Conceptualizing impulsivity as a construct in relation to posttraumatic stress disorder symptom severity among women.

Despite the established association between posttraumatic stress disorder (PTSD) and impulsivity, the literature is limited regarding impulsivity as a multifaceted construct. That is, the field's understanding of how PTSD symptoms may increase particular impulsive tendencies and behaviors is constrained by examining impulsivity solely as an umbrella term. The aim of the present study was to determine if there are differential associations between PTSD symptom severity and various components of impulsivity across multiple self-report measures. A sample of 215 undergraduate women (M age = 19.77 years, SD = 1.91, Range: 18-39 years) completed the PTSD Checklist for DSM-5 (PCL-5), Barratt Impulsiveness Scale (BIS-11), short version of the UPPS-P Impulsive Behavior Scale (SUPPS-P), and Delaying Gratification Inventory (DGI). Structural equation modeling was used to examine associations between PTSD symptoms and each measure's subscales. The findings included significant predictions from PTSD symptoms to the BIS-11 Attentional Impulsiveness subscale, ß = .23, SE = .07, 95% CI [.09, .37]; DGI Physical Pleasures, ß = -.24, SE = .07, 95% CI [-.38, -.11], and Achievement subscales, ß = -.19, SE = .08, 95% CI [-.34, -.04]; and the SUPPS-P Positive Urgency, ß = .22, SE = .08, 95% CI [.07, .37], and Negative Urgency subscales, ß = .32, SE = .07, 95% CI [.19, .46]. These results have implications for precision medicine approaches that emphasize targeting these specific facets of impulsivity, with likely downstream effects on health risk behaviors for emerging adult women.

The contribution of brain banks to knowledge discovery in amyotrophic lateral sclerosis: A systematic review.

Over the past decade, considerable efforts have been made to accelerate pathophysiological understanding of fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) with brain banks at the forefront. In addition to exploratory disease mechanisms, brain banks have aided our understanding with regard to clinical diagnosis, genetics and cell biology. Across neurodegenerative disorders, the impact of brain tissue in ALS research has yet to be quantified. This review aims to outline (i) how postmortem tissues from brain banks have influenced our understanding of ALS over the last 15 years, (ii) correlate the location of dedicated brain banks with the geographical prevalence of ALS, (iii) identify the frequency of features reported from postmortem studies and (iv) propose common reporting standards for materials obtained from dedicated brain banks. A systematic review was conducted using PubMed and Web of Science databases using key words. From a total of 1439 articles, 73 articles were included in the final review, following PRISMA guidelines. Following a thematic analysis, articles were categorised into five themes; clinico-pathological (13), genetic (20), transactive response DNA binding protein 43 (TDP-43) pathology (12), non-TDP-43 neuronal pathology (nine) and extraneuronal pathology (19). Research primarily focused on the genetics of ALS, followed by protein pathology. About 63% of the brain banks were in the United States of America and United Kingdom. The location of brain banks overall aligned with the incidence of ALS worldwide with 88% of brain banks situated in Europe and North America. An overwhelming lack of consistency in reporting and replicability was observed, strengthening the need for a standardised reporting system. Overall, postmortem material from brain banks generated substantial new knowledge in areas of genetics and proteomics and supports their ongoing role as an important research tool.

A laboratory examination of risky sexual behavior among female sexual trauma survivors.

Sexual violence against women is highly prevalent on college campuses. Survivors of sexual violence often engage in coping strategies such as risky sexual behavior. The present study used a behavioral task to measure sexual risk-taking following experiences of positive or negative affect and an emotion suppression experimental manipulation. Sexually active adult female undergraduates (N = 175) completed measures of sexual traumatization and affective experiences as well as an autobiographical recall task and a delay discounting task for hypothetical sexual outcomes. Half of the participants (n = 87) were asked to suppress their emotional response to the autobiographical recall task. The findings indicate that sexual traumatization had a significant effect on risky sexual decision-making, F(1, 167) = 23.27, p < .001, ηp 2 = .12, but affective condition, F(1, 167) = .57, p = .451, and emotion suppression, F(1, 167) = .69, p = .412, exhibited no significant associations with sexual risk-taking. These findings suggest other factors may underlie the association between sexual trauma and risky sexual behavior, but further research is warranted.

A prospective examination of health care costs associated with posttraumatic stress disorder diagnostic status and symptom severity among veterans.

Posttraumatic stress disorder (PTSD) is associated with increased health care costs; however, most studies exploring this association use PTSD diagnostic data in administrative records, which can contain inaccurate diagnostic information and be confounded by the quantity of service use. We used a diagnostic interview to determine PTSD diagnostic status and examined associations between PTSD symptom severity and health care costs and utilization, extracted from Veteran Health Administration (VHA) administrative databases. Using a nationwide longitudinal sample of U.S. veterans with and without PTSD (N = 1,377) enrolled in VHA health care, we determined the costs and utilization of mental health and non-mental health outpatient, pharmacy, and inpatient services for 1 year following cohort enrollment. Relative to veterans without PTSD, those with PTSD had higher total health care, B = 0.47; mental health clinic care, B = 0.72; non-mental health clinic care, B = 0.30; and pharmacy costs, B = 0.72, ps < .001. More severe PTSD symptoms were associated with mental health clinic care costs, B = 0.12; non-mental health clinic care costs, B = 0.27; and higher odds of inpatient, B = 0.63, and emergency service use, B = 0.39, p < .001-p = .012. These findings indicate that veterans' PTSD status, determined by a clinician-administered semistructured diagnostic interview, was associated with higher health care costs and increased use of mental health and non-mental health clinic services. The findings also suggest that more severe PTSD is associated with increased costs and utilization, including costly emergency and inpatient utilization.

Behavioural changes predict poorer survival in amyotrophic lateral sclerosis.

OBJECTIVE: The Motor Neuron Disease Behavioural Scale (MiND-B) is a clinically validated tool that was developed to detect behavioural dysfunction in patients with amyotrophic lateral sclerosis (ALS). The current study aimed to evaluate behavioural impairment using MiND-B, as well as cognitive dysfunction in ALS patients, and to determine their prognostic implications. METHOD: Patients with a clinical diagnosis of ALS were prospectively recruited from a specialised multidisciplinary ALS clinic. Patients underwent behavioural assessment with the Motor Neuron Disease Behavioural Scale (MiND-B) and cognitive evaluation using the Addenbrooke's Cognitive Examination (ACE). Primary outcome measure was selected as survival time, defined by time from assessment to time of death or censor date. Univariate assessment of survival effect was carried out using Kaplan-Meier survival analysis followed by cox regression analysis to assess the effect of MiND-B and ACE scores on survival time. RESULTS: A total of 134 patients were included in the study. MiND-B testing determined that 59% were classified as having behavioural dysfunction, with deficits associated with a significantly shorter survival time (HR 2.53, p = 0.003, 95% CI 1.3-4.6). Furthermore, regression analysis demonstrated that for every 1-point reduction in the MiND-B score, risk of death increased by 3%. ACE testing established that 33% of the cohort had evidence of cognitive dysfunction. Patients with cognitive dysfunction on ACE testing had a significantly shorter survival time than patients without cognitive impairment (HR 2.0, p = 0.042, 95% CI 1.04-3.3). CONCLUSION: The presence of behavioural and cognitive impairments in ALS patients was associated with poor survival. The MiND-B and ACE inventories are simple and efficient clinical tools that can be administered in the multidisciplinary ALS clinic, that aid in the prognostication of this patient population.

Cross-lagged effects of posttraumatic stress disorder symptom severity and cigarette smoking among OEF/OIF/OND veterans.

OBJECTIVES: Veterans with posttraumatic stress disorder (PTSD) are known to smoke cigarettes at elevated levels in comparison to both veterans without PTSD and civilians. This study aims to elucidate how cigarette smoking and PTSD symptoms interact over time. MATERIALS AND METHODS: This study examined the directionality and strength of the relationship between average daily cigarette smoking and PTSD symptom severity across three (T1-T3) time points in a large cohort (N = 851) of male and female Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn returning veterans who were either current or former smokers at T1 (mean age = 37.56; standard deviation = 10.10). We used cross-lagged panel analyses to evaluate their temporal relations. RESULTS: The analyses indicated that PTSD symptom severity at T1 significantly predicted cigarette smoking at T2, and this predictive association was maintained from T2 to T3. Conversely, smoking at T1 and T2 did not predict PTSD symptom severity at T2 and T3, respectively. Although effect sizes were small, PTSD symptom severity was cross-sectionally related to smoking at T1 and T2, but not T3. In addition, when analyses were examined by gender, the same results were found except these associations were stronger for women than for men cross-sectionally. CONCLUSION: Our findings provide some evidence of a longitudinal association between PTSD symptom severity and tobacco use and highlight potential targets of intervention.

The Role of Impulsivity in the Association Between Posttraumatic Stress Disorder Symptom Severity and Substance Use in Male Military Veterans.

High rates of posttraumatic stress disorder (PTSD) and comorbid substance use disorder (SUD) are prevalent in military veterans. However, few studies have investigated impulsivity as a risk factor for engaging in substance use behavior for individuals who are experiencing PTSD symptoms. The present study evaluated impulsivity as a moderator of the association between PTSD symptoms and alcohol/drug use. Male military veterans (N = 106) completed self-report measures of alcohol use behavior, drug use behavior, and impulsivity. Participants also completed a structured diagnostic interview to assess for PTSD. The findings indicated that impulsivity moderated the relation between total PTSD symptoms and alcohol use, B = 0.01, p = .035, along with associations between alcohol use and two of the symptom clusters: PTSD reexperiencing symptoms, B = 0.01, p = .016; and PTSD avoidance/numbing symptoms, B = 0.01, p = .029. Veterans with high levels of impulsivity were at significantly higher risk of engaging in alcohol use than veterans with low-to-average levels. Impulsivity did not potentiate the relation between PTSD hyperarousal symptoms and alcohol use nor did it moderate the association between any of the PTSD variables and drug use. Impulsivity appears to serve as a significant risk factor for alcohol use, but not drug use, for male veterans experiencing PTSD symptoms. Future studies are necessary to replicate and expand upon these findings, particularly to facilitate the development of integrated evidence-based treatments that target both alcohol use and impulsivity within the context of PTSD.

The Temporal Relationship Between Coping Self-Efficacy and Dissociation in Undergraduate Students.

Dissociation is a lack of information integration resulting from a process that ranges on a continuum from normative experiences (e.g., daydreaming) to a pervasive traumatic response involving alterations and/or fragmentation in mental processes such as memory, emotion, and perception. Perceived coping self-efficacy (CSE) is a cognitive appraisal ability utilized to regulate internal and external stressors that arise from traumatic events, and is crucial for effective adaptation after extreme stress or trauma. Thus, CSE may be a critical component in decreasing dissociative experiences following a traumatic event. In the present study, 136 undergraduate students (M age = 22.36 years, SD = 6.27; 81% female, 69.1% Caucasian, 77.2% attended some college) completed self-report measures of trauma, dissociation, and coping self-efficacy. All measures were completed by the same participants at two different time points (Time 1 and Time 2) two months apart; all participants reported a history of exposure to at least one Criterion A traumatic event (according to the DSM-5) at Time 1. We hypothesized that CSE for posttraumatic coping demands at Time 2 would mediate the relationship between dissociation at Time 1 and dissociation at Time 2, and subsequently found evidence of significant mediation, 95% CI [.02, .18]. These findings suggest that initial levels of persistent dissociation negatively predict CSE, which in turn directly and negatively influence persistent dissociation at a later time point. This highlights how CSE may serve as a protective factor against persistent dissociation.

Domain-Specific Relationships in Sexual Measures of Impulsive Behavior.

Impulsivity is an important construct for understanding sexual behaviors, but behavioral and self-report measures of impulsivity often are not correlated. One possible explanation for this is that there is little shared variance in the measures because behavioral measures index impulsivity by asking questions about monetary preferences, while self-report measures index impulsivity by asking about a broad range of real-world outcomes (including those of a sexual nature) largely unrelated to money-related preferences. Undergraduate students (total N = 105; female n = 77, male n = 28) completed laboratory measures-delay discounting (DD) and probability discounting (PD)-for two different outcomes-money and sexual activity. Participants also completed the Delaying Gratification Inventory (DGI), which measures difficulty with delaying gratification (i.e., impulsivity) across different domains, including money and physical pleasures. Findings indicated that DD and PD for money were not related to any of the DGI subscales. However, DD for sexual activity was significantly related to the DGI Physical Pleasures subscale, but not other subscales. These findings suggest that the relationship between behavioral and self-report measures of impulsive choice may be stronger when both are measuring domain-specific rather than domain-general behavioral patterns, but further research is warranted.

Silent sinus syndrome: an unusual case of facial numbness.

A 49-year-old man presented with a 1-week history of right facial paraesthesia with blurred vision and diplopia. Examination was normal apart from reduced facial sensation. Following appropriate neuroimaging, we considered a diagnosis of silent sinus syndrome. He underwent a middle meatal antrostomy with complete resolution of symptoms. Silent sinus syndrome results from occlusion of the osteomeatal complex, preventing normal aeration of the maxillary sinus. Maxillary sinus hypoventilation typically causes inferior displacement of the globe in the orbit (unilateral hypoglobus). Neurologists will only infrequently see people with silent sinus syndrome but it can have devastating consequences if left untreated and so must be considered in the appropriate clinical context.

Developmental regulation of tau splicing is disrupted in stem cell-derived neurons from frontotemporal dementia patients with the 10 + 16 splice-site mutation in MAPT.

The alternative splicing of the tau gene, MAPT, generates six protein isoforms in the adult human central nervous system (CNS). Tau splicing is developmentally regulated and dysregulated in disease. Mutations in MAPT that alter tau splicing cause frontotemporal dementia (FTD) with tau pathology, providing evidence for a causal link between altered tau splicing and disease. The use of induced pluripotent stem cell (iPSC)-derived neurons has revolutionized the way we model neurological disease in vitro. However, as most tau mutations are located within or around the alternatively spliced exon 10, it is important that iPSC-neurons splice tau appropriately in order to be used as disease models. To address this issue, we analyzed the expression and splicing of tau in iPSC-derived cortical neurons from control patients and FTD patients with the 10 + 16 intronic mutation in MAPT. We show that control neurons only express the fetal tau isoform (0N3R), even at extended time points of 100 days in vitro. Neurons from FTD patients with the 10 + 16 mutation in MAPT express both 0N3R and 0N4R tau isoforms, demonstrating that this mutation overrides the developmental regulation of exon 10 inclusion in our in vitro model. Further, at extended time points of 365 days in vitro, we observe a switch in tau splicing to include six tau isoforms as seen in the adult human CNS. Our results demonstrate the importance of neuronal maturity for use in in vitro modeling and provide a system that will be important for understanding the functional consequences of altered tau splicing.

Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population.

Hexanucleotide repeat expansions in C9orf72 are a major cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Understanding the disease mechanisms and a method for clinical diagnostic genotyping have been hindered because of the difficulty in estimating the expansion size. We found 96 repeat-primed PCR expansions: 85/2,974 in six neurodegenerative diseases cohorts (FTLD, ALS, Alzheimer disease, sporadic Creutzfeldt-Jakob disease, Huntington disease-like syndrome, and other nonspecific neurodegenerative disease syndromes) and 11/7,579 (0.15%) in UK 1958 birth cohort (58BC) controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in cases was 800-4,400. Similarly, large expansions were detected in the population controls. Differences in expansion size and morphology were detected between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. We found that morphology in the expansion smear varied among different individuals and among different brain regions in the same individual. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, support multiple expansion events on the same haplotype background. Our method of estimating the size of large expansions has potential clinical utility. C9orf72-related disease might mimic several neurodegenerative disorders and, with potentially 90,000 carriers in the United Kingdom, is more common than previously realized.

Longitudinal diffusion tensor imaging in frontotemporal dementia.

OBJECTIVE: Novel biomarkers for monitoring progression in neurodegenerative conditions are needed. Measurement of microstructural changes in white matter (WM) using diffusion tensor imaging (DTI) may be a useful outcome measure. Here we report trajectories of WM change using serial DTI in a cohort with behavioral variant frontotemporal dementia (bvFTD). METHODS: Twenty-three patients with bvFTD (12 having genetic mutations), and 18 age-matched control participants were assessed using DTI and neuropsychological batteries at baseline and ~1.3 years later. Baseline and follow-up DTI scans were registered using a groupwise approach. Annualized rates of change for DTI metrics, neuropsychological measures, and whole brain volume were calculated. DTI metric performances were compared, and sample sizes for potential clinical trials were calculated. RESULTS: In the bvFTD group as a whole, rates of change in fractional anisotropy (FA) and mean diffusivity (MD) within the right paracallosal cingulum were greatest (FA: -6.8%/yr, p < 0.001; MD: 2.9%/yr, p = 0.01). MAPT carriers had the greatest change within left uncinate fasciculus (FA: -7.9%/yr, p < 0.001; MD: 10.9%/yr, p < 0.001); sporadic bvFTD and C9ORF72 carriers had the greatest change within right paracallosal cingulum (sporadic bvFTD, FA: -6.7%/yr, p < 0.001; MD: 3.8%/yr, p = 0.001; C9ORF72, FA: -6.8%/yr, p = 0.004). Sample size estimates using FA change were substantially lower than neuropsychological or whole brain measures of change. INTERPRETATION: Serial DTI scans may be useful for measuring disease progression in bvFTD, with particular trajectories of WM damage emerging. Sample size calculations suggest that longitudinal DTI may be a useful biomarker in future clinical trials.

Temporal Variant Frontotemporal Dementia is Associated with Globular Glial Tauopathy.

Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative disorder associated with atrophy of the frontal and temporal lobes. Most patients with focal temporal lobe atrophy present with either the semantic dementia subtype of FTD or the behavioral variant subtype. For patients with temporal variant FTD, the most common cause found on post-mortem examination has been a TDP-43 (transactive response DNA-binding protein 43 kDa) proteinopathy, but tauopathies have also been described, including Pick's disease and mutations in the microtubule-associated protein tau (MAPT) gene. We report the clinical and imaging features of 2 patients with temporal variant FTD associated with a rare frontotemporal lobar degeneration pathology known as globular glial tauopathy. The pathologic diagnosis of globular glial tauopathy should be considered in patients with temporal variant FTD, particularly those who have atypical semantic dementia or an atypical parkinsonian syndrome in association with the right temporal variant.

Profiles of white matter tract pathology in frontotemporal dementia.

Despite considerable interest in improving clinical and neurobiological characterisation of frontotemporal dementia and in defining the role of brain network disintegration in its pathogenesis, information about white matter pathway alterations in frontotemporal dementia remains limited. Here we investigated white matter tract damage using an unbiased, template-based diffusion tensor imaging (DTI) protocol in a cohort of 27 patients with the behavioral variant of frontotemporal dementia (bvFTD) representing both major genetic and sporadic forms, in relation both to healthy individuals and to patients with Alzheimer's disease. Widespread white matter tract pathology was identified in the bvFTD group compared with both healthy controls and Alzheimer's disease group, with prominent involvement of uncinate fasciculus, cingulum bundle and corpus callosum. Relatively discrete and distinctive white matter profiles were associated with genetic subgroups of bvFTD associated with MAPT and C9ORF72 mutations. Comparing diffusivity metrics, optimal overall separation of the bvFTD group from the healthy control group was signalled using radial diffusivity, whereas optimal overall separation of the bvFTD group from the Alzheimer's disease group was signalled using fractional anisotropy. Comparing white matter changes with regional grey matter atrophy (delineated using voxel based morphometry) in the bvFTD cohort revealed co-localisation between modalities particularly in the anterior temporal lobe, however white matter changes extended widely beyond the zones of grey matter atrophy. Our findings demonstrate a distributed signature of white matter alterations that is likely to be core to the pathophysiology of bvFTD and further suggest that this signature is modulated by underlying molecular pathologies.

A pathogenic progranulin mutation and C9orf72 repeat expansion in a family with frontotemporal dementia.

AIMS: Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disease and is the second most common form of young onset dementia after Alzheimer's disease (AD). An autosomal dominant pattern of inheritance is present in around 25-50% of FTLD cases indicating a strong genetic component. Major pathogenic mutations of FTLD have been demonstrated independently in the progranulin (GRN) gene and the C9orf72 hexanucleotide expansion repeat. In this study we present a family that have been identified as carrying both a GRN Cys31fs mutation and the C9orf72 hexanucleotide expansion repeat. METHODS: In the present study we describe the clinical and genetic details of family members and pathological features of two family members that have come to post-mortem. RESULTS: The mean age at disease onset was 57 years (48-61 years) and mean duration 4 years (2-7 years). The most common presenting syndrome was behavioural variant frontotemporal dementia. Brain imaging from available cases showed a symmetrical pattern of atrophy particularly affecting the frontal and temporal lobes. Pathologically two cases were classified as FTLD-TDP type A with TDP-43 positive inclusions, with additional p62-positive 'star-like' inclusions found in the hippocampal formation and cerebellum. CONCLUSIONS: The type and distribution of the pathological lesions in these two cases were in keeping with FTLD cases carrying only the C9orf72 hexanucleotide repeat. However the driving force of the pathological process may be either pathogenic mutation or a combination of both converging on a singular mechanism.

Altered body schema processing in frontotemporal dementia with C9ORF72 mutations.

BACKGROUND: Mutations in C9ORF72 are an important cause of frontotemporal dementia (FTD) and motor neuron disease. Accumulating evidence suggests that FTD associated with C9ORF72 mutations (C9ORF72-FTD) is distinguished clinically by early prominent neuropsychiatric features that might collectively reflect deranged body schema processing. However, the pathophysiology of C9ORF72-FTD has not been elucidated. METHODS: We undertook a detailed neurophysiological investigation of five patients with C9ORF72-FTD, in relation to patients with FTD occurring sporadically and on the basis of mutations in the microtubule-associated protein tau gene and healthy older individuals. We designed or adapted behavioural tasks systematically to assess aspects of somatosensory body schema processing (tactile discrimination, proprioceptive and body part illusions and self/non-self differentiation). RESULTS: Patients with C9ORF72-FTD selectively exhibited deficits at these levels of body schema processing in relation to healthy individuals and other patients with FTD. CONCLUSIONS: Altered body schema processing is a novel, generic pathophysiological mechanism that may link the distributed cortico-subcortical network previously implicated in C9ORF72-FTD with a wide range of neuropsychiatric and behavioural symptoms, and constitute a physiological marker of this neurodegenerative proteinopathy.