Does falls efficacy predict gait performance in high-functioning older people?

Introduction: Falls efficacy, defined as confidence in performing activities without falling, is a measure of fear of falling associated with gait impairment, falls and functional decline in frail older people. This relationship has not been well studied in high-functioning older people. Objective: To evaluate the relationship between falls efficacy and gait performance in a cohort of high-functioning older people. Methods: Subjects (N = 864) were a subsample of communitydwelling older people aged 65 to 70 years, enrolled in the "Lc65+" cohort, who completed gait assessment at baseline. Data were collected on demographics, functional, cognitive, affective, and health status. Falls efficacy was assessed using the Falls Efficacy Scale- International (FES-I) that measures confidence in performing 16 activities of daily life (ADL) without falling (score from 16 to 64, higher score indicates lower confidence). Gait parameters were measured over a 20 m walk at preferred gait speed using Physilog, an ambulatory gait monitoring system. Results: Participants (mean age 68.0 ± 1.4 years, 55.0% women) had excellent physical (92.2% independent in basic ADL, mean gait speed 1.13 ± 0.16 m/sec) and cognitive (98.0% with MMSE 024) performance. Nevertheless, 22.1% reported depressive symptoms and 16.1% one or more fall in the previous year. Mean FES-I score was 18.8 ± 4.1. Falls efficacy was associated with gait speed (Spearman rho -0.23, P <.001) and gait variability (Spearman rho 0.10, P = .006), measured by the coefficient of variation of stride velocity. These associations remained in multivariate analysis for both gait speed (adj [beta] coeff: -0.008, 95%CI -0.005 to -0.010, P <.001) and gait variability (adj [beta] coeff 0.024, 95%CI 0.003 to 0.045, P = .023) independent of gender, falls, functional, affective, cognitive, and frailty (Fried's criteria) status. On average, compared to subjects with poor confidence in performing one ADL without falling, those with full confidence had a 0.02 m/sec (2%) faster gait speed and a 2% decrease in gait variability. Conclusion: Even in high-functioning older people, poor falls efficacy is associated with reduced gait speed and stability, independent of health, functional, and frailty status. The direction of this relationship needs to be investigated prospectively to determine causality and design interventions to improve gait performance, reduce fall risk, and prevent functional decline.

Complex syntax in autism spectrum disorders: a study of relative clauses.

BACKGROUND: The few studies that have evaluated syntax in autism spectrum disorder (ASD) have yielded conflicting findings: some suggest that once matched on mental age, ASD and typically developing controls do not differ for grammar, while others report that morphosyntactic deficits are independent of cognitive skills in ASD. There is a need for a better understanding of syntax in ASD and its relation to, or dissociation from, nonverbal abilities. AIMS: Syntax in ASD was assessed by evaluating subject and object relative clause comprehension in adolescents and adults diagnosed with ASD with a performance IQ within the normal range, and with or without a history of language delay. METHODS & PROCEDURES: Twenty-eight participants with ASD (mean age 21.8) and 28 age-matched controls (mean age 22.07) were required to point to a character designated by relative clauses that varied in syntactic complexity. OUTCOMES & RESULTS: Scores indicate that participants with ASD regardless of the language development history perform significantly worse than age-matched controls with object relative clauses. In addition, participants with ASD with a history of language delay (diagnosed with high-functioning autism in the DSM-IV-TR) perform worse on subject relatives than ASD participants without language delay (diagnosed with Asperger syndrome in the DSM-IV-TR), suggesting that these two groups do not have equivalent linguistic abilities. Performance IQ has a positive impact on the success of the task for the population with ASD. CONCLUSIONS & IMPLICATIONS: This study reveals subtle grammatical difficulties remaining in adult individuals with ASD within normal IQ range as compared with age-matched peers. Even in the absence of a history of language delay in childhood, the results suggest that a slight deficit may nevertheless be present and go undetected by standardized language assessments. Both groups with and without language delay have a similar global performance on relative clause comprehension; however, the study also indicates that the participants with reported language delay show more difficulty with subject relatives than the participants without language delay, suggesting the presence of differences in linguistic abilities between these subgroups of ASD.

Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2.

Recent genetic studies have implicated a number of candidate genes in the pathogenesis of Autism Spectrum Disorder (ASD). Polymorphisms of CNTNAP2 (contactin-associated like protein-2), a member of the neurexin family, have already been implicated as a susceptibility gene for autism by at least 3 separate studies. We investigated variation in white and grey matter morphology using structural MRI and diffusion tensor imaging. We compared volumetric differences in white and grey matter and fractional anisotropy values in control subjects characterised by genotype at rs7794745, a single nucleotide polymorphism in CNTNAP2. Homozygotes for the risk allele showed significant reductions in grey and white matter volume and fractional anisotropy in several regions that have already been implicated in ASD, including the cerebellum, fusiform gyrus, occipital and frontal cortices. Male homozygotes for the risk alleles showed greater reductions in grey matter in the right frontal pole and in FA in the right rostral fronto-occipital fasciculus compared to their female counterparts who showed greater reductions in FA of the anterior thalamic radiation. Thus a risk allele for autism results in significant cerebral morphological variation, despite the absence of overt symptoms or behavioural abnormalities. The results are consistent with accumulating evidence of CNTNAP2's function in neuronal development. The finding suggests the possibility that the heterogeneous manifestations of ASD can be aetiologically characterised into distinct subtypes through genetic-morphological analysis.

Copy number variations and cognitive phenotypes in unselected populations

IMPORTANCE: The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear. OBJECTIVE: To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency ≤0.05%; size ≥250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population. DESIGN, SETTING, AND PARTICIPANTS: The population biobank of Estonia contains 52,000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. MAIN OUTCOMES AND MEASURES: Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. RESULTS: Of the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, ≤0.05%; ≥250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (P = 1.06e-04) among 248 (≥250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (≥1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom. CONCLUSIONS AND RELEVANCE: Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health.

Treatment motivation in adolescents with psychosis or at high risk: Determinants and impact on improvements in symptoms and cognitive functioning, preliminary results.

Abstract Low motivation is frequent in chronic disorders such as psychosis and may limit treatment efficacy. Although some evidence supports this view in adults, few studies so far have focused on adolescents. We assessed the impact of baseline symptoms, cognitive deficits and cognitive treatment characteristics on treatment motivation (TM), and examined whether TM affected treatment outcome. Twenty-eight adolescents with psychotic disorders participated in 16 sessions of computerized cognitive remediation or games. TM was assessed for each session. Lower TM was predicted by more severe symptoms at baseline, and was associated with smaller improvements in symptoms and both cognitive and psychosocial functioning at the end of the intervention. Experiencing success in the treatment exercises enhanced TM in all patients.

The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity

Anatomical structures and mechanisms linking genes to neuropsychiatric disorders are not deciphered. Reciprocal copy number variants at the 16p11.2 BP4-BP5 locus offer a unique opportunity to study the intermediate phenotypes in carriers at high risk for autism spectrum disorder (ASD) or schizophrenia (SZ). We investigated the variation in brain anatomy in 16p11.2 deletion and duplication carriers. Beyond gene dosage effects on global brain metrics, we show that the number of genomic copies negatively correlated to the gray matter volume and white matter tissue properties in cortico-subcortical regions implicated in reward, language and social cognition. Despite the near absence of ASD or SZ diagnoses in our 16p11.2 cohort, the pattern of brain anatomy changes in carriers spatially overlaps with the well-established structural abnormalities in ASD and SZ. Using measures of peripheral mRNA levels, we confirm our genomic copy number findings. This combined molecular, neuroimaging and clinical approach, applied to larger datasets, will help interpret the relative contributions of genes to neuropsychiatric conditions by measuring their effect on local brain anatomy.Molecular Psychiatry advance online publication, 25 November 2014; doi:10.1038/mp.2014.145.

Cognitive and Emotional Deficits Associated with Minor and Serious Delinquency in High-Risk Adolescents

This study aims at evaluating how minor and serious delinquency relates to cognitive and emotional functioning in high-risk adolescents, taking problematic substance use into account. In 80 high-risk adolescent males (13-19 years), the frequency of minor and serious offences committed over the last year was predicted, in multiple regression analyses, from problematic substance use, intellectual efficiency, trait impulsivity, alexithymia (inability to express feelings in words), and cognitive coping strategies. Both minor and serious delinquency were more frequent in adolescents with more problematic substance use and higher intellectual efficacy. Minor delinquency was further related to a tendency to act out when experiencing negative emotions, and difficulties in focusing energy on instrumental action when under stress; while serious delinquency was predominantly and strongly related to rigid and dichotomous thinking. The results underline the heterogeneous nature of delinquency, minor offences being primarily associated with emotional regulation deficits, while major offences are related with a lack of cognitive flexibility.

Transmission disequilibrium of small CNVs in simplex autism.

We searched for disruptive, genic rare copy-number variants (CNVs) among 411 families affected by sporadic autism spectrum disorder (ASD) from the Simons Simplex Collection by using available exome sequence data and CoNIFER (Copy Number Inference from Exome Reads). Compared to high-density SNP microarrays, our approach yielded ∼2× more smaller genic rare CNVs. We found that affected probands inherited more CNVs than did their siblings (453 versus 394, p = 0.004; odds ratio [OR] = 1.19) and that the probands' CNVs affected more genes (921 versus 726, p = 0.02; OR = 1.30). These smaller CNVs (median size 18 kb) were transmitted preferentially from the mother (136 maternal versus 100 paternal, p = 0.02), although this bias occurred irrespective of affected status. The excess burden of inherited CNVs among probands was driven primarily by sibling pairs with discordant social-behavior phenotypes (p < 0.0002, measured by Social Responsiveness Scale [SRS] score), which contrasts with families where the phenotypes were more closely matched or less extreme (p > 0.5). Finally, we found enrichment of brain-expressed genes unique to probands, especially in the SRS-discordant group (p = 0.0035). In a combined model, our inherited CNVs, de novo CNVs, and de novo single-nucleotide variants all independently contributed to the risk of autism (p < 0.05). Taken together, these results suggest that small transmitted rare CNVs play a role in the etiology of simplex autism. Importantly, the small size of these variants aids in the identification of specific genes as additional risk factors associated with ASD.

The effect of retirement on cognitive functioning

Cognitive impairment has emerged as a major driver of disability in old age, with profound effects on individual well-being and decision making at older ages. In the light of policies aimed at postponing retirement ages, an important question is whether continued labour supply helps to maintain high levels of cognition at older ages. We use data of older men from the US Health and Retirement Study to estimate the effect of continued labour market participation at older ages on later-life cognition. As retirement itself is likely to depend on cognitive functioning and may thus be endogenous, we use offers of early retirement windows as instruments for retirement in econometric models for later-life cognitive functioning. These offers of early retirement are legally required to be nondiscriminatory and thus, inter alia, unrelated to cognitive functioning. At the same time, these offers of early retirement options are significant predictors of retirement. Although the simple ordinary least squares estimates show a negative relationship between retirement duration and various measures of cognitive functioning, instrumental variable estimates suggest that these associations may not be causal effects. Specifically, we find no clear relationship between retirement duration and later-life cognition for white-collar workers and, if anything, a positive relationship for blue-collar workers. Copyright © 2011 John Wiley & Sons, Ltd.

A randomized controlled trial of the effectiveness of a Computer-Assisted Cognitive Remediation (CACR) program in adolescents with psychosis or at high risk of psychosis: Short term and long term outcomes

The present study investigates the short- and long-term outcomes of a computer-assisted cognitive remediation (CACR) program in adolescents with psychosis or at high risk. 32 adolescents participated in a blinded 8-week randomized controlled trial of CACR treatment compared to computer games (CG). Clinical and neuropsychological evaluations were undertaken at baseline, at the end of the program and at 6-month. At the end of the program (n = 28), results indicated that visuospatial abilities (Repeatable Battery for the Assessment of Neuropsychological Status, RBANS; P = .005) improved signifi cantly more in the CACR group compared to the CG group. Furthermore, other cognitive functions (RBANS), psychotic symptoms (Positive and Negative Symptom Scale) and psychosocial functioning (Social and Occupational Functioning Assessment Scale) improved signifi cantly, but at similar rates, in the two groups. At long term (n = 22), cognitive abilities did not demonstrated any amelioration in the control group while, in the CACR group, signifi cant long-term improvements in inhibition (Stroop; P = .040) and reasoning (Block Design Test; P = .005) were observed. In addition, symptom severity (Clinical Global Improvement) decreased signifi cantly in the control group (P = .046) and marginally in the CACR group (P = .088). To sum up, CACR can be successfully administered in this population. CACR proved to be effective over and above CG for the most intensively trained cognitive ability. Finally, on the long-term, enhanced reasoning and inhibition abilities, which are necessary to execute higher-order goals or to adapt behavior to the ever-changing environment, were observed in adolescents benefi ting from a CACR.

Interregional compensatory mechanisms of motor functioning in progressing preclinical neurodegeneration.

Understanding brain reserve in preclinical stages of neurodegenerative disorders allows determination of which brain regions contribute to normal functioning despite accelerated neuronal loss. Besides the recruitment of additional regions, a reorganisation and shift of relevance between normally engaged regions are a suggested key mechanism. Thus, network analysis methods seem critical for investigation of changes in directed causal interactions between such candidate brain regions. To identify core compensatory regions, fifteen preclinical patients carrying the genetic mutation leading to Huntington's disease and twelve controls underwent fMRI scanning. They accomplished an auditory paced finger sequence tapping task, which challenged cognitive as well as executive aspects of motor functioning by varying speed and complexity of movements. To investigate causal interactions among brain regions a single Dynamic Causal Model (DCM) was constructed and fitted to the data from each subject. The DCM parameters were analysed using statistical methods to assess group differences in connectivity, and the relationship between connectivity patterns and predicted years to clinical onset was assessed in gene carriers. In preclinical patients, we found indications for neural reserve mechanisms predominantly driven by bilateral dorsal premotor cortex, which increasingly activated superior parietal cortices the closer individuals were to estimated clinical onset. This compensatory mechanism was restricted to complex movements characterised by high cognitive demand. Additionally, we identified task-induced connectivity changes in both groups of subjects towards pre- and caudal supplementary motor areas, which were linked to either faster or more complex task conditions. Interestingly, coupling of dorsal premotor cortex and supplementary motor area was more negative in controls compared to gene mutation carriers. Furthermore, changes in the connectivity pattern of gene carriers allowed prediction of the years to estimated disease onset in individuals. Our study characterises the connectivity pattern of core cortical regions maintaining motor function in relation to varying task demand. We identified connections of bilateral dorsal premotor cortex as critical for compensation as well as task-dependent recruitment of pre- and caudal supplementary motor area. The latter finding nicely mirrors a previously published general linear model-based analysis of the same data. Such knowledge about disease specific inter-regional effective connectivity may help identify foci for interventions based on transcranial magnetic stimulation designed to stimulate functioning and also to predict their impact on other regions in motor-associated networks.

Copy number variation characteristics in subpopulations of patients with autism spectrum disorders.

Autism spectrum disorders (ASDs) are a heterogeneous group of disorders with a complex genetic etiology. We used high-resolution whole genome array-based comparative genomic hybridization (array-CGH) to screen 223 ASD patients for gene dose alterations associated with susceptibility for autism. Clinically significant copy number variations (CNVs) were identified in 18 individuals (8%), of which 9 cases (4%) had de novo aberrations. In addition, 20 individuals (9%) were shown to have CNVs of unclear clinical relevance. Among these, 13 cases carried rare but inherited CNVs that may increase the risk for developing ASDs, while parental samples were unavailable in the remaining seven cases. Classification of all patients into different phenotypic and inheritance pattern groups indicated the presence of different CNV patterns in different patient groups. Clinically relevant CNVs were more common in syndromic cases compared to non-syndromic cases. Rare inherited CNVs were present in a higher proportion of ASD cases having first- or second-degree relatives with an ASD-related neuropsychiatric phenotype in comparison with cases without reported heredity (P = 0.0096). We conclude that rare CNVs, encompassing potential candidate regions for ASDs, increase the susceptibility for the development of ASDs and related neuropsychiatric disorders giving us further insight into the complex genetics underlying ASDs.