Cognitive aging in persons with minimal amyloid-β and white matter hyperintensities

Substantial individual differences exist in the magnitude of the cognitive decline associated with normal aging. Potential contributors to this intersubject variability include white matter hyperintensities (WMH) and preclinical Alzheimer′s disease, evident as increased brain amyloid. This study examined whether older individuals with minimal evidence of WMH and/or brain amyloid-beta (seen on positron emission tomography with the Pittsburgh compound B radiotracer—PiB) still showed significant cognitive decrements compared to the young. Older individuals, conservatively screened for normal range performance on an extensive neuropsychological battery, underwent structural magnetic resonance imaging (MRI) and PiB scans and performed tests of information processing speed, working memory and inhibitory function. The elderly were divided into PiB(+) and PiB(−) groups based on radiotracer retention. There were no significant differences in cognitive performance between PiB(+) and PiB(−) elderly. However, both PiB groups performed significantly worse than did the young on cognitive testing. WMH burden in the same individuals was quantified by consensus ratings using a 10 point scale with a median split defining two groups, WMH(+) and WMH(−). There were no differences in cognitive performance between WMH(+) and WMH(−) individuals, but both WMH groups performed significantly worse than did the young. Older participants who were both PiB(−) and WMH(−) also performed significantly worse than did the young in all three cognitive domains. The present results suggest that normal-elderly individuals whose brain scans show minimal evidence of amyloid deposition or WMH, still demonstrate a major decrement in comparison to younger persons on measures of processing resources and inhibitory efficiency.     

Phenomics: the systematic study of phenotypes on a genome-wide scale

Phenomics is an emerging transdiscipline dedicated to the systematic study of phenotypes on a genome-wide scale. New methods for high-throughput genotyping have changed the priority for biomedical research to phenotyping, but the human phenome is vast and its dimensionality remains unknown. Phenomics research strategies capable of linking genetic variation to public health concerns need to prioritize development of mechanistic frameworks that relate neural systems functioning to human behavior. New approaches to phenotype definition will benefit from crossing neuropsychiatric syndromal boundaries, and defining phenotypic features across multiple levels of expression from proteome to syndrome. The demand for high throughput phenotyping may stimulate a migration from conventional laboratory to web-based assessment of behavior, and this offers the promise of dynamic phenotyping—the iterative refinement of phenotype assays based on prior genotype-phenotype associations. Phenotypes that can be studied across species may provide greatest traction, particularly given rapid development in transgenic modeling. Phenomics research demands vertically integrated research teams, novel analytic strategies and informatics infrastructure to help manage complexity. The Consortium for Neuropsychiatric Phenomics at UCLA has been supported by the National Institutes of Health Roadmap Initiative to illustrate these principles, and is developing applications that may help investigators assemble, visualize, and ultimately test multi-level phenomics hypotheses. As the transdiscipline of phenomics matures, and work is extended to large-scale international collaborations, there is promise that systematic new knowledge bases will help fulfill the promise of personalized medicine and the rational diagnosis and treatment of neuropsychiatric syndromes.     

Functional recovery of stepping in rats after a complete neonatal spinal cord transection is not due to regrowth across the lesion site

Rats receiving a complete spinal cord transection (ST) at a neonatal stage spontaneously can recover significant stepping ability, whereas minimal recovery is attained in rats transected as adults. In addition, neonatally spinal cord transected rats trained to step more readily improve their locomotor ability. We hypothesized that recovery of stepping in rats receiving a complete spinal cord transection at postnatal day 5 (P5) is attributable to changes in the lumbosacral neural circuitry and not to regeneration of axons across the lesion. As expected, stepping performance measured by several kinematics parameters was significantly better in ST (at P5) trained (treadmill stepping for 8 weeks) than age-matched non-trained spinal rats. Anterograde tracing with biotinylated dextran amine showed an absence of labeling of corticospinal or rubrospinal tract axons below the transection. Retrograde tracing with Fast Blue from the spinal cord below the transection showed no labeled neurons in the somatosensory motor cortex of the hindlimb area, red nucleus, spinal vestibular nucleus, and medullary reticular nucleus. Retrograde labeling transsynaptically via injection of pseudorabies virus (Bartha) into the soleus and tibialis anterior muscles showed no labeling in the same brain nuclei. Furthermore, re-transection of the spinal cord at or rostral to the original transection did not affect stepping ability. Combined, these results clearly indicate that there was no regeneration across the lesion after a complete spinal cord transection in neonatal rats and suggest that this is an important model to understand the higher level of locomotor recovery in rats attributable to lumbosacral mechanisms after receiving a complete ST at a neonatal compared to an adult stage.     

Effect of cigarette smoking on prefrontal cortical function in nondeprived smokers performing the Stroop Task.

Some reports indicate that cigarette smoking can help smokers focus attention, even when they have not abstained from smoking for a substantial period of time (eg, >1 h). Understanding the mechanisms by which smoking affects attention may help in designing smoking cessation treatments. Thirteen nonsmokers and nine smokers participated in two tests of blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). During fMRI, the participants performed the Stroop Task. There was a 15-min break between the two tests. During the break, each smoker smoked one cigarette. For smokers, the first test began 45-60 min after the last cigarette of ad libitum smoking. The differences in BOLD signal changes between Stroop conditions (ie, incongruent minus congruent) showed a group x test interaction in the right precentral sulcus, including the putative human frontal eye field (FEF). Smokers, but not nonsmokers, showed greater changes (relative to rest) in BOLD signal in the incongruent than in the congruent condition in the first fMRI test but not in the second. Even after brief abstinence from smoking, therefore, smokers exhibit compromised functional efficiency in the right FEF and adjacent precentral sulcus in a test of selective attention; and smoking ameliorates this condition.     

Expression of bcl-X(L) restores cell survival, but not proliferation off effector differentiation, in CD28-deficient T lymphocytes

Lymphocytes deficient in the T cell costimulatory molecule CD28 exhibit defects in cell survival, clonal expansion, and differentiation into effector cells. It is known that CD28-mediated signaling results in the upregulation of the Bcl family member Bcl-X(L). To investigate the role that Bcl-X(L) plays in the various functions of CD28, we expressed Bcl-X(L) in CD28-deficient primary T lymphocytes using retrovirus-mediated gene transfer. T cells were activated in vitro and infected with Bcl-X(L) or control retroviruses; this method allows gene expression in activated, cycling cells. Expression of Bcl-X(L) in naive T cells was achieved by reconstitution of the immune system of lethally irradiated recipient mice with retrovirus-infected purified bone marrow stem cells from CD28(-/)- or wild-type donor mice. Our studies demonstrate that Bcl-X(L) prolongs the survival of CD28(-/)- T cells but does not restore normal proliferation or effector cell development. These results indicate that the various functions of CD28 can be dissociated, and provide an experimental approach for testing the roles of downstream signals in the functions of cellular receptors such as CD28.     

Use of Balloon-expandable stents to treat experimental peripheral pulmonary artery and superior vena caval stenosis: Preliminary experience

Summary Current therapy of congenital or acquired stenoses of the peripheral pulmonary arteries and superior vena cava are frequently ineffective. This report describes our initial experience with the use of a balloon-expandable stainless steel stent to treat experimentally created branch pulmonary artery and superior vena cava stenosis. Fifteen adult mongrel dogs had surgically created stenoses of either a branch pulmonary artery and/or superior vena cava. A balloon-expandable stainless steel (0.076 mm), 3 cm long, intravascular stent was used in all animals. Stents were successfully placed in 13 of 15 dogs (nine with branch pulmonary stenosis and four with superior vena caval stenosis) with hemodynamic and angiographic relief of the stenoses in all. In three animals, successful stent placement was not accomplished because the distal right pulmonary artery was found to be totally obstructed in two and in one dog with combined vena cava and pulmonary stenosis the distal right pulmonary artery was so severely stenotic that the stenosis could not be crossed. Repeat catheterization performed 6 months following stent placement documented persistent gradient relief and angiographic evidence of unobstructed flow through the stent without thrombus formation and with patent side branch vessels. Our preliminary results suggests that balloon-expandable stents are a potential therapy for the treatment of branch pulmonary artery and superior vena cava stenoses.     

Efficacy of alpha-tocopherol in the treatment of the premenstrual syndrome

In a preliminary study, alpha-tocopherol supplementation was effective in reducing specific symptoms of the premenstrual syndrome (PMS). To confirm these findings, we performed a randomized, double-blind study using d,alpha-tocopherol and placebo in a carefully screened population of women with PMS. Standardized PMS questionnaires were administered in the luteal phase of the menstrual cycle to all subjects, before and after daily treatment with 400 IU d,alpha-tocopherol or placebo for three cycles. Of the 46 subjects enrolled, 41 completed the clinical trial. A significant improvement in certain affective and physical symptoms was noted in subjects treated with d,alpha-tocopherol.