Disturbed sleep is associated with reduced verbal episodic memory and entorhinal cortex volume in younger middle-aged women with risk-reducing early ovarian removal

INTRODUCTION: Women with early ovarian removal (&lt;48 years) have an elevated risk for both late-life Alzheimer's disease (AD) and insomnia, a modifiable risk factor. In early midlife, they also show reduced verbal episodic memory and hippocampal volume. Whether these reductions correlate with a sleep phenotype consistent with insomnia risk remains unexplored.METHODS: We recruited thirty-one younger middleaged women with risk-reducing early bilateral salpingo-oophorectomy (BSO), fifteen of whom were taking estradiol-based hormone replacement therapy (BSO+ERT) and sixteen who were not (BSO). Fourteen age-matched premenopausal (AMC) and seventeen spontaneously peri-postmenopausal (SM) women who were ~10y older and not taking ERT were also enrolled. Overnight polysomnography recordings were collected at participants' home across multiple nights (M=2.38 SEM=0.19), along with subjective sleep quality and hot flash ratings. In addition to group comparisons on sleep measures, associations with verbal episodic memory and medial temporal lobe volume were assessed.RESULTS: Increased sleep latency and decreased sleep efficiency were observed on polysomnography recordings of those not taking ERT, consistent with insomnia symptoms. This phenotype was also observed in the older women in SM, implicating ovarian hormone loss. Further, sleep latency was associated with more forgetting on the paragraph recall task, previously shown to be altered in women with early BSO. Both increased sleep latency and reduced sleep efficiency were associated with smaller anterolateral entorhinal cortex volume.DISCUSSION: Together, these findings confirm an association between ovarian hormone loss and insomnia symptoms, and importantly, identify an younger onset age in women with early ovarian removal, which may contribute to poorer cognitive and brain outcomes in these women.</p

Extra-cellular matrix proteins induce matrix metalloproteinase-1 (MMP-1) activity and increase airway smooth muscle contraction in asthma

Airway remodelling describes the histopathological changes leading to fixed airway obstruction in patients with asthma and includes extra-cellular matrix (ECM) deposition. Matrix metalloproteinase-1 (MMP-1) is present in remodelled airways but its relationship with ECM proteins and the resulting functional consequences are unknown. We used airway smooth muscle cells (ASM) and bronchial biopsies from control donors and patients with asthma to examine the regulation of MMP-1 by ECM in ASM cells and the effect of MMP-1 on ASM contraction. Collagen-I and tenascin-C induced MMP-1 protein expression, which for tenascin-C, was greater in asthma derived ASM cells. Tenascin-C induced MMP-1 expression was dependent on ERK1/2, JNK and p38 MAPK activation and attenuated by function blocking antibodies against the β1 and β3 integrin subunits. Tenascin-C and MMP-1 were not expressed in normal airways but co-localised in the ASM bundles and reticular basement membrane of patients with asthma. Further, ECM from asthma derived ASM cells stimulated MMP-1 expression to a greater degree than ECM from normal ASM. Bradykinin induced contraction of ASM cells seeded in 3D collagen gels was reduced by the MMP inhibitor ilomastat and by siRNA knockdown of MMP-1. In summary, the induction of MMP-1 in ASM cells by tenascin-C occurs in part via integrin mediated MAPK signalling. MMP-1 and tenascin-C are co-localised in the smooth muscle bundles of patients with asthma where this interaction may contribute to enhanced airway contraction. Our findings suggest that ECM changes in airway remodelling via MMP-1 could contribute to an environment promoting greater airway narrowing in response to broncho-constrictor stimuli and worsening asthma symptoms

Brain regions involved in the acquisition and reversal of tone-visual associations in humans, a PET study

grantor: University of TorontoPositron emission tomography (PET) was used to identify brain regions that showed changes in regional cerebral blood flow (rCBF) as subjects participated in voluntary response differential conditioning study. Two tones (T1 and T2) served as the conditioned excitor (CS+) and conditioned inhibitor (CS$-$) and a visual stimulus served as the unconditioned stimulus (UCS). In phase one of the experiment T1 was the CS+ and T2 the CS$-$. In phase 2 of the experiment the contingencies were reversed. Sixteen subjects (9 males and 7 females) between the ages of 19 and 35 participated in this study. Subjects were told to press a button with their right index finger each time they were presented with the UCS. Eight PET scans were obtained from each subject. The scans were obtained while subjects were being presented with predictive CS+ and UCS trials or while subjects were presented with nonpredictive CS$-$ and UCS trials. The scan types were alternated across the experiment and four scans were obtained during each of the phases. During the acquisition of the phase two association subjects engaged a network of brain regions consisting of: right middle frontal gyrus, right inferior parietal lobule, right precentral and postcentral gyri, and right precuneus. In addition a network of brain regions involved in extinction to the first association during phase two was identified. This network consisted of right middle frontal gyrus, right thalamus, left inferior parietal lobule, and left cerebellum. Right hippocampal gyrus, right middle occipital gyrus and left middle temporal gyrus were found to involved in both learning the second association and extinction of the first association. The analysis did not identify any significant patterns of brain activation related to phase one of the experiment. (Abstract shortened by UMI.)M.A

Sex and gender differences in cognitive and brain reserve: Implications for Alzheimers disease in women

Women represent (2)/(3) of the cases of Alzheimers disease (AD). Current research has focused on differential risks to explain higher rates of AD in women. However, factors that reduce risk for AD, like cognitive/brain reserve, are less well explored. We asked: what is known about sex and gender differences in how reserve mitigates risk for AD? We conducted a narrative review of the literature, with keywords: "sex/gender differences", "cognitive/brain reserve", "Alzheimers Disease", and the following cognitive reserve contributors: "education", "IQ", "occupation", "cognitive stimulation", "bilingualism", "socioeconomic status", "physical activity", "social support". Sixteen papers disaggregated their data by sex. Those papers observed sex and gender differences in reserve contributors. There is also evidence that greater reserve may be more beneficial in lowering AD risk in women, although more research is needed. We discuss how traditional reserve contributors are gendered and may not capture factors that support cognition in aging women.Funding Agencies|Canadian Consortium on Neurodegeneration and Aging; Wilfred and Joyce Posluns Chair in Womens Brain Health and Aging (the Womens Brain Health Initiative, Ontario Brain Institute); Wilfred and Joyce Posluns Chair in Womens Brain Health and Aging (Canadian Institutes of Health Research)Canadian Institutes of Health Research (CIHR); Canadian Institute of Health ResearchCanadian Institutes of Health Research (CIHR) [PJT 201610-153321, GS9-171369]; Natural Science and Engineering Research CouncilNatural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-2018-05761]; Alzheimers Society; Natural Science and Engineering Research CouncilNatural Sciences and Engineering Research Council of Canada (NSERC)</p

Sex differences in longitudinal changes of episodic memory-related brain activity and cognition in cognitively unimpaired older adults with a family history of Alzheimer’s disease

Episodic memory decline is an early symptom of Alzheimer’s disease (AD) – a neurodegenerative disease that has a higher prevalence rate in older females compared to older males. However, little is known about why these sex differences in prevalence rate exist. In the current longitudinal task fMRI study, we explored whether there were sex differences in the patterns of memory decline and brain activity during object-location (spatial context) encoding and retrieval in a large sample of cognitively unimpaired older adults from the Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer’s Disease (PREVENT-AD) program who are at heightened risk of developing AD due to having a family history (+FH) of the disease. The goal of the study was to gain insight into whether there are sex differences in the neural correlates of episodic memory decline, which may advance knowledge about sex-specific patterns in the natural progression to AD. Our results indicate that +FH females performed better than +FH males at both baseline and follow-up on neuropsychological and task fMRI measures of episodic memory. Moreover, multivariate data-driven task fMRI analysis identified generalized patterns of longitudinal decline in medial temporal lobe activity that was paralleled by longitudinal increases in lateral prefrontal cortex, caudate and midline cortical activity during successful episodic retrieval and novelty detection in +FH males, but not females. Post-hoc analyses indicated that higher education had a stronger effect on +FH females neuropsychological scores compared to +FH males. We conclude that higher educational attainment may have a greater neuroprotective effect in older +FH females compared to +FH males