White matter lesions are prevalent but differentially related with cognition in aging and early Alzheimer disease

BACKGROUND: White matter lesions (WMLs) are prevalent in nondemented aging and in Alzheimer disease (AD). Their relationship with cognition in the earliest stages of AD is unknown. OBJECTIVE: To assess the relationship between WMLs and cognition in nondemented aging and in early-stage AD. DESIGN: Cross-sectional study. SETTING: Alzheimer Disease Research Center, St Louis, MO. PARTICIPANTS: Participants were nondemented (n = 88) or had very mild (n = 48) or mild (n = 20) AD. MAIN OUTCOME MEASURES: Regression coefficients for deep WMLs and periventricular WMLs (PVWMLs) as predictors of cognition, after controlling for age, educational achievement, brain atrophy, and infarctlike lesions. RESULTS: White matter lesions were present in nondemented aging and in early-stage AD, with no group differences in deep WML burden and a modest PVWML burden increase in the AD group. The prevalence of infarctlike lesions was equivalent between groups. Age and hypertension were related to deep WML burden and PVWML burden. Deep WML burden and PVWML burden were associated with reduced global cognition in AD but not in nondemented aging. A PVWML x AD status interaction for global cognition suggests that the relationship between PVWMLs and cognition is modified by AD. In AD, global cognitive reductions were related to impairments in visual memory, processing speed, and executive function. CONCLUSIONS: White matter lesions are prevalent in nondemented aging and in early-stage AD, and their presence influences cognitive impairment in the earliest stages of AD. Individuals with early-stage AD may be more vulnerable to the cognitive effect of WMLs than nondemented aging individuals with similar WML burden.     

Chronic melatonin therapy fails to alter amyloid burden or oxidative damage in old Tg2576 mice: implications for clinical trials

Melatonin has been proposed as a treatment for Alzheimer's disease based on the demonstration of antioxidant and "anti-amyloid" effects in vitro and in vivo. Chronic melatonin therapy in old, amyloid plaque-bearing transgenic mice was studied. Tg2576 mice started melatonin treatment at 14 months of age. After 4 months of treatment, there were no differences between untreated and melatonin-treated mice in cortical levels of soluble, formic acid extracted, or histologically detectable beta amyloid (Abeta), nor in brain levels of lipid peroxidation product (total 8,12-isoprostane F(2alpha)-VI), despite marked elevations in plasma melatonin. We conclude that melatonin fails to produce anti-amyloid or antioxidant effects when initiated after the age of amyloid plaque deposition. These findings diminish the possibility that melatonin will be useful for the treatment of established Alzheimer's disease.     

Development of posttraumatic stress disorder in adult bipolar patients with histories of severe childhood abuse

Little is known about the nature and extent of posttraumatic stress disorder (PTSD) in adults with bipolar disorder, particularly in relation to the presence of past childhood or adult forms of abuse, and its impact on course of illness. The authors studied 100 consecutive DSM-IV bipolar patients who were evaluated for childhood physical, sexual and emotional abuse, traumatic events in adulthood, and lifetime PTSD. Adult comorbid PTSD was evident in 24% of subjects and was significantly associated with childhood sexual abuse, adult sexual assault, and adult survival of the suicide, homicide, or accidental death of a close friend or relative. Severe childhood abuse was reported by about half of bipolar patients, but only one-third of abused patients developed PTSD. Risk for PTSD rose in linear fashion to the number of childhood abuse subtypes present. Adult sexual assault was significantly more likely to be associated with PTSD if childhood sexual abuse was present rather than absent. The findings suggest that about one-third of bipolar patients with severe childhood abuse histories, particularly sexual abuse, manifest comorbid adult PTSD. Childhood sexual abuse, as well as severe interpersonal loss, may sensitize individuals who are predisposed to bipolar disorder also to develop eventual PTSD.     

Role of microglia in the central nervous system's immune response

Microglial cells comprise a network of endogenous immunocompetent cells that pervade the brain and spinal cord. The primary function of this system is to provide continuous surveillance of the parenchyma and protect the central nervous system (CNS) during injury and disease. Here we discuss the involvement of microglia during brain aging and aging-related neurodegenerative disease, i.e. Alzheimer's disease, and briefly summarize their possible roles in amyotrophic lateral sclerosis (ALS). In addition, we provide an overview of the neuroinflammation associated with primary brain tumors and how microglial tumor cytotoxicity could be targeted for immunotherapeutic approaches designed to treat these lesions.     

Ontogeny of respiratory sensitivity and tolerance to the mu-opioid agonist fentanyl in rat

Whereas developmental changes in analgesic sensitivity and tolerance to the mu-opioid agonist fentanyl have been reported, knowledge of respiratory responses to that drug is lacking. Using 7- and 14-day-old (P7, P14) and adult conscious rats, we first established, using whole body plethysmography, the fentanyl dose that decreased minute ventilation by 50% (ED50) at each age. ED50 increased with postnatal age (40, 60 and 120 microg/kg sc, respectively), indicating a high sensitivity to fentanyl in the youngest rats that decreased with maturation. In separate rat groups of the 3 ages, we injected each ED50 dose, once a day, for several consecutive days, until tolerance was established. Tolerance was defined as a reduction in respiratory depression from 50% to 75% of baseline. All age groups reached tolerance in minute ventilation, respiratory frequency, tidal volume and instantaneous flow (equivalent to respiratory drive). The P14 rat pups attained tolerance more rapidly (at 2.6 days) than did either the younger (5.1 days) or the adult rats (4.4 days). These results indicate that respiratory sensitivity and tolerance to fentanyl in rat vary in a distinct manner during maturation.     

Prevalence, course, and predictors of emotional distress in pregnant and parenting adolescents

This study examines trajectories and correlates of emotional distress symptoms in pregnant adolescents (n = 203) and nulliparous adolescents (n = 188) from economically disadvantaged communities over an 18-month period. For both groups, the prevalence of significant emotional distress exceeded expectation based on adolescent norms; however, the severity of symptoms did not differ between the 2 groups. Results from growth curve modeling revealed a significant decline in symptoms during the study period for both groups, but pregnant adolescents experienced a different pattern of decline. Also, certain interpersonal factors (e.g., history of physical maltreatment, partner support) appeared to play a more important role in the emotional well-being of pregnant and parenting adolescents relative to nulliparous adolescents. Implications for early identification and intervention are discussed.     

Tibial aplasia, lower extremity mirror image polydactyly, brachyphalangy, craniofacial dysmorphism and genital hypoplasia: further delineation and mutational analysis

Congenital anomalies involving tibial aplasia are rare. Recently, four children with an unusual combination of limb anomalies, facial dysmorphism and genital hypoplasia have been reported. All affected children reported were male. One case noted father to son transmission, implying autosomal dominant inheritance. We report the first female patient with this syndrome. The patient had tibial aplasia, mirror image preaxial polydactyly involving her feet, brachyphalangy, genital hypoplasia as well as facial dysmorphism including telecanthus, blepharophimosis, a flat nasal bridge with a small nose and a small mouth. Consistent with reports in males of a micropenis and hypoplastic scrotum, our patient had absent labia minora and a very small clitoris. Her father had very minor anomalies suggestive of somatic mosaicism or marked variability. Mouse models affecting limb development are powerful tools in the study of human syndromes. The clinical phenotype of patients with this syndrome is reminiscent of some luxoid mouse mutants suggesting Alx4 and related members of the paired homeodomain class as candidate genes. ALX4 haploinsufficiency in humans causes parietal foramina, which one patient with this syndrome was reported to have. Sequencing of coding exons of ALX4 and its related homologue, ALX3, in the proband failed to reveal coding sequence alterations. Our father/daughter pair is the second family reported, supporting a dominant mode of inheritance. Moreover, the very mild phenotype in the father suggests the need for very careful attention to parental examination in such cases.