Age-associated memory impairment (AAMI) occurs in many mammalian species, including humans. In contrast to Alzheimer's disease (AD), in which circuit disruption occurs through neuron death, AAMI is due to circuit and synapse disruption in the absence of significant neuron loss and thus may be more amenable to prevention or treatment. We have investigated the effects of aging on pyramidal neurons and synapse density in layer III of area 46 in dorsolateral prefrontal cortex of young and aged, male and female rhesus monkeys (Macaca mulatta) that were tested for cognitive status through the delayed non-matching-to-sample (DNMS) and delayed response tasks. Cognitive tests revealed an age-related decrement in both acquisition and performance on DNMS. Our morphometric analyses revealed both an age-related loss of spines (33%, p Ͻ 0.05) on pyramidal cells and decreased density of axospinous synapses (32%, p Ͻ 0.01) in layer III of area 46. In addition, there was an age-related shift in the distribution of spine types reflecting a selective vulnerability of small, thin spines, thought to be particularly plastic and linked to learning. While both synapse density and the overall spine size average of an animal were predictive of number of trials required for acquisition of DNMS (i.e., learning the task), the strongest correlate of behavior was found to be the head volume of thin spines, with no correlation between behavior and mushroom spine size or density. No synaptic index correlated with memory performance once the task was learned.

We previously reported that long-term cyclic estrogen (E) treatment reverses age-related impairment of cognitive function mediated by the dorsolateral prefrontal cortex (dlPFC) in ovariectomized (OVX) female rhesus monkeys, and that E induces a corresponding increase in spine density in layer III dlPFC pyramidal neurons. We have now investigated the effects of the same E treatment in young adult females. In contrast to the results for aged monkeys, E treatment failed to enhance dlPFC-dependent task performance relative to vehicle control values (group young OVX؉Veh) but nonetheless led to a robust increase in spine density. This response was accompanied by a decline in dendritic length, however, such that the total number of spines per neuron was equivalent in young OVX؉Veh and OVX؉E groups. Robust effects of chronological age, independent of ovarian hormone status, were also observed, comprising significant age-related declines in dendritic length and spine density, with a preferential decrease in small spines in the aged groups. Notably, the spine effects were partially reversed by cyclic E administration, although young OVX؉Veh monkeys still had a higher complement of small spines than did aged E treated monkeys. In summary, layer III pyramidal neurons in the dlPFC are sensitive to ovarian hormone status in both young and aged monkeys, but these effects are not entirely equivalent across age groups. The results also suggest that the cognitive benefit of E treatment in aged monkeys is mediated by enabling synaptic plasticity through a cyclical increase in small, highly plastic dendritic spines in the primate dlPFC.aging ͉ estradiol ͉ hormone ͉ neocortex ͉ plasticity N umerous studies have demonstrated that E affects synaptic structure and function in multiple brain regions important for memory and cognition (1). In the hippocampus of young female rats, 17␤-estradiol [the dominant estrogen (E) in rats, monkeys, and humans] increases the density of dendritic spines and axospinous synapses on CA1 pyramidal cells (2, 3). These effects are N-methyl-D-aspartate (NMDA) receptor-dependent (4), and E both directly increases NMDA receptor levels and facilitates NMDA receptor-mediated responses in CA1 pyramidal neurons (5, 6). E also affects GABAergic (7) and cholinergic (8) systems in the CA1 field of the young female rat hippocampus. The data from young adult monkeys are generally consistent with these observations, which is particularly relevant to humans given the reported similarities in cyclicity and menopause between women and female rhesus monkeys (9, 10). Of particular note, E increases CA1 spine number in ovariectomized (OVX) young African green (11) and rhesus monkeys (12). Estrogen administration also increases spine number in layer I of dorsolateral prefrontal cortex (dlPFC) of young rhesus monkeys (13) and enhances cholinergic and monoaminergic inputs to this region (14, 15), demonstrating that potential targets for ovarian hormone influences on cognitive function extend beyond the hippocampus in primates.G...

In nonalcoholic fatty liver disease, hepatic gene expression and fatty acid (FA) composition have been reported independently, but a comprehensive gene expression profiling in relation to FA composition is lacking. The aim was to assess this relationship. In a cross‐sectional study, hepatic gene expression (Illumina Microarray) was first compared among 20 patients with simple steatosis (SS), 19 with nonalcoholic steatohepatitis (NASH), and 24 healthy controls. The FA composition in hepatic total lipids was compared between SS and NASH, and associations between gene expression and FAs were examined. Gene expression differed mainly between healthy controls and patients (SS and NASH), including genes related to unsaturated FA metabolism. Twenty‐two genes were differentially expressed between NASH and SS; most of them correlated with disease severity and related more to cancer progression than to lipid metabolism. Biologically active long‐chain polyunsaturated FAs (PUFAs; eicosapentaenoic acid + docosahexaenoic acid, arachidonic acid) in hepatic total lipids were lower in NASH than in SS. This may be related to overexpression of FADS1, FADS2, and PNPLA3. The degree and direction of correlations between PUFAs and gene expression were different among SS and NASH, which may suggest that low PUFA content in NASH modulates gene expression in a different way compared with SS or, alternatively, that gene expression influences PUFA content differently depending on disease severity (SS versus NASH). Conclusion: Well‐defined subjects with either healthy liver, SS, or NASH showed distinct hepatic gene expression profiles including genes involved in unsaturated FA metabolism. In patients with NASH, hepatic PUFAs were lower and associations with gene expression were different compared to SS. (Hepatology 2015;61:1565–1578)

Objective. To evaluate whether osteoarthritis (OA) pain determines depressed mood, taking into consideration fatigue and disability and controlling for other factors. Methods. In a community cohort with hip/knee OA, telephone interviews assessed OA pain and disability (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]), fatigue (Multidimensional Fatigue Symptom Inventory), depressed mood (Center for Epidemiologic Studies Depression Scale), and covariates (demographics, self-rated health, comorbidity, pain coping, pain catastrophizing, and social support) at 3 time points over 2 years. Drawing on previous research, a path model was developed to test the interrelationships among the key concepts (pain, depression, fatigue, disability) over time, controlling for covariates. Results. The baseline mean age was 75.4 years; 78.5% of the subjects were women, 37.2% were living alone, and 15.5% had >3 comorbid conditions. WOMAC scores indicated moderate OA symptoms and disability. From the final model with 529 subjects, adjusting for covariates, we found that current OA pain strongly predicted future fatigue and disability (both short and long term), that fatigue and disability in turn predicted future depressed mood, that depressed mood and fatigue were interrelated such that depressed mood exacerbated fatigue and vice versa, and that fatigue and disability, but not depressed mood, led to worsening of OA pain. Conclusion. Controlling for other factors, OA pain determined subsequent depressed mood through its effect on fatigue and disability. These effects led to worsening of pain and disability over time. These results support the need for improved pain management in OA to prevent or attenuate the downstream effects of pain on disability and mood.

This study aimed to determine if there is an association between dysbiosis and nonalcoholic fatty liver disease (NAFLD) independent of obesity and insulin resistance (IR). This is a prospective cross-sectional study assessing the intestinal microbiome (IM) of 39 adults with biopsy-proven NAFLD (15 simple steatosis [SS]; 24 nonalcoholic steatohepatitis [NASH]) and 28 healthy controls (HC). IM composition (llumina MiSeq Platform) in NAFLD patients compared to HC were identified by two statistical methods (Metastats, Wilcoxon). Selected taxa was validated using quantitative PCR (qPCR). Metabolites in feces and serum were also analyzed. In NAFLD, 8 operational taxonomic units, 6 genera, 6 families and 2 phyla (Bacteroidetes, Firmicutes) were less abundant and; 1 genus (Lactobacillus) and 1 family (Lactobacillaceae) were more abundant compared to HC. Lower abundance in both NASH and SS patients compared to HC were confirmed by qPCR for Ruminococcus, Faecalibacterium prausnitzii and Coprococcus. No difference was found between NASH and SS. This lower abundance in NAFLD (NASH+SS) was independent of BMI and IR. NAFLD patients had higher concentrations of fecal propionate and isobutyric acid and serum 2-hydroxybutyrate and L-lactic acid. These findings suggest a potential role for a specific IM community and functional profile in the pathogenesis of NAFLD.

Long-term cyclic treatment with 17␤-estradiol reverses age-related impairment in ovariectomized rhesus monkeys on a test of cognitive function mediated by the prefrontal cortex (PFC). Here, we examined potential neurobiological substrates of this effect using intracellular loading and morphometric analyses to test the possibility that the cognitive benefits of hormone treatment are associated with structural plasticity in layer III pyramidal cells in PFC area 46. 17␤-Estradiol did not affect several parameters such as total dendritic length and branching. In contrast, 17␤-estradiol administration increased apical and basal dendritic spine density, and induced a shift toward smaller spines, a response linked to increased spine motility, NMDA receptor-mediated activity, and learning. These results document that, although the aged primate PFC is vulnerable in the absence of factors such as circulating estrogens, it remains responsive to long-term cyclic 17␤-estradiol treatment, and that increased dendritic spine density and altered spine morphology may contribute to the cognitive benefits of such treatment.

Outcome measures to assess therapeutic interventions in cystic fibrosis (CF) patients with mild lung disease are lacking. Our aim was to determine if the lung clearance index (LCI) can detect a treatment response to dornase alfa in paediatric CF patients with normal spirometry.CF patients between 6-18 yrs of age with FEV1 o80% pred were eligible. In a crossover design, 17 patients received 4 weeks of dornase alfa and placebo in a randomised sequence separated by a 4-week washout period. The primary end-point was the change in LCI from dornase alfa versus placebo. A mixed model approach incorporating period-dependent baselines was used.The mean¡SD age was 10.32¡3.35 yrs. Dornase alfa improved LCI versus placebo (0.90¡1.44; p50.022). Forced expiratory flow at 25-75% expired volume measured by % pred and z-scores also improved in subjects on dornase alfa (6.1%¡10.34%; p50.03 and 0.28¡0.46 z-score; p50.03).Dornase alfa significantly improved LCI. Therefore the LCI may be a suitable tool to assess early intervention strategies in this patient population.

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