Childhood Maltreatment and Dementia Risk Factors in Midlife: A Prospective Investigation.

BACKGROUND: Previous studies have linked childhood adversities to dementia risk, yet most studies are cross-sectional in design and utilize retrospective self-reports to assess childhood experiences. These design characteristics make it difficult to establish temporal order and draw firm conclusions. OBJECTIVES: Using a longitudinal design, we sought to determine whether childhood maltreatment predicts dementia risk factors in middle adulthood. METHODS: Data have been obtained from a prospective cohort design study of children with documented cases of childhood maltreatment (ages 0-11 years at case identification) and demographically matched controls who were followed up and interviewed in middle adulthood. Outcomes were assessed through a medical examination and interview, and 807 of the cases that included blood collection at mean age 41. Dementia risk were investigated using 11 potentially modifiable risk factors. RESULTS: Compared to controls, individuals with histories of childhood maltreatment had a higher risk of low educational attainment, low social contact, smoking, and clinical depression, and a higher total number of dementia risk factors. In general, childhood maltreatment predicted a higher risk of dementia for females, males, and Black and White participants. Black maltreated participants had a greater risk for traumatic brain injury compared to Black controls. Physical abuse, sexual abuse, and neglect, each predicted a higher number of dementia risk factors in mid-life. CONCLUSION: These findings provide evidence that childhood maltreatment increases the risk for dementia in mid-life and has a demonstrable impact lasting over 30 years. Reducing the prevalence of mid-life dementia risk factors could reduce the risk of later-life dementia.

Childhood maltreatment and cognitive functioning in middle adulthood.

BACKGROUND: Childhood maltreatment (physical abuse, sexual abuse, and/or neglect) is associated with cognitive deficits in adulthood. Little is known about how childhood maltreatment affects the trajectory of cognitive functioning during early to middle adulthood. OBJECTIVE: To explore the relationship between childhood maltreatment and change in cognitive functioning over a 10-year period in adulthood. METHODS: Utilizing a prospective cohort design, a large group of court-substantiated cases of childhood maltreatment (ages 0-11) and demographically matched controls were followed into adulthood (N = 1196). Verbal intelligence and reading ability were assessed at age 29, and executive functioning was assessed at age 41. Linear, mixed-effects modeling was used to evaluate childhood maltreatment as a predictor of cognitive functioning and change in cognitive functioning over time. RESULTS: Childhood maltreatment was associated with lower cognitive functioning at age 29 compared to controls (ß = -0.28, p < .001), and this association was stronger for childhood neglect (ß = -0.33, p < .001). Controls declined in cognitive functioning over the 10-year period (ß = -0.12, p = .039), whereas childhood maltreatment overall was associated with no change. Adults with histories of neglect demonstrated an increase in cognitive functioning (ß = 0.13, p = .021). CONCLUSIONS: Our results demonstrate that childhood maltreatment is associated with cognitive functioning deficits in adulthood and suggest that cognitive change in adulthood may be differentially impacted by type of maltreatment. The initial deficit demonstrated by adults with childhood neglect was largely erased by a subsequent increase in cognitive functioning over 10 years.

Autobiographical recall of a stressful negative event in veterans with PTSD.

Posttraumatic stress disorder (PTSD) is characterised by alterations in autobiographical memory for traumatic and non-traumatic events. Studies that focus on event construction - the ability to search for and identify a specific event - have documented overgeneral memory in PTSD. However, the quality of autobiographical memory also depends on the ability to elaborate on an event once constructed by providing additional details. In a prior study, individuals with PTSD generated as many episodic (event-specific) details as trauma-exposed controls when demands on event construction were minimized, albeit the PTSD group generated more non-episodic details. The current study sought to further characterize PTSD-related alterations in event elaboration by asking participants to describe a stressful negative event specified by the experimenter, thus minimizing event construction demands. Narratives were scored for episodic and non-episodic details and relations with measures of executive function and self-reported avoidance were examined. Compared to controls, the PTSD group generated narratives with equivalent episodic detail but greater non-episodic detail, including semantic information and repeated or extended events. Non-episodic detail generation was associated with greater avoidance but not executive functions. Elaborated non-trauma memories may be perceived as overgeneral in PTSD due to greater generation of non-episodic details, rather than diminished episodic detail.

The status of semantic memory in medial temporal lobe amnesia varies with demands on scene construction.

Semantic memory is typically preserved in medial temporal lobe (MTL) amnesia. However, there are instances of impairment, such as in the recall of semantic narratives. As some forms of semantic knowledge play out in a spatial context, one possible explanation is that semantic memory impairments, when observed, relate to demands on scene construction - the ability to bind and maintain spatial information in a coherent representation. To investigate whether semantic memory impairments in MTL amnesia can be understood with reference to a deficit in scene construction, the current study examined knowledge of scripts that vary in the extent to which they play out in a scene context in nine patients with MTL amnesia and eighteen healthy control subjects. Scripts are routine activities characterized by an ordered set of actions, including some that are essential for completing the activity. Comparing performance on scene-based scripts (e.g., buying groceries at the grocery store) and object-based scripts (e.g., addressing a letter), we found that patients generated the same number of total action steps as controls for both types of script, but patients were selectively impaired at generating essential actions steps for scene-based scripts. Furthermore, patients made more sequencing and idiosyncratic errors than controls in the scene-based, but not in the object-based, scripts. These findings demonstrate that the hippocampus plays a critical role in the retrieval of semantic knowledge about everyday activities when such retrieval entails scene construction.

The Effects of Lifetime Trauma Exposure on Cognitive Functioning in Midlife.

Accumulating evidence suggests that lifetime trauma exposure is associated with adulthood cognitive functioning. However, the nature and extent of this relation have yet to be fully explored. We used multilevel modeling to examine trauma exposure and age at first trauma exposure as predictors of the level of and change in cognitive functioning over a 9-year period. Data were from the Midlife in the United States study, a national survey that began in 1995. Data regarding trauma exposure and age at first exposure were obtained from the 2004 wave, whereas cognitive data were obtained from the 2004 and 2013 waves. The analyses were conducted using data from the 2,471 participants (age range: 28-84 years) who had complete data on all variables from the 2004 wave. Lifetime trauma exposure predicted change in executive functioning (EF), B = -0.03, SE = 0.01, p = .015, 95% CI [-0.05, -0.01]; and episodic memory, B = -0.05, SE = 0.02, p = .023, 95% CI [-0.10, -0.01], such that individuals with more trauma exposure had more decline over 9 years. Age at first exposure also predicted change in EF, B = -0.002, SE = 0.00, p = .009, 95% CI [-0.004, -0.001], such that individuals who were first exposed to trauma later in life had greater EF decline than individuals whose first traumatic event occurred earlier in life. Delta pseudo- R 2 values were moderate, ΔpseudoR2 = .17-.39. These findings identify trauma exposure as a risk factor for cognitive decline in adulthood and highlight the elevated risk associated with adulthood trauma exposure.

Peripheral administration of antisense oligonucleotides targeting the amyloid-ß protein precursor reverses AßPP and LRP-1 overexpression in the aged SAMP8 mouse brain.

The senescence accelerated mouse-prone 8 (SAMP8) mouse model of Alzheimer's disease has a natural mutation leading to age-related increases in the amyloid-ß protein precursor (AßPP) and amyloid-ß (Aß) in the brain, memory impairment, and deficits in Aß removal from the brain. Previous studies show that centrally administered antisense oligonucleotide directed against AßPP can decrease AßPP expression and Aß production in the brains of aged SAMP8 mice, and improve memory. The same antisense crosses the blood-brain barrier and reverses memory deficits when injected intravenously. Here, we give 6 µg of AßPP or control antisense 3 times over 2 week intervals to 12 month old SAMP8 mice. Object recognition test was done 48 hours later, followed by removal of whole brains for immunoblot analysis of AßPP, low-density lipoprotein-related protein-1 (LRP-1), p-glycoprotein (Pgp), receptor for advanced glycation endproducts (RAGE), or ELISA of soluble Aß(40). Our results show that AßPP antisense completely reverses a 30% age-associated increase in AßPP signal (p < 0.05 versus untreated 4 month old SAMP8). Soluble Aß(40) increased with age, but was not reversed by antisense. LRP-1 large and small subunits increased significantly with age (147.7%, p < 0.01 and 123.7%, p < 0.05 respectively), and AßPP antisense completely reversed these increases (p < 0.05). Pgp and RAGE were not significantly altered with age or antisense. Antisense also caused improvements in memory (p < 0.001). Together, these data support the therapeutic potential of AßPP antisense and show a unique association between AßPP and LRP-1 expression in the SAMP8 mouse.

Insulin detemir is not transported across the blood-brain barrier.

Insulin detemir has a different profile of action on the central nervous system (CNS) than human insulin. It has been hypothesized that this is caused by an altered ability of insulin detemir to cross the blood-brain barrier (BBB). Here, we measured the permeability of the BBB to insulin detemir. We labeled insulin detemir with radioactive iodine (I-Det) and examined its ability to cross the BBB of the mouse. Permeation was assessed after intravenous injection and by brain perfusion in the presence or absence of excess insulin detemir. The ability of insulin detemir to inhibit human insulin transport across the BBB was also assessed. I-Det did not cross the BBB either after intravenous injection or when studied by brain perfusion, a method which removes or reduces the influence of circulating proteins. Unlabeled detemir was about 10 times less potent than human insulin at inhibiting the transport of radioactive human insulin across the BBB. The altered CNS profile of insulin detemir may be caused by its poor access to CNS receptors and by a block of human insulin from crossing the BBB.

Ovine proinflammatory cytokines cross the murine blood-brain barrier by a common saturable transport mechanism.

OBJECTIVES: The cytokines interleukin (IL)-1beta and IL-6 are modulators of the neuroimmune axis and have been implicated in neuronal cell death cascades after ischemia or infection. Previous work has shown that some cross-species conservation exists between human and rodent blood-brain barrier (BBB) transport systems. To further assess cross-species conservation of cytokine transport across the BBB, the current studies investigated permeability and inhibition of ovine IL-1beta and IL-6 in the mouse. METHODS: IL-1beta or IL-6 was radioactively labeled with (131)I and injected into the jugular vein at time zero. A subset of mice received 1 or 3 microg/mouse of an unlabeled ovine or murine cytokine (IL-1beta or IL-6) to assess self- and/or cross-inhibition of transport. Permeability was assessed using multiple-regression analysis. RESULTS: There was a significant linear relationship for both ovine (131)I-IL-1beta and (131)I-IL-6 between brain/serum ratios and exposure time, indicating BBB permeability. Inclusion of 3 microg/mouse unlabeled ovine IL-1beta or IL-6 significantly reduced the transport of ovine (131)I-IL-1beta or (131)I-IL-6, respectively, across the BBB. Transport of both ovine (131)I-IL-1beta and (131)I-IL-6 was significantly inhibited by 1 microg/mouse of murine IL-1beta or IL-6, respectively. In contrast, 1 microg/mouse of unlabeled ovine IL-1beta or IL-6 did not inhibit the transport of murine (131)I-IL-1beta or (131)I-IL-6. CONCLUSIONS: Ovine IL-1beta and IL-6 cross the mouse BBB by saturable transport. Inhibition of transport by murine homologs indicates that both species use the same transport mechanisms. Conversely, an inability of ovine cytokines to significantly inhibit the transport of murine cytokines indicates that mouse BBB has a lower affinity for ovine than murine cytokines. Knowledge of species-conserved BBB transport mechanisms may facilitate the development of novel animal models of central nervous system pathogenesis.

Gastric trichobezoar: an important cause of abdominal pain presenting to the pediatric emergency department.

Abdominal pain is a common presenting complaint of children seen in urgent care settings. It is the manifestation of a wide variety of disease processes ranging from benign to immediately life-threatening. Gastric bezoars are among the etiologies of chronic childhood abdominal pain that, when undiagnosed, may result acutely in serious complications, including gastric ulceration, bleeding and perforation, intussusception, and small bowel obstruction. To reinforce the importance of including this entity in the differential diagnosis of abdominal pain, we present the case of a 10-year-old girl with a history of chronic epigastric complaints who was ultimately presented with acute small bowel obstruction following fragmentation and distal migration of her gastric trichobezoar. Finally, we review and briefly summarize the current literature regarding the etiology, diagnosis, and management of this disorder in children.