Prognostic value of changes in resting-state functional connectivity patterns in cognitive recovery after stroke: A 3T fMRI pilot study.

Resting-state studies conducted with stroke patients are scarce. First objective was to explore whether patients with good cognitive recovery showed differences in resting-state functional patterns of brain activity when compared to patients with poor cognitive recovery. Second objective was to determine whether such patterns were correlated with cognitive performance. Third objective was to assess the existence of prognostic factors for cognitive recovery. Eighteen right-handed stroke patients and eighteen healthy controls were included in the study. Stroke patients were divided into two groups according to their cognitive improvement observed at three months after stroke. Probabilistic independent component analysis was used to identify resting-state brain activity patterns. The analysis identified six networks: frontal, fronto-temporal, default mode network, secondary visual, parietal, and basal ganglia. Stroke patients showed significant decrease in brain activity in parietal and basal ganglia networks and a widespread increase in brain activity in the remaining ones when compared with healthy controls. When analyzed separately, patients with poor cognitive recovery (n=10) showed the same pattern as the whole stroke patient group, while patients with good cognitive recovery (n=8) showed increased activity only in the default mode network and fronto-temporal network, and decreased activity in the basal ganglia. We observe negative correlations between basal ganglia network activity and performance in Semantic Fluency test and Part A of the Trail Making Test for patients with poor cognitive recovery. A reverse pattern was observed between frontal network activity and the above mentioned tests for the same group. .

COMT and ANKK1 gene-gene interaction modulates contextual updating of mental representations.

The differential expression of the dopamine transmitter through its prefrontostriatal pathway has been proposed to account for individual differences in the updating of higher order task representations. Here we examined the interaction between two polymorphic variations of genes involved in the regulation of prefrontal and striatal dopamine (catechol-O-methyltransferase-COMT and ANKK1) on the neural mechanisms of task-set switching. A task-cueing paradigm was employed to measure behavioral costs and a scalp-recorded specific brain potential (novelty-P3) associated to distinct context updating operations in the face of either sensory or task novelty. The interaction between the COMT and ANKK1 genes was evidenced by corresponding specific behavioral costs and novelty-P3 amplitude enhancements reflecting task-set updating mechanisms. This effect was found only in individuals combining genes that yielded a balance between dopamine concentrations and receptor densities. Individuals displaying a putative "unbalance" showed enhanced novelty-P3 responses to all sensory changes, indicative of a task-set updating to sensory cues in a task-context independent fashion. These results support the epistasis of COMT and ANKK1 phenotypes in the flexible control of contextual information in humans.

The role of DAT1 gene on the rapid detection of task novelty.

In an environment with a myriad of different stimuli, the fast detection of novel and behaviorally relevant signals becomes crucial for an adaptive behavior. The detection of task-novelty has been related to striatum-prefrontal cortex (PFC) pathways involving dopaminergic (DA) neurotransmission. Here we thus tested the hypothesis that DA regulates the detection of task novelty through the modulation of the auditory N1 potential, an auditory potential peaking at 100 ms and previously shown to be modulated by the detection of sensory novelty. Thirty-five healthy volunteers were divided in two groups according to the presence or absence of the 9-repetition allele (9R) of the SLC6A3/DAT1 gene for the dopamine transporter. Participants performed a cued task-switching paradigm that dissociated the effects of exogenous sensory novelty from those of endogenous task novelty. Individuals with the 9R allele showed an amplitude enhancement of the auditory N1 elicited to sensory changes requiring a task-set reconfiguration as compared to sensory changes with no task novelty. In contrast, individuals without the 9R allele did not have their N1 waveform modulated by task novelty. The present results suggest that individuals homozygous for the 10-repeat allele fail to detect the behavioral relevance of new stimuli at early stages.

The role of the dopamine transporter DAT1 genotype on the neural correlates of cognitive flexibility.

Cognitive flexibility, the ability to adapt goal-oriented behaviour in response to changing environmental demands, varies widely amongst individuals, yet its underlying neural mechanisms are not fully understood. Neuropharmacological and human clinical studies have suggested a critical role for striatal dopaminergic function mediated by the dopamine transporter (DAT). The present study aimed at revealing the role of the DAT in the individual brain response stereotypy underlying cognitive flexibility. A task-switching protocol was administered to a sample divided according to the presence or absence of the 9-repeat (9R) allele of the DAT1 polymorphism, while registering behavioural and electrophysiological novelty-P3 responses. The absence of the 9R (higher gene expression) is related to less striatal DA availability. Individuals lacking the 9R (9R-) showed specific response time (RT) increases for sensory change and task-set reconfiguration, as well as brain modulations not observed in participants with the 9R allele (9R+), suggesting that task performance of the former group depended on immediate local context. In contrast, individuals displaying high striatal DA showed larger RT costs than 9R- individuals to any sensory change, with no further increase for task-set reconfiguration, and a larger early positive brain response irrespective of the task condition, probably reflecting larger inhibition of any previous interference as well as stronger activation of the current task set. However, the polymorphic groups did not differ in their mean RTs in trials requiring task-set reconfiguration. This distinct stereotypy of cerebral responses reveals different patterns of cognitive control according to the DAT1 gene polymorphism.

Posibilidades y limitaciones de un seguro de cuidados de larga duración para mayores dependientes en España / The possibilities and constrains of long term care insurance in Spain

En este articulo se examina la problemática de la financiaciónde la dependencia en España. Se revisa la evidencia empíricarelevante con en fin de evaluar los instrumentos de financiaciónal alcance, y en especial un seguro de dependencia comomecanismo de cobertura de los gastos asociados a cuidados delarga duración. Se argumenta que el riesgo de dependencia esun riesgo asegurable, si bien la existencia de fallos de mercadoapunta a la necesidad de instrumentalizar un seguro obligatorio.El rol del seguro privado un papel complementario o suplementario.La evidencia empírica apunta a que la opción preferidapor la población española es una financiación pública

This paper examines the financial policy constrains andpossibilities of funding long term care in Spain. To this end, werevise the existing empirical evidence to evaluate the financingtools available , and specially the applicability of a long term careinsurance as a means to insure the costs of long term care. Weargue that the dependency risks are insurable risks subjected tomarket failures that justify the need for a compulsory insurance.The role of the private long-term care insurance in that caseis restricted to a complementary or a supplementary role. Evidencefrom Spanish social attitudes suggests that the public prefersa publicly funded system to private alternatives

Polimorfismo T102C del receptor 5HT2A y rendimiento cognitivo en la alteración cognitiva leve / T102C polymorphism in the 5HT2A gene and cognition in mild cognitive impairment

La Alteración Cognitiva Leve es un estado de transición entreel envejecimiento normal y la enfermedad de Alzheimer y espor ello una condición de riesgo para la demencia. La serotoninay sus receptores tienen un papel importante en los procesosde aprendizaje y memoria. El receptor 5HT2A está localizadopredominantemente en áreas frontales e hipocampales. En esteestudio hemos valorado la influencia del genotipo del polimorfismoT102C del gen 5HT2A en el rendimiento cognitivo de unamuestra de 59 sujetos con Alteración Cognitiva Leve. Los sujetosheterocigotos (T102/C102) para este polimorfismo puntuabansignificativamente menos en el Mini-Mental, pruebas dememoria visual y verbal y en funciones premotoras, sugiriendoque este genotipo sería un nuevo marcador genético de riesgoen la alteración cognitiva

Mild Cognitive Impairment (MCI) is a transitional statebetween normal aging and Alzheimer’s disease and thus, it is ahigh-risk condition for dementia. Serotonin and its receptorsare associated with memory and learning processes. The5HT2A receptor is expressed in prefrontal cortex and hippocampus,above all. We have studied the role of the polymorphismT102C in the 5HT2A gene in cognition in a sample of 59MCI subjects. Those individuals carrying the heterozygous variant(T102/C102) performed significantly worse in the Mini-Mental State Examination, visual and verbal memory tests aswell as premotor functions. These results suggest that this genotypecould be a new genetic risk factor for cognitive impairmentin the elderly

Apolipoproteins E and C1 and brain morphology in memory impaired elders.

Previous research has shown that polymorphisms of the apolipoproteins E ( APOE) and APOC1 represent genetic risk factors for dementia and for cognitive impairment in the elderly. The brain mechanisms by which these genetic variations affect behavior or clinical severity are poorly understood. We studied the effect of APOE and APOC1 genes on magnetic resonance imaging measures in a sample of 50 subjects with age-associated memory impairment. The APOE E4 allele was associated with reduced left hippocampal volumes and APOE*E3 status was associated with greater frontal lobe white matter volumes. However, no APOE effects were observed when analyses accounted for other potential confounding variables. The effects of APOC1 on hippocampal volumes appeared to be more robust than those of the APOE polymorphism. However, no modulatory effects on brain morphology outside the medial temporal lobe region were observed when demographic variables, clinical status, and other anatomical brain measurements were taken into consideration. Our results suggest that the role of the APOC1 polymorphism in brain morphology of the cognitively impaired elderly should be examined in further studies.

Relation of Apo E and ACE genes to cognitive performance in chronic alcoholic patients.

Apolipoprotein E epsilon4 and ACE genes have been related to several conditions involving cognitive impairment, including Alzheimer's disease, normal ageing and cerebrovascular disease. However, it has not been established whether their genotypes are associated with alcoholism or its cognitive functioning. Genotypic distributions of 140 chronic alcoholic patients were compared with a non-alcoholic sample, and the cognitive performance of a subsample of the alcoholic subjects was assessed with standard neuropsychological tests. No differences in allele or genotype distributions of Apo E or ACE genes were found when comparing controls and alcoholics (Apo E epsilon2/2; patients 1.4%, controls 0% p < 0.06; epsilon2/epsilon3; patients 9.3%, controls 6.6% p < 0.29; epsilon2/epsilon4; patients 0%, controls 1% p < 0.31; epsilon3/epsilon3 patients 71.4%, controls 72% p < 0.89; epsilon3/epsilon4; patients 15.7%, controls 19.2%, p < 0.36; epsilon4/epsilon4; patients 2.1%, controls 1.2% p < 0.44; ACE D/D; patients 35%, controls 28.5% p < 0.14; I/D; patients 47.5%, controls 51.1% p < 0.51; I/I; patients 14.5%, controls 20.4% p < 0.19). In terms of cognitive performance, epsilon4/epsilon3 patients did better on visuoconstructive (p < 0.001) and visual memory (p < 0.04) functions compared with epsilon2/epsilon3 bearers. Furthermore, ACE D/D patients performed better on a test of abstract reasoning (p < 0.03) compared with the ACE I/I homozygous group. The cognitive results suggest that Apo E or ACE genotypes may modify the effects of ethanol on cognitive deterioration in alcoholic patients. However, the data do not support an association between the Apo E epsilon4 allele and reduced cognitive performance in alcoholism.

APOE and APOC1 genetic polymorphisms in age-associated memory impairment.

We studied the distribution of two genetic polymorphisms (APOE and APOC1) in a sample of 100 subjects fulfilling the NIMH criteria for age-associated memory impairment (AAMI) and 124 controls. We found significant associations both for APOE and APOC1 loci and their combinations with the AAMI condition. The findings in our sample suggest that memory-impaired subjects as described by the NIMH may be genetically differentiated from normally aging subjects in relation to these two polymorphisms and indicate the interest of considering variations in the APOC1 gene for further studies in cognitive aging.

[White matter changes and cognitive performance in aging]. / Cambios en la sustancia blanca y rendimiento cognitivo en el envejecimiento.

OBJECTIVE: In this paper we review the main magnetic resonance studies to show a possible relationship between changes in the white matter of the brain or leukoaraiosis, and the neuropsychological profile of elderly persons without dementia. DEVELOPMENT: The articles published to date show contradictory data, and in nearly half the cases reviewed no clear relationship could be established between leukoaraiosis and conduct. However, by using sensitive cognitive tests it is possible to detect and association between the presence and degree of change in the white matter and decline in frontal function such as speed of processing information, visuomotor function, verbal fluency, classification and mental sequences. Other cognitive areas such as language, memory or visuospatial, visuoconstructive and visuoperceptive functions appear less frequently related to the presence or intensity of lesions of the white matter of the brain. From a neuropsychological point of view, periventricular localization of the leukoaraiosis seems to be more important than subcortical localization. CONCLUSIONS: The neuropsychological functions most frequently associated with the presence of leukoaraiosis are those dependent on the frontal lobes, and are a disconnection favoured by the presence of the white matter of the brain, the most probable underlying physiopathological mechanism. Although there is evidence showing a genetic effect in the appearance of the white matter of the brain, study of the genes associated with cognitive deterioration in normal ageing has not given conclusive findings.

Neuropsychological and genetic differences between age-associated memory impairment and mild cognitive impairment entities.

OBJECTIVE: To neuropsychologically and genetically compare age-associated memory impairment (AAMI) and mild cognitive impairment (MCI) entities and to determine what proportion of AAMI diagnosed individuals could also receive a MCI diagnosis. To compare the distribution of a previously known genetic risk factor for Alzheimer's disease (apolipoprotein E common polymorphism) associated with these two conditions with a sample of the normal aging. DESIGN: Neuropsychological and genetic assessments in AAMI and MCI individuals. Genetic assessment in AAMI, MCI, and control subjects. SETTING: General health centers and geriatric homes from northeastern Spain (Catalunya). PARTICIPANTS: One hundred and four subjects presenting subjective memory complaints were selected and the AAMI and MCI criteria were applied. One hundred and twenty-four healthy Spanish subjects age 50 and older were defined as controls. MEASUREMENTS: Memory, language, and frontal lobe functions were assessed using standard neuropsychological tests. The apolipoprotein E (apo E) polymorphism was obtained by using polymerase chain reaction (PCR) and HhaI restriction endonuclease. RESULTS: Sixty-seven percent of previously diagnosed AAMI individuals could also be identified as MCI subjects. These MCI cases differed from those only-AAMI individuals both in neuropsychological and genetic analyses, performing worse not only on memory but also on language and frontal lobe tests and presenting high and low prevalences of the apo E epsilon 3/epsilon 4 and epsilon 3/epsilon 3 genotypes, respectively. The general AAMI sample of 93 individuals also differed from controls in the apo E genotype and allele distributions but these differences were no longer present after subtracting the MCI cases (63 subjects). These findings reflect that the differences between the memory impaired sample and the control sample regarding the apo E polymorphism were mainly attributable to MCI individuals and not to those who received only a diagnosis of AAMI alone. CONCLUSIONS: Our findings suggest that among AAMI subjects, those who also fulfill the MCI criteria present a neuropsychological and genetic profile closer to that previously related to Alzheimer's disease than those individuals only eligible for a diagnosis of AAMI. However, our findings also suggest that using only the AAMI criteria still appears to select a population that differs genetically from the normal older population.

Cambios en la sustancia blancay rendimiento cognitivo en el envejecimiento / White matter changes and cognitive performance in aging

Objetivo. En el presente trabajo se revisan los principales estudios de resonancia magnética dirigidos a evidenciar la posible relación entre los cambios en la sustancia blanca cerebral (CSB) o leucoaraiosis y el perfil neuropsicológico de sujetos envejecidos son demencia. Desarrollo. Los artículos publicados hasta la fecha aportan resultados contradictorios, y en casi la mitad de los casos revisados la relación entre la leucoaraiosis y la conducta no se ha podido establecer claramente. No obstante, con la utilización de pruebas cognitivas sensibles es posible detectar una asociación entre la presencia o el grado de CSB y el declive en las funciones frontales, como la velocidad de procesamiento de la información, la función visuomotora, la fluidez verbal, la categorización o la secuenciación mentales. Otras áreas cognitivas como el lenguaje, la memoria o las funciones visuoespaciales, visuoconstructivas y visuoperceptivas aparecen menos frecuentemente relacionadas con la presencia o intensidad de lesiones en la sustancia blanca cerebral. La localización periventricular de la leucoaraiosis parece más importante desde un punto de vista neuropsicológico en contraposición a la localización subcortical. Conclusiones. Las funciones neuropsicológicas más frecuentemente asociadas a la presencia de leucoaraiosis son las dependientes de los lóbulos frontales; el mecanismo fisiopatológico más plausible consiste en una "desconexión" propiciada por la presencia de los CSB. aunque existe evidencia que señala un efecto genético en la manifestación de los CSB, el estudio de genes asociados al deterioro cognitivo en el envejecimiento normal no ha aportado resultados concluyentes (AU)

MRI and genetic correlates of cognitive function in elders with memory impairment.

The present study investigated the relationship between genetic variation, MRI measurements and neuropsychological function in a sample of 58 elders exhibiting memory decline. In agreement with previous reports, we found that the epsilon4 allele of the apolipoprotein E (APOE) and the D allele of the angiotensin converting enzyme (ACE) polymorphisms negatively modulated the cognitive performance. Further, we found an association between the A allele of the apolipoprotein C1 (APOC1) polymorphism and poorer memory and frontal lobe function. No clear associations emerged between MRI measures of white matter lesions (WML) or hippocampal sulcal cavities (HSC) and the cognitive performance after controlling for age effects. Further, the degree of WML or HSC lesions was in general not predisposed genetically except for the presence of the A allele of the APOC1 polymorphism that was related to a higher severity of HSC scores. Our results suggest that WML or HSC do not represent important brain correlates of genetic influences on cognitive performance in memory impaired subjects.

Angiotensin I converting enzyme polymorphism in humans with age-associated memory impairment: relationship with cognitive performance.

We compared the distribution of an insertion (I)/deletion (D) polymorphism coding for the angiotensin I converting enzyme (ACE) gene in 100 subjects fulfilling NIMH criteria for Age-associated memory impairment (AAMI) and 124 controls. We found significantly reduced prevalences of the ACE I/I genotype together with increases of the ACE D allele in the AAMI group. We further compared the neuropsychological performance of the AAMI group according to their ACE genotype. Those AAMI subjects presenting the ACE I/I genotype exhibited better performance on a measure of frontal lobe function. Our results suggest that the lack of the ACE I/I genotype and the presence of the ACE D allele are associated with memory impairment in the elderly.

A study of the association of alcoholism with A1A2B0 and MNSs polymorphisms.

Polymorphic variants of A1A2B0 and MNSs systems were analysed in a sample of 300 alcoholic patients subdivided according to gender and family history of alcoholism. There was agreement between observed and expected frequencies assuming genetic equilibrium. No association between phenotypes or genes of the A1A2B0 polymorphism and alcoholism was found when the Woolf method was used to evaluate possible associations. In the MNSs polymorphism, when the Woolf method was applied, significant values of chi 2 suggest a possible association between alcoholism and this blood marker, but after Bonferroni correction this association was rejected.

Evolution of the Simiiformes and the phylogeny of human chromosomes.

This paper is based on the results of Primate chromosome studies obtained using high resolution techniques in our and other laboratories. We discuss the origin and the evolution of the chromosomes in the human karyotype and the time in evolution of the Simiiformes when they acquired their present morphology. Our results indicate that the chromosomes that underwent a higher number of reorganizations during the evolution of the Simiiformes coincide with the chromosomes most often implicated in human chromosome pathology. We describe the main reorganizations that took place during Primate evolution. Centromere activation and inactivation and heterochromatin changes are discussed as mechanisms of chromosome evolution.

Fragile sites, chromosome evolution, and human neoplasia.

In a study of the possible relationship between human fragile sites, chromosomal rearrangements related to neoplasia, and chromosome regions involved in evolutionary changes, we have found that 17 fragile sites related to cancer, 15 fragile sites not related to cancer, and 17 non-fragile regions also related to human malignancy correspond or are close to bands involved in rearrangements that have taken place during chromosomal evolution in primates.

High-resolution chromosome banding studies in Cebus apella, Cebus albifrons, and Lagothrix lagothricha: Comparison with the human karyotype.

Karyotypes of three species of South American primates (Cebus apella, Cebus albifrons, and Lagothrix lagothricha) were studied using high-resolution banding techniques, and were compared to the human karyotype. The number of homologies was very high for the three species. Some of the breakpoints implicated in chromosome rearrangements corresponded with human fragile sites. The fragile sites in human chromosomes often correspond with the localization of latent centromeres in the platyrrhines or with large heterochromatic regions that may have been lost or newly added during evolution.