Altered Energy Metabolism Pathways in the Posterior Cingulate in Young Adult Apolipoprotein E ɛ4 Carriers.

The APOE gene, encoding apolipoprotein E, is the primary genetic risk factor for late-onset Alzheimer's disease (AD). Apolipoprotein E ɛ4 allele (APOE4) carriers have alterations in brain structure and function (as measured by brain imaging) even as young adults. Examination of this population is valuable in further identifying details of these functional changes and their association with vulnerability to AD decades later. Previous work demonstrates functional declines in mitochondrial activity in the posterior cingulate cortex, a key region in the default mode network, which appears to be strongly associated with functional changes relevant to AD risk. Here, we demonstrate alterations in the pathways underlying glucose, ketone, and mitochondrial energy metabolism. Young adult APOE4 carriers displayed upregulation of specific glucose (GLUT1 & GLUT3) and monocarboxylate (MCT2) transporters, the glucose metabolism enzyme hexokinase, the SCOT & AACS enzymes involved in ketone metabolism, and complexes I, II, and IV of the mitochondrial electron transport chain. The monocarboxylate transporter (MCT4) was found to be downregulated in APOE4 carriers. These data suggest that widespread dysregulation of energy metabolism in this at-risk population, even decades before possible disease onset. Therefore, these findings support the idea that alterations in brain energy metabolism may contribute significantly to the risk that APOE4 confers for AD.

Chronic widespread pain after motor vehicle collision typically occurs through immediate development and nonrecovery: results of an emergency department-based cohort study.

Motor vehicle collision (MVC) can trigger chronic widespread pain (CWP) development in vulnerable individuals. Whether such CWP typically develops through the evolution of pain from regional to widespread or through the early development of widespread pain with nonrecovery is currently unknown. We evaluated the trajectory of CWP development (American College of Rheumatology criteria) among 948 European-American individuals who presented to the emergency department (ED) for care in the early aftermath of MVC. Pain extent was assessed in the ED and 6 weeks, 6 months, and 1 year after MVC on 100%, 91%, 89%, and 91% of participants, respectively. Individuals who reported prior CWP at the time of ED evaluation (n = 53) were excluded. Trajectory modeling identified a 2-group solution as optimal, with the Bayes Factor value (138) indicating strong model selection. Linear solution plots supported a nonrecovery model. Although the number of body regions with pain in the non-CWP group steadily declined, the number of body regions with pain in the CWP trajectory group (192/895, 22%) remained relatively constant over time. These data support the hypothesis that individuals who develop CWP after MVC develop widespread pain in the early aftermath of MVC, which does not remit.

µ-Opioid receptor gene A118G polymorphism predicts pain recovery after sexual assault.

UNLABELLED: Pain is common after sexual assault (SA), but etiology of pain symptoms after SA is unknown. Preclinical studies suggest that the release of endogenous opioids during stress produces delayed-onset hyperalgesia. In human studies, individuals with ≥1 G allele at the µ-opioid receptor functional single nucleotide polymorphism A118G have been shown to have a reduced response to opioids. We hypothesized that if opioid-mediated hyperalgesia contributes to pain after SA, women SA survivors with 1 or more G alleles at A118G would experience reduced postassault pain. Among 52 European American women SA survivors presenting for care within 48 hours of SA, those with a G allele (12/52, 23%) experienced less severe pain (F[1,39] = 11.55, P = .002) and a reduced extent of pain (F[1,41] = 11.01, P = .002) during the 6 weeks after SA. These associations between the presence of 1 or more G alleles and reduced pain severity and reduced pain extent after SA remained significant in multivariable models controlling for age, income, education, reported pain prior to assault, and pain at the time of initial evaluation. PERSPECTIVE: These results suggest that endogenous opioid-mediated hyperalgesia may contribute to pain symptoms after sexual assault. Further studies examining mechanisms mediating the development of pain after sexual assault, and the potential influence of opioid-mediated hyperalgesia, are needed.

Acute severe pain is a common consequence of sexual assault.

UNLABELLED: Sexual assault (SA) is common, but the epidemiology of acute pain after SA has not previously been reported. We evaluated the severity and distribution of pain symptoms in the early aftermath of SA among women receiving Sexual Assault Nurse Examiner (SANE) care, and the treatment of pain by SANE nurses. Severe pain (≥7 on a 0-10 numeric rating scale) was reported by 53/83 women sexual assault survivors (64% [95% CI, 53-74%]) at the time of SANE evaluation and 43/83 women (52% [95% CI, 41-63%]) 1 week later. Pain in 4 or more body regions was reported by 44/83 women (53% [95% CI, 42-64%]) at the time of initial evaluation and 49/83 women (59% [95% CI, 48-70%]) at 1 week follow-up. Among survivors with severe pain at the time of initial postassault evaluation, only 7/53 (13% [95% CI, 6-26%]) received any pain medication at the time of initial SANE treatment. These findings suggest that pain is common in SA survivors in the early postassault period, but rarely treated. PERSPECTIVE: Acute pain is common after sexual assault. Practice guidelines for SANE nurses and others who provide care to sexual assault survivors in the early aftermath of assault should include specific recommendations for pain evaluation and treatment. Prospective longitudinal studies of pain outcomes among sexual assault survivors are needed.

Using emergency department-based inception cohorts to determine genetic characteristics associated with long term patient outcomes after motor vehicle collision: methodology of the CRASH study.

BACKGROUND: Persistent musculoskeletal pain and psychological sequelae following minor motor vehicle collision (MVC) are common problems with a large economic cost. Prospective studies of pain following MVC have demonstrated that demographic characteristics, including female gender and low education level, and psychological characteristics, including high pre-collision anxiety, are independent predictors of persistent pain. These results have contributed to the psychological and social components of a biopsychosocial model of post-MVC pain pathogenesis, but the biological contributors to the model remain poorly defined. Recent experimental studies indicate that genetic variations in adrenergic system function influence the vulnerability to post-traumatic pain, but no studies have examined the contribution of genetic factors to existing predictive models of vulnerability to persistent pain. METHODS/DESIGN: The Project CRASH study is a federally supported, multicenter, prospective study designed to determine whether variations in genes affecting synaptic catecholamine levels and alpha and beta adrenergic receptor function augment social and psychological factors in a predictive model of persistent musculoskeletal pain and posttraumatic stress disorder (PTSD) following minor MVC. The Project CRASH study will assess pain, pain interference and PTSD symptoms at 6 weeks, 6 months, and 1 year in approximately 1,000 patients enrolled from 8 Emergency Departments in four states with no-fault accident laws. DISCUSSION: The results from this study will provide insights into the pathophysiology of persistent pain and PTSD following MVC and may serve to improve the ability of clinicians and researchers to identify individuals at high risk for adverse outcomes following minor MVC.

Persistent expression of methamphetamine-induced CTA in periadolescent rats.

It is well documented that the transition from periadolescence to adulthood produces profound changes in motivated behavior, and furthermore, attenuates the aversive experience of abused drugs. Little is known, however, about adolescent memory for the conditioned aversive effects of abused drugs following retention intervals that span this developmental transition. The present experiment investigated methamphetamine-induced conditioned taste aversion (CTA) in periadolescent rats to determine if the magnitude of conditioning was altered following retention intervals that extend to adulthood. Rats consumed saccharin (0.1%, w/v) and were immediately injected with saline or methamphetamine (3.0mg/kg) either once (PND 40) or three times (PND 38-40), and memory was assessed one or 50 days later on post natal days 41 or 90, respectively. Rats exhibited robust methamphetamine-induced CTA one and 50 days after conditioning, and the strength of responding did not change as a function of retention interval, regardless if animals were trained with one or three saccharin-methamphetamine pairings. These findings indicate that the expression of memory for the aversive effects of methamphetamine was resistant to degradation throughout the developmental period of periadolescence to adulthood.