Breda Cullen

A review of screening tests for cognitive impairment

The merit of screening for dementia and cognitive impairment has been the subject of recent debate. One of the main limitations in this regard is the lack of robust evidence to support the many screening tests available. Although plentiful in number, few such instruments have been well validated in the populations for which they are intended to be used. In addition, it is likely that “one size does not fit all” in cognitive screening, leading to the development of many specialised tests for particular types of impairment. In this review, we sought to ascertain the number of screening tools currently available, and to examine the evidence for their validity in detecting different diagnoses in a variety of populations. A further consideration was whether each screen elicited indices of a range of cognitive, affective and functional domains or abilities, as such information is a valuable adjunct to simple cut-off scores. Thirty-nine screens were identified and discussed with reference to three purposes: brief assessment in the doctor’s office; large scale community screening programmes; and identifying profiles of impairment across different cognitive, psychiatric and functional domains/abilities, to guide differential diagnosis and further assessment. A small number of screens rated highly for both validity and content. This review is intended to serve as an evaluative resource, to guide clinicians and researchers in choosing among the wide range of screens which are currently available.

Genome-wide association study of cognitive functions and educational attainment in UK Biobank (N=112 151)

People’s differences in cognitive functions are partly heritable and are associated with important life outcomes. Previous genome-wide association (GWA) studies of cognitive functions have found evidence for polygenic effects yet, to date, there are few replicated genetic associations. Here we use data from the UK Biobank sample to investigate the genetic contributions to variation in tests of three cognitive functions and in educational attainment. GWA analyses were performed for verbal–numerical reasoning (N=36u2009035), memory (N=112u2009067), reaction time (N=111u2009483) and for the attainment of a college or a university degree (N=111u2009114). We report genome-wide significant single-nucleotide polymorphism (SNP)-based associations in 20 genomic regions, and significant gene-based findings in 46 regions. These include findings in the ATXN2, CYP2DG, APBA1 and CADM2 genes. We report replication of these hits in published GWA studies of cognitive function, educational attainment and childhood intelligence. There is also replication, in UK Biobank, of SNP hits reported previously in GWA studies of educational attainment and cognitive function. GCTA-GREML analyses, using common SNPs (minor allele frequency>0.01), indicated significant SNP-based heritabilities of 31% (s.e.m.=1.8%) for verbal–numerical reasoning, 5% (s.e.m.=0.6%) for memory, 11% (s.e.m.=0.6%) for reaction time and 21% (s.e.m.=0.6%) for educational attainment. Polygenic score analyses indicate that up to 5% of the variance in cognitive test scores can be predicted in an independent cohort. The genomic regions identified include several novel loci, some of which have been associated with intracranial volume, neurodegeneration, Alzheimer’s disease and schizophrenia.

Shared genetic aetiology between cognitive functions and physical and mental health in UK Biobank ( N =112 151) and 24 GWAS consortia

Causes of the well-documented association between low levels of cognitive functioning and many adverse neuropsychiatric outcomes, poorer physical health and earlier death remain unknown. We used linkage disequilibrium regression and polygenic profile scoring to test for shared genetic aetiology between cognitive functions and neuropsychiatric disorders and physical health. Using information provided by many published genome-wide association study consortia, we created polygenic profile scores for 24 vascular–metabolic, neuropsychiatric, physiological–anthropometric and cognitive traits in the participants of UK Biobank, a very large population-based sample (N=112u2009151). Pleiotropy between cognitive and health traits was quantified by deriving genetic correlations using summary genome-wide association study statistics and to the method of linkage disequilibrium score regression. Substantial and significant genetic correlations were observed between cognitive test scores in the UK Biobank sample and many of the mental and physical health-related traits and disorders assessed here. In addition, highly significant associations were observed between the cognitive test scores in the UK Biobank sample and many polygenic profile scores, including coronary artery disease, stroke, Alzheimer’s disease, schizophrenia, autism, major depressive disorder, body mass index, intracranial volume, infant head circumference and childhood cognitive ability. Where disease diagnosis was available for UK Biobank participants, we were able to show that these results were not confounded by those who had the relevant disease. These findings indicate that a substantial level of pleiotropy exists between cognitive abilities and many human mental and physical health disorders and traits and that it can be used to predict phenotypic variance across samples.

Prevalence and Characteristics of Probable Major Depression and Bipolar Disorder within UK Biobank: Cross-Sectional Study of 172,751 Participants

Objectives UK Biobank is a landmark cohort of over 500,000 participants which will be used to investigate genetic and non-genetic risk factors for a wide range of adverse health outcomes. This is the first study to systematically assess the prevalence and validity of proposed criteria for probable mood disorders within the cohort (major depression and bipolar disorder). Methods This was a descriptive epidemiological study of 172,751 individuals assessed for a lifetime history of mood disorder in relation to a range of demographic, social, lifestyle, personality and health-related factors. The main outcomes were prevalence of a probable lifetime (single) episode of major depression, probable recurrent major depressive disorder (moderate), probable recurrent major depressive disorder (severe), probable bipolar disorder and no history of mood disorder (comparison group). Outcomes were compared on age, gender, ethnicity, socioeconomic status, educational attainment, functioning, self-reported health status, current depressive symptoms, neuroticism score, smoking status and alcohol use. Results Prevalence rates for probable single lifetime episode of major depression (6.4%), probable recurrent major depression (moderate) (12.2%), probable recurrent major depression (severe) (7.2%) and probable bipolar disorder (1.3%) were comparable to those found in other population studies. The proposed diagnostic criteria have promising validity, with a gradient in evidence from no mood disorder through major depression and probable bipolar disorder in terms of gender distribution, socioeconomic status, self-reported health rating, current depressive symptoms and smoking. Significance The validity of our proposed criteria for probable major depression and probable bipolar disorder within this cohort are supported by these cross-sectional analyses. Our findings are likely to prove useful as a framework for a wide range of future genetic and non-genetic studies.

Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci

Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91u2009370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form’s Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10−15) spanning 4u2009Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ∼1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.

The efficacy of cognitive prosthetic technology for people with memory impairments: A systematic review and meta-analysis

Technology can compensate for memory impairment. The efficacy of assistive technology for people with memory difficulties and the methodology of selected studies are assessed. A systematic search was performed and all studies that investigated the impact of technology on memory performance for adults with impaired memory resulting from acquired brain injury (ABI) or a degenerative disease were included. Two 10-point scales were used to compare each study to an ideally reported single case experimental design (SCED) study (SCED scale; Tate et al., 2008) or randomised control group study (PEDro-P scale; Maher, Sherrington, Herbert, Moseley, & Elkins, 2003). Thirty-two SCED (meanu2009=u20095.9 on the SCED scale) and 11 group studies (meanu2009=u20094.45 on the PEDro-P scale) were found. Baseline and intervention performance for each participant in the SCED studies was re-calculated using non-overlap of all pairs (Parker & Vannest, 2009) giving a mean score of 0.85 on a 0 to 1 scale (17 studies, nu2009=u200936). A meta-analysis of the efficacy of technology vs. control in seven group studies gave a large effect size (du2009=u20091.27) (nu2009=u2009147). It was concluded that prosthetic technology can improve performance on everyday tasks requiring memory. There is a specific need for investigations of technology for people with degenerative diseases.

Age and Gender in the Phenomenology of Depression

OBJECTIVEnAuthors investigated the effects of current age, age at onset, and gender on the phenomenology of depression.nnnMETHODSnA mixed-age sample of 810 Mood Disorders Unit attendees with a diagnosis of unipolar major depressive episode at or near its nadir were interviewed by clinician-rated and self-report instruments assessing symptoms and severity of depression.nnnRESULTSnDifferences were found in depressive phenomenology according to current age but not age at onset, confirming previous findings. Age differences on several variables were found in women only. Subjective ratings of depression severity decreased with age, whereas objective, clinician-rated severity increased.nnnCONCLUSIONSnThe pattern and severity of depression change with increasing age. Longitudinal prospective studies would further elucidate this age-gender relationship. Clinicians should be aware of the decreased likelihood of older patients reporting of depressive symptoms themselves.

Prevalence and correlates of cognitive impairment in euthymic adults with bipolar disorder: A systematic review

BACKGROUNDnPrevious reviews have identified medium-large group differences in cognitive performance in adults with bipolar disorder (BD) compared to healthy peers, but the proportion with clinically relevant cognitive impairment has not yet been established. This review aimed to quantify the prevalence of cognitive impairment in euthymic adults with BD, and to describe sociodemographic, clinical and other factors that are significantly associated with cognitive impairment.nnnMETHODSnSystematic literature review. The population was euthymic community-dwelling adults with BD, aged 18-70 years, and recruited consecutively or randomly. The outcome was cognitive impairment, relative to healthy population norms. Electronic databases and reference lists of relevant articles were searched, and authors were contacted. Original cross-sectional studies published in peer-reviewed English-language journals from January 1994 to February 2015 were included. Methodological bias and reporting bias were assessed using standard tools. A narrative synthesis is presented together with tables and forest plots.nnnRESULTSnThirty articles were included, of which 15 contributed prevalence data. At the 5th percentile impairment threshold, prevalence ranges were: executive function 5.3-57.7%; attention/working memory 9.6-51.9%; speed/reaction time 23.3-44.2%; verbal memory 8.2-42.1%; visual memory 11.5-32.9%. More severe or longstanding illness and antipsychotic medication were associated with greater cognitive impairment.nnnLIMITATIONSnThe synthesis was limited by heterogeneity in cognitive measures and impairment thresholds, precluding meta-analysis.nnnCONCLUSIONSnCognitive impairment affects a substantial proportion of euthymic adults with BD. Future research with more consistent measurement and reporting will facilitate an improved understanding of cognitive impairment burden in BD.

Pleiotropy between neuroticism and physical and mental health: findings from 108 038 men and women in UK Biobank.

People with higher levels of neuroticism have an increased risk of several types of mental disorder. Higher neuroticism has also been associated, less consistently, with increased risk of various physical health outcomes. We hypothesised that these associations may, in part, be due to shared genetic influences. We tested for pleiotropy between neuroticism and 17 mental and physical diseases or health traits using linkage disequilibrium regression and polygenic profile scoring. Genetic correlations were derived between neuroticism scores in 108u2009038 people in the UK Biobank and health-related measures from 14 large genome-wide association studies (GWASs). Summary information for the 17 GWASs was used to create polygenic risk scores for the health-related measures in the UK Biobank participants. Associations between the health-related polygenic scores and neuroticism were examined using regression, adjusting for age, sex, genotyping batch, genotyping array, assessment centre and population stratification. Genetic correlations were identified between neuroticism and anorexia nervosa (rg=0.17), major depressive disorder (rg=0.66) and schizophrenia (rg=0.21). Polygenic risk for several health-related measures were associated with neuroticism, in a positive direction in the case of bipolar disorder, borderline personality, major depressive disorder, negative affect, neuroticism (Genetics of Personality Consortium), schizophrenia, coronary artery disease, and smoking (β between 0.009–0.043), and in a negative direction in the case of body mass index (β=−0.0095). A high level of pleiotropy exists between neuroticism and some measures of mental and physical health, particularly major depressive disorder and schizophrenia.

Cognitive Test Scores in UK Biobank: Data Reduction in 480,416 Participants and Longitudinal Stability in 20,346 Participants

UK Biobank includes 502,649 middle- and older-aged adults from the general population who have undergone detailed phenotypic assessment. The majority of participants completed tests of cognitive functioning, and on average four years later a sub-group of N = 20,346 participants repeated most of the assessment. These measures will be used in a range of future studies of health outcomes in this cohort. The format and content of the cognitive tasks were partly novel. The aim of the present study was to validate and characterize the cognitive data: to describe the inter-correlational structure of the cognitive variables at baseline assessment, and the degree of stability in scores across longitudinal assessment. Baseline cognitive data were used to examine the inter-correlational/factor-structure, using principal components analysis (PCA). We also assessed the degree of stability in cognitive scores in the subsample of participants with repeat data. The different tests of cognitive ability showed significant raw inter-correlations in the expected directions. PCA suggested a one-factor solution (eigenvalue = 1.60), which accounted for around 40% of the variance. Scores showed varying levels of stability across time-points (intraclass correlation range = 0.16 to 0.65). UK Biobank cognitive data has the potential to be a significant resource for researchers looking to investigate predictors and modifiers of cognitive abilities and associated health outcomes in the general population.