Comparison of Neuropsychological Assessment by Videoconference and Face to Face.

OBJECTIVE: To compare the administration of neuropsychological tests by teleneuropsychology (TeleNP) and face to face (F-F) in order to determine the feasibility and reliability of TeleNP. METHOD: At the inclusion visit, all participants underwent a traditional F-F neuropsychological assessment as part of their standard care. Four months after inclusion, they were randomized to undergo an additional neuropsychological assessment either by F-F administration or by TeleNP. RESULTS: A total of 150 adults with cognitive complaints, but with no major cognitive or sensorial impairment were included. At 4 months, 69 participants were randomized in the F-F arm and 71 in TeleNP arm (10 lost in the follow-up). The overall satisfaction was high: 87.1% in the TeleNP arm were "very satisfied", and 82.9% indicated no preference between F-F and TeleNP. In agreement with previous data from the literature, neuropsychological assessments gave similar results across both administration conditions for a large majority of tests [Mini-Mental State Examination (MMSE), Free and Cued Selective Reminding Test (FCSRT) French version, Mahieux gestural praxis battery, Frontal Assessment Battery (FAB), time of completion of the Trail making Test (TMT) A and B, number of errors of the TMT B, Rey complex figure test, categorical et phonological verbal fluency tests] and minor differences for others [80-picture naming test (DO-80), FAB, Digit Span forward and backward and number of errors in the TMT A]. CONCLUSIONS: TeleNP is a promising method to be able to test patients as an alternative to F-F condition. Before this procedure can be generalized, it is now necessary to standardize the adaptation of certain tests and to test them in populations with more significant cognitive disorders.

Atrophy, metabolism and cognition in the posterior cortical atrophy spectrum based on Alzheimer's disease cerebrospinal fluid biomarkers.

INTRODUCTION: In vivo clinical, anatomical and metabolic differences between posterior cortical atrophy (PCA) patients presenting with different Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers profiles are still unknown. METHODS: Twenty-seven PCA patients underwent CSF examination and were classified as 1) PCA with a typical CSF AD profile (PCA-tAD; abnormal amyloid and T-tau/P-tau biomarkers, n = 13); 2) PCA with an atypical AD CSF profile (PCA-aAD; abnormal amyloid biomarker only, n = 9); and 3) PCA not associated with AD (PCA-nonAD; normal biomarkers, n = 5). All patients underwent clinical and cognitive assessment, structural MRI, and a subset of them underwent brain 18F-FDG PET. RESULTS: All patients' groups showed a common pattern of posterior GM atrophy and hypometabolism typical of PCA, as well as equivalent demographics and clinical/cognitive profiles. PCA-tAD patients showed a group-specific pattern of hypometabolism in the left fusiform gyrus and inferior temporal gyrus. PCA-aAD did not present a group-specific atrophy pattern. Finally, group-specific gray matter atrophy in the right dorsolateral prefrontal cortex, left caudate nucleus and right medial temporal regions and hypometabolism in the right supplementary motor area and paracentral lobule were observed in PCA-nonAD patients. CONCLUSION: Our findings suggest that both PCA-tAD and PCA-aAD patients are on the AD continuum, in agreement with the recently suggested A/T/N model. Furthermore, in PCA, the underlying pathology has an impact at least on the anatomo-functional presentation. Brain damage observed in PCA-tAD and PCA-aAD was mostly consistent with the well-described presentation of the disease, although it was more widespread in PCA-tAD group, especially in the left temporal lobe. Additional fronto-temporal (especially dorsolateral prefrontal) damage seems to be a clue to underlying non-AD pathology in PCA, which warrants the need for longitudinal follow-ups to investigate frontal symptoms in these patients.

Free and Cued Selective Reminding Test - accuracy for the differential diagnosis of Alzheimer's and neurodegenerative diseases: A large-scale biomarker-characterized monocenter cohort study (ClinAD).

INTRODUCTION: The International Working Group recommended the Free and Cued Selective Reminding Test (FCSRT) as a sensitive detector of the amnesic syndrome of the hippocampal type in typical Alzheimer's disease (AD). But does it differentiate AD from other neurodegenerative diseases? METHODS: We assessed the FCSRT and cerebrospinal fluid (CSF) AD biomarkers in 992 cases. Experts, blinded to biomarker data, attributed in 650 cases a diagnosis of typical AD, frontotemporal dementia, posterior cortical atrophy, Lewy body disease, progressive supranuclear palsy, corticobasal syndrome, primary progressive aphasias, "subjective cognitive decline," or depression. RESULTS: The FCSRT distinguished typical AD from all other conditions with a sensitivity of 100% and a specificity of 75%. Non-AD neurodegenerative diseases with positive AD CSF biomarkers ("atypical AD") did not have lower FCSRT scores than those with negative biomarkers. DISCUSSION: The FCSRT is a reliable tool for diagnosing typical AD among various neurodegenerative diseases. At an individual level, however, its specificity is not absolute. Our findings also widen the spectrum of atypical AD to multiple neurodegenerative conditions.

Cognitive dissonance resolution depends on episodic memory.

The notion that past choices affect preferences is one of the most influential concepts of social psychology since its first report in the 50 s, and its theorization within the cognitive dissonance framework. In the free-choice paradigm (FCP) after choosing between two similarly rated items, subjects reevaluate chosen items as more attractive and rejected items as less attractive. However the relations prevailing between episodic memory and choice-induced preference change (CIPC) remain highly debated: is this phenomenon dependent or independent from memory of past choices? We solve this theoretical debate by demonstrating that CIPC occurs exclusively for items which were correctly remembered as chosen or rejected during the choice stage. We used a combination of fMRI and intra-cranial electrophysiological recordings to reveal a modulation of left hippocampus activity, a hub of episodic memory retrieval, immediately before the occurrence of CIPC during item reevaluation. Finally, we show that contrarily to a previous influential report flawed by a statistical artifact, this phenomenon is absent in amnesic patients for forgotten items. These results demonstrate the dependence of cognitive dissonance on conscious episodic memory. This link between current preferences and previous choices suggests a homeostatic function of this regulative process, aiming at preserving subjective coherence.

Functional Connectivity of Ventral and Dorsal Visual Streams in Posterior Cortical Atrophy.

BACKGROUND: Posterior cortical atrophy (PCA) induces progressive dysfunction of ventral and dorsal visual networks. Little is known, however, about corresponding changes in functional connectivity (FC). OBJECTIVES: To investigate FC changes in the visual networks, their relationship with cortical atrophy, and the association with Alzheimer's disease (AD) pathology. METHODS: Ten PCA patients and 28 age-matched controls participated in the study. Using resting state fMRI, we measured FC in ventral and dorsal cortical visual networks, defined on the basis of a priori knowledge of long-range white matter connections. To assess the relationships with AD, we determined AD biomarkers in cerebrospinal fluid and FC in the default mode network (DMN), which is vulnerable to AD pathology. Voxel-based morphometry analysis assessed the pattern of grey matter (GM) atrophy. RESULTS: PCA patients showed GM atrophy in bilateral occipital and inferior parietal regions. PCA patients had lower FC levels in a ventral network than controls, but higher FC in inferior components of the dorsal network. In particular, the increased connectivity correlated with greater GM atrophy in occipital regions. All PCA patients had positive cerebrospinal fluid biomarkers for AD; however, FC in global DMN did not differ from controls. CONCLUSIONS: FC in PCA reflects brain structure in a non-univocal way. Hyperconnectivity of dorsal networks may indicate aberrant communication in response to posterior brain atrophy or processes of neural resilience during the initial stage of brain dysfunction. The lack of difference from controls in global DMN FC highlights the atypical nature of PCA with respect to typical AD.

Partial deletions of the GRN gene are a cause of frontotemporal lobar degeneration.

Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD). Most known GRN mutations are null mutations, such as nonsense and frameshift mutations, which create a premature stop codon resulting in loss of function of the progranulin protein. Complete or near-complete genomic GRN deletions have also been found in three families, but heterozygous partial deletions that remove only one or two exons have not been reported to date. In this study, we analysed three unrelated FTLD patients with low plasma progranulin levels but no point GRN mutations by multiplex ligation-dependent probe amplification (MLPA) and quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF). We detected two heterozygous partial GRN deletions in two patients. One deletion removed exon 1 and part of intron 1. The second deletion was complex: it removed 1,410 bp extending from the part of intron 1 to the part of exon 3, with a small 5-bp insertion at the breakpoint junction (c.-7-1121_159delinsGATCA). Our findings illustrate the usefulness of a quantitative analysis in addition to GRN gene sequencing for a comprehensive genetic diagnosis of FTLD, particularly in patients with low plasma progranulin levels.

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.

Population pharmacokinetic study of memantine: effects of clinical and genetic factors.

BACKGROUND AND OBJECTIVE: Memantine, a frequently prescribed anti-dementia drug, is mainly eliminated unchanged by the kidneys, partly via tubular secretion. Considerable inter-individual variability in plasma concentrations has been reported. We aimed to investigate clinical and genetic factors influencing memantine disposition. METHODS: A population pharmacokinetic study was performed including data from 108 patients recruited in a naturalistic setting. Patients were genotyped for common polymorphisms in renal cation transporters (SLC22A1/2/5, SLC47A1, ABCB1) and nuclear receptors (NR1I2, NR1I3, RXR, PPAR) involved in transporter expression. RESULTS: The average clearance was 5.2 L/h with a 27 % inter-individual variability (percentage coefficient of variation). Glomerular filtration rate (p = 0.007) and sex (p = 0.001) markedly influenced memantine clearance. NR1I2 rs1523130 was identified as the unique significant genetic covariate for memantine clearance (p = 0.006), with carriers of the NR1I2 rs1523130 CT/TT genotypes presenting a 16 % slower memantine elimination than carriers of the CC genotype. CONCLUSION: The better understanding of inter-individual variability of memantine disposition might be beneficial in the context of individual dose optimization.

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-ß 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 Aß metabolism or signalling, and for which animal or cellular models have already been developed.

Early disturbances of gamma band dynamics in mild cognitive impairment.

Recent studies have indicated that gamma band oscillations participate in the temporal binding needed for the synchronization of cortical networks involved in short-term memory and attentional processes. To date, no study has explored the temporal dynamics of gamma band in the early stages of dementia. At baseline, gamma band analysis was performed in 29 cases with mild cognitive impairment (MCI) during the n-back task. Based on phase diagrams, multiple linear regression models were built to explore the relationship between the cognitive status and gamma oscillation changes over time. Individual measures of phase diagram complexity were made using fractal dimension values. After 1 year, all cases were assessed neuropsychologically using the same battery. A total of 16 MCI patients showed progressive cognitive decline (PMCI) and 13 remained stable (SMCI). When adjusted for gamma values at lag -2, and -3 ms, PMCI cases displayed significantly lower average changes in gamma values than SMCI cases both in detection and 2-back tasks. Gamma fractal dimension of PMCI cases displayed significantly higher gamma fractal dimension values compared to SMCI cases. This variable explained 11.8% of the cognitive variability in this series. Our data indicate that the progression of cognitive decline in MCI is associated with early deficits in temporal binding that occur during the activation of selective attention processes.

The concept of mild cognitive impairment: relevance and limits in clinical practice.

Subtle cognitive impairments without dementia are common in the elderly population and numerous nosological entities have been proposed for their classification. The concept of mild cognitive impairment has become increasingly popular both in clinical practice and in research. It has been developed to describe a transitional zone between the cognitive changes of normal aging and early Alzheimer's disease or other forms of dementia. Its interest lies mainly in early identification of individuals who might be at risk of developing rapid cognitive decline. But the further one tends towards the early detection, the greater is the risk to lose in specificity. A number of other factors such as depression, metabolic or nutritional disorders, medication use, may cause cognitive dysfunctions and are reversible. The concept of mild cognitive impairment arouses a debate about its heterogeneity,limits, and relevance in clinical practice and research.

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 Alzheimer's 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.

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

OBJECTIVES: Self-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. METHOD: Prospective 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. RESULTS: Mean 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. DISCUSSION: The 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.

Structured assessment of mental health status in psychogeriatrics: validity of the French HoNOS65+.

OBJECTIVE: To assess the reliability, validity, and feasibility of a French version of the Health of the Nation Outcome Scales for Elderly People (HoNOS65+). METHOD: Twenty mental health professionals completed the scale for 126 elderly patients. We assessed interrater reliability in inpatient and outpatient settings, together with construct and discriminant validity, as well as concurrent validity compared with several widely used clinical instruments. RESULTS: Excellent agreement among raters was observed in the outpatient subgroup (kappa range 0.77 to 1.00), whereas interrater reliability was modest in the inpatient subgroup (kappa values < 0.55). In cases where the patient-caregiver relationship lasted more than 1 month, the reliability of the scale improved. Construct validity analysis revealed no subscale structure. All items except "self-injury" displayed high concurrent validity (significant Spearman correlations with 8 other questionnaires). In terms of discriminant validity, the "cognitive impairment" (area under the curve [AUC] 0.91) and "depressive symptoms" (AUC 0.79) items showed high sensitivity and specificity values. CONCLUSION: Our results indicate that the French version of HoNOS65+ is a promising clinical assessment tool to evaluate mental disorders in the elderly in outpatient settings. We support its use in routine clinical practice, with the condition that a relatively long and individualized patient-caregiver relationship has been established.

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.

Pain in severe dementia: self-assessment or observational scales?

OBJECTIVES: To assess the performance of self-assessment scales in severely demented hospitalized patients and to compare it with observational data. DESIGN: Prospective clinical study. SETTING: Geriatrics hospital and a geriatric psychiatry service. PARTICIPANTS: All patients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for dementia, with a Mini-Mental State Examination score less than 11 and a Clinical Dementia Rating score of 3. MEASUREMENTS: Three self-assessment tools--the verbal, horizontal visual, and faces pain scales--were administered in randomized order. A nursing team independently completed an observational pain rating scale. Main outcomes were comprehension (ability to explain scale use and correctly indicate positions for no pain and extreme pain, on two separate occasions), inter- and intrarater reliability, and comparison of pain intensities measured by the different scales. RESULTS: Sixty-one percent of 129 severely demented patients (mean age 83.7, 69% women) demonstrated comprehension of at least one scale. Comprehension rates were significantly better for the verbal and the faces pain scales. For patients who demonstrated good comprehension, the inter- and intrarater reliability of the three self-assessment scales was high (intraclass correlation coefficient=0.88-0.98). Correlation between the three self-assessment scales was moderate to strong (Spearman correlation coefficient (r)=0.45-0.94; P<.001). Observational rating correlated at least moderately with self-assessment (r=0.25-0.63), although for patients reporting pain, the observational rating scale underestimated severity compared with all three self-assessment scales. CONCLUSION: Clinicians should not apply observational scales routinely in severely demented patients, because many are capable of reliably reporting their own pain.

[Crisis intervention in dementia]. / La gestion de la crise dans la démence.

A crisis is an episode of acute disorganization with apparition of symptoms, leading the individual and his relatives to have recourse to the health system in emergency. It refers to a period of intra-psychic or interpersonal balance discontinuity. The management of the crisis, as it was proposed in psychiatric models since the seventies, aims not only to provide a psychological and immediate answer but also to use this crucial moment as an opportunity of change. Based on our experience in an acute care unit for demented patients, we discuss how the concept of crisis can be applied in psychiatric care of demented patients.

Early event-related potential changes during working memory activation predict rapid decline in mild cognitive impairment.

BACKGROUND: The conversion of mild cognitive impairment (MCI) to Alzheimer's disease is associated with substantial compromise of neocortical circuits subserving rapid cognitive functions such as working memory. Event-related potential (ERP) analysis is a powerful tool to identify early impairment of these circuits, yet research for an electrophysiological marker of cognitive deterioration in MCI is scarce. Using a "2-back" activation paradigm, we recently described an electrophysiological correlate of working memory activation (positive-negative working memory [PN(wm)] component) over parietal electrodes. METHODS: Ours was a longitudinal study of 24 MCI patients with ERP analysis at inclusion and neuropsychological follow-up after 1 year. We used ERP waveform subtraction analysis between the n-back and control tasks. Analysis of variance (ANOVA) was used to compare electroencephalograph latencies between progressive MCI (PMCI) and stable MCI (SMCI), and univariate regression was used to assess the relationship between neuropsychological measures at baseline and clinical outcome. RESULTS: Thirteen (54%) MCI patients showed PMCI, and 11 (46%) remained stable (SMCI). In SMCI, a PN(wm) component with significantly larger density compared to baseline was identified when subtracting the detection task for both the 1- and 2-back tasks. In contrast, in PMCI, the PN(wm) component was absent in both 1-back and 2-back conditions. Neuropsychological variables and n-back test performance at inclusion did not predict cognitive deterioration 1 year later. CONCLUSIONS: In conjunction with recent functional imaging data, the present results support the notion of an early dysfunction of neural generators within the parietal cortex in MCI. They also reveal that the absence of the PN(wm) component may provide an easily applicable qualitative predictive marker of rapid cognitive deterioration in MCI.