Midlife managerial experience is linked to late life hippocampal morphology and function.

An active cognitive lifestyle has been suggested to have a protective role in the long-term maintenance of cognition. Amongst healthy older adults, more managerial or supervisory experiences in midlife are linked to a slower hippocampal atrophy rate in late life. Yet whether similar links exist in individuals with Mild Cognitive Impairment (MCI) is not known, nor whether these differences have any functional implications. 68 volunteers from the Sydney SMART Trial, diagnosed with non-amnestic MCI, were divided into high and low managerial experience (HME/LME) during their working life. All participants underwent neuropsychological testing, structural and resting-state functional MRI. Group comparisons were performed on hippocampal volume, morphology, hippocampal seed-based functional connectivity, memory and executive function and self-ratings of memory proficiency. HME was linked to better memory function (p = 0.024), mediated by larger hippocampal volume (p = 0.025). More specifically, deformation analysis found HME had relatively more volume in the CA1 sub-region of the hippocampus (p < 0.05). Paradoxically, this group rated their memory proficiency worse (p = 0.004), a result correlated with diminished functional connectivity between the right hippocampus and right prefrontal cortex (p < 0.001). Finally, hierarchical regression modelling substantiated this double dissociation.

Therapeutically relevant structural and functional mechanisms triggered by physical and cognitive exercise.

Physical and cognitive exercise may prevent or delay dementia in later life but the neural mechanisms underlying these therapeutic benefits are largely unknown. We examined structural and functional magnetic resonance imaging (MRI) brain changes after 6 months of progressive resistance training (PRT), computerized cognitive training (CCT) or combined intervention. A total of 100 older individuals (68 females, average age=70.1, s.d.±6.7, 55-87 years) with dementia prodrome mild cognitive impairment were recruited in the SMART (Study of Mental Activity and Resistance Training) Trial. Participants were randomly assigned into four intervention groups: PRT+CCT, PRT+SHAM CCT, CCT+SHAM PRT and double SHAM. Multimodal MRI was conducted at baseline and at 6 months of follow-up (immediately after training) to measure structural and spontaneous functional changes in the brain, with a focus on the hippocampus and posterior cingulate regions. Participants' cognitive changes were also assessed before and after training. We found that PRT but not CCT significantly improved global cognition (F(90)=4.1, P<0.05) as well as expanded gray matter in the posterior cingulate (Pcorrected <0.05), and these changes were related to each other (r=0.25, P=0.03). PRT also reversed progression of white matter hyperintensities, a biomarker of cerebrovascular disease, in several brain areas. In contrast, CCT but not PRT attenuated decline in overall memory performance (F(90)=5.7, P<0.02), mediated by enhanced functional connectivity between the hippocampus and superior frontal cortex. Our findings indicate that physical and cognitive training depend on discrete neuronal mechanisms for their therapeutic efficacy, information that may help develop targeted lifestyle-based preventative strategies.

Ganciclovir pharmacokinetics and cytokine dynamics in renal transplant recipients with cytomegalovirus infection.

Ganciclovir is considered to be the first-line treatment for cytomegalovirus (CMV) in renal transplant recipients. This infection is also associated with elevations of specific plasma cytokines post-transplantation. To investigate daily cytokine response to therapy and ganciclovir pharmacokinetics, 4 transplant recipients (3 males, 1 female) with stable renal allograft function diagnosed with CMV infection were enrolled less than 4 months post-transplant. A creatinine clearance (ClCr) was generated by the Cockroft-Gault (C-G) equation (range: 42.3-68.5 mL/min) to determine ganciclovir dosing. Blood samples were collected for ganciclovir and cytokine [including interleukin (IL)-1beta, IL-2, IL-3, IL-4, IL-6, IL-8, IL-10, TNF-alpha, GM-CSF, and interferon (IFN)-gamma analyses after 7 d of intravenous (i.v.) ganciclovir (dosage range: 165-400 mg daily) therapy and again after 7 d of oral (p.o.) ganciclovir (dosage range: 1000 mg, 2-3 times daily) therapy. Pharmacokinetic ganciclovir was described with a two-compartment model. Total clearance of ganciclovir was consistently greater than ClCr, suggesting tubular secretion. Peak concentrations for i.v. ganciclovir averaged 8.39+/-1.87 microg/mL with minimum concentrations of 0.48+/-0.35 microg/mL. Plasma concentrations were lower but more sustained during a p.o. dosing interval (max=2.12+/-0.58 microg/mL, min=1.15+/-0.34 microg/mL). IL-6, IL-8, IL-10, and TNF-alpha were detectable at multiple times during the study periods while the remainder of the cytokines were only intermittently detectable. Average concentrations (i.v. versus p.o. study period) for TNF-alpha were 40.1+/-17.5 versus 22.1+/-11.2 pg/mL, for IL-8 were 17.1+/-15.6 versus 4.12+/-2.59 pg/mL, and for IL-10 were 7.39+/-5.54 versus 2.64+/-1.06 pg/mL. Concentrations were similar for IL-6 during both studies (9.39+/-5.42 versus 14.7+/-14.8 pg/mL). TNF-alpha, IL-8, and IFN-gamma appeared to correlate with CMV antigenemia. Further investigation of ganciclovir disposition and changes in plasma cytokines in renal transplant recipients during CMV infection may provide insight into variable antiviral responses in renal transplant recipients.