Conjoint Professor Peter Schofield

© 2018 Lippincott Williams and Wilkins. All rights reserved. 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.

© 2018 Elsevier B.V. Background: Many factors contribute to exceptional longevity, with genetics playing a significant role. However, to date, genetic studies examining exceptional longevity have been inconclusive. This comprehensive review seeks to determine the genetic variants associated with exceptional longevity by undertaking meta-analyses. Methods: Meta-analyses of genetic polymorphisms previously associated with exceptional longevity (85+) were undertaken. For each variant, meta-analyses were performed if there were data from at least three independent studies available, including two unpublished additional cohorts. Results: Five polymorphisms, ACE rs4340, APOE e2/3/4, FOXO3A rs2802292, KLOTHO KL-VS and IL6 rs1800795 were significantly associated with exceptional longevity, with the pooled effect sizes (odds ratios) ranging from 0.42 (APOE e4) to 1.45 (FOXO3A males). Conclusion: In general, the observed modest effect sizes of the significant variants suggest many genes of small influence play a role in exceptional longevity, which is consistent with results for other polygenic traits. Our results also suggest that genes related to cardiovascular health may be implicated in exceptional longevity. Future studies should examine the roles of gender and ethnicity and carefully consider study design, including the selection of appropriate controls.

© 2017, Southern Criminal Justice Association. 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.

© 2016 AMDA ¿ The Society for Post-Acute and Long-Term Care Medicine Background The nature and commonality of late-life risk factors for mild cognitive impairment (MCI), dementia, and mortality remain unclear. Our aim was to investigate potential risk factors, simultaneously in a single cohort including many individuals initially with normal cognition and followed for 6¿years. Methods We classified 873 community-dwelling individuals (70¿90¿years old and without dementia at baseline) from the Sydney Memory and Ageing Study as cognitively normal (CN), having MCI or dementia, or deceased 6¿years after baseline. Associations with baseline demographic, lifestyle, health, and medical factors were investigated, including apolipoprotein (APOE) genotype, MCI at baseline, and reversion from MCI to CN within 2¿years of baseline. Results Eighty-three (9.5%) participants developed dementia and 114 (13%) died within 6¿years; nearly 33% had MCI at baseline, of whom 28% reverted to CN within 2¿years. A core set of baseline factors was associated with MCI and dementia at 6¿years, including older age (per year: odds ratios and 95% confidence intervals¿=¿1.08, 1.01¿1.14 for MCI; 1.19, 1.09¿1.31 for dementia), MCI at baseline (5.75, 3.49¿9.49; 8.23, 3.93¿17.22), poorer smelling ability (per extra test point: 0.89, 0.79¿1.02; 0.80, 0.68¿0.94), slower walking speed (per second: 1.12, 1.00¿1.25; 1.21, 1.05¿1.39), and being an APOE e4 carrier (1.84, 1.07¿3.14; 3.63, 1.68¿7.82). All except APOE genotype were also associated with mortality (age: 1.11, 1.03¿1.20; MCI: 3.87, 1.97¿7.59; smelling ability: 0.83, 0.70¿0.97; walking speed: 1.18, 1.03¿1.34). Compared with stable CN participants, individuals reverting from MCI to CN after 2¿years were at greater risk of future MCI (3.06, 1.63¿5.72). Those who reverted exhibited some different associations between baseline risk factors and 6-year outcomes than individuals with stable MCI. Conclusion A core group of late-life risk factors indicative of physical and mental frailty are associated with each of dementia, MCI, and mortality after 6¿years. Tests for slower walking speed and poorer smelling ability may help screen for cognitive decline. Individuals with normal cognition are at greater risk of future cognitive impairment if they have a history of MCI.

© 2017, American Psychiatric Association. All rights reserved. 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.

© 2017 Elsevier Inc. 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.

© 2017 - IOS Press and the authors. All rights reserved. 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.

© 2016 Macmillan Publishers Limited All rights reserved. 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.

© 2015, BMJ Publishing Group. All rights reserved. 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.

© 2015 Macmillan Publishers Limited. 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.

© 2015 Society of Biological Psychiatry. 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.

© 2014 - IOS Press and the authors. All rights reserved. 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.

Alzheimer disease (AD) is a genetically heterogenous disorder; in rare cases autosomal dominantly inherited mutations typically cause early-onset familial AD (EOAD), whereas the risk for late-onset AD (LOAD) is generally modulated by genetic variants with relatively low penetrance but high prevalence, with variants in apolipoprotein E (APOE) being a firmly established risk factor. This article presents an overview of the current literature on the psychological and behavioral impact of genetic testing for AD. The few studies available for presymptomatic testing for EOAD showed that only a very small proportion of individuals had poor psychological outcomes as a result. Initial interest in testing for EOAD decreases significantly after identification of a specific mutation in a kindred, suggesting that interest and potential for knowledge may not translate into actual testing uptake. The majority of individuals from both the general population and those with a family history of AD had positive attitudes towards, and were interested in, susceptibility testing for APOE. Motivations for genetic testing included to provide information for future planning and to learn about one's own and one's children's risks of developing AD. Although susceptibility testing for APOE genotype is not currently recommended due to the lack of clinical utility, this review demonstrates that there is interest in testing and no obvious adverse psychological effects to those who have been tested. © 2012 Mary Ann Liebert, Inc.