Gene-Specific Effects on Brain Volume and Cognition of TMEM106B in Frontotemporal Lobar Degeneration.

BACKGROUND AND OBJECTIVES: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN pathogenic variant carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study was to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in patients with sporadic FTD. METHODS: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic variant in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic nonpathogenic variant carriers, and noncarrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex, and CDR+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. RESULTS: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN pathogenic variant carriers under the recessive dosage model (N = 82, beta = 3.25, 95% CI [0.37-6.19], p = 0.034). This was most pronounced in the thalamus in the left hemisphere (beta = 0.03, 95% CI [0.01-0.06], p = 0.006), with a retained association when considering presymptomatic GRN pathogenic variant carriers only (N = 42, beta = 0.03, 95% CI [0.01-0.05], p = 0.003). The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 pathogenic variant carriers (N = 229, beta = 0.36, 95% CI [0.05-0.066], p = 0.021) and in presymptomatic C9orf72 pathogenic variant carriers (N = 106, beta = 0.33, 95% CI [0.03-0.63], p = 0.036), under the recessive dosage model. DISCUSSION: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 pathogenic variants. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 pathogenic variant carriers could additionally reflect TMEM106B's effect on divergent pathophysiologic changes before the appearance of clinical symptoms.

Gene specific effects on brain volume and cognition of TMEM106B in frontotemporal lobar degeneration.

Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients. Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR®+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model. Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.

Childhood Sexual Abuse and Lifetime Aggression.

This study of college undergraduates (N = 873) examined three hypotheses regarding associations between childhood sexual abuse and lifetime aggression: 1) childhood sexual abuse was expected to account for unshared variance in the lifetime aggression indicators after controlling for the potential effects of parental physical abuse, sibling physical abuse, exposure to intimate partner violence, peer bullying, and respondent age; 2) childhood sexual abuse associations were expected to be relatively stronger among the women than the men; 3) childhood sexual abuse links to lifetime aggression were expected to vary as a function of age of victimization (adolescent < childhood < dual-age victims). Aggression histories varied widely with over 20% reporting prior injuries inflicted on others (3.2% > five injuries). Sexual abuse links to aggression tended to be stronger (p < .001) for the women than the men, and rates of aggression were higher when sexual abuse recurred across both childhood and adolescence. Partial support was found for all three hypotheses.

Revisiting the link between childhood sexual abuse and adult sexual aggression.

BACKGROUND: Childhood maltreatment poses a risk factor for adult sexual aggression among men. OBJECTIVE: Efforts were made to examine links between childhood sexual abuse (CSA) and sexual aggression after controlling variance associated with other forms of abuse. PARTICIPANTS AND SETTING: This sample was comprised of men (n = 489) who completed a national survey regarding their history of possible abuse and/or sexual aggression. METHODS: Maltreatment indices included CSA, parental and sibling physical abuse, exposure to domestic violence, peer bullying, and family emotional abuse. Self-report indicators of sexual frotteurism, coercion and rape were provided by the Sexual Experiences Survey-Short Form Perpetration. RESULTS: CSA links with the criterion indicators were relatively stronger (r = 0.36, d = 0.65, p <  .001) than those found for non-sexual forms of abuse. CSA accounted for unshared variance in sexual aggression with these effects magnified by the addition of parental physical abuse (d = 2.1) or exposure to domestic violence (d = 2.2). The relative risks of prior acts of rape were elevated by CSA (RR = 4.39, p <  .001), parental physical abuse (RR = 3.85, p < 0.001), exposure to domestic violence (RR = 3.81, p <  .001), or sibling physical abuse (RR = 2.56, p = 0.007). These risks of completed rape were higher as well among respondents polyvictimized by two (RR = 4.92, p <  .001) or more (RR = 8.94, p < 0.001) forms of abuse. CONCLUSIONS: Multiple forms of child maltreatment, particularly CSA, were strongly associated with adult sexual aggression in this sample of men from the general population.