Gonzalo Sánchez-Benavides

Spanish Multicenter Normative Studies (NEURONORMA Project): Norms for the Rey–Osterrieth Complex Figure (Copy and Memory), and Free and Cued Selective Reminding Test

The Rey-Osterrieth complex figure (ROCF) and the free and cued selective reminding test (FCSRT) are frequently used in clinical practice. The ROCF assesses visual perception, constructional praxis, and visuospatial memory, and the FCSRT assesses verbal learning and memory. As part of the Spanish Normative Studies (NEURONORMA), we provide age- and education-adjusted norms for the ROCF (copy and memory) and for the FCSRT. The sample consists of 332 and 340 participants, respectively, who are cognitively normal, community dwelling, and ranging in age from 50 to 94 years. Tables are provided to convert raw scores to age-adjusted scaled scores. These were further converted into education-adjusted scaled scores by applying regression-based adjustments. Although age and education affected the score of the ROCF and FCSRT, sex was found to be unrelated in this normal sample. The normative data presented here were obtained from the same study sample as all other NEURONORMA norms and the same statistical procedures were applied. These co-normed data will allow clinicians to compare scores from one test with all the tests included in the project.

Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial

BACKGROUND Early cognitive intervention is the only routine therapeutic approach used for amelioration of intellectual deficits in individuals with Downs syndrome, but its effects are limited. We hypothesised that administration of a green tea extract containing epigallocatechin-3-gallate (EGCG) would improve the effects of non-pharmacological cognitive rehabilitation in young adults with Downs syndrome. METHODS We enrolled adults (aged 16-34 years) with Downs syndrome from outpatient settings in Catalonia, Spain, with any of the Downs syndrome genetic variations (trisomy 21, partial trisomy, mosaic, or translocation) in a double-blind, placebo-controlled, phase 2, single centre trial (TESDAD). Participants were randomly assigned at the IMIM-Hospital del Mar Medical Research Institute to receive EGCG (9 mg/kg per day) or placebo and cognitive training for 12 months. We followed up participants for 6 months after treatment discontinuation. We randomly assigned participants using random-number tables and balanced allocation by sex and intellectual quotient. Participants, families, and researchers assessing the participants were masked to treatment allocation. The primary endpoint was cognitive improvement assessed by neuropsychologists with a battery of cognitive tests for episodic memory, executive function, and functional measurements. Analysis was on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01699711. FINDINGS The study was done between June 5, 2012, and June 6, 2014. 84 of 87 participants with Downs syndrome were included in the intention-to-treat analysis at 12 months (43 in the EGCG and cognitive training group and 41 in the placebo and cognitive training group). Differences between the groups were not significant on 13 of 15 tests in the TESDAD battery and eight of nine adaptive skills in the Adaptive Behavior Assessment System II (ABAS-II). At 12 months, participants treated with EGCG and cognitive training had significantly higher scores in visual recognition memory (Pattern Recognition Memory test immediate recall, adjusted mean difference: 6·23 percentage points [95% CI 0·31 to 12·14], p=0·039; d 0·4 [0·05 to 0·84]), inhibitory control (Cats and Dogs total score, adjusted mean difference: 0·48 [0·02 to 0·93], p=0·041; d 0·28 [0·19 to 0·74]; Cats and Dogs total response time, adjusted mean difference: -4·58 s [-8·54 to -0·62], p=0·024; d -0·27 [-0·72 to -0·20]), and adaptive behaviour (ABAS-II functional academics score, adjusted mean difference: 5·49 [2·13 to 8·86], p=0·002; d 0·39 [-0·06 to 0·84]). No differences were noted in adverse effects between the two treatment groups. INTERPRETATION EGCG and cognitive training for 12 months was significantly more effective than placebo and cognitive training at improving visual recognition memory, inhibitory control, and adaptive behaviour. Phase 3 trials with a larger population of individuals with Downs syndrome will be needed to assess and confirm the long-term efficacy of EGCG and cognitive training. FUNDING Jérôme Lejeune Foundation, Instituto de Salud Carlos III FEDER, MINECO, Generalitat de Catalunya.

VNTR-DAT1 and COMTVal158Met Genotypes Modulate Mental Flexibility and Adaptive Behavior Skills in Down Syndrome

Down syndrome (DS) is an aneuploidy syndrome that is caused by trisomy for human chromosome 21 resulting in a characteristic cognitive and behavioral phenotype, which includes executive functioning and adaptive behavior difficulties possibly due to prefrontal cortex (PFC) deficits. DS also present a high risk for early onset of Alzheimer Disease-like dementia. The dopamine (DA) system plays a neuromodulatory role in the activity of the PFC. Several studies have implicated trait differences in DA signaling on executive functioning based on genetic polymorphisms in the genes encoding for the catechol-O-methyltransferase (COMTVal158Met) and the dopamine transporter (VNTR-DAT1). Since it is known that the phenotypic consequences of genetic variants are modulated by the genetic background in which they occur, we here explore whether these polymorphisms variants interact with the trisomic genetic background to influence gene expression, and how this in turn mediates DS phenotype variability regarding PFC cognition. We genotyped 69 young adults of both genders with DS, and found that VNTR-DAT1 was in Hardy-Weinberg equilibrium but COMTVal158Met had a reduced frequency of Met allele homozygotes. In our population, genotypes conferring higher DA availability, such as Met allele carriers and VNTR-DAT1 10-repeat allele homozygotes, resulted in improved performance in executive function tasks that require mental flexibility. Met allele carriers showed worse adaptive social skills and self-direction, and increased scores in the social subscale of the Dementia Questionnaire for People with Intellectual Disabilities than Val allele homozygotes. The VNTR-DAT1 was not involved in adaptive behavior or early dementia symptoms. Our results suggest that genetic variants of COMTVal158Met and VNTR-DAT1 may contribute to PFC-dependent cognition, while only COMTVal158Met is involved in behavioral phenotypes of DS, similar to euploid population.

A new cognitive evaluation battery for Down syndrome and its relevance for clinical trials

The recent prospect of pharmaceutical interventions for cognitive impairment of Down syndrome (DS) has boosted a number of clinical trials in this population. However, running the trials has raised some methodological challenges and questioned the prevailing methodology used to evaluate cognitive functioning of DS individuals. This is usually achieved by comparing DS individuals to matched healthy controls of the same mental age. We propose a new tool, the TESDAD Battery that uses comparison with age-matched typically developed adults. This is an advantageous method for probing the clinical efficacy of DS therapies, allowing the interpretation and prediction of functional outcomes in clinical trials. In our DS population the TESDAD battery permitted a quantitative assessment of cognitive defects, which indicated language dysfunction and deficits in executive function, as the most important contributors to other cognitive and adaptive behavior outcomes as predictors of functional change in DS. Concretely, auditory comprehension and functional academics showed the highest potential as end-point measures of therapeutic intervention for clinical trials: the former as a cognitive key target for therapeutic intervention, and the latter as a primary functional outcome measure of clinical efficacy. Our results also emphasize the need to explore the modulating effects of IQ, gender and age on cognitive enhancing treatments. Noticeably, women performed significantly better than men of the same age and IQ in most cognitive tests, with the most consistent differences occurring in memory and executive functioning and negative trends rarely emerged on quality of life linked to the effect of age after adjusting for IQ and gender. In sum, the TESDAD battery is a useful neurocognitive tool for probing the clinical efficacy of experimental therapies in interventional studies in the DS population suggesting that age-matched controls are advantageous for determining normalization of DS.

Using artificial neural networks in clinical neuropsychology: High performance in mild cognitive impairment and Alzheimer's disease

Mild cognitive impairment (MCI) is a transitional state between normal aging and Alzheimer disease (AD). Artificial neural networks (ANNs) are computational tools that can provide valuable support to clinical decision making, classification, and prediction of cognitive functioning. The aims of this study were to develop, train, and explore and develop the ability of ANNs to differentiate MCI and AD, and to study the relevant variables in MCI and AD diagnosis. The sample consisted of 346 controls and 79 MCI and 97 AD patients. A linear discriminant analysis (LDA) and ANNs with 12 input neurons (10 subtests of a neuropsychological test, the abbreviated Barcelona Test; age; and education), 4 hidden neurons, and output neuron (diagnosis) were used to classify the patients. The ANNs were superior to LDA in its ability to classify correctly patients (100–98.33% vs. 96.4–80%, respectively) and showed better predictive performance. Semantic fluency, working and episodic memory and education showed up as the most significant and sensitive variables for classification. Our results indicate that ANNs have an excellent capacity to discriminate MCI and AD patients from healthy controls. These findings provide evidence that ANNs can be a useful tool for the analysis of neuropsychological profiles related to clinical syndromes.

Psychometric Properties of the Memory Binding Test: Test-Retest Reliability and Convergent Validity

BACKGROUND Episodic memory testing is fundamental for the diagnosis of Alzheimers disease (AD). Although the Free and Cued Selective Reminding Test (FCSRT) is widely used for this purpose, it may not be sensitive enough for early detection of subtle decline in preclinical AD. The Memory Binding Test (MBT) intends to overcome this limitation. OBJECTIVES To analyze the test-retest reliability of the MBT and its convergent validity with the FCRST. METHODS 36 cognitively healthy participants of the ALFA Study, aged 45 to 65, were included for the test-retest study and 69 for the convergent analysis. They were visited twice in a period of 6 ± 2 weeks. Test-retest reliability was determined by the calculation of the intra-class correlation coefficient (ICC). Score differences were studied by computing the mean percentage of score variation between visits and visualized by Bland-Altman plots. Convergent validity was determined by Pearsons correlations. RESULTS ICC values in the test-retest reliability analysis of the MBT direct scores ranged from 0.64 to 0.76. Subjects showed consistent practice effects, with mean amounts of score increasing between 10% and 26%. Pearson correlation between MBT and FCSRT direct scores showed r values between 0.40 and 0.53. The FCSRT displayed ceiling effects not observed in the MBT. CONCLUSIONS The MBT shows adequate test-retest reliability and overall moderate convergent validity with the FCSRT. Unlike the FCSRT, the MBT does not have ceiling effects and it may therefore be especially useful in longitudinal studies, facilitating the measurement of subtle memory performance decline and the detection of very early AD.

The ALFA project: A research platform to identify early pathophysiological features of Alzheimer's disease

The preclinical phase of Alzheimers disease (AD) is optimal for identifying early pathophysiological events and developing prevention programs, which are shared aims of the ALFA project, including the ALFA registry and parent cohort and the nested ALFA+ cohort study.

Effect of long-term exposure to air pollution on anxiety and depression in adults: A cross-sectional study

BACKGROUND The association between exposure to air pollutants and mental disorders among adults has been suggested, although results are not consistent. OBJECTIVE To analyze the association between long-term exposure to air pollution and history of anxiety and depression disorders and of medication use (benzodiazepines and antidepressants) in adults living in Barcelona. METHODS A total of 958 adults (45-74 years old) residents in Barcelona, most of them having at least one of their parents diagnosed with dementia (86%), and participating in the ALFA (Alzheimer and Families) study, were included. We used Land Use Regression (LUR) models to estimate long-term residential exposure (period 2009-2014) to PM2.5, PM2.5 absorbance (PM2.5 abs), PM10, PM coarse, NO2 and NOx. Between 2013 and 2014 participants self-reported their history of anxiety and depression disorders and related medication use. The analysis was focused on those participants reporting outcome occurrence from 2009 onwards (until 2014). RESULTS We observed an increased odds of history of depression disorders with increasing concentrations of all air pollutants [e.g. an increased odds of depression of 2.00 (95% CI; 1.37, 2.93) for each 10μg/m3 NO2 increase]. Such associations were consistent with an increased odds of medication use in relation to higher concentrations of air pollutants [e.g. an increased odds of antidepressants use of 1.23 (1.04, 1.44) for each 20μg/m3 NOx increase]. Associations regarding anxiety disorders did not reach statistical significance. CONCLUSIONS Our study shows that increasing long-term exposure to air pollution may increase the odds of depression and the use of antidepressants and benzodiazepines. Further studies are needed to replicate our results and confirm this association.

Spanish Version of the Bayer Activities of Daily Living Scale in Mild Cognitive Impairment and Mild Alzheimer Disease: Discriminant and Concurrent Validity

Aims: To test the discriminant and concurrent validity of the Spanish version of the Bayer Activities of Daily Living scale (B-ADL) in mild cognitive impairment (MCI) and mild Alzheimer disease (AD). Methods: The B-ADL scale, the Blessed Dementia Rating Scale (BDRS), and the Interview for Deterioration in Daily Living in Dementia (IDDD) were administered to 277 elderly Spanish patients (78 MCI and 199 AD). Correlations between scales were performed, and ROC curves were plotted. Results: In MCI and mild AD discrimination, an area under the ROC curve of 0.84 was found; a cut-off point of 3.3 was proposed with values of 0.81 for sensitivity and 0.72 for specificity. The B-ADL correlated positively to both the BDRS (r = 0.7) and the IDDD (r = 0.8). Conclusion: The B-ADL is a valid and sensitive scale that can be used to discriminate mild AD from MCI.

Semantic Verbal Fluency Pattern, Dementia Rating Scores and Adaptive Behavior Correlate With Plasma Aβ42 Concentrations in Down Syndrome Young Adults.

Down syndrome (DS) is an intellectual disability (ID) disorder in which language and specifically, verbal fluency are strongly impaired domains; nearly all adults show neuropathology of Alzheimer’s disease (AD), including amyloid deposition by their fifth decade of life. In the general population, verbal fluency deficits are considered a strong AD predictor being the semantic verbal fluency task (SVFT) a useful tool for enhancing early diagnostic. However, there is a lack of information about the association between the semantic verbal fluency pattern (SVFP) and the biological amyloidosis markers in DS. In the current study, we used the SVFT in young adults with DS to characterize their SVFP, assessing total generated words, clustering, and switching. We then explored its association with early indicators of dementia, adaptive behavior and amyloidosis biomarkers, using the Dementia Questionnaire for Persons with Intellectual Disability (DMR), the Adaptive Behavior Assessment System-Second Edition (ABAS-II), and plasma levels of Aβ peptides (Aβ40 and Aβ42), as a potent biomarker of AD. In DS, worse performance in SVFT and poorer communication skills were associated with higher plasma Aβ42 concentrations, a higher DMR score and impaired communication skills (ABAS–II). The total word production and switching ability in SVFT were good indicators of plasma Aβ42 concentration. In conclusion, we propose the SVFT as a good screening test for early detection of dementia and amyloidosis in young adults with DS.