Objective: The authors sought to identify predictive factors of new-onset or novel oppositional defiant disorder or conduct disorder assessed 24 months after traumatic brain injury (TBI). Methods: Children ages 5 to 14 years who had experienced TBI were recruited from consecutive hospital admissions. Soon after injury, participants were assessed for preinjury characteristics, including psychiatric disorders, socioeconomic status (SES), psychosocial adversity, and family function, and the presence and location of lesions were documented by MRI. Psychiatric outcomes, including novel oppositional defiant disorder or conduct disorder, were assessed 24 months after injury. Results: Of the children without preinjury oppositional defiant disorder, conduct disorder, or disruptive behavior disorder not otherwise specified who were recruited in this study, 165 were included in this sample; 95 of these children returned for the 24-month assessment. Multiple imputation was used to address attrition. The prevalence of novel oppositional defiant disorder or conduct disorder was 23.7 out of 165 (14%). In univariable analyses, novel oppositional defiant disorder or conduct disorder was significantly associated with psychosocial adversity (p=0.049) and frontal white matter lesions (p=0.016) and was marginally but not significantly associated with SES. In the final multipredictor model, frontal white matter lesions were significantly associated with novel oppositional defiant disorder or conduct disorder (p=0.021), and psychosocial adversity score was marginally but not significantly associated with the outcome. The odds ratio of novel oppositional defiant disorder or conduct disorder among the children with versus those without novel depressive disorder was significantly higher for girls than boys (p=0.025), and the odds ratio of novel oppositional defiant disorder or conduct disorder among the children with versus those without novel attention-deficit hyperactivity disorder (ADHD) was significantly higher for boys than girls (p=0.006). Conclusion: Approximately 14% of children with TBI developed oppositional defiant disorder or conduct disorder. The risk for novel oppositional defiant disorder or conduct disorder can be understood from a biopsychosocial perspective. Sex differences were evident for comorbid novel depressive disorder and comorbid novel ADHD.

OBJECTIVE:The investigators aimed to assess predictive factors of novel oppositional defiant disorder (ODD) among children and adolescents in the first 6 months following traumatic brain injury (TBI).METHODS:Children ages 5-14 years who experienced a TBI were recruited from consecutive admissions to five hospitals. Testing of a biopsychosocial model that may elucidate the development of novel ODD included assessment soon after injury (baseline) of preinjury characteristics, including psychiatric disorders, adaptive function, family function, psychosocial adversity, family psychiatric history, socioeconomic status, injury severity, and postinjury processing speed (which may be a proxy for brain injury). MRI analyses were also conducted to examine potential brain lesions. Psychiatric outcome, including that of novel ODD, was assessed 6 months after the injury.RESULTS:A total of 177 children and adolescents were recruited for the study, and 134 who were without preinjury ODD, conduct disorder, or disruptive behavior disorder not otherwise specified (DBD NOS) returned for the 6-month assessment. Of those who returned 6 months postinjury, 11 (8.2%) developed novel ODD, and none developed novel conduct disorder or DBD NOS. Novel ODD was significantly associated with socioeconomic status, preinjury family functioning, psychosocial adversity, and processing speed.CONCLUSIONS:These findings show that an important minority of children with TBI developed ODD. Psychosocial and injury-related variables, including socioeconomic status, lower family function, psychosocial adversity, and processing speed, significantly increase risk for this outcome.

OBJECTIVE:The investigators examined the factors predictive of novel oppositional defiant disorder in the 6-12 months following traumatic brain injury (TBI).METHODS:Children ages 5-14 years old who experienced a TBI were recruited from consecutive admissions to five hospitals. Participants were evaluated soon after injury (baseline) for preinjury characteristics, including psychiatric disorders, adaptive function, family function, psychosocial adversity, family psychiatric history, socioeconomic status, and injury severity, to develop a biopsychosocial predictive model for development of novel oppositional defiant disorder. MRI analyses were conducted to examine potential brain lesions. Psychiatric outcome, including that of novel oppositional defiant disorder, was assessed 12 months after injury.RESULTS:Although 177 children were recruited for the study, 120 children without preinjury oppositional defiant disorder, conduct disorder, or disruptive behavior disorder not otherwise specified (DBD NOS) returned for the 12-month assessment. Of these 120 children, seven (5.8%) exhibited novel oppositional defiant disorder, and none developed conduct disorder or DBD NOS in the 6-12 months postinjury. Novel oppositional defiant disorder was significantly associated with lower socioeconomic status, higher psychosocial adversity, and lower preinjury adaptive functioning.CONCLUSIONS:These results demonstrate that novel oppositional defiant disorder following TBI selectively and negatively affects an identifiable group of children. Both proximal (preinjury adaptive function) and distal (socioeconomic status and psychosocial adversity) psychosocial variables significantly increase risk for this outcome.

ObjectiveThere is a critical need to establish genetic markers that explain the complex phenotypes and pathogenicity of ALS. This study identified a polymorphism in the Stathmin-2 gene and investigated its association with sporadic ALS (sALS) disease risk, age-of onset and survival duration.MethodsThe candidate CA repeat was systematically analyzed using PCR, Sanger sequencing and high throughput capillary separation for genotyping. Stathmin-2 expression was investigated using RT-PCR in patient olfactory neurosphere-derived (ONS) cells and RNA sequencing in laser-captured spinal motor neurons.ResultsIn a case-control analysis of a combined North American sALS cohort (n = 321) and population control group (n = 332), long/long CA genotypes were significantly associated with disease risk (p = 0.042), and most strongly when one allele was a 24 CA repeat (p = 0.0023). In addition, longer CA allele length was associated with earlier age-of-onset (p = 0.039), and shorter survival duration in bulbar-onset cases (p = 0.006). In an Australian longitudinal sALS cohort (n = 67), ALS functional rating scale scores were significantly lower in carriers of the long/long genotype (p = 0.034). Stathmin-2 mRNA expression was reduced in sporadic patient ONS cells. Additionally, sALS patients and controls exhibited variable expression of Stathmin-2 mRNA according to CA genotype in laser-captured spinal motor neurons.ConclusionsWe report a novel non-coding CA repeat in Stathmin-2 which is associated with sALS disease risk and has disease modifying effects. The potential value of this variant as a disease marker and tool for cohort enrichment in clinical trials warrants further investigation.

The underlying genetic and molecular mechanisms that drive amyotrophic lateral sclerosis (ALS) remain poorly understood. Structural variants within the genome can play a significant role in neurodegenerative disease risk, such as the repeat expansion in C9orf72 and the tri-nucleotide repeat in ATXN2, both of which are associated with familial and sporadic ALS. Many such structural variants reside in uncharacterized regions of the human genome, and have been under studied. Therefore, characterization of structural variants located in and around genes associated with ALS could provide insight into disease pathogenesis, and lead to the discovery of highly informative genetic tools for stratification in clinical trials. Such genomic variants may provide a deeper understanding of how gene expression can affect disease etiology, disease severity and trajectory, patient response to treatment, and may hold the key to understanding the genetics of sporadic ALS. This article outlines the current understanding of amyotrophic lateral sclerosis genetics and how structural variations may underpin some of the missing heritability of this disease.

A variable-length poly-T variant in intron 6 of the TOMM40 gene, rs10524523, is associated with risk and age-of-onset of sporadic (late-onset) Alzheimer's disease. In Caucasians, the three predominant alleles at this locus are Short (S), Long (L) or Very long (VL). On an APOE ε3/3 background, the S/VL and VL/VL genotypes are more protective than S/S. The '523 poly-T has regulatory properties, in that the VL poly-T results in higher expression than the S poly-T in luciferase expression systems. The aim of the current work was to identify effects on cellular bioenergetics of increased TOM40 protein expression. MitoTracker Green fluorescence and autophagic vesicle staining was the same in control and over-expressing cells, but TOM40 over-expression was associated with increased expression of TOM20, a preprotein receptor of the TOM complex, the mitochondrial chaperone HSPA9, and PDHE1a, and increased activities of the oxidative phosphorylation complexes I and IV and of the TCA member α-ketoglutaric acid dehydrogenase. Consistent with the complex I findings, respiration was more sensitive to inhibition by rotenone in control cells than in the TOM40 over-expressing cells. In the absence of inhibitors, total cellular ATP, the mitochondrial membrane potential, and respiration were elevated in the over-expressing cells. Spare respiratory capacity was greater in the TOM40 over-expressing cells than in the controls. TOM40 over-expression blocked Ab-elicited decreases in the mitochondrial membrane potential, cellular ATP levels, and cellular viability in the control cells. These data suggest elevated expression of TOM40 may be protective of mitochondrial function.

A variable-length poly-T variant in intron 6 of the TOMM40 gene, rs10524523, is associated with risk and age-of-onset of sporadic (late-onset) Alzheimer's disease (AD). In Caucasians, the three predominant alleles at this locus are Short (S, T=15), Long (L, 15˂T˂30) or Very long (VL, T≥30). On an APOE e3/3 background, the S/VL and VL/VL genotypes have later ages of disease onset than S/S. TOMM40 expression is higher in AD brain lysates than in lysates of age-matched control brain. In normal tissue and in luciferase expression systems, the VL poly-T variant is more highly expressed than the S poly-T. The goal of this research was to determine how elevated Tom40 protein expression affected mitochondrial function and cellular bioenergetics. We used HeLa cells stably expressing FLAG-tagged Tom40 and control cells transfected with a vector lacking the expression sequence. We estimated mitochondrial protein abundance by Western blot, mitochondrial abundance with MitoTracker Green, autophagy by staining autophagic vesicles, the mitochondrial membrane potential via TMRM fluorescence, and we used a luminescence assay kit to quantify ATP. We measured the activities of a-ketoglutarate dehydrogenase, and oxidative phosphorylation complexes I and IV in immune-enriched fractions by spectrophotometric assays. We used the phosphorescent dye MitoXpress-Xtra to measure cellular respiration. Tom40 over-expression increased expression of Tom20, HSPA9, and increased complex I, complex IV and a-ketoglutaric acid dehydrogenase activities. There was no detectable difference in the Mitotracker green staining or staining of autophagy-related vesicles between over-expressing and control cells. The respiratory control ratio and spare respiratory capacity were greater in the Tom40 over-expressing cells than in the controls, and respiration was more sensitive to inhibition by rotenone in control cells than in the Tom40 cells. In the absence of inhibitors, total cellular ATP, the mitochondrial membrane potential, and respiration were elevated in the over-expressing cells. TOM40 over-expression blocked Ab-elicited decreases in the mitochondrial membrane potential, cellular ATP levels, and cellular viability in the control cells. These data show elevated expression of Tom40 may protect and enhance mitochondrial function.

A variable-length poly-T variant in intron 6 of the TOMM40 gene, rs10524523, is associated with risk and age-of onset of sporadic (late-onset) Alzheimer's disease. In Caucasians, the three predominant alleles at this locus are Short (S), Long (L) or Very long (VL). On an APOE epsilon 3/3 background, the S/VL and VL/VL genotypes are more protective than S/S. The '523 poly-T has regulatory properties, in that the VL poly-T results in higher expression than the S poly-T in luciferase expression systems. The aim of the current work was to identify effects on cellular bioenergetics of increased TOM40 protein expression. MitoTracker Green fluorescence and autophagic vesicle staining was the same in control and over-expressing cells, but TOM40 over-expression was associated with increased expression of TOM20, a preprotein receptor of the TOM complex, the mitochondrial chaperone HSPA9, and PDHE1a, and increased activities of the oxidative phosphorylation complexes I and IV and of the TCA member alpha-ketoglutaric acid dehydrogenase. Consistent with the complex I findings, respiration was more sensitive to inhibition by rotenone in control cells than in the TOM40 over-expressing cells. In the absence of inhibitors, total cellular ATP, the mitochondrial membrane potential, and respiration were elevated in the over expressing cells. Spare respiratory capacity was greater in the TOM40 over-expressing cells than in the controls. TOM40 over-expression blocked Ab-elicited decreases in the mitochondrial membrane potential, cellular ATP levels, and cellular viability in the control cells. These data suggest elevated expression of TOM40 may be protective of mitochondrial function.

The methodology of Genome-Wide Association Screening (GWAS) has been applied for more than a decade. Translation to clinical utility has been limited, especially in Alzheimer's Disease (AD). It has become standard practice in the analyses of more than two dozen AD GWAS studies to exclude the apolipoprotein E (APOE) region because of its extraordinary statistical support, unique thus far in complex human diseases. New genes associated with AD are proposed frequently based on SNPs associated with odds ratio (OR) < 1.2. Most of these SNPs are not located within the associated gene exons or introns but are located variable distances away. Often pathologic hypotheses for these genes are presented, with little or no experimental support. By eliminating the analyses of the APOE-TOMM40 linkage disequilibrium region, the relationship and data of several genes that are co-located in that LD region have been largely ignored. Early negative interpretations limited the interest of understanding the genetic data derived from GWAS, particularly regarding the TOMM40 gene. This commentary describes the history and problem(s) in interpretation of the genetic interrogation of the "APOE" region and provides insight into a metabolic mitochondrial basis for the etiology of AD using both APOE and TOMM40 genetics.

Personality change due to traumatic brain injury (PC) in children is an important psychiatric complication of injury and is a form of severe affective dysregulation. This study aimed to examine neurocognitive correlates of PC. The sample included 177 children 5-14 years old with traumatic brain injury who were enrolled from consecutive admissions to five trauma centers. Patients were followed up prospectively at baseline and at 6 months, and they were assessed with semistructured psychiatric interviews. Injury severity, socioeconomic status, and neurocognitive function (measures of attention, processing speed, verbal memory, IQ, verbal working memory, executive function, naming/reading, expressive language, motor speed, and motor inhibition) were assessed with standardized instruments. Unremitted PC was present in 26 (18%) of 141 participants assessed at 6 months postinjury. Attention, processing speed, verbal memory, IQ, and executive function were significantly associated with PC even after socioeconomic status, injury severity, and preinjury attention deficit hyperactivity disorder were controlled. These findings are a first step in characterizing concomitant cognitive impairments associated with PC. The results have implications beyond brain injury to potentially elucidate the neurocognitive symptom complex associated with mood instability regardless of etiology.

The objective of this prospective longitudinal study was to assess the nature, rate, predictive variables, and neuroimaging characteristics of novel (new-onset) anxiety disorders (compared with no novel anxiety disorders) 6-12 months after pediatric traumatic brain injury (TBI). Psychiatric and psy chosocial interviews were administered to children who sustained mild to severe TBI at baseline (soon after injury) and at the 12-month follow-up post-injury (n= 125). The psychiatric outcome of children 12-months post-injury revealed that novel anxiety disorders present in the second six months after TBI were heterogeneous and occurred in 13 (10.4%) participants. Novel anxiety disorder was significantly associated with concurrent novel depressive disorder and with novel personality change due to TBI. Novel anxiety disorder was marginally associated with younger age at injury and with pre-injury anxiety disorder in univariate analyses. Age at injury, pre-injury anxiety disorder, and personality change due to TBI were each significantly and independently related to novel anxiety disorder in a logistic regression analysis. There were no significant neuroimaging group differences. These findings suggest that the emergence of novel anxiety disorder after TBI might be related to a broader problem of affective dysregulation especially in younger children and those with a vulnerability even to pre-injury anxiety disorder.

Genome-wide association studies (GWAS) based on meta-analysis of large pooled studies have produced extensive lists of variants associated with late-onset Alzheimer's disease (LOAD) and diseases of aging. However, translation of this data into new clinical applications, or biochemical targets with defined mechanisms that are appropriate drug intervention points, lags behind. Most GWAS-identified variants for LOAD with the exception of APOE have a relatively weak association with disease (OR 0.9 - 1.2), and the biological function of the variants is unclear. This presentation builds on previous work to identify structural variants in the TOMM40 gene that involve noncoding variants associated with tissue-specific modulation of APOE and TOMM40. It extends the work to other loci tagged by GWAS and to other diseases of aging. Two published bioinformatics methods (preferential linkage disequilibrium and localization of a minimal region containing a causal variant) developed to prioritize causal variants based on published GWAS data and a novel database of structural variation were used to interrogate specific genomic regions associated with LOAD and human longevity. The Alzheimer's Disease Neuroimaging Initiative (ADNI) database was used to provide a cohort of LOAD cases and controls for these analytical methods. The GWAS tracks for an extended 1 megabase region of chromosome 19 were congruent for the LOAD and aging data. Variants in this region were scored for likelihood of causality. Highly polymorphic structural variants in the region were identified. This analysis was repeated for LOAD susceptibility loci (in APOE, TOMM40, CR1, CLU, PICALM, BIN1, EPHA1, MS4A, CD33, CD2AP and ABCA7) reported in 2011 and the 11 LOAD-risk loci reported by IGAP in 2013. This presentation describes the application of innovative bioinformatics tools to identify and prioritize regulatory genetic variants associated with LOAD and other diseases of aging. It is highly likely that variants in non-coding RNA, promoters and distal regulatory elements are associated with these complex phenotypes. Application of these methods has the potential to elucidate the biochemical basis for disease-gene associations, the identification of genetic biomarkers for clinical application, and analysis of biochemical pathways associated with LOAD.

The present study compared executive dysfunction among children with attention-deficit/hyperactivity disorder (ADHD) after traumatic brain injury (TBI), also called secondary ADHD (S-ADHD), pre-injury ADHD and children with TBI only (i.e., no ADHD). Youth aged 6-16 years admitted for TBI to five trauma centers were enrolled (n = 177) and evaluated with a semi-structured psychiatric interview scheduled on three occasions (within 2 weeks of TBI, i.e., baseline assessment for pre-injury status; 6-months and 12-months post-TBI). This permitted the determination of 6- and 12-month post-injury classifications of membership in three mutually exclusive groups (S-ADHD; pre-injury ADHD; TBI-only). Several executive control measures were administered. Unremitted S-ADHD was present in 17/141 (12%) children at the 6-month assessment, and in 14/125 (11%) children at 12-months post-injury. The study found that children with S-ADHD exhibited deficient working memory, attention, and psychomotor speed as compared to children with pre-injury ADHD. Furthermore, the children with S-ADHD and the children with TBI-only were impaired compared to the children with pre-injury ADHD with regard to planning. No group differences related to response inhibition emerged. Age, but not injury severity, gender, or adaptive functioning was related to executive function outcome. Neuropsychological sequelae distinguish among children who develop S-ADHD following TBI and those with TBI only. Moreover, there appears to be a different pattern of executive control performance in those who develop S-ADHD than in children with pre-injury ADHD suggesting that differences exist in the underlying neural mechanisms that define each disorder, underscoring the need to identify targeted treatment interventions.

The increasing number of individuals at risk for developing late onset Alzheimer's disease (LOAD) has shifted attention from treatment to delaying symptom onset. Research is focusing on early intervention in the AD cognitive decline continuum. Length variation of a polyT tract (rs10524523) in the TOMM40 gene has been associated with LOAD age of onset. TOMM40 is adjacent to, and in linkage disequilibrium with, the APOE gene. A biomarker risk assignment algorithm (BRAA) will identify individuals at high risk for developing mild cognitive impairment (MCI) due to AD in the next 5 years. The BRAA incorporates an individual's age and TOMM40 and APOE genotypes. TOMMORROW will simultaneously qualify a BRAA for assigning 5-year risk for developing MCI due to AD and evaluate the efficacy of low-dose pioglitazone to delay onset of MCI due to AD in cognitively normal, high-risk individuals.Low - risk subjects will be assigned to placebo; high-risk subjects will be evenly randomized to either low-dose pioglitazone or placebo. The study will enroll approximately 5800 subjects (ages 65- 83) and will apply operationalized criteria for MCI due to AD, a primary endpoint event. The anticipated treatment period is 4 years, ending when a target number (410 in the high - risk group) of primary endpoint diagnoses have been reached. Along with the Clinical Dementia Rating scale, key assessments that enable the diagnosis are 12 neuropsychological measures representing 5 key cognitive domains affected in early AD. A separate neuropsychological instrument validation strategy will ensure that the test measures perform consistently across cultures and languages.Approximately 50 sites in 7 countries will participate. The study was initiated in summer 2013 in the US and in the EU and Australia in late 2013/early 2014. To date, over 1,000 subjects have been screened and over 160 subjects randomized. The study was designed with input from international experts and finalized following discussions with US and EU regulatory authorities. It represents a unique opportunity to qualify the BRAA to stratify risk of developing MCI due to AD in the next 5 years and to explore therapeutic intervention in the earliest phase of the AD continuum.

The objective was to assess the nature, rate, predictive factors, and neurocognitive correlates of novel psychiatric disorders (NPD) after mild traumatic brain injury (MTBI). Children age 5-14 years with MTBI (N=87) from consecutive admissions to five trauma centers were enrolled and studied with semistructured psychiatric interviews soon after injury (baseline), and 70 of these children were assessed again 6 months post-injury. Injury severity; lesion characteristics; pre-injury variables, including psychiatric disorder, family psychiatric history, family functioning, socioeconomic status, psychosocial adversity, and adaptive functioning; and post-injury neurocognitive and adaptive functioning measures were assessed with standardized instruments. NPD occurred in 25 of 70 participants (36%) in the first 6 months after injury. NPD at 6 months was predicted by the presence of frontal white-matter lesions on MRI at 3 months post-injury, and was associated with concurrent decrements on neurocognitive indices of processing speed, expressive language, and intellectual functioning. NPD was not predicted by other indices of severity, pre-injury psychosocial variables, estimated pre-injury academic functioning, or adaptive and executive function decrements 6 months post-injury. These findings suggest that short-term psychiatric morbidity associated with MTBI in children and adolescents may be more common than previously thought and may have readily identifiable neuroimaging and neurocognitive correlates.

The use of biomarkers to identify individuals at risk for developing late-onset Alzheimer's disease (LOAD) is of interest for the design of therapeutic prevention or delay - of - onset clinical trials. A biomarker risk assignment algorithm (BRAA) based on APOE and TOMM40 '523 genotypes and age is being used to enrich an international phase 3, double-blind, randomized, placebo-controlled clinical trial. This presentation reports preliminary data on the performance of the BRAA, specifically precision of the BRAA as a function of the experimental variation of the genotype assays, predictive characteristics of the algorithm to identify MCI due to AD, and comparative data for CSF and imaging (fMRI) based biomarkers. A simulation study was performed to determine how the experimental variation of the APOE and TOMM40 '523 assays impacts the risk assignment by the BRAA. Performance of the BRAA (odds ratio, improvement in net reclassification rate vs. versions of the algorithm based only on age and/or APOE genotype) was calculated in a retrospective analysis of the Alzheimer's Disease Neuroimaging Initiative data (n = 660). Its performance (sensitivity and specificity) was compared to data from literature reports for proposed CSF and fMRI biomarkers. The simulation study shows the expected precision of the BRAA to be >98%, based on the observed experimental variation of the TOMM40 '523 and APOE assays. The odds ratio for using the algorithm to predict MCI or LOAD ranges from 3 to 5, and comparison of the full algorithm to a version based on APOE and age alone shows a significant (p < 0.0001) improvement in the net reclassification rate. The performance of this informative genotype BRAA compares favorably (PPV, NPV 70–80%) with CSF and imaging (fMRI) biomarkers. The performance characteristics of the biomarker risk algorithm support its use as a pharmacogenetic enrichment tool for stratification of individuals at high or low risk for developing MCI due to AD in a phase 3 clinical trial. The data from this prospective trial will be used to support qualification of the BRAA by regulatory agencies.

The objective of this study was to understand how novel psychiatric disorders (NPD) in children with mild traumatic brain injury (MTBI) are related to pre-injury variables, injury-related variables, and concurrent neurocognitive outcome. A group of 79 children, ages 5 to 14 years, who had experienced MTBI, were studied from consecutive hospital admissions with semistructured psychiatric interviews soon after injury (baseline); 60 children were reassessed 12 months post-injury. Standardized instruments were used to assess injury severity; lesion characteristics; pre-injury variables, including psychiatric disorder, family psychiatric history, family functioning, socioeconomic status, psychosocial adversity, adaptive functioning, and post-injury neurocognitive and adaptive functioning. NPD occurred in 17 of 60 participants (28%) in the 6-12-month interval after injury, with disorders that were significantly associated with socioeconomic status, psychosocial adversity, estimated pre-injury academic functioning, and concurrent deficits in adaptive functioning, academic performance, processing speed, memory, and expressive language. NPD was not significantly associated with pre-injury adaptive functioning, injury severity, family psychiatric history, pre-injury psychiatric disorder, lesion location, gender, or age at injury. These findings suggest that the short-term psychiatric morbidity associated with MTBI in children occurs more commonly than previously reported and is related to both pre-injury social factors and concurrent neurocognitive functioning.

TOMM40 encodes the channel subunit of the t ranslocase of the o uter m itochondrial m embrane and the gene is in linkage disequilibrium with APOE. The length of a poly-T variant ('523') within intron 6 of TOMM40 predicts the age of onset of late onset AD (LOAD), however the functional mechanism associated with this variant is unknown. Additionally, homozygosity for the longer allele (VL,VL) demonstrates dichotomy in age of disease onset (i.e. either early or very-late onset). Recently, Bekris et al. (2011) analyzed the function of cis-elements within the TOMM40 - APOE locus using human cell lines and demonstrated that multiple haplotypes of polymorphic sites, including ‘523’, differentially influence APOE and TOMM40 expression in different cell types. Our analysis shows that regulatory haplotypes are also associated with age of LOAD onset. We examined the association of the APOE - TOMM40 haplotypes described by Bekris et al. with age of LOAD onset for two cohorts from the Duke and Arizona (TGEN) ADRCs for which Sanger sequencing data was available for much of the TOMM40 - APOE region. The IVS2–4 haplotype described by Bekris et al. is significantly (P< 0.04) associated with age of disease onset; haplotype 2 is associated with later age of onset (approximately 80 years vs. 70 years) in the cohort where this region was sequenced (n = 44). Haplotypes containing IVS6 ('523') demonstrated the same rank order of age of onset in both cohorts although statistical significance (P = 0.015) was reached only in the second cohort (n = 66). In the second cohort, APOE4 allele linked to a ‘523’ L shows a difference in age of onset (67 years vs. 71 years) conditional with a SNP at 45,403,216. Our results show an association between the extended haplotypes and age of disease onset. These results support the findings of Bekris et al. and further suggest that the association of age of LOAD onset with TOMM40 polymorphisms might be modified by an extended TOMM40 - APOE haplotype. Further investigation is needed to determine if specific polymorphic loci within these haplotypes explain the dichotomy in age of LOAD onset observed in the VL/VL subgroup of the TOMM40 ‘523’ genotype.

The objective was to assess the nature, rate, predictive factors, and neuroimaging correlates of novel (new-onset) depressive disorders, both definite and subclinical, after traumatic brain injury (TBI). Children with TBI from consecutive admissions were enrolled and studied with psychiatric interviews soon after injury (baseline), and again 6 months post-injury. Novel definite/subclinical depressive disorders at 6-month follow up occurred in 11% (n=15) of the children and subsets of children with non-anxious depression (n=9) and anxious depression (n=6) were identified. Novel definite/subclinical depressive disorder was significantly associated with older age at the time of injury, family history of anxiety disorder, left inferior frontal gyrus (IFG) lesions, and right frontal white matter lesions. Non-anxious depressions were associated with older age at injury, left IFG and left temporal pole lesions. Anxious depressions were associated with family history of anxiety disorder, Personality Change due to TBI, right frontal white matter lesions, and left parietal lesions. These findings, which are similar to those reported after adult TBI, identify both similarities and differences in non-anxious and anxious depression following childhood TBI with respect to lesion laterality, genetic factors (in the form of family psychiatric history of anxiety disorder), age at injury, and more generalized affective dysregulation.