Conjoint Professor Peter Schofield

Preventing dropout (attrition) from clinical trials is vital for improving study validity. Dropout is particularly important in justice-involved populations as they can be very challenging to engage and recruit in the first instance. This study identifies factors associated with dropout in a double-blind, placebo-controlled randomised control trial of a selective serotonin reuptake inhibitor (SSRI) aimed at reducing reoffending in highly impulsive men with histories of violent offending. Age, education, social support, psychiatric history, and length of previous incarceration were identified as factors that predict attrition. These findings are consistent with previous research examining variables associated with attrition in clinical trials for community and offender populations. We also explored referral source and treatment allocation as attrition predictors. Although neither significantly predicted attrition, we identified that there are discernible differences in the median time to attrition among the referral source subgroups. Understanding factors that predict treatment completion and attrition will allow researchers to identify participants for whom additional provisions may optimise retention and inform development of targeted interventions.

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

Background: An association exists between psychosis and criminal offending, which evidence suggests can be reduced by effective mental health care for this vulnerable population. However mental health services often lose contact with people after diagnosis. The association between the first episode of psychosis and criminal offending highlights the need for effective mental health care for this vulnerable population. Aims: To investigate the association between the first diagnosis of psychosis (FDP) in prison or hospital and subsequent mental health service contact following release from prison or discharge from hospital. Materials and methods: Individuals with a FDP either in prison (n = 492) or hospital setting (n = 24,910) between July 2006 and December 2011 in NSW (Australia), were followed post-release or discharge until their first mental health service contact in the community, the occurrence of an offence, death, or completion of the study period at the end of December 2012. Cox regression models were used to examine the predictors for the mental health service contacts following release or discharge. Results: Over 70% of those with a FDP in prison or hospital had a psychosis-related or any community-based mental health service contact following release or discharge between July 2006 and December 2012. Those with a FDP in prison were more likely to have no contact with mental health services than those in hospital with no prior offence record (hazard ratio, HR = 3.14, 95% CI: 2.66¿3.72 and adjusted hazard ratio, aHR = 3.05, 95% CI: 2.56¿3.63) within a median follow-up time of 25 days for the prison group and 26 days for hospital group. Males, individuals of Aboriginal heritage and individuals diagnosed with substance-related psychoses compared to those with schizophrenia and related psychoses were less likely to have a mental health service contact following release or discharge in both the univariable and multivariable analysis. Conclusion: This study suggests that prior offending or a previous prison episode represents a barrier to mental health service contact in the community for those with a FDP. Effective rehabilitation planning while exiting prison and discharge planning from hospital are essential to the successful reintegration of these individuals with a FDP.

There is a lack of evidence to determine if diet quality is associated with cognitive performance in older adults. Therefore, the aim of this study was to examine whether diet quality is associated with cognitive performance among older adults. A cross-sectional, secondary analysis of baseline data from the Hunter Community Study (HCS), comparing diet quality, measured using the Australian Recommended Food Score (ARFS), along with validated cognitive performance instruments the Audio Recorded Cognitive Screen (ARCS) and the Mini-Mental State Examination (MMSE) were undertaken in adults aged 55¿85 years, living in Newcastle, NSW, Australia. Adjusted linear regression analyses showed that, compared with the lowest ARFS quintile, those in the highest quintile had an ARCS score 5.883 units greater (p < 0.001; R2 = 0.0098). Furthermore, when quintiles of ARFS score were tested against each ARCS sub-scale score, statistically significant associations were observed with the greatest effect for the Memory (ß = 4.055; p = 0.001; R2 = 0.0065) and Attention (ß = 4.136; p = 0.002; R2 = 0.0047) domains. No statistically significant associations were observed between quintiles of ARFS and MMSE score in the adjusted linear regression analyses. In conclusion, a positive association was observed between diet quality and cognitive performance within this sample of older Australian adults. Further investigation of the above association over time, when follow-up data becomes available, in longitudinal analysis is recommended.

This population-based case-control study examines the association between psychosis and criminal convictions in New South Wales (NSW), Australia, using data from several health and offending administrative data collections. Cases were individuals diagnosed with psychosis between 2001 and 2012 (n = 86,461). For each case, two age- and sex-matched controls with no diagnosis of psychosis were selected. Criminal convictions were identified using the NSW Reoffending Database. Cases were approximately 5 times more likely to offend compared with controls, adjusted odds ratio (aOR) = 4.68, 95% confidence interval (CI) = [4.55, 4.81], and accounted for 10% of all criminal convictions in NSW between 2001 and 2015. The prevalence of at least one criminal conviction was 30% among cases compared with 6% among controls. The results from this study confirm previous work regarding the association between psychosis and criminal convictions. More work is needed to better articulate the mechanisms for this association to enable prevention strategies to be developed.

Structural grey matter covariance networks provide an individual quantification of morphological patterns in the brain. The network integrity is disrupted in sporadic Alzheimer's disease, and network properties show associations with the level of amyloid pathology and cognitive decline. Therefore, these network properties might be disease progression markers. However, it remains unclear when and how grey matter network integrity changes with disease progression. We investigated these questions in autosomal dominant Alzheimer's disease mutation carriers, whose conserved age at dementia onset allows individual staging based upon their estimated years to symptom onset. From the Dominantly Inherited Alzheimer Network observational cohort, we selected T1-weighted MRI scans from 269 mutation carriers and 170 non-carriers (mean age 38 ± 15 years, mean estimated years to symptom onset-9 ± 11), of whom 237 had longitudinal scans with a mean follow-up of 3.0 years. Single-subject grey matter networks were extracted, and we calculated for each individual the network properties which describe the network topology, including the size, clustering, path length and small worldness. We determined at which time point mutation carriers and non-carriers diverged for global and regional grey matter network metrics, both cross-sectionally and for rate of change over time. Based on cross-sectional data, the earliest difference was observed in normalized path length, which was decreased for mutation carriers in the precuneus area at 13 years and on a global level 12 years before estimated symptom onset. Based on longitudinal data, we found the earliest difference between groups on a global level 6 years before symptom onset, with a greater rate of decline of network size for mutation carriers. We further compared grey matter network small worldness with established biomarkers for Alzheimer disease (i.e. amyloid accumulation, cortical thickness, brain metabolism and cognitive function). We found that greater amyloid accumulation at baseline was associated with faster decline of small worldness over time, and decline in grey matter network measures over time was accompanied by decline in brain metabolism, cortical thinning and cognitive decline. In summary, network measures decline in autosomal dominant Alzheimer's disease, which is alike sporadic Alzheimer's disease, and the properties show decline over time prior to estimated symptom onset. These data suggest that single-subject networks properties obtained from structural MRI scans form an additional non-invasive tool for understanding the substrate of cognitive decline and measuring progression from preclinical to severe clinical stages of Alzheimer's disease.

Context: Long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFAs) are widely considered as nootropic agents that may be beneficial in reversing cognitive impairment. Objective: The present systematic review of randomized controlled trials was conducted to determine the changes in cognitive function after intervention with LCn-3PUFA supplementation in non-demented adults, including those with mild cognitive impairment. Data Sources: Five databases (MEDLINE, CINAHL, Scopus, EMBASE, and the Cochrane Library) were searched systematically along with reference lists of selected articles. Study Selection: Studies were eligible for inclusion if they measured the effect of LCn-3PUFA supplementation on cognition in non-demented adults. Data Extraction: A total of 787 records were screened, of which 25 studies were eligible for inclusion. Treatment effects were summarized as global cognitive function for primary outcome and measured using the Mini-Mental State Examination and individual cognitive domains for secondary outcome. The pooled effect sizes were estimated using Hedge's g and random-effects modeling. Data Analysis: Results from randomized controlled trials indicate that LCn-3PUFAs have no effect on global cognitive function (Hedge's g = 0.02; 95% confidence interval, -0.12 to 0.154), and among the specific cognitive domains, only memory function showed a mild benefit (Hedge's g = 0.31; P = 0.003; z = 2.945). Conclusion: The existing literature suggests that LCn-3PUFA supplementation could provide a mild benefit in improving memory function in non-demented older adults. Systematic Review Registration: PROSPERO registration no. CRD42017078664.

Background: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer¿s disease (AD) pathology, and short-term change in odor identification impairment with cholinesterase inhibitor (CheI) treatment may predict longer term cognitive outcomes. Objective: In patients with mild cognitive impairment (MCI) treated prospectively with donepezil, a CheI, for 52 weeks, to determine if 1) acute decline in odor identification ability with anticholinergic challenge can predict cognitive improvement, and 2) change in odor identification over 8 weeks can predict cognitive improvement. Methods: MCI was diagnosed clinically without AD biomarkers. At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5mg daily, increased to 10 mg daily if tolerated, and this dose was maintained for 52 weeks. Main outcomes were ADAS-Cog total score and Selective Reminding Test (SRT) total immediate recall score measured at baseline, 26 and 52 weeks. Results: In 100 study participants, mean age 70.14 (SD 9.35) years, atropine-induced decrease in UPSIT score at baseline was not associated with change in ADAS-Cog or SRT scores over 52 weeks. Change in UPSIT score from 0 to 8 weeks did not show a significant association with change in the ADAS-Cog or SRT measures over 52 weeks. Conclusion: These negative findings in a relatively large sample of patients with MCI did not replicate results in much smaller samples. Change in odor identification with anticholinergic challenge, and over 8 weeks, may not be useful predictors of cognitive improvement with CheI in patients with MCI.

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

Primary objective: To identify correlates of past traumatic brain injury (TBI) in a population of young offenders. Research design: Cross-sectional analyses were conducted on available data from a sample derived from the NSW Young People on Community Orders Health Survey. Procedures: Study participants were administered questionnaires to collect history relating to past TBI, childhood trauma, substance abuse, and psychological/psychiatric symptoms and underwent assessments of intellectual functioning. Information on offending history was accessed through Juvenile Justice administrative records. Outcomes and results: Analyses were undertaken on data from 788 young offenders (672 males and 116 females). A past TBI was reported in 39%. Symptoms of psychological distress were more prevalent in females. A history of TBI was associated with more symptoms on a Childhood Trauma Questionnaire, as well as higher psychological distress (K-10), and higher levels on standardized measures of anger/violence, post-traumatic stress, and substance abuse. Conclusions: The experience of early life trauma warrants further consideration as an antecedent to both childhood TBI and offending which might account for some of the previously observed association of mild TBI with subsequent offending behavior.

Background With significant numbers of individuals in the criminal justice system having mental health problems, court-based diversion programmes and liaison services have been established to address this problem.AimsTo examine the effectiveness of the New South Wales (Australia) court diversion programme in reducing re-offending among those diagnosed with psychosis by comparing the treatment order group with a comparison group who received a punitive sanction.MethodThose with psychoses were identified from New South Wales Ministry of Health records between 2001 and 2012 and linked to offending records. Cox regression models were used to identify factors associated with re-offending.ResultsA total of 7743 individuals were identified as diagnosed with a psychotic disorder prior to their court finalisation date for their first principal offence. Overall, 26% of the cohort received a treatment order and 74% received a punitive sanction. The re-offending rate in the treatment order group was 12% lower than the punitive sanction group. 'Acts intended to cause injury' was the most common type of the first principal offence for the treatment order group compared with the punitive sanction group (48% v. 27%). Drug-related offences were more likely to be punished with a punitive sanction than a treatment order (12% v. 2%).ConclusionsAmong those with a serious mental illness (i.e. psychosis), receiving a treatment order by the court rather than a punitive sanction was associated with reduced risk for subsequent offending. We further examined actual mental health treatment received and found that receiving no treatment following the first offence was associated with an increased risk of re-offending and, so, highlighting the importance of treatment for those with serious mental illness in the criminal justice system.

Objective: To evaluate the individual- and population-level impact of a combination of factors, including traumatic brain injury (TBI) and certain maternal characteristics, on subsequent criminal conviction. Design and Participants: A retrospective record linkage study involving a cohort of 30 599 individuals born between 1980 and 1985, with ratio of 1 (with TBI): 3 (no TBI), matched by sex and the year of birth. Methods and procedures: Cox proportional hazard regression models and population attributable risk percentages (PAR%) were used to assess the contribution of TBI and other risk factors on subsequent criminal convictions. Main Outcomes and results: Overall, individuals born to the teenaged mothers (<20 years) have significantly higher proportion of TBI than those born to older mothers (35% vs 22%; P <.001). In the gender-specific analyses, a history of TBI was associated with increased risk for criminal convictions (adjusted hazard ratio [aHR]: 1.48, 95% confidence interval [CI]: 1.36-1.60, and aHR: 1.45, 95% CI: 1.22-1.73, for men and women, respectively). Maternal characteristics (maternal age, single parent, multiparity) were identified as the greater contributor to the criminal convictions (PAR%: 57% and 67% for men and women, respectively). The combined impact of mental illness, maternal factors, and TBI was estimated to be 67% and 74% (for men and women, respectively); with nonoverlapping 95% CIs for PAR%, these factors were estimated to have had a higher impact among females than among males. Conclusion: More than half of the criminal convictions were associated with a relatively small number of risk factors, including poor mental health, low socioeconomic status, and TBI as well as certain maternal characteristics.

Public expenditure on the criminal justice system represents a significant fiscal burden to government worldwide, making the economic evaluation of interventions aimed at improving justice outcomes critical to informing resource allocation. This study systematically reviews and assesses the scope and quality of economic evaluations of behavioral interventions aimed at reducing reoffending. Only seventeen studies met the inclusion criteria, with wide variation in methodological approaches, including differences in costing perspectives, study design, and the definition of cost and outcome measures. The majority of behavioral interventions for offenders remain unevaluated from an economic perspective, representing a significant evidence gap for informing cost-effective and efficient allocation decision. Based on the studies reviewed, economic benefit can be derived from investing in offender behavioral programs. However, whether this investment represents ¿value for money¿ remains unclear. What is clear is that economic evaluations in the justice health sector lag behind research in other areas of public policy.

Neurological and psychological symptoms in multiple sclerosis can affect cognitive function. The objective of this study was to explore the relationship between psychological measures and cognitive performance in a patient cohort. In 322 multiple sclerosis patients, psychological symptoms were measured using the Depression Anxiety and Stress Scale, and cognitive function was evaluated using Audio Recorded Cognitive Screen. Multifactor linear regression analysis, accounting for all clinical covariates, found that anxiety was the only psychological measure to remain a significant predictor of cognitive performance (p<0.001), particularly memory function (p<0.001). Further prospective studies are required to determine whether treatment of anxiety improves cognitive impairment.

Apolipoproteins play a crucial role in lipid metabolism with implications in cardiovascular disease, obesity, diabetes, Alzheimer's disease, and longevity. We quantified 7 apolipoproteins in plasma in 1067 individuals aged 56¿105 using immunoassays and explored relationships with APOE polymorphism e2/3/4, vascular health, frailty, and cognition. ApoA1, ApoA2, ApoB, ApoC3, ApoE, ApoH, and ApoJ decreased from mid-life, although ApoE and ApoJ had U-shaped trends. Centenarians had the highest ApoE levels and the lowest frequency of APOE e4 allele relative to younger groups. Apolipoprotein levels trended lower in APOE e4 homozygotes and heterozygotes compared with noncarriers, with ApoE and ApoJ being significantly lower. Levels of all apolipoproteins except ApoH were higher in females. Sex- and age-related differences were apparent in the association of apolipoproteins with cognitive performance, as only women had significant negative associations of ApoB, ApoE, ApoH, and ApoJ in mid-life, whereas associations at older age were nonsignificant or positive. Our findings suggest levels of some apolipoproteins, especially ApoE, are associated with lifespan and cognitive function in exceptionally long-lived individuals.

Background: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer's disease pathology. Objective: To determine if decline in odor identification ability with anticholinergic challenge can predict improvement with donepezil, a cholinesterase inhibitor (ChEI), in patients with mild cognitive impairment (MCI). Methods: At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and then the dose was kept constant for 52 weeks. Main outcomes were change in Selective Reminding Test (SRT) total immediate recall and ADAS-Cog total score from baseline to 26 and 52 weeks. Results: In 37 participants, mean age 70.4 (SD 9.8) y, greater atropine-induced decrease in UPSIT score at baseline was associated with greater improvement in SRT total recall score from baseline to 26 and 52 weeks (p < 0.03). This effect remained after adjusting for time, age, education, gender, APOE ¿4 status, and baseline cognitive score (p < 0.05). Decrease in UPSIT score was associated with global improvement (CIBIC-plus) over 52 weeks (p < 0.02). After excluding patients with congential anosmia, increase in UPSIT score from 0 to 8 weeks showed a trend-level association with improvement on the ADAS-Cog (p = 0.07). Conclusions: Anticholinergic challenge-induced odor identification decline was associated with cognitive improvement, and short-term improvement in odor identification tended to predict longer term cognitive improvement. These simple inexpensive strategies have the potential to improve selection of patients with MCI for ChEI treatment.

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10 -8) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10 -9 after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10 -4). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10 -15), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10 -11) and neuron cell-cell adhesion (P-value=1.48 × 10 -13). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

Apolipoprotein H (ApoH) is a multi-functional plasma glycoprotein that has been associated with negative health outcomes. ApoH levels have high heritability. We undertook a genome-wide association study of ApoH levels using the largest sample to date and replicated the results in an independent cohort (total N = 1,255). In the discovery phase, a meta-analysis of two cohorts, the Sydney Memory and Ageing Study (Sydney MAS) and the Older Australian Twins Study (OATS) (n = 942) revealed genome-wide significant results in or near the APOH gene on chromosome 17 (top SNP, rs7211380, p = 1 × 10-11). The results were replicated in an independent cohort, the Hunter Community Study (p < 0.002) (n = 313). Conditional and joint analysis (COJO) confirmed the association of the chromosomal 17 region with ApoH levels. The set of independent SNPs identified by COJO explained 23% of the variance. The relationships between the top SNPs and cardiovascular/lipid/cognition measures and diabetes were assessed in Sydney MAS, with suggestive results observed for diabetes and cognitive performance. However, replication of these results in the smaller OATS cohort was not found. This work provides impetus for future research to better understand the contribution of genetics to ApoH levels and its possible impacts on health.

Objectives: Concussion remains one of the inherent risks of participation in rugby league. While other injuries incurred by rugby league players have been well studied, less focus and attention has been directed towards concussion. Review method: The current review examined all articles published in English from 1900 up to June 2013 pertaining to concussion in rugby league players. Data sources: Publications were retrieved via six databases using the key search terms: rugby league, league, football; in combination with injury terms: athletic injuries, concussion, sports concussion, sports-related concussion, brain concussion, brain injury, brain injuries, mild traumatic brain injury, mTBI, traumatic brain injury, TBI, craniocerebral trauma, head injury and brain damage. Observational, cohort, correlational, cross-sectional and longitudinal studies were all included. Results: 199 rugby league injury publications were identified. 39 (20%) were related in some way to concussion. Of the 39 identified articles, 6 (15%) had the main aim of evaluating concussion, while the other 33 reported on concussion incidence as part of overall injury data analyses. Rugby league concussion incidence rates vary widely from 0.0 to 40.0/1000 playing hours, depending on the definition of injury (time loss vs no time loss). The incidence rates vary across match play versus training session, seasons (winter vs summer) and playing position (forwards vs backs). The ball carrier has been found to be at greater risk for injury than tacklers. Concussion accounts for 29% of all injuries associated with illegal play, but only 9% of injuries sustained in legal play. Conclusions: In comparison with other collision sports, research evaluating concussion in rugby league is limited. With such limited published rugby league data, there are many aspects of concussion that require attention, and future research may be directed towards these unanswered questions.

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10-9, MIR2113; rs17522122, P=2.55 × 10-8, AKAP6; rs10119, P=5.67 × 10-9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10-6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10-17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged =45 years. Replication of suggestive associations (p < 5 × 10-6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10-10) and replication cohorts (p = 5.65 × 10-8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10-8, and rs6813517 [SPOCK3], p = 2.58 × 10-8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

There are a growing number of large cohorts of older persons with genome-wide genotyping data available, but APOE is not included in any of the common microarray platforms. We compared directly measured APOE genotypes with those imputed using microarray data and the '1000 Genomes' dataset in a sample of 320 Caucasians. We find 90% agreement for e2/e3/e4 genotypes and 93% agreement for predicting e4 status, yielding kappa values of 0.81 and 0.84, respectively. More stringent thresholds around allele number estimates can increase this agreement to 90-97% and kappas of 0.90-0.93.

The brain changes associated with Alzheimer's disease (AD) develop slowly over many years before the onset of dementia. Biomarkers for AD that allow its detection during this clinically silent phase will be hugely important when disease-modifying treatments that halt or slow its progression become available. Early detection, leading to early treatment, may in some cases avert dementia. Biomarkers aid our understanding of the presymptomatic stages of the disease and enable the identification of individuals with early disease who, by participating in clinical trials of investigational treatments with disease-modifying potential, contribute unique and vital information necessary to evaluate novel therapies. Most currently available AD biomarkers are expensive and not widely available and there are major efforts underway to find cheaper, simpler options. The olfactory system is affected by AD and the results from simple and inexpensive tests of the sense of smell, especially when paired with other information, can help identify individuals early in the disease. We review recent literature relevant to the use of simple olfactory tests, including some novel approaches, as aids to the early detection of AD. We consider their possible role in the design and conduct of clinical trials and suggest how in the future, when more effective treatments become available, they might be integrated into screening programs for early AD detection. © 2014 Springer Science+Business Media New York.

Traumatic brain injury (TBI) is a common condition that is often complicated by neuropsychiatric sequelae that can have major impacts on function and quality of life. An alteration in the sense of smell is recognized as a relatively common complication of TBI; however in clinical practice, this complication may not be sought or adequately characterized. We conducted a systematic review of studies concerned with olfactory functioning following TBI. Our predetermined criteria led to the identification of 25 studies published in English, which we examined in detail. We have tabulated the data from these studies in eight separate tables, beginning with Table 1, which highlights each study's key findings, and we provide a summary/synthesis of the findings in the accompanying results and discussion sections. Despite widely differing methodologies, the studies attest to a high frequency of post-TBI olfactory dysfunction and indicate that its presence can serve as a potential marker of additional structural or functional morbidities. © 2014 Schofield, Moore and Gardner.