Sex Differences in Dementia.

BackgroundWomen in many cohorts have a higher risk for Alzheimer's disease (AD), the most common form of dementia. Sex is a biological construct whereby differences in disease manifestation and prevalence are rooted in genetic differences between XX and XY combinations of chromosomes. This chapter focuses specifically on sex-driven differences in dementia, as opposed to differences driven by gender - a social construct referring to the societal norms that influence people's roles, relationships, and positional power throughout their lifetime.MethodsUsing a narrative review, this chapter explored the characteristics and risk factors for the dementias, alongside a discussion of sex differences including loss of sex steroid hormones in middle-aged women, differences in the prevalence of cardiovascular diseases and engagement in lifestyle protective factors for dementia.ResultsThe sex difference in AD prevalence may exist because of systematic and historic differences in risk and protective factors for dementia, including level of education obtained and socioeconomic status differences, which can impact on health and dementia risk.Levels of sex steroids decline significantly after menopause in women, whereas this is more gradual in men with age. Animal and cell culture studies show strong biological plausibility for sex steroids to protect the ageing brain against dementia. Sex steroid hormone replacement therapy has in some observational studies shown to protect against AD, but treatment studies in humans have mainly shown disappointing results. Cardiovascular disease (CVD) shares midlife medical risk (e.g. hypertension, hyperlipidaemia, obesity etc.) factors with AD and other forms of dementia, but also with related lifestyle risk - and protective factors (e.g. exercise, not smoking etc.). Men tend to die earlier of CVD, so fewer survive to develop AD at an older age. Those who do survive may have healthier lifestyles and fewer risk factors for both CVD and AD. An earlier age at menopause also confers great risk for both without hormone treatment.DiscussionIt could be the case that the decline in sex steroids around the menopause make women more susceptible to lifestyle-related risk factors associated with dementia and CVD, but this remains to be further investigated. Combining hormone treatment with lifestyle changes in midlife (e.g. exercise) could be an important preventative treatment for dementia and CVD in later life, but this also requires further research.

INTERGROWTH-21st Project international INTER-NDA standards for child development at 2 years of age: an international prospective population-based study.

OBJECTIVES: To describe the construction of the international INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) standards for child development at 2 years by reporting the cognitive, language, motor and behaviour outcomes in optimally healthy and nourished children in the INTERGROWTH-21st Project. DESIGN: Population-based cohort study, the INTERGROWTH-21st Project. SETTING: Brazil, India, Italy, Kenya and the UK. PARTICIPANTS: 1181 children prospectively recruited from early fetal life according to the prescriptive WHO approach, and confirmed to be at low risk of adverse perinatal and postnatal outcomes. PRIMARY MEASURES: Scaled INTER-NDA domain scores for cognition, language, fine and gross motor skills and behaviour; vision outcomes measured on the Cardiff tests; attentional problems and emotional reactivity measured on the respective subscales of the preschool Child Behaviour Checklist; and the age of acquisition of the WHO gross motor milestones. RESULTS: Scaled INTER-NDA domain scores are presented as centiles, which were constructed according to the prescriptive WHO approach and excluded children born preterm and those with significant postnatal/neurological morbidity. For all domains, except negative behaviour, higher scores reflect better outcomes and the threshold for normality was defined as ≥10th centile. For the INTER-NDA's cognitive, fine motor, gross motor, language and positive behaviour domains these are ≥38.5, ≥25.7, ≥51.7, ≥17.8 and ≥51.4, respectively. The threshold for normality for the INTER-NDA's negative behaviour domain is ≤50.0, that is, ≤90th centile. At 22-30 months of age, the cohort overlapped with the WHO motor milestone centiles, showed low postnatal morbidity (<10%), and vision outcomes, attentional problems and emotional reactivity scores within the respective normative ranges. CONCLUSIONS: From this large, healthy and well-nourished, international cohort, we have constructed, using the WHO prescriptive methodology, international INTER-NDA standards for child development at 2 years of age. Standards, rather than references, are recommended for population-level screening and the identification of children at risk of adverse outcomes.

Late weaning and maternal closeness, associated with advanced motor and visual maturation, reinforce autonomy in healthy, 2-year-old children.

We studied neurodevelopmental outcomes and behaviours in healthy 2-year old children (N = 1306) from Brazil, India, Italy, Kenya and the UK participating in the INTERGROWTH-21st Project. There was a positive independent relationship of duration of exclusive breastfeeding (EBF) and age at weaning with gross motor development, vision and autonomic physical activities, most evident if children were exclusively breastfed for ≥7 months or weaned at ≥7 months. There was no association with cognition, language or behaviour. Children exclusively breastfed from birth to <5 months or weaned at >6 months had, in a dose-effect pattern, adjusting for confounding factors, higher scores for "emotional reactivity". The positive effect of EBF and age at weaning on gross motor, running and climbing scores was strongest among children with the highest scores in maternal closeness proxy indicators. EBF, late weaning and maternal closeness, associated with advanced motor and vision maturation, independently influence autonomous behaviours in healthy children.

Neurodevelopmental milestones and associated behaviours are similar among healthy children across diverse geographical locations.

It is unclear whether early child development is, like skeletal growth, similar across diverse regions with adequate health and nutrition. We prospectively assessed 1307 healthy, well-nourished 2-year-old children of educated mothers, enrolled in early pregnancy from urban areas without major socioeconomic or environmental constraints, in Brazil, India, Italy, Kenya and UK. We used a specially developed psychometric tool, WHO motor milestones and visual tests. Similarities across sites were measured using variance components analysis and standardised site differences (SSD). In 14 of the 16 domains, the percentage of total variance explained by between-site differences ranged from 1.3% (cognitive score) to 9.2% (behaviour score). Of the 80 SSD comparisons, only six were >±0.50 units of the pooled SD for the corresponding item. The sequence and timing of attainment of neurodevelopmental milestones and associated behaviours in early childhood are, therefore, likely innate and universal, as long as nutritional and health needs are met.