMCI) and 13 remained stable (SMCI). Both P200 and N200 latencies in the two-back task were longer in PMCI and AD cases compared with EC and SMCI cases. During the interval 1000 ms to 1700 ms after stimulus, beta ERS at parietal electrodes was of lower amplitude in PMCI and AD compared with EC and SMCI cases. Univariate models showed that P200, N200 and log% beta values were significantly related to the SMCI/PMCI distinction with areas under the receiver operating characteristic curve of 0.93, 0.78 and 0.72, respectively. The combination of all three EEG hallmarks was the stronger predictor of MCI deterioration with 90% of correctly classified MCI cases. Our data reveal that PMCI and clinically overt AD share the same pattern of working memory-related EEG activation characterized by increased P200-N200 latencies and decreased beta ERS. They also show that P200 latency during the two-back task may be a simple and promising EEG marker of rapid cognitive decline in MCI.

Decreased Theta Event-Related Synchronization during Working Memory Activation Is Associated with Progressive Mild Cognitive Impairment

Background: Among the different quantitative electroencephalographic markers, theta activity is known to reflect neural resources involved in memory processes and directed attention. Previous studies suggested that synchronization likelihood analysis in theta-band frequency might be a sensitive method to identify early alterations of neuronal networks in mild cognitive impairment (MCI). Methods: We report here a longitudinal study of 24 MCI patients with theta event-related synchronization (ERS) analysis during the n-back working memory task and neuropsychological follow-up after 1 year. Statistical analysis included analysis of variance and logistic regression to assess the relationship between cognitive decline and theta ERS. Results: Upon follow-up, 13 MCI patients showed progressive MCI and 11 remained stable. In both groups, the phasic increase in theta amplitude after stimulus presentation did not depend on working memory load and electrode sites. Progressive MCI cases displayed significantly lower theta ERS power over all electrode sites compared to stable MCI cases. Theta ERS was significantly related to the cognitive outcome explaining 15.5% of its variability. In terms of MCI classification, the best combination of sensitivity and specificity was 0.87 and 0.60, respectively, with an area under the corresponding receiver operating characteristic curve reaching 76%. Conclusions: The present data indicate that a decrease in the early phasic theta ERS power during working memory activation may predict cognitive decline in MCI. This phenomenon is not related to working memory load but may reflect the presence of early deficits in directed attention-related neural circuits in MCI.

Psychometric properties of the Doloplus-2 observational pain assessment scale and comparison to self-assessment in hospitalized elderly.

ObjectivesSelf-report is the “gold standard” for pain assessment, however, observational pain scales, such as Doloplus-2 must be used for patients who cannot communicate. In this follow-up study, we report the psychometric properties of the observational Doloplus-2 scale using the visual analog scale (VAS) pain score as a gold standard and evaluate its performance. MethodProspective clinical study of 180 hospitalized older patients who demonstrated good comprehension and reliable use of the VAS: 131 participants with dementia and 49 without. All participants assessed their chronic pain using the VAS. Doloplus-2 was independently completed by the nursing team. ResultsMean age of patients (133 women, 47 men) was 83.7±6.5. Median mini-mental state examination of patients with diagnosis of dementia was 18.0±7.7. Nearly half of the patients (49%) reported that they experienced pain in response to a direct question. The administration of Doloplus-2 was possible in all 180 patients. Doloplus-2 correlated moderately with self-assessment (Spearman coefficient: 0.46). In a multiple regression model, Doloplus-2 predicted 41% of the variability in pain intensity measured by VAS. The somatic dimension alone explained 36% of the variance, the psychosocial bloc 5% with no better contribution of the psychomotor bloc. To shorten Doloplus-2, we constructed a version with only the 5 items that were significantly associated with the VAS score in the multiple regression models. DiscussionThe observational Doloplus-2 scale correlates moderately with self-assessment pain score and has adequate internal consistency. Our data also suggest that Doloplus-2 could be substantially shortened as the brief version performed similarly to the complete Doloplus-2.

A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease

Studying rare extreme forms of Alzheimer disease (AD) may prove to be a useful strategy in identifying new genes involved in monogenic determinism of AD. Amyloid precursor protein (APP), PSEN1, and PSEN2 mutations account for only 85% of autosomal dominant early-onset AD (ADEOAD) families. We hypothesised that rare copy number variants (CNVs) could be involved in ADEOAD families without mutations in known genes, as well as in rare sporadic young-onset AD cases. Using high-resolution array comparative genomic hybridisation, we assessed the presence of rare CNVs in 21 unrelated ADEOAD cases, having no alteration on known genes, and 12 sporadic AD cases, with an age of onset younger than 55 years. The analysis revealed the presence of 7 singleton CNVs (4 in ADEOAD and 3 in sporadic cases) absent in 1078 controls and 912 late-onset AD cases. Strikingly, 4 out of 7 rearrangements target genes (KLK6, SLC30A3, MEOX2, and FPR2) encoding proteins that are tightly related to amyloid-β peptide metabolism or signalling. Although these variants are individually rare and restricted to particular subgroups of patients, these findings support the causal role, in human pathology, of a set of genes coding for molecules suspected for a long time to modify Aβ metabolism or signalling, and for which animal or cellular models have already been developed.

Specific BACE1 genotypes provide additional risk for late‐onset alzheimer disease in APOE ε4 carriers

Alzheimer disease (AD) is characterized neuropathologically by neurofibrillary tangles and senile plaques. A key component of plaques is Aβ, a polypeptide derived from Aβ‐precursor protein (APP) through proteolytic cleavage catalyzed by β and γ‐secretase. We hypothesized that sequence variation in genes BACE1 (on chromosome 11q23.3) and BACE2 (on chromosome 21q22.3), which encode two closely related proteases that seem to act as the APP β‐secretase, may represent a genetic risk factor for AD. We analyzed the frequencies of single nucleotide polymorphisms (SNPs) in BACE1 and BACE2 genes in a community‐based sample of 96 individuals with late‐onset AD and 170 controls selected randomly among residents of the same community. The genotype data in both study groups did not demonstrate any association between AD and BACE1 or BACE2. After stratification for APOE status, however, an association between a BACE1 polymorphism located within codon V262 and AD in APOE ε4 carriers was observed (P = 0.03). We conclude that sequence variation in the BACE1 or BACE 2 gene is not a significant risk factor for AD; however, a combination of a specific BACE1 allele and APOE ε4 may increase the risk for Alzheimer disease over and above that attributed to APOE ε4 alone.

Electrophysiological Markers of Rapid Cognitive Decline in Mild Cognitive Impairment

Electroencephalography (EEG) is an easily accessible and low-cost modality that might prove to be a particularly powerful tool for the identification of subtle functional changes preceding structural or metabolic deficits in progressive mild cognitive impairment (PMCI). Most previous contributions in this field assessed quantitative EEG differences between healthy controls, MCI and Alzheimers disease(AD) cases leading to contradictory data. In terms of MCI conversion to AD, certain longitudinal studies proposed various quantitative EEG parameters for an a priori distinction between PMCI and stable MCI. However, cross-sectional comparisons revealed a substantial overlap in these parameters between MCI patients and elderly controls. Methodological differences including variable clinical definition of MCI cases and substantial interindividual differences within the MCI group could partly explain these discrepancies. Most importantly, EEG measurements without cognitive demand in both cross-sectional and longitudinal designs have demonstrated limited sensitivity and generally do not produce significant group differences in spectral EEG parameters. Since the evolution of AD is characterized by the progressive loss of functional connectivity within neocortical association areas, event-modulated EEG dynamic analysis which makes it possible to investigate the functional activation of neocortical circuits may represent a more sensitive method to identify early alterations of neuronal networks predictive of AD development among MCI cases. The present review summarizes clinically significant results of EEG activation studies in this field and discusses future perspectives of research aiming to reach an early and individual prediction of cognitive decline in healthy elderly controls.

Metabolic correlates of behavioral and affective disturbances in frontal lobe pathologies

Abstract.Objective: Although previous studies have shown that the human frontal cortex is involved in the experience of emotions as well as in social behavior, data regarding the exact anatomical substrates of behavioral and affective deficits in frontal lobe pathologies are still scarce. The aim of this study was to investigate the metabolic correlates of these deficits in a group of non-selected consecutive patients with frontal lobe lesions. Patients and Methods: Clinicometabolic correlations between several emotional and social parameters and metabolic patterns in the frontal cortex and amygdala were investigated in 32 patients with frontal lobe pathologies. The behavioral disturbances were evaluated using the Lhermitte’s informant questionnaire. Regional cerebral glucose metabolism was measured with [18F] fluorodeoxyglucose and high-resolution positron emission tomography. Statistical analysis was performed using both single variable correlation and multiple regression analyses. Results: Both single variable and multivariate analyses demonstrate that decreased regional glucose metabolism in the right medial area 10 was associated with apathy. There were also significant negative relationships between metabolism in the right orbitofrontal cortex and stereotypy and indifference to rules. Impulsiveness, personality disturbances and loss of emotional control were associated with decreased metabolism in the left amygdala. Conclusions: In terms of clinicometabolic correlations, the present data support the implication of different functional anatomic systems in frontal lobe-related behavioral and affective disturbances. In particular, they imply that the classically described symptoms of impaired behavioral control may be related to right orbitofrontal cortex hypometabolism whereas impaired regulation of emotions may result from a functional damage of the left amygdala.

Neuropathological analysis of an adult case of the Cornelia de Lange syndrome

Abstract. Cornelia de Lange syndrome (CDLS) is a rare multisystemic malformative syndrome of uncertain etiology characterized by severe psychomotor and mental retardation. Here we report the neuropathological analysis of a 35-year-old patient who displayed the classical clinical symptomatology of CDLS. A congenital dysgenesis of the brain was evident including abnormal convolution patterns of the cerebral gyri, frontal lobe hypoplasia and focal lack of myelination in layers V and VI of the left temporal cortex. In addition, there were vascular scars in the CA2–3 region of the left hippocampus and in the right parietal cortex as well as a few neurofibrillary tangles in the CA fields of the hippocampus and in the entorhinal cortex. In contrast to previous reports, there were no midline cerebral dysgenesis and no ectopic neuron formations in the present case. Neuronal loss and gliosis were also absent in all cortical and subcortical areas. Our observations suggest that the main neurodevelopmental deficits in CDLS occur during the late phase of gestation. Conversely, early neurodegenerative changes are not characteristic of CDLS. In the light of previous studies in younger CDLS patients, the vascular and degenerative lesions observed in the present case may be secondary to his severe congenital heart abnormalities and self-injury behavior, respectively.

Population pharmacokinetic approach to evaluate the effect of CYP2D6, CYP3A, ABCB1, POR and NR1I2 genotypes on donepezil clearance

AIMS A large interindividual variability in plasma concentrations has been reported in patients treated with donepezil, the most frequently prescribed antidementia drug. We aimed to evaluate clinical and genetic factors influencing donepezil disposition in a patient population recruited from a naturalistic setting. METHODS A population pharmacokinetic study was performed including data from 129 older patients treated with donepezil. The patients were genotyped for common polymorphisms in the metabolic enzymes CYP2D6 and CYP3A, in the electron transferring protein POR and the nuclear factor NR1I2 involved in CYP activity and expression, and in the drug transporter ABCB1. RESULTS The average donepezil clearance was 7.3 l h(-1) with a 30% interindividual variability. Gender markedly influenced donepezil clearance (P < 0.01). Functional alleles of CYP2D6 were identified as unique significant genetic covariate for donepezil clearance (P < 0.01), with poor metabolizers and ultrarapid metabolizers demonstrating, respectively, a 32% slower and a 67% faster donepezil elimination compared with extensive metabolizers. CONCLUSION The pharmacokinetic parameters of donepezil were well described by the developed population model. Functional alleles of CYP2D6 significantly contributed to the variability in donepezil disposition in the patient population and should be further investigated in the context of individual dose optimization to improve clinical outcome and tolerability of the treatment.

Dynamic process of family burden in dementia caregiving: a new field for psychotherapeutic interventions

Families caring for a patient with dementia are prone to significant physical, psychological and social stress. It is now well established that the caregiver burden does not only negatively affect the caregivers physical and mental health, but is also associated with an increase in behavioural and psychiatric symptoms of dementia. Burden determinants include the quality of the relationship between the patient and caregiver; patient variables, such as the need to manage the behavioural and psychological symptoms of dementia; and also caregiver variables, such as the satisfaction of caring, demographic characteristics and societal roles. The standardised assessment of interventions for caregivers in dementia care remains a difficult task. In recent years, family interventions that focus on the process of burden itself in relation to the caregivers subjective experience of personal growth and enrichment have been proposed. This new approach is based on the identification of tasks and challenges faced by family members throughout the different stages of the disease. In this context, brief crisis interventions transform periods of disorganisation experienced by the family into opportunities for change, whereas rehabilitation interventions developed by professional caring networks offer a continuous assessment and advice to the family. This article provides a critical review of the consequences and determinants of caregiver burden in dementia care with special reference to the emerging notion of the caregivers subjective experience in the context of family processes.