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Background: Targeted exercise training is a promising strategy for promoting cognitive function and preventing dementia in older age. Despite the utility of exercise as an intervention, variation still exists in exercise-induced cognitive gains and questions remain regarding the type of training (i.e., what), as well as moderators (i.e., for whom) and mechanisms (i.e., how) of benefit. Both aerobic training (AT) and resistance training (RT) enhance cognitive function in older adults without cognitive impairment; however, the vast majority of trials have focused exclusively on AT. Thus, more research is needed on RT, as well as on the combination of AT and RT, in older adults with mild cognitive impairment (MCI), a prodromal stage of dementia. Therefore, we aim to conduct a 6-month, 2 × 2 factorial randomized controlled trial in older adults with MCI to assess the individual effects of AT and RT, and the combined effect of AT and RT on cognitive function and to determine the possible underlying biological mechanisms.Methods: Two hundred and sixteen community-dwelling adults, aged 65 to 85 years, with MCI from metropolitan Vancouver will be recruited to participate in this study. Randomization will be stratified by biological sex and participants will be randomly allocated to one of the four experimental groups: (1) 4×/week balance and tone (BAT; i.e., active control); (2) combined 2×/week AT + 2×/week RT; (3) 2×/week AT + 2×/week BAT; or (4) 2×/week RT + 2×/week BAT. The primary outcome is cognitive function as measured by the Alzheimer's Disease Assessment Scale-Cognitive-Plus. Secondary outcomes include cognitive function, health-related quality of life, physical function, actigraphy measures, questionnaires, and falls. Outcomes will be measured at baseline, 6 months (i.e., trial completion), and 18 months (i.e., 12-month follow-up).Discussion: Establishing the efficacy of different types and combinations of exercise training to minimize cognitive decline will advance our ability to prescribe exercise as "medicine" to treat MCI and delay the onset and progression of dementia. This trial is extremely timely as cognitive impairment and dementia pose a growing threat to global public health.Trial Registration: ClinicalTrials.gov NCT02737878 . Registered on April 14, 2016. [ABSTRACT FROM AUTHOR]

Exercise is a non-pharmacological strategy to mitigate the deleterious effects of aging on brain health. However, a large amount of variation exists in its efficacy. Sex of participants and exercise type are two possible factors contributing to this variation. To better understand this, we conducted a concurrent systematic review and meta-analysis of cognitively healthy older adults. Executive functions, episodic memory, visuospatial function, word fluency, processing speed and global cognitive function were examined for exercise- and sex-dependent effects. For executive functions, three types of exercise interventions – aerobic training, resistance training, and multimodal training (i.e., both aerobic and resistance training) – were associated with larger effect sizes in studies comprised of a higher percentage of women compared to studies with a lower percentage of women. This suggests that women’s executive processes may benefit more from exercise than men. Regardless of sex, compared to control, all three exercise training approaches enhanced visuospatial function, but only multimodal training enhanced episodic memory. Overall, aerobic training led to greater benefits than resistance training in global cognitive function and executive functions, while multimodal combined training led to greater benefits than aerobic training for global cognitive function, episodic memory, and word fluency. Possible underlying mechanisms, including brain-derived neurotrophic factor and sex steroid hormones, are discussed. [ABSTRACT FROM AUTHOR]

Research in humans indicates that women may show greater cognitive benefits from aerobic training (AT) than men. To determine whether this sex difference extends to rodents, we conducted a systematic review and meta-analysis of studies in healthy, older rodents. Results indicate that compared to controls, AT improved hippocampus-dependent and -independent learning and memory. A sex difference was found with males showing larger benefits from AT on conditioned-avoidance and non-spatial memory tasks. AT also increased brain-derived neurotrophic factor compared to controls, with larger effects in females. As an exploratory analysis, sex differences in voluntary AT were examined separately from forced AT. Voluntary AT enhanced non-spatial memory to a greater extent in males. Forced AT enhanced hippocampus-dependent learning and memory more so in females. These findings suggest that sex is an important factor to consider, and studies directly assessing sex differences in the ability of exercise to improve brain function are needed. [ABSTRACT FROM AUTHOR]

Menopause is associated with cognitive decline, and previous parity can increase or delay the trajectory of cognitive aging. Furthermore, parity enables the hippocampus to respond to estrogens in middle age. The present study investigated how previous parity and estrogens influence cognition, neurogenesis, and neuronal activation in response to memory retrieval in the hippocampus of middle-aged females. Multiparous and nulliparous rats were ovariectomized (OVX) or received sham surgery and were treated with vehicle, 17β-estradiol, 17α-estradiol, or estrone. Rats were trained on the spatial working and reference memory versions of the Morris water maze. Multiparous rats had a significantly greater density of immature neurons in the hippocampus, enhanced acquisition of working memory, but poorer reference memory compared with nulliparous rats. Furthermore, OVX increased, while treatment with estrogens reduced, the density of immature neurons, regardless of parity. OVX improved reference memory only in nulliparous rats. Thus, motherhood has long-lasting effects on the neuroplasticity and function of the hippocampus. These findings have wide-ranging implications for the treatment of age-associated decline in women. [ABSTRACT FROM AUTHOR]

Objectives: Physical activity (PA) and total sleep time (TST) are each associated with cognition; however, whether these relationships vary by age and biological sex is unclear. We examined the relationships of PA or TST with cognition, and whether age and sex moderated these relationships, using baseline data from the Canadian Longitudinal Study on Aging (CLSA; 2010-2015).Study Design: A cross-sectional analysis of participants from the Comprehensive cohort of the CLSA with complete PA and sleep data (n = 20,307; age range 45-86 years).Main Outcome Measures: PA and TST were measured using the Physical Activity Scale for the Elderly (PASE) and self-reported TST over the past month. Cognition was indexed using a three-factor structural equation model (i.e., memory, executive function, and verbal fluency).Results: Non-linear restricted cubic spline models indicated that PA and TST explained statistically significant (p < 0.01) but modest variance of each cognitive domain (<1 % of 23-24 % variance). Age and sex did not moderate associations of PA with any cognitive domain. However, age and sex moderated relationships of TST with cognition, whereby: 1) associations of TST with memory decreased with age for males and females; and 2) males and females had different age-associated relationships of TST with executive function and verbal fluency.Conclusions: PA and TST modestly contribute to multiple domains of cognition across middle and older adulthood. Importantly, the association of PA with cognition does not appear to vary across middle or older adulthood, nor does it vary by biological sex; however, TST appears to have a complex relationship with multiple domains of cognition which is both age- and sex-dependent. [ABSTRACT FROM AUTHOR]

Abstract: Although controversial, estrogen replacement therapy has been implicated as a possible therapeutic agent for ameliorating age-related cognitive decline in postmenopausal women. We have shown previously that different types of estrogen promote hippocampal neurogenesis in a dose-dependent manner in young adult female rats. However, previous studies have not found a beneficial effect of 17β-estradiol in middle-aged female rats. The aim of the present study was to determine the acute effects of 17β-estradiol, 17α-estradiol, and estrone on hippocampal cell proliferation in middle-aged ovariectomized female rats and to determine whether effects are dependent on previous reproductive experience. Middle-aged multiparous female rats or age-matched virgin female rats were injected subcutaneously with vehicle or 10μg dose of 17β-estradiol, 17α-estradiol, or estrone, and then given BrdU 30min later and perfused 24h later to assess cell proliferation. All estrogens significantly upregulated cell proliferation in the hippocampus in middle-aged multiparous females but none of the estrogens upregulated cell proliferation in the middle-aged virgins. Therefore, previous reproductive experience may make the older brain more responsive to estrogens later in life. We also found that 17α-estradiol upregulated cell proliferation to a greater degree than the other estrogens in the multiparous females. Together these findings may lead to the development of new therapeutic advances in the treatment of symptoms associated with menopause in women. [Copyright &y& Elsevier]

Background: Subcortical ischemic vascular cognitive impairment (SIVCI) is the most common form of vascular cognitive impairment. Importantly, SIVCI is considered the most treatable form of cognitive impairment in older adults, due to its modifiable risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia. Exercise training is a promising intervention to delay the progression of SIVCI, as it actively targets these cardiometabolic risk factors. Despite the demonstrated benefits of resistance training on cognitive function and emerging evidence suggesting resistance training may reduce the progression of white matter hyperintensities (WMHs), research on SIVCI has predominantly focused on the use of aerobic exercise. Thus, the primary aim of this proof-of-concept randomized controlled trial is to investigate the efficacy of a 12-month, twice-weekly progressive resistance training program on cognitive function and WMH progression in adults with SIVCI. We will also assess the efficiency of the intervention.Methods: Eighty-eight community-dwelling adults, aged > 55 years, with SIVCI from metropolitan Vancouver will be recruited to participate in this study. SIVCI will be determined by the presence of cognitive impairment (Montreal Cognitive Assessment < 26) and cerebral small vessel disease using computed tomography or magnetic resonance imaging. Participants will be randomly allocated to a twice-weekly exercise program of (1) progressive resistance training or (2) balance and tone training (i.e., active control). The primary outcomes are cognitive function measured by the Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-13 with additional cognitive tests) and WMH progression.Discussion: The burden of SIVCI is immense, and to our knowledge, this will be the first study to quantify the effect of progressive resistance training on cognitive function and WMH progression among adults with SIVCI. Slowing the rate of cognitive decline and WMH progression could preserve functional independence and quality of life. This could lead to reduced health care costs and avoidance of early institutional care.Trial Registration: ClinicalTrials.gov NCT02669394 . Registered on February 1, 2016. [ABSTRACT FROM AUTHOR]

Background: Myelin damage is a salient feature in cerebral small vessel disease (cSVD). Of note, myelin damage extends into the normal appearing white matter (NAWM). Currently, the specific role of myelin content in cognition is poorly understood.Objective: The objective of this exploratory study was to investigate the association between NAWM myelin and cognitive function in older adults with cSVD.Methods: This exploratory study included 55 participants with cSVD. NAWM myelin was measured using myelin water imaging and was quantified as myelin water fraction (MWF). Assessment of cognitive function included processing speed (Trail Making Test Part A), set shifting (Trail Making Test Part B minus A), working memory (Verbal Digit Span Backwards Test), and inhibition (Stroop Test). Multiple linear regression analyses assessed the contribution of NAWM MWF on cognitive outcomes controlling for age, education, and total white matter hyperintensity volume. The overall alpha was set at ≤0.05.Results: After accounting for age, education, and total white matter hyperintensity volume, lower NAWM MWF was significantly associated with slower processing speed (β  = -0.29, p = 0.037) and poorer working memory (β= 0.30, p = 0.048). NAWM MWF was not significantly associated with set shifting or inhibitory control (p > 0.132).Conclusion: Myelin loss in NAWM may play a role in the evolution of impaired processing speed and working memory in people with cSVD. Future studies, with a longitudinal design and larger sample sizes, are needed to fully elucidate the role of myelin as a potential biomarker for cognitive function. [ABSTRACT FROM AUTHOR]