Behavioral and psychological symptoms and cognitive decline in patients with amnestic MCI and mild AD: a two-year follow-up study.

BACKGROUND: Mild cognitive impairment (MCI) has been defined as a transitional state between normal aging and dementia. In many cases, MCI represents an early stage of developing cognitive impairment. Patients diagnosed with MCI do not meet the criteria for dementia as their general intellect and everyday activities are preserved, although minor changes in instrumental activities of daily living (ADL) may occur. However, they may exhibit significant behavioral and psychological signs and symptoms (BPS), also frequently observed in patients with Alzheimer's disease (AD). Hence, we wondered to what extent specific BPS are associated with cognitive decline in participants with MCI or AD. METHODS: Our sample consisted of 164 participants, including 46 patients with amnestic (single or multi-domain) MCI and 54 patients with AD, as well as 64 control participants without cognitive disorders. Global cognitive performance, BPS, and ADL were assessed using validated clinical methods at baseline and at two-year follow-up. RESULTS: The BPS variability over the follow-up period was more pronounced in the MCI group than in patients with AD: some BPS improve, others occur newly or worsen, while others still remain unchanged. Moreover, specific changes in BPS were associated with a rapid deterioration of the global cognitive level in MCI patients. In particular, an increase of euphoria, eating disorders, and aberrant motor behavior, as well as worsened sleep quality, predicted a decline in cognitive functioning. CONCLUSIONS: Our findings confirm a higher variability of BPS over time in the MCI group than in AD patients. Moreover, our results provide evidence of associations between specific BPS and cognitive decline in the MCI group that might suggest a risk of conversion of individuals with amnestic MCI to AD.

Sex biased spatial strategies relying on the integration of multimodal cues in a rat model of schizophrenia: impairment in predicting future context?

Male and female Wistar rats were treated postnatally (PND 5-16) with BSO (l-buthionine-(S,R)-sulfoximine) to provide a rat model of schizophrenia based on transient glutathione deficit. In the watermaze, BSO-treated male rats perform very efficiently in conditions where a diversity of visual information is continuously available during orientation trajectories [1]. Our hypothesis is that the treatment impairs proactive strategies anticipating future sensory information, while supporting a tight visual adjustment on memorized snapshots, i.e. compensatory reactive strategies. To test this hypothesis, BSO rats' performance was assessed in two conditions using an 8-arm radial maze task: a semi-transparent maze with no available view on the environment from maze centre [2], and a modified 2-parallel maze known to induce a neglect of the parallel pair in normal rats [3-5]. Male rats, but not females, were affected by the BSO treatment. In the semi-transparent maze, BSO males expressed a higher error rate, especially in completing the maze after an interruption. In the 2-parallel maze shape, BSO males, unlike controls, expressed no neglect of the parallel arms. This second result was in accord with a reactive strategy using accurate memory images of the contextual environment instead of a representation based on integrating relative directions. These results are coherent with a treatment-induced deficit in proactive decision strategy based on multimodal cognitive maps, compensated by accurate reactive adaptations based on the memory of local configurations. Control females did not express an efficient proactive capacity in the semi-transparent maze, neither did they show the significant neglect of the parallel arms, which might have masked the BSO induced effect. Their reduced sensitivity to BSO treatment is discussed with regard to a sex biased basal cognitive style.

Evaluation of a summary score of cognitive performance for use in trials in perioperative and critical care.

Background/Aims: Cognitive dysfunction after medical treatment is increasingly being recognized. Studies on this topic require repeated cognitive testing within a short time. However, with repeated testing, practice effects must be expected. We quantified practice effects in a demographically corrected summary score of a neuropsychological test battery repeatedly administered to healthy elderly volunteers. Methods: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Neuropsychological Assessment Battery (for which a demographically corrected summary score was developed), phonemic fluency tests, and trail-making tests were administered in healthy volunteers aged 65 years or older on days 0, 7, and 90. This battery allows calculation of a demographically adjusted continuous summary score. Results: Significant practice effects were observed in the CERAD total score and in the word list (learning and recall) subtest. Based on these volunteer data, we developed a threshold for diagnosis of postoperative cognitive dysfunction (POCD) with the CERAD total score. Conclusion: Practice effects with repeated administration of neuropsychological tests must be accounted for in the interpretation of such tests. Ignoring practice effects may lead to an underestimation of POCD. The usefulness of the proposed demographically adjusted continuous score for cognitive function will have to be tested prospectively in patients.

Programme de remédiation cognitive pour patients présentant une schizophrénie ou un trouble associé (Recos) : résultats préliminaires [Cognitive remediation program for individuals living with schizophrenia (Recos): preliminary results].

BACKGROUND: Nowadays, cognitive remediation is widely accepted as an effective treatment for patients with schizophrenia. In French-speaking countries, techniques used in cognitive remediation for patients with schizophrenia have been applied from those used for patients with cerebral injury. As cognitive impairment is a core feature of schizophrenia, the Département de psychiatrie du CHUV in Lausanne (DP-CHUV) intended to develop a cognitive remediation program for patients with a schizophrenia spectrum disease (Recos-Vianin, 2007). Numerous studies show that the specific cognitive deficits greatly differ from one patient to another. Consequently, Recos aims at providing individualized cognitive remediation therapy. In this feasibility trial, we measured the benefits of this individualized therapy for patients with schizophrenia. Before treatment, the patients were evaluated with a large battery of cognitive tests in order to determine which of the five specific training modules - Verbal memory, visuospatial memory and attention, working memory, selective attention, reasoning - could provide the best benefit depending on their deficit. OBJECTIVES: The study was designed to evaluate the benefits of the Recos program by comparing cognitive functioning before and after treatment. METHOD: Twenty-eight patients with schizophrenia spectrum disorders (schizophrenia [n=18], schizoaffective disorder [n=5], schizotypal disorder [n=4], schizophreniform disorder [n=1], DSM-IV-TR) participated in between one and three of the cognitive modules. The choice of the training module was based on the results of the cognitive tests obtained during the first evaluation. The patients participated in 20 training sessions per module (one session per week). At the end of the training period, the cognitive functioning of each patient was reevaluated by using the same neuropsychological battery. RESULTS: The results showed a greater improvement in the cognitive functions, which were specifically trained, compared to the cognitive functions, which were not trained. However, an improvement was also observed in both types of cognitive functions, suggesting an indirect cognitive gain. CONCLUSION: In our view, the great heterogeneity of the observed cognitive deficits in schizophrenia necessitates a detailed neuropsychological investigation as well as an individualized cognitive remediation therapy. These preliminary results need to be confirmed with a more extended sample of patients.

Accurate performance of a rat model of schizophrenia in the water maze depends on visual cue availability and stability: a distortion in cognitive mapping abilities?

Rats were treated postnatally (PND 5-16) with BSO (l-buthionine-(S,R)-sulfoximine) in an animal model of schizophrenia based on transient glutathione deficit. The BSO treated rats were impaired in patrolling a maze or a homing table when adult, yet demonstrated preserved escape learning, place discrimination and reversal in a water maze task [37]. In the present work, BSO rats' performance in the water maze was assessed in conditions controlling for the available visual cues. First, in a completely curtained environment with two salient controlled cues, BSO rats showed little accuracy compared to control rats. Secondly, pre-trained BSO rats were impaired in reaching the familiar spatial position when curtains partially occluded different portions of the room environment in successive sessions. The apparently preserved place learning in a classical water maze task thus appears to require the stability and the richness of visual landmarks from the surrounding environment. In other words, the accuracy of BSO rats in place and reversal learning is impaired in a minimal cue condition or when the visual panorama changes between trials. However, if the panorama remains rich and stable between trials, BSO rats are equally efficient in reaching a familiar position or in learning a new one. This suggests that the BSO accurate performance in the water maze does not satisfy all the criteria for a cognitive map based navigation on the integration of polymodal cues. It supports the general hypothesis of a binding deficit in BSO rats.

Pathological substrates of cognitive decline in Alzheimer's disease

The progressive development of Alzheimer's disease (AD)-related lesions such as neurofibrillary tangles,amyloid deposits and synaptic loss within the cerebral cortex is a main event of brain aging.Recent neuropathologic studies strongly suggested that the clinical diagnosis of dementia depends more on the severity and topography of pathologic changes than on the presence of a qualitative marker. However, several methodological problems such as selection biases, case-control design,density-based measures, and masking effects of concomitant pathologies should be taken into account when interpreting these data. In last years, the use of stereologic counting permitted to define reliably the cognitive impact of AD lesions in the human brain. Unlike fibrillar amyloid deposits that are poorly or not related to the dementia severity, the use of this method documented that total neurofibrillary tangles and neuron numbers in the CA1 field are the best correlates of cognitive deterioration in brain aging. Loss of dendritic spines in neocortical but not hippocampal areas has a modest but independent contribution to dementia. In contrast, the importance of early dendritic and axonal tau-related pathologic changes such as neuropil threads remains doubtful. Despite these progresses, neuronal pathology and synaptic loss in cases with pure AD pathology cannot explain more than 50% of clinical severity. The present review discusses the complex structure/function relationships in brain aging and AD within the theoretical framework of the functional neuropathology of brain aging.

Personality traits and behavioural and psychological symptoms in patients with mild cognitive impairment.

BACKGROUND AND AIMS: Both personality changes and behavioural and psychological symptoms (BPS) may be associated with mild cognitive impairment (MCI) in later life and help identify incipient dementia. We wished to investigate the links between personality and BPS in MCI. METHOD: We studied premorbid personality traits as estimated 5 years back and their changes in 83 control subjects and 52 MCI patients using the revised NEO Personality Inventory for the Five-Factor Model completed by a proxy. Information on BPS was obtained using the Neuropsychiatric Inventory (NPI). Analyses were controlled for current depression and anxiety. RESULTS: Premorbid neuroticism and openness to experience were associated with the total NPI score. The changes in neuroticism, extraversion, openness to experiences, and conscientiousness were associated with apathy and affective symptoms. CONCLUSIONS: Personality changes and BPS occur in MCI. The occurrence of affective BPS and apathy is associated with both premorbid personality traits and their changes.

Estudi de les alteracions en la capacitat neuroprotectora dels astròcits reactius en l'envelliment

En el periodo 2005-2008 hemos publicado tres artículos sobre las alteraciones de los astrocitos reactivos en el cerebro durante el envejecimiento. En el primer estudio, evaluamos la capacidad neuroprotectora de los astrocitos en un modelo experimental in vitro de envejecimiento. Los cambios en el estrés oxidativo, la captación del glutamato y la expresión proteica fueron evaluados en los astrocitos corticales de rata cultivados durante 10 y 90 días in vitro (DIV). Los astrocitos envejecidos tenían una capacidad reducida de mantener la supervivencia neuronal. Estos resultados indican que los astrocitos pueden perder parcialmente su capacidad neuroprotectora durante el envejecimiento. En el segundo estudio el factor neurotrófico derivado de la línea glial (GDNF) fue probado para observar sus efectos neurotróficos contra la atrofia neuronal que causa déficits cognitivos en la vejez. Las ratas envejecidas Fisher 344 con deficiencias en el laberinto de Morris recibieron inyecciones intrahippocampales de un vector lentiviral que codifica GDNF humano en los astrocitos o del mismo vector que codifica la proteína fluorescente verde humana como control. El GDNF secretado por los astrocitos mejoró la función de la neurona como se muestra por aumentos locales en la síntesis de los neurotransmisores acetilcolina, dopamina y serotonina. El aprendizaje espacial y la prueba de memoria demostraron un aumento significativo en las capacidades cognitivas debido a la exposición de GDNF, mientras que las ratas control mantuvieron sus resultados al nivel del azar. Estos resultados confirman el amplio espectro de la acción neurotrófica del GDNF y abre nuevas posibilidades de terapia génica para reducir la neurodegeneración asociada al envejecimiento. En el último estudio, examinamos cambios en la fosforilación de tau, el estrés oxidativo y la captación de glutamato en los cultivos primarios de astrocitos corticales de ratones neonatos de senescencia acelerada (SAMP8) y ratones resistentes a la senescencia (SAMR1). Nuestros resultados indican que las alteraciones en cultivos del astrocitos de los ratones SAMP8 son similares a las detectadas en cerebros enteros de los ratones SAMP8 de 1-5 meses de edad. Por otra parte, nuestros resultados sugieren que esta preparación in vitro es adecuada para estudiar en este modelo murino el envejecimiento temprano y sus procesos moleculares y celulares.

Increased activation in Broca's area after cognitive remediation in schizophrenia.

Functional magnetic resonance imaging (fMRI) was used to measure changes in cerebral activity in patients with schizophrenia after participation in the Cognitive Remediation Program for Schizophrenia and other related disorders (RECOS). As RECOS therapists make use of problem-solving and verbal mediation techniques, known to be beneficial in the rehabilitation of dysexecutive syndromes, we expected an increased activation of frontal areas after remediation. Executive functioning and cerebral activation during a covert verbal fluency task were measured in eight patients with schizophrenia before (T1) and after (T2) 14 weeks of RECOS therapy. The same measures were recorded in eight patients with schizophrenia who did not participate in RECOS at the same intervals of time (TAU group). Increased activation in Broca's area, as well as improvements in performance of executive/frontal tasks, was observed after cognitive training. Metacognitive techniques of verbalization are hypothesized to be the main factor underlying the brain changes observed in the present study.

PGE2-Induced IDO1 Inhibits the Capacity of Fully Mature DCs to Elicit an In Vitro Antileukemic Immune Response.

In the last years, dendritic cells (DC) have been evaluated for antitumor vaccination. Although DC-based vaccines have raised great expectations, their clinical translation has been largely disappointing. For these results, several explanations have been proposed. In particular, the concomitant expression by DCs of tolerogenic pathways, such as the immunosuppressive agent indoleamine 2,3-dioxygenase-1 (IDO1), has been demonstrated. The aim of this study is to evaluate both the stimulatory and the tolerogenic feature of monocyte-derived DCs (Mo-DCs) after maturation with PGE2. In particular, the role of IDO1 expression in PGE2-matured Mo-DCs has been addressed. Here we show that PGE2, which is required for full maturation of DCs, is one mediator of DC tolerance by enhancing IDO1. PGE2-mediated expression of IDO1 results in the production of kynurenine, in the generation of Tregs, and in the inhibition of either the allogeneic or the autologous antigen-specific stimulatory capacity of DCs. When pulsed with leukemic lysates and matured with PGE2, DCs are impaired in the induction of IFN-γ secreting CD4(+) and CD8(+) T cells due to IDO1 upregulation. Moreover, the inhibition of IDO1 enhances the antileukemic response. Overall, these results point toward the use of IDO1 inhibitors to enhance the vaccination capacity of DCs, matured with PGE2.

Quasiconformal maps, analytic capacity, and non linear potentials

"Vegeu el resum a l'inici del document del fitxer adjunt."

Traffic forecasts under uncertainty and capacity constraints

Traffic forecasts provide essential input for the appraisal of transport investment projects. However, according to recent empirical evidence, long-term predictions are subject to high levels of uncertainty. This paper quantifies uncertainty in traffic forecasts for the tolled motorway network in Spain. Uncertainty is quantified in the form of a confidence interval for the traffic forecast that includes both model uncertainty and input uncertainty. We apply a stochastic simulation process based on bootstrapping techniques. Furthermore, the paper proposes a new methodology to account for capacity constraints in long-term traffic forecasts. Specifically, we suggest a dynamic model in which the speed of adjustment is related to the ratio between the actual traffic flow and the maximum capacity of the motorway. This methodology is applied to a specific public policy that consists of suppressing the toll on a certain motorway section before the concession expires.

Thérapie cognitive et comportementale pour les hallucinations auditives résistantes au traitement neuroleptique

The aim of this study is to test the feasibility and the efficacy of a cognitive and behavior therapy manual for auditory hallucinations with persons suffering from schizophrenia in a French-speaking environment and under natural clinical conditions. Eight patients met ICD-10 criteria for paranoid schizophrenia, 2 for hebephrenic schizophrenia and 1 for schizoaffective disorder. All were hearing voices daily. Patients followed the intervention for 3 to 6 months according to their individual rhythms. Participants filled up questionnaires at pre-test, post-test and three months follow-up. The instruments were the Belief About Voice Questionnaire--Revised and two seven points scales about frequency of hallucinations and attribution of the source of the voices. Results show a decrease of voices' frequency and improvement in attributing the voices rather to an internal than to an external source. Malevolent or benevolent beliefs about voices are significantly decreased at follow-up as well as efforts at coping with hallucinations. Results should be interpreted with caution because of the small number of subjects. The sample may not be representative of patients with persistent symptoms since there is an over representation of patients with benevolent voices and an under representation of patients with substance misuse

Subjective cognitive decline in patients with mild cognitive impairment and healthy older adults: association with personality traits.

AIM: In normal aging, subjective cognitive decline (SCD) might reflect personality traits or affective states rather than objective cognitive decline. However, little is known on the correlates of SCD in mild cognitive impairment (MCI). The present study investigates SCD in MCI patients and healthy older adults, and explores the association of SCD with personality traits, affective states, behavioral and psychological symptoms (BPS), and episodic memory in patients with MCI as compared with healthy older adults. METHODS: A total of 55 patients with MCI and 84 healthy older adults were recruited. Standard instruments were used to evaluate SCD, episodic memory, BPS and affective states. Premorbid and current personality traits were assessed by proxies using the NEO Personality Inventory Revised. RESULTS: Patients with MCI generally reported SCD more often than healthy older adults. SCD was positively associated with depressive symptoms in both groups. With regard to personality, no significant relationship was found in the healthy older group, whereas agreeableness was significantly negatively related to SCD in the MCI group. No significant association was found between SCD and episodic memory. CONCLUSIONS: SCD is more prevalent in patients with MCI than in the healthy elderly, but it does not reflect an objective cognitive impairment. SCD rather echoes depressive symptoms in both patients with MCI and healthy subjects. The negative association of SCD with agreeableness observed in patients with MCI could indicate that MCI patients scoring high on the agreeableness trait would not report SCD in order to prevent their relatives worrying about their increasing cognitive difficulties.

Aging and motor programming: differential effects according to the selection of action

There are controversial reports about the effect of aging on movement preparation, and it is unclear to which extent cognitive and/or motor related cerebral processes may be affected. This study examines the age effects on electro-cortical oscillatory patterns during various motor programming tasks, in order to assess potential differences according to the mode of action selection. Twenty elderly (EP, 60-84 years) and 20 young (YP, 20-29 years) participants with normal cognition underwent 3 pre-cued response tasks (S1-S2 paradigm). S1 carried either complete information on response side (Full; stimulus-driven motor preparation), no information (None; general motor alertness), or required free response side selection (Free; internally-driven motor preparation). Electroencephalogram (EEG) was recorded using 64 surface electrodes. Alpha (8-12 Hz) desynchronization (ERD)/synchronization (ERS) and motor-related amplitude asymmetries (MRAA) were analyzed during the S1-S2 interval. Reaction times (RTs) to S2 were slower in EP than YP, and in None than in the other 2 tasks. There was an Age x Task interaction due to increased RTs in Free compared to Full in EP only. Central bilateral and midline activation (alpha ERD) was smaller in EP than YP in None. In Full just before S2, readiness to move was reflected by posterior midline inhibition (alpha ERS) in both groups. In Free, such inhibition was present only in YP. Moreover, MRAA showed motor activity lateralization in both groups in Full, but only in YP in Free. The results indicate reduced recruitment of motor regions for motor alertness in the elderly. They further show less efficient cerebral processes subtending free selection of movement in elders, suggesting reduced capacity for internally-driven action with age.