The pattern of cortical thickness associated with executive dysfunction in MCI and SCC: The MEMENTO cohort.

BACKGROUND: The association between the pattern of cortical thickness (CT) and executive dysfunction (ED) in mild cognitive impairment (MCI) and subjective cognitive complaints (SCC) is still poorly understood. We aimed to investigate the association between CT and ED in a large French cohort (MEMENTO) of 2323 participants with MCI or SCC. METHODS: All participants with available CT and executive function data (verbal fluency and Trail Making Test [TMT]) were selected (n=1924). Linear regressions were performed to determine relationships between executive performance and the brain parenchymal fraction (BPF) and CT using FreeSurfer. RESULTS: The global executive function score was related to the BPF (sß: 0.091, P<0.001) and CT in the right supramarginal (sß: 0.060, P=0.041) and right isthmus cingulate (sß: 0.062, P=0.011) regions. Literal verbal fluency was related to the BPF (sß: 0.125, P<0.001) and CT in the left parsorbitalis region (sß: 0.045, P=0.045). Semantic verbal fluency was related to the BPF (sß: 0.101, P<0.001) and CT in the right supramarginal region (sß: 0.061, P=0.042). The time difference between the TMT parts B and A was related to the BPF (sß: 0.048, P=0.045) and CT in the right precuneus (sß: 0.073, P=0.019) and right isthmus cingulate region (sß: 0.054, P=0.032). CONCLUSIONS: In a large clinically based cohort of participants presenting with either MCI or SCC (a potential early stage of Alzheimer's disease [AD]), ED was related to the BPF and CT in the left pars orbitalis, right precuneus, right supramarginal, and right isthmus cingulate regions. This pattern of lesions adds knowledge to the conventional anatomy of ED and could contribute to the early diagnosis of AD.

The RAPID-II Neuropsychological Test battery for subjects aged 20 to 49 years: Norms and cognitive profile.

INTRODUCTION: Cognitive evaluation of young subjects is now widely carried out for non-traumatic diseases such as multiple sclerosis, HIV, or sleep disorders. This evaluation requires normative data based on healthy adult samples. However, most clinicians use a set of tests that were normed in an isolated manner from different samples using different cutoff criteria. Thus, the score of an individual may be considered either normal or impaired according to the norms used. It is well established that healthy adults obtained low-test scores when a battery of tests is administered. Thus, the knowledge of low base rates is required so as to minimize false diagnosis of cognitive impairment. The aim of this study was twofold (1) to provide normative data for RAPID-II battery in healthy adults, and (2) estimate the proportion of healthy adults having low scores across this battery. METHODS: Norms for the 44 test scores of the RAPID-II test battery were developed using the overall sample of 335 individuals based on three categories of age (20 to 29, 30 to 39, and 40 to 49 years) and two educational levels: Baccalaureate or higher educational degree (high educational level), lower than baccalaureate (low educational level). The 5th, 25th, 50th, and 75th percentiles were calculated from the six age and education subsamples and used to define norms. The frequency of low scores on the RAPID-II battery was calculated by simultaneously examining the performance of 33 primary scores. A low score was defined as less than or equal to the 5th percentile drawn from the six age and education normative subsamples. In addition, the percentages of low scores were also determined when all possible combinations of two-test scores across the RAPID-II were considered in the overall normative sample. RESULTS: Our data showed that 59.4% subjects of the normative sample obtained at least one or more low score. With more than 9 test scores, this percentage was equal to 0% in the normative sample. Among all combinations of two-test scores, 96% had a false positive rate<2%. CONCLUSION: Low scores are very common in young healthy subjects and are more obvious when simultaneously analyzing test scores across a battery of tests and are thus not necessarily indicative of cognitive impairment. The combinations of two-test scores can be a useful tool to improve the interpretation of low scores.

Slowing of information processing speed without motor slowing in multiple sclerosis observed during two crossing-off tasks.

INTRODUCTION: Slowing of information processing speed (IPS) is often considered one of the primary deficits seen in multiple sclerosis (MS). IPS is usually measured by tasks that involve many cognitive functions. The aim of this study was to determine whether similar IPS slowing can also be observed during two simple, timed, psychomotor crossing-off tasks. METHOD: The Crossing-Off Test (COT), a simple psychomotor task, was performed under two conditions (COT1 corresponded to writing habits, COT2 used horizontal sweeping) in 25 relapsing-remitting MS patients (EDSS 0-1) and 25 healthy controls. RESULTS: The MS group compared with the control group was impaired on COT1 (P=0.0043) and not on COT2 (P=0.4), and the COT1 performance of MS patients with EDSS 1 was more impaired than those of patients with EDSS 0 (P=0.008). DISCUSSION/CONCLUSION: These results indicate that only some of the IPS cognitive subcomponents linked with COT1 tasks are initially involved in the slowing of IPS during MS, suggesting that different mechanisms are involved in each tested version of the COT.

Mast cells' involvement in inflammation pathways linked to depression: evidence in mastocytosis.

Converging sources of evidence point to a role for inflammation in the development of depression, fatigue and cognitive dysfunction. More precisely, the tryptophan (TRP) catabolism is thought to play a major role in inflammation-induced depression. Mastocytosis is a rare disease in which chronic symptoms, including depression, are related to mast cell accumulation and activation. Our objectives were to study the correlations between neuropsychiatric features and the TRP catabolism pathway in mastocytosis in order to demonstrate mast cells' potential involvement in inflammation-induced depression. Fifty-four patients with mastocytosis and a mean age of 50.1 years were enrolled in the study and compared healthy age-matched controls. Depression and stress were evaluated with the Beck Depression Inventory revised and the Perceived Stress Scale. All patients had measurements of TRP, serotonin (5-HT), kynurenine (KYN), indoleamine 2,3-dioxygenase 1 (IDO1) activity (ratio KYN/TRP), kynurenic acid (KA) and quinolinic acid (QA). Patients displayed significantly lower levels of TRP and 5-HT without hypoalbuminemia or malabsorption, higher IDO1 activity, and higher levels of KA and QA, with an imbalance towards the latter. High perceived stress and high depression scores were associated with low TRP and high IDO1 activity. In conclusion, TRP metabolism is altered in mastocytosis and correlates with perceived stress and depression, demonstrating mast cells' involvement in inflammation pathways linked to depression.

[Assessment of 10 years of memory consultations in the Franche-Comté: Description and analysis of the RAPID regional database]. / Bilan de 10ans de consultations mémoire en Franche-Comté: description et analyse de la base de données RAPID.

The aim of this study was to evaluate the impact, on a regional scale (Franche-Comté), of 3 National Alzheimer care plans, particularly concerning the development of the offer of care management by clinicians as well as the panel of diagnoses concerned. Data on sociodemographic, neuropsychological and diagnostic characteristics were retrieved from the RAPID regional database between 1st January 2003 and 31st December 2012. These analyses focused exclusively on patients who had an initial consultation (n=12,017) during the same period. The existence of a previously established health network capable of carrying out governmental health plans has produced an effective interface between regional administrative structures responsible for the implementation of these plans and health professionals responsible for carrying out them out. This network study, the use of a battery of tests and a common software database have enabled the development of patient care management throughout the Franche-Comté region. It also showed the diversification of diagnoses mentioned over the past years as well as changes in clinical practices on how to address the issue of cognitive impairment.

[Specificities of the logopenic variant of primary progressive aphasia]. / Particularités du variant logopénique au sein des aphasies progressives primaires.

The logopenic variant of primary progressive aphasia is a syndrome with neuropsychological and linguistic specificities, including phonological loop impairment for which diagnosis is currently mainly based on the exclusion of the two other variants, semantic and nonfluent/agrammatic primary progressive aphasia. The syndrome may be underdiagnosed due (1) to mild language difficulties during the early stages of the disease or (2) to being mistaken for mild cognitive impairment or Alzheimer's disease when the evaluation of episodic memory is based on verbal material and (3) finally, it is not uncommon that the disorders are attributed to psychiatric co-morbidities such as, for example, anxiety. Moreover, compared to other variants of primary progressive aphasia, brain abnormalities are different. The left temporoparietal junction is initially affected. Neuropathology and biomarkers (cerebrospinal fluid, molecular amyloid nuclear imaging) frequently reveal Alzheimer's disease. Consequently this variant of primary progressive aphasia does not fall under the traditional concept of frontotemporal lobar degeneration. These distinctive features highlight the utility of correct diagnosis, classification, and use of biomarkers to show the neuropathological processes underlying logopenic primary progressive aphasia. The logopenic variant of primary progressive aphasia is a specific form of Alzheimer's disease frequently presenting a rapid decline; specific linguistic therapies are needed. Further investigation of this syndrome is needed to refine screening, improve diagnostic criteria and better understand the epidemiology and the biological mechanisms involved.

Pilot study of feasibility of the effect of treatment with tDCS in patients suffering from treatment-resistant depression treated with escitalopram.

OBJECTIVE: This double-blind, sham-controlled trial investigated the effects of two daily tDCS sessions over a 5-day period in treatment-resistant depression. METHOD: Twenty-four treatment-resistant depressed patients received two daily sessions of active or sham anodal tDCS to the left prefrontal cortex (2 mA, 10 sessions over 1 week). Depression severity, psychomotor retardation and cognitive function were assessed. RESULTS: Active tDCS was not significantly superior to sham tDCS on the HDRS at week 4, as well as on the MADRS and SRRS scales, and on neuropsychological tests. Response rates were not significantly higher with active tDCS. tDCS was well tolerated, with mild adverse events limited to transient scalp discomfort. CONCLUSION: tDCS did not induce clinically relevant antidepressant effect in active and sham stimulation groups. There was no impact on psychomotor and neuropsychological functioning. SIGNIFICANCE: tDCS efficacy on specific symptom profiles in pharmacotherapy-resistant depression is limited. The use of optimized stimulation protocol and longer period of follow up may valuably contribute to specify the place of tDCS in treatment-resistant depression.

[Sexual dysfunction and depression: Validity of a French version of the ASEX scale]. / Validation française de l'échelle psychométrique ASEX d'évaluation des troubles sexuels dans la dépression.

BACKGROUND: Since the Beck study (1967), it is well known that sexual dysfunction is particularly prevalent in depressive patients compared to the general population, at 70% and 30% respectively. Depression, psychotropics and antidepressants are responsible for altering sexuality, and patients are considerably affected by these symptoms that dramatically decrease their quality of life. Screening for sexual dysfunctions seems essential, and a scale such as the Arizona Sexual Experience Scale (ASEX) may help practitioners. The English version of this scale was validated in 2000 (McGahuey et al. [9]), and is widely used in scientific research. The aim of this study was to assess the validity of the French version of the ASEX scale. METHODS: Following authorization from the University of Arizona, the ASEX scale was translated into French by our team at the University hospital of Besançon (France), by the back translation technique, and then checked by a professional translator. ASEX, Mini International Neuropsychiatric Interview (MINI), Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS) were filled out by 37 depressed inpatients, and ASEX and PHQ-9 by 64 controls (hospital employees, residents and students at the University of Besançon), and again one to two weeks later. Bivariate correlations were performed using total ASEX scores to determine the test-retest reliability. Internal consistency of the ASEX scale was assessed using Cronbach's alpha analysis. Analyses of variance (Anova) were performed to determine the validity of the ASEX scale to compare patients to controls for total ASEX score and for individual ASEX item scores. In order to determine whether the ASEX criteria accurately reflect sexual dysfunction (determined by the HDRS rating or self-report), positive and negative predictive value and sensitivity and specificity were measured. To determine how well the total ASEX score differentiates between individuals with sexual dysfunction and those without, a Receiver Operating Characteristic (ROC) analysis was performed. We expected similar results between the French version of the ASEX scale and the original one (McGahuey and al., 2000). RESULTS: Patients and controls were similar in terms of sex and age. The test-retest reliability was good, and the internal consistency was excellent using Cronbach's alpha analysis (alpha=0.9451). Analyses of variance (Anova) showed strong differences between the two groups, confirming the validity of the ASEX scale to compare patients to controls for total ASEX score and individual ASEX item scores. Positive and negative predictive values were respectively 89.66% (PPV) and 85.33% (NPV). Specificity and sensitivity were respectively 95.31% (Sp) and 70.27% (Se). The ROC analysis showed the area under the curve (AUC=0.8457) and the best ASEX criteria to demonstrate that sexual dysfunction had been correctly identified (total ASEX score ≥ 18). CONCLUSION: This study assessed the validity and reliability of the French version of the ASEX scale. These findings demonstrate the highly acceptable psychometric properties of ASEX in patients with depression.

[Diagnostic norms of RAPID neuropsychological battery tests for subjects aged 60 to 89 years with Alzheimer's disease]. / Normes diagnostiques de la batterie de tests neuropsychologiques RAPID pour les sujets âgés de 60 à 89ans présentant une maladie d'Alzheimer.

INTRODUCTION: The aim of this study was to propose diagnostic norms for the rapid neuropsychological battery, in the detection of cognitive impairment due to Alzheimer's disease. POPULATION AND METHODS: Three hundred and fifty-two control subjects (mean MMSE : 27.3 ± 2.5) and 676 patients with Alzheimer's disease (mean MMSE : 22.9 ± 2.6) at a mild stage (CDR = 1) were selected according to age (60-69, 70-79 and 80-89 years) and educational level (French primary Education Certificate or lower versus Certificate of Professional Aptitude or the School Leaving Certificate versus the Baccalaureate or higher). Age and education-adjusted cut-off scores were calculated using Receiver Operating Characteristic curves so as to determine the discriminative ability (sensitivity, specificity) of each test from the RAPID neuropsychological battery. Cut-off scores with a specificity set at least at 90% were also proposed. RESULTS: The Free and Cued Recall Test exhibited good sensitivity (from 87% to 100% for free recall and from 85% to 98% for total recall) and specificity (from 85% to 96% for free recall and from 86% to 100% for total recall). For the other tests, sensitivities and specificities were lower. CONCLUSION: The use of these two types of cut-off scores should help the clinician in the diagnosis of Alzheimer's disease by limiting the risk of false positives and false negatives. The choice of the cut-off scores will depend on the patient's individual clinical context.

[Comparative norms of RAPID neuropsychological battery tests for subjects aged between 50 and 89 years]. / Normes comparatives de la batterie de tests neuropsychologiques RAPID pour les sujets âgés de 50 à 89 ans.

INTRODUCTION: RAPID, a battery of rapid neuropsychological tests, includes neuropsychological tests calibrated for different populations according to diverse methodologies. This makes the comparison and interpretation of the results difficult. The aim of this study was to build comparative norms for the RAPID battery using a single methodology in a unique population. POPULATION AND METHODS: The RAPID Battery includes nine different tests: the Memory Impairment Screen, the Isaacs Set Test, the Mini-Mental State Examination, the Free and Cued Recall Test, the Trail Making Test, a test for copying geometric figures as part of the BEC 96, a test for verbally naming images and a test for matching categories. A cohort of 476 subjects aged 50 to 89 were randomly selected from the medical records of 11 practitioners. RESULTS: The norms were stratified according to age (50-59, 60-69, 70-79 and 80-89 years) and education level of the subjects. The first level includes subjects with the French Primary Education Certificate or lower. The second level includes subjects with the Certificate of Professional Aptitude or the Brevet (equivalent to the GCSE). The third level includes subjects with the Baccalaureate or higher. Given that most of the tests did not satisfy the normal distribution, percentiles (tenth, twenty-fifth, seventy-fifth, ninetieth percentile and median) were used to define age and education norms. The results show a high participation rate (75 %) and are similar to those obtained in the literature: The results decreased with age and improved in grade level. Nevertheless, the results exhibited great variability for the tenth percentile in comparison with results reported in the literature. CONCLUSION: The development of comparative norms for the RAPID battery from a same sample facilitates the interpretation of individual results in terms of cognitive profile.

Pharmacogenetics and drug therapy in psychiatry--the role of the CYP2D6 polymorphism.

The importance of pharmacogenetics in medicine is growing with the identification of genetic variability by faster screening methods using automatic sequencers. A particularly interesting finding is that apart from environmental and psychological factors, drug response may be influenced by several biological factors as a result of genetic determinants leading to interindividual variability. Several mutations in genes coding for enzymes of the drug metabolizing system, as well as for neurotransmitter receptors or degrading enzymes and monoamine transport proteins, have been identified and investigated in psychiatry. But, despite the fact that some genetic polymorphisms of enzymes (mainly cytochrome P450 2D6) are well known, the application of pharmacogenetics as a therapeutic tool for improving patient care is rare. This review has three parts. In the first an overview is given of CYP450 characteristics and the genetic polymorphisms of interest to psychiatry. In the second the clinical implications of the CYP2D6 polymorphism are reviewed and in the third part other aspects on pharmacogenetic research in psychiatry are discussed. The aim of our review is to promote the application of pharmacogenetics in everyday clinical practice.

Clomipramine, fluoxetine and CYP2D6 metabolic capacity in depressed patients.

Cytochrome P450-2D6 may be involved in the metabolism of many drugs such as psychotropic drugs and its genetic polymorphism is responsible for inter-individual differences in the therapeutic effect and toxicity of these drugs. Moreover with the same genetic basis, CYP2D6 metabolic capacity variations are observed. Different factors of variation may be involved, among them the prescribed drugs. The aim of this study was to compare the influence of two types of antidepressants, tricyclic (clomipramine) and serotonergic specific recapture inhibitor (SSRI) (fluoxetine), on the CYP2D6 metabolic capacity of depressed inpatients. The CYP2D6 phenotype (dextromethorphan test) was determined in 56 genotyped (PCR-SSCP) depressed caucasian inpatients with a heterozygous genotype. Forty-five subjects were treated with clomipramine and eleven received fluoxetine. The dextromethorphan metabolic ratio (MR) median was significantly higher in the fluoxetine group (0.255) than in the clomipramine group (0.083, p < 0.014). In this study, fluoxetine involved a greater decrease of CYP2D6 metabolic capacity than clomipramine. Clinical implications and the possible connection between a decreased CYP2D6 activity and adverse drug effects were discussed. Caution should be taken when drugs with a low therapeutic index must be coprescribed in such patients.

Drug extrapyramidal side-effects or not: is there a dextromethorphan phenotype difference?

A recent hypothesis suggests the possible role of cytochrome P450 2D6 (CYP2D6) polymorphism (involved in the metabolism of a large number of drugs), as a potential risk factor for the development of extrapyramidal side-effects of psychotropic drugs. The CYP2D6 metabolizer phenotype (dextromethorphan test) of 31 drug treated psychiatric adult patients suffering from extrapyramidal side-effects (group 1) and of 31 matched patients without drug side effects (group 2) were compared. In the first group, 13 poor metabolizer patients (41.9 per cent) were found, characterized by a dextromethorphan metabolic ratio > 0.3, and only two patients in the second group (6.4 per cent). These data provide some support for the notion that in subjects in whom CYP2D6 is probably saturated, the risk of drug extrapyramidal side-effects may be increased. In such patients the choice of psychotropic drugs 'without' this risk must be preferred.

[Extrapyramidal side effects of neuroleptic and antidepressant treatment: assessment of potential risk factors through CYP2D6 genetic polymorphism]. / Effets indésirables extrapyramidaux des neuroleptiques et antidépresseurs--recherche de facteurs de risque: rôle du polymorphisme génétique du CYP2D6.

The objective of this study was to assign metabolizer phenotype (cytochrome P450 2D6 or CYP2D6) to drug treated psychiatric adult patients to assess if the CYP2D6 polymorphism could be a potential risk factor for the development of extrapyramidal side effects of psychotropic drugs. Twenty-eight unrelated in-patients (16 men and 12 women) treated with antidepressants and/or antipsychotic drug were phenotyped using dextromethorphan. Two groups of patients were considered depending on the presence (n = 14) or not (n = 14) of extrapyramidal side effects. The mean dextromethorphan/dextrorphan metabolic ratio (log10) did not differ between the two groups of patients (-1.13 +/- 0.9 and -1.56 +/- 0.5, NS). But significantly more patients with extrapyramidal side effects (n = 4) than patients without side effects (n = 0) were poor metabolizers. This result could be due to a quantitative difference between the 2 groups of drug treatment cosegregated with dextromethorphan, but several authors reported that extrapyramidal side effects seemed not to be always related to high plasma drug levels. So the authors concluded that the 2D6 polymorphism could be a risk factor of poor neurologic tolerance of psychotropic drugs, but not only through pharmacokinetic consequences. CYP 2D6 is indeed expressed in brain and seems to interfer with the metabolism of dopamine and other related neurotransmitters.