Dementia, a syndrome of cognitive decline severe enough to interfere with daily functioning and independent living, has been the subject of increasing focus for policymakers, civil organisations and multidisciplinary researchers. A substantial body of the most recent descriptive epidemiological research on dementia is allowing investigation of how prevalence and incidence might be changing across time. To establish clear trends, such comparisons need to be based on population-based studies using similar diagnostic and research methods over time. This review synthesises findings from nine prevalence trend studies and five incidence trend studies from western European countries (Sweden, Spain, UK, the Netherlands and France), the US, Japan and Nigeria. These population-based studies, apart from the Japanese study, have reported stable or declining prevalence and incidence and evidence of both inconsistent and similar changes in men and women within and across countries. No single risk or protective factor has been identified to fully explain these trends, but major societal changes in western societies and improvement in factors potentially associated with risk and protecting such as living conditions, higher education attainment and wider availability of healthcare might have favourably influenced multiple factors related to physical, mental and cognitive health across the lifecourse and could be responsible for this reduced risk of dementia in later life. Analytical epidemiologic approaches combined with translational neuroscientific research may provide a unique opportunity to explore underlying mechanisms of neuropathology and dementia in the general population. The findings from these studies provide robust evidence for developing fruitful avenues for prevention, diagnosis and treatment.

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Diabetes mellitus (DM) is considered to be a risk factor for dementia including Alzheimer's disease (AD). However, the molecular mechanism underlying this risk is not well understood. We examined gene expression profiles in postmortem human brains donated for the Hisayama study. Three-way analysis of variance of microarray data from frontal cortex, temporal cortex, and hippocampus was performed with the presence/absence of AD and vascular dementia, and sex, as factors. Comparative analyses of expression changes in the brains of AD patients and a mouse model of AD were also performed. Relevant changes in gene expression identified by microarray analysis were validated by quantitative real-time reverse-transcription polymerase chain reaction and western blotting. The hippocampi of AD brains showed the most significant alteration in gene expression profile. Genes involved in noninsulin-dependent DM and obesity were significantly altered in both AD brains and the AD mouse model, as were genes related to psychiatric disorders and AD. The alterations in the expression profiles of DM-related genes in AD brains were independent of peripheral DM-related abnormalities. These results indicate that altered expression of genes related to DM in AD brains is a result of AD pathology, which may thereby be exacerbated by peripheral insulin resistance or DM.

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In this study, we investigated hepatic fibrogenesis caused by long-term thioacetamide (TAA) administration in ob/ob mice, a naturally occurring leptin deficient animal. In the lean littermates, prominent hepatic fibrosis, as well as positive staining for ␣ smooth muscle actin (␣-SMA), was induced by treatment with TAA (200 g/g, IP, 3 times per week) for 4 to 8 weeks as expected. In sharp contrast, almost no hepatic fibrosis developed in ob/ob mice given the equivalent doses of TAA, where specific staining for ␣-SMA barely was detected. Induction of ␣1(I) procollagen mRNA caused by TAA also was prevented in ob/ob mice almost completely. Further, transforming growth factor ␤ (TGF-␤) mRNA was increased in the liver after TAA treatment for 4 weeks in lean littermates, which also was prevented in ob/ob mice. Interestingly, fibrotic septa in the hepatic lobules, as well as increases in ␣1(I) procollagen mRNA, was observed in ob/ob mice, when they were injected with recombinant murine leptin (1 g/g daily) in combination with TAA treatment. Leptin per se did not cause any fibrotic changes in the liver in ob/ob mice. These findings clearly indicated that leptin deficiency is responsible for the resistance to TAA-induced profibrogenic responses in ob/ob mice. R egardless of etiologies, progression of hepatic fibrosis is a major and common problem in chronic liver diseases. Activation of hepatic stellate cells (HSCs, also called Ito cells, lipocytes, and fat-storing cells) is now believed to be the essential event in hepatic fibrogenesis, because HSCs transactivate to myofibroblast-like cells that produce a large, excess amount of extracellular matrix proteins (e.g., fibrillar collagen, fibronectin, laminin, proteoglycans) in injured liver. 1 On the other hand, emerging attention has been paid on the relationship between obesity and progression of chronic liver diseases. Lines of evidence indicated that obesity is an important risk factor for the progression of a variety of liver diseases including chronic hepatitis C, 2 alcohol-induced liver diseases 3 and nonalcoholic fatty liver diseases. 4 Especially, nonalcoholic steatohepatitis often is found in patients with obesity and type 2 diabetes, 4 suggesting the close correlation between obesity, impaired glucose tolerance and hepatic injury. However, the mechanisms by which obesity facilitates hepatic inflammation, fibrogenesis, or both, remain unclear.Leptin, an obese gene product, is a 16-kd peptide hormone that is produced predominantly from adipose tissue. 5 Original findings by Friedman et al. 6 indicate that leptin plays a crucial role in the regulation of appetite and the size of body fat mass, mainly through actions on central nervous system. Indeed, naturally occurring knockout animals of leptin and leptin receptor genes, known as ob/ob mice and db/db mice, respectively, present remarkable obesity and impaired glucose tolerance. 7,8 Further, a long-form leptin receptor has been identified predominantly in hypothalamic neurons, 9,10 which activates the intracellula...