Association between dietary magnesium intake, inflammation, and neurodegeneration.

BACKGROUND: Consistent evidence shows that magnesium (Mg) intake is associated with lower blood pressure (BP), and that lower BP is associated with improved cerebral health. However, recent findings indicate that the positive effect of dietary Mg intake on cerebral health is not mediated by a decrease in BP. As Mg's anti-inflammatory action is a plausible alternative mechanism, the objective of this study was to investigate the associations between Mg intake and inflammation to determine whether it mediates any neuroprotective effect. METHODS: Participants from the UK Biobank (n = 5775, aged 40-73 years, 54.7% female) were assessed for dietary magnesium using an online food questionnaire, brain and white matter lesion (WML) volumes were segmented with FreeSurfer software, and inflammation markers including high-sensitivity C-reactive protein (hs-CRP), leukocyte, erythrocyte count, and Glycoprotein acetylation (GlycA) were measured using specific laboratory techniques such as immunoturbidimetry, automated cell counting, and nuclear magnetic resonance. Hierarchical linear regression models were performed to investigate the association between dietary Mg, and inflammatory markers and between dietary Mg, brain and WMLs volumes. Mediation analysis was performed to test a possible mediation role of inflammation on the association between dietary Mg and brain and WMLs volumes. RESULTS: Higher dietary Mg intake was associated with lower inflammation: hs-CRP level (- 0.0497%; 95% confidence interval [CI] - 0.0497%,  - 0.0199%) leukocytes count (- 0.0015%; 95%CI - 0.00151%,  - 0.0011%), and GlycA (- 0.0519%; 95%CI - 0.1298%,  - 0.0129%). Moreover, higher dietary Mg intake was associated with larger grey matter volume (0.010%; 95%CI 0.004%, 0.017%), white matter volume (0.012%; 95%CI 0.003,  0.022) and right hippocampal volume (0.002%; 95%CI 0.0007, -0.0025%). Lower hs-CRP levels mediated the positive association between higher dietary Mg intake and larger grey matter volume. CONCLUSIONS: The anti-inflammatory effects of dietary Mg intake in the general population, appears to mediate its neuroprotective effect.

Cognitive Function Is Associated with the Genetically Determined Efficiency of DNA Repair Mechanisms.

Several modifiable risk factors for neurodegeneration and dementia have been identified, although individuals vary in their vulnerability despite a similar risk of exposure. This difference in vulnerability could be explained at least in part by the variability in DNA repair mechanisms' efficiency between individuals. Therefore, the aim of this study was to test associations between documented, prevalent genetic variation (single nucleotide polymorphism, SNP) in DNA repair genes, cognitive function, and brain structure. Community-living participants (n = 488,159; 56.54 years (8.09); 54.2% female) taking part in the UK Biobank study and for whom cognitive and genetic measures were available were included. SNPs in base excision repair (BER) genes of the bifunctional DNA glycosylases OGG1 (rs1052133, rs104893751), NEIL1 (rs7402844, rs5745906), NEIL2 (rs6601606), NEIL3 (rs10013040, rs13112390, rs13112358, rs1395479), MUTYH (rs34612342, rs200165598), NTHL1 (rs150766139, rs2516739) were considered. Cognitive measures included fluid intelligence, the symbol-digit matching task, visual matching, and trail-making. Hierarchical regression and latent class analyses were used to test the associations between SNPs and cognitive measures. Associations between SNPs and brain measures were also tested in a subset of 39,060 participants. Statistically significant associations with cognition were detected for 12 out of the 13 SNPs analyzed. The strongest effects amounted to a 1-6% difference in cognitive function detected for NEIL1 (rs7402844), NEIL2 (rs6601606), and NTHL1 (rs2516739). Associations varied by age and sex, with stronger effects detected in middle-aged women. Weaker associations with brain measures were also detected. Variability in some BER genes is associated with cognitive function and brain structure and may explain variability in the risk for neurodegeneration and dementia.

Investigating the synergistic effects of hormone replacement therapy, apolipoprotein E and age on brain health in the UK Biobank.

Global prevalence of Alzheimer's Disease has a strong sex bias, with women representing approximately two-thirds of the patients. Yet, the role of sex-specific risk factors during midlife, including hormone replacement therapy (HRT) and their interaction with other major risk factors for Alzheimer's Disease, such as apolipoprotein E (APOE)-e4 genotype and age, on brain health remains unclear. We investigated the relationship between HRT (i.e., use, age of initiation and duration of use) and brain health (i.e., cognition and regional brain volumes). We then consider the multiplicative effects of HRT and APOE status (i.e., e2/e2, e2/e3, e3/e3, e3/e4 and e4/e4) via a two-way interaction and subsequently age of participants via a three-way interaction. Women from the UK Biobank with no self-reported neurological conditions were included (N = 207,595 women, mean age = 56.25 years, standard deviation = 8.01 years). Generalised linear regression models were computed to quantify the cross-sectional association between HRT and brain health, while controlling for APOE status, age, time since attending centre for completing brain health measure, surgical menopause status, smoking history, body mass index, education, physical activity, alcohol use, ethnicity, socioeconomic status, vascular/heart problems and diabetes diagnosed by doctor. Analyses of structural brain regions further controlled for scanner site. All brain volumes were normalised for head size. Two-way interactions between HRT and APOE status were modelled, in addition to three-way interactions including age. Results showed that women with the e4/e4 genotype who have used HRT had 1.82% lower hippocampal, 2.4% lower parahippocampal and 1.24% lower thalamus volumes than those with the e3/e3 genotype who had never used HRT. However, this interaction was not detected for measures of cognition. No clinically meaningful three-way interaction between APOE, HRT and age was detected when interpreted relative to the scales of the cognitive measures used and normative models of ageing for brain volumes in this sample. Differences in hippocampal volume between women with the e4/e4 genotype who have used HRT and those with the e3/e3 genotype who had never used HRT are equivalent to approximately 1-2 years of hippocampal atrophy observed in typical health ageing trajectories in midlife (i.e., 0.98%-1.41% per year). Effect sizes were consistent within APOE e4/e4 group post hoc sensitivity analyses, suggesting observed effects were not solely driven by APOE status and may, in part, be attributed to HRT use. Although, the design of this study means we cannot exclude the possibility that women who have used HRT may have a predisposition for poorer brain health.

Poorer sleep impairs brain health at midlife.

Sleep is an emerging risk factor for dementia but its association with brain health remains unclear. This study included UK Biobank (n = 29,545; mean age = 54.65) participants at imaging visit with sleep measures and brain scans, and a subset (n = 14,206) with cognitive measures. Multiple linear regression analyses were conducted to study the associations between sleep and brain health. Every additional hour of sleep above 7 h/day was associated with 0.10-0.25% lower brain volumes. In contrast, a negative non-linear association was observed between sleep duration, grey matter, and hippocampal volume. Both longer (> 9 h/day) and shorter sleep (< 6 h/day) durations were associated with lower brain volumes and cognitive measures (memory, reaction time, fluid intelligence). Additionally, daytime dozing was associated with lower brain volumes (grey matter and left hippocampus volume) and lower cognitive measures (reaction time and fluid intelligence). Poor sleep (< 6 h/day, > 9 h/day, daytime dozing) at midlife was associated with lower brain health. Sleep may be an important target to improve brain health into old age and delay the onset of dementia.

Cardiometabolic health across menopausal years is linked to white matter hyperintensities up to a decade later.

Introduction: The menopause transition is associated with several cardiometabolic risk factors. Poor cardiometabolic health is further linked to microvascular brain lesions, which can be detected as white matter hyperintensities (WMHs) using T2-FLAIR magnetic resonance imaging (MRI) scans. Females show higher risk for WMHs post-menopause, but it remains unclear whether changes in cardiometabolic risk factors underlie menopause-related increase in brain pathology. Methods: In this study, we assessed whether cross-sectional measures of cardiometabolic health, including body mass index (BMI) and waist-to-hip ratio (WHR), blood lipids, blood pressure, and long-term blood glucose (HbA1c), as well as longitudinal changes in BMI and WHR, differed according to menopausal status at baseline in 9,882 UK Biobank females (age range 40-70 years, n premenopausal = 3,529, n postmenopausal = 6,353). Furthermore, we examined whether these cardiometabolic factors were associated with WMH outcomes at the follow-up assessment, on average 8.78 years after baseline. Results: Postmenopausal females showed higher levels of baseline blood lipids (HDL ß = 0.14, p < 0.001, LDL ß = 0.20, p < 0.001, triglycerides ß = 0.12, p < 0.001) and HbA1c (ß = 0.24, p < 0.001) compared to premenopausal women, beyond the effects of age. Over time, BMI increased more in the premenopausal compared to the postmenopausal group (ß = -0.08, p < 0.001), while WHR increased to a similar extent in both groups (ß = -0.03, p = 0.102). The change in WHR was however driven by increased waist circumference only in the premenopausal group. While the group level changes in BMI and WHR were in general small, these findings point to distinct anthropometric changes in pre- and postmenopausal females over time. Higher baseline measures of BMI, WHR, triglycerides, blood pressure, and HbA1c, as well as longitudinal increases in BMI and WHR, were associated with larger WMH volumes (ß range = 0.03-0.13, p ≤ 0.002). HDL showed a significant inverse relationship with WMH volume (ß = -0.27, p < 0.001). Discussion: Our findings emphasise the importance of monitoring cardiometabolic risk factors in females from midlife through the menopause transition and into the postmenopausal phase, to ensure improved cerebrovascular outcomes in later years.

A review of menopause nomenclature.

Menopause nomenclature varies in the scholarly literature making synthesis and interpretation of research findings difficult. Therefore, the present study aimed to review and discuss critical developments in menopause nomenclature; determine the level of heterogeneity amongst menopause definitions and compare them with the Stages of Reproductive Aging Workshop criteria. Definitions/criteria used to characterise premenopausal and postmenopausal status were extracted from 210 studies and 128 of these studies were included in the final analyses. The main findings were that 39.84% of included studies were consistent with STRAW classification of premenopause, whereas 70.31% were consistent with STRAW classification of postmenopause. Surprisingly, major inconsistencies relating to premenopause definition were due to a total lack of reporting of any definitions/criteria for premenopause (39.84% of studies). In contrast, only 20.31% did not report definitions/criteria for postmenopause. The present findings indicate that there is a significant amount of heterogeneity associated with the definition of premenopause, compared with postmenopause. We propose three key suggestions/recommendations, which can be distilled from these findings. Firstly, premenopause should be transparently operationalised and reported. Secondly, as a minimum requirement, regular menstruation should be defined as the number of menstrual cycles in a period of at least 3 months. Finally, the utility of introducing normative age-ranges as supplementary criterion for defining stages of reproductive ageing should be considered. The use of consistent terminology in research will enhance our capacity to compare results from different studies and more effectively investigate issues related to women's health and ageing.

The meaning of menopause is widely understood, but often imprecisely defined in research. The present findings revealed that there is a significant amount of heterogeneity associated with the definition of premenopause, compared with postmenopause. Three key suggestions/recommendations can be distilled from these findings. Firstly, premenopause should be transparently operationalised and reported. Secondly, as a minimum requirement, regular menstruation should be defined as the number of menstrual cycles in a period of at least 3 months. Finally, the utility of introducing normative age-ranges as supplementary criterion for defining stages of reproductive ageing should be considered. The use of consistent terminology in research will enhance our capacity to compare results from different studies and more effectively investigate issues related to women's health and ageing.

Age, menstruation history, and the brain.

OBJECTIVES: To investigate the cross-sectional association between measures of menstruation history (including menopausal status, age of menopause, age of menarche, and duration of reproductive stage) and brain volume. METHODS: Women (aged 45 to 79 years) from the UK Biobank were included (n = 5,072) after excluding those who had (1) hysterectomy or bilateral oophorectomy, (2) ever used menopausal hormone therapy, (3) ever had a stroke, or (4) were perimenopausal. Multiple linear hierarchical regression models were computed to quantify the cross-sectional association between measures of menstruation history and brain volume. Sensitivity analysis based on propensity matching for age (and other demographic/health covariates) were applied to estimate differences in brain volumes between matched premenopausal and postmenopausal women. RESULTS: Postmenopausal women had 1.06% (95% confidence interval [CI]; 1.05-1.06) and 2.17% (95% CI, 2.12-2.22) larger total brain volume (TBV) and hippocampal volumes (HV), respectively, than premenopausal women. Sensitivity analysis with age matched samples produced consistent results (TBV: 0.82%, 95% CI, 0.25-1.38; HV: 1.33%, 95% CI, 0.01-2.63). For every year increase in age above 45 years, postmenopausal women experienced 0.23% greater reduction in TBV than premenopausal women (95% CI, -0.60 to -0.14), which was not observed for HV. Moreover, every 1 year delayed onset of menopause after 45 was associated with 0.32% (95% CI, -0.35 to -0.28) and 0.31% (95% CI, -0.40 to -0.22) smaller TBV and HV, respectively. Every additional year in age of menarche was associated with 0.10% (95% CI, 0.04-0.16) larger TBV, which was not detected for HV. Similarly, every 1 year increase in duration of reproductive stage was associated with 0.09% smaller TBV (95% CI, -0.15 to -0.03), which was not detected for HV. CONCLUSIONS: Menopause may contribute to brain volume beyond typical aging effects. Furthermore, early age of menarche, delayed age of menopause and increasing duration of reproductive stage were negatively associated with brain volume. Further research is required to determine whether the negative association between age of menopause and HV is potentially an indicator of future vulnerability for dementia.

Longitudinal Changes in Fat Mass and the Hippocampus.

OBJECTIVE: This study aimed to investigate cross-sectional and longitudinal associations between fat mass (i.e., body mass index [BMI], waist circumference [WC], and waist to hip ratio [WTHR]) and hippocampal volumes. METHODS: UK Biobank participants (N = 20,395) aged 40 to 70 years (mean follow-up = 7.66 years), were included and categorized into one of four groups, which represented their baseline fat mass status and trajectory of change by follow-up assessment: normal weight to overweight/obesity, overweight/obesity to normal weight (ON), normal weight stable (NS), or overweight/obesity stable (OS). Regression models used NS (WC < 80 cm in women and < 94 cm in men; WTHR < 0.85 in women and < 0.90 in men; BMI < 25 kg/m2 in women and men) as the reference group. Hippocampal volumes were automatically segmented using the FMRIB Software Library. RESULTS: Compared with NS, OS (BMI: B = -62.23 [SE = 16.76]; WC: B = -145.56 [SE = 16.97]; WTHR: B = -101.26 [SE = 19.54]) and ON (BMI: B = -61.1 [SE = 30.3]; WC: B = -93.77 [SE = 24.96]; WTHR: B = -69.92 [SE = 26.22]) had significantly lower hippocampal volumes. CONCLUSIONS: The detrimental effects of overweight/obesity may extend beyond the duration of overweight/obesity itself.

Lipid profile differences during menopause: a review with meta-analysis.

OBJECTIVES: The aim of the study was to determine lipid profile differences between premenopausal and postmenopausal women. METHODS: The present review used a meta-analytic approach. Sixty-six studies were included, which provided a total sample of 114,655 women consisting of 68,394 that were premenopausal and 46,261 that were postmenopausal. RESULTS: The main findings were that (1) lipoproteins were significantly higher in postmenopausal women compared to premenopausal women including triglycerides (0.27 mmol/L, 95% confidence interval, 0.22-0.31), total cholesterol (0.58, 0.50-0.65), low-density lipoprotein (0.45, 0.38-0.53), and total cholesterol to high-density lipoprotein levels (0.39, 0.16-0.62); (2) there was no difference in high-density lipoprotein levels between premenopausal and postmenopausal women (0.02, -0.00-0.04); and (3) the differences in lipid levels was partly attributable to the mean age difference between premenopausal and postmenopausal women. CONCLUSIONS: These findings are important as they provide precise estimates of lipid differences in women around menopause. Furthermore the results suggest that the unfavorable lipid profile that develops in postmenopausal women puts them at higher risk of cardiovascular disease such as heart disease and stroke if appropriate lifestyle/pharmacological interventions are not implemented.

Fat mass changes during menopause: a metaanalysis.

OBJECTIVE: Data: Fat mass has been shown to increase in aging women; however, the extent to which menopausal status mediates these changes remains unclear. The purpose of this review was to determine (1) how fat mass differs in quantity and distribution between premenopausal and postmenopausal women, (2) whether and how age and/or menopausal status moderates any observed differences, and (3) which type of fat mass measure is best suited to the detection of differences in fat mass between groups. STUDY: This review with metaanalyses is reported according to Metaanalysis of Observational Studies in Epidemiology guidelines. STUDY APPRAISAL AND SYNTHESIS METHODS: Studies (published up to May 2018) were identified via PubMed to provide fat mass measures in premenopausal and postmenopausal women. We included 201 cross-sectional studies in the metaanalysis, which provided a combined sample size of 1,049,919 individuals and consisted of 478,734 premenopausal women and 571,185 postmenopausal women. Eleven longitudinal studies were included in the metaanalyses, which provided a combined sample size of 2472 women who were premenopausal at baseline and postmenopausal at follow up. RESULTS: The main findings of this review were that fat mass significantly increased between premenopausal and postmenopausal women across most measures, which included body mass index (1.14 kg/m2; 95% confidence interval, 0.95-1.32 kg/m2), bodyweight (1 kg; 95% confidence interval, 0.44-1.57 kg), body fat percentage (2.88%; 95% confidence interval, 2.13-3.63%), waist circumference (4.63 cm; 95% confidence interval, 3.90-5.35 cm), hip circumference (2.01 cm; 95% confidence interval, 1.36-2.65 cm), waist-hip ratio (0.04; 95% confidence interval, 0.03-0.05), visceral fat (26.90 cm2; 95% confidence interval, 13.12-40.68), and trunk fat percentage (5.49%; 95% confidence interval, 3.91-7.06 cm2). The exception was total leg fat percentage, which significantly decreased (-3.19%; 95% confidence interval, -5.98 to -0.41%). No interactive effects were observed between menopausal status and age across all fat mass measures. CONCLUSION: The change in fat mass quantity between premenopausal and postmenopausal women was attributable predominantly to increasing age; menopause had no significant additional influence. However, the decrease in total leg fat percentage and increase in measures of central fat are indicative of a possible change in fat mass distribution after menopause. These changes are likely to, at least in part, be due to hormonal shifts that occur during midlife when women have a higher androgen (ie, testosterone) to estradiol ratio after menopause, which has been linked to enhanced central adiposity deposition. Evidently, these findings suggest attention should be paid to the accumulation of central fat after menopause, whereas increases in total fat mass should be monitored consistently across the lifespan.

First Behavioural Characterisation of a Knockout Mouse Model for the Transforming Growth Factor (TGF)-ß Superfamily Cytokine, MIC-1/GDF15.

Macrophage inhibitory cytokine-1 (MIC-1), also known as growth differentiation factor 15 (GDF15), is a stress response cytokine. MIC-1/GDF15 is secreted into the cerebrospinal fluid and increased levels of MIC-1/GDF15 are associated with a variety of diseases including cognitive decline. Furthermore, Mic-1/Gdf15 knockout mice (Mic-1 KO) weigh more, have increased adiposity, associated with increased spontaneous food intake, and exhibit reduced basal energy expenditure and physical activity. The current study was designed to comprehensively determine the role of MIC-1/GDF15 on behavioural domains of male and female knockout mice including locomotion, exploration, anxiety, cognition, social behaviours, and sensorimotor gating. Mic-1 KO mice exhibited a task-dependent increase in locomotion and exploration and reduced anxiety-related behaviours across tests. Spatial working memory and social behaviours were not affected by Mic-1/Gdf15 deficiency. Interestingly, knockout mice formed an increased association with the conditioned stimulus in fear conditioning testing and also displayed significantly improved prepulse inhibition. Overall sex effects were evident for social behaviours, fear conditioning, and sensorimotor gating. This is the first study defining the role of Mic-1/Gdf15 in a number of behavioural domains. Whether the observed impact is based on direct actions of Mic-1/Gdf15 deficiency on the CNS or whether the behavioural effects are mediated by indirect actions on e.g. other neurotransmitter systems must be clarified in future studies.

A visual MRI atrophy rating scale for the amyotrophic lateral sclerosis-frontotemporal dementia continuum.

Our objective was to distinguish ALS, ALS-FTD and bvFTD via a novel visual MRI cortical atrophy scale that can be employed in a clinical setting. MRI images of 100 participants (33 ALS, 11 ALS-FTD, 22 bvFTD and 34 controls) were rated in four brain areas: orbitofrontal cortex, anterior temporal pole, anterior cingulate, and motor cortex. Areas were rated on a 5- point Likert scale by two raters blinded to the diagnosis. Results demonstrated that bvFTD patients showed the highest levels of atrophy across all regions, while ALS patients had the lowest atrophy scores. ALS-FTD patients have higher atrophy ratings compared to ALS patients for the motor cortex, anterior cingulate and anterior temporal lobe, with a statistical trend for the orbitofrontal cortex. ALS-FTD patients were not significantly different from bvFTD for any of the brain regions. These findings were confirmed in a post hoc VBM analysis of the same participants. Our study demonstrates that a simple visual MRI rating scale can reliably distinguish ALS, ALS-FTD and bvFTD atrophy patterns in a clinical setting. Motor cortex, anterior cingulate and anterior temporal atrophy emerged as good diagnostic markers for ALS-FTD. Employment of this MRI rating scale can complement clinical diagnostics of patients in the ALS-FTD continuum.