C-reactive protein and cognition are unrelated to leukoaraiosis.

Elevated serum levels of C-reactive protein (CRP) have been associated with leukoaraiosis in elderly brain. However, several studies indicate that leukoaraiosis is associated with an increased risk of cognitive impairment. It is unknown how the effect of CRP on cognition is mediated by leukoaraiosis. The purpose of this study is to assess the relationship between serum levels of CRP, the presence of leukoaraiosis, and cognitive impairment in a population of coronary patients over 50 years old. CRP levels explained 7.18% (P: 0.002) of the variance of the MMSE. The adjustment for the presence of leukoaraiosis little changed this variance (5.98%, P: 0.005), indicating that only a small portion of the CRP influence on cognition was mediated via leukoaraiosis. Patients with CRP levels ≥ 5.0 had 2.9 (95% CI: 1.26-6.44) times more chance to present cognitive impairment (P: 0.012). We found that elevated serum levels of CRP were associated with increased risk of cognitive impairment in elderly and it was not mediated by presence of leukoaraiosis.

[Tendencies of studies addressing the eldest individuals of aged population in the community: a (inter)national systematic review]. / Tendências dos estudos com idosos mais velhos na comunidade: uma revisão sistemática (inter)nacional.

The purpose of this study was to identify and analyze the tendencies and types of studies published in Brazil and abroad, involving elders aged>80 years, living in the community. A systematic review of national literature was performed using the LILACS and SciELO databases, and PUBMED and EMBASE for international literature, covering publications of the last two decades. Twelve national and 162 international references were selected. Biological sciences were the prevalent area both at the national (50%) and international (74.1%) levels. All national studies were observational, 91.7% of which were cross-sectional. Of the international studies, 93.3% were observational, 48.1% of which were cross-sectional and 37.6% were cohort studies. The United States were the country responsible for 41.4% of all international publications. Brazil and China were the only developing countries with international publications. Despite the significant number of international scientific publications as of 2005, this fact has not been observed at the national level.

(Pre)diabetes, brain aging, and cognition.

Cognitive dysfunction and dementia have recently been proven to be common (and underrecognized) complications of diabetes mellitus (DM). In fact, several studies have evidenced that phenotypes associated with obesity and/or alterations on insulin homeostasis are at increased risk for developing cognitive decline and dementia, including not only vascular dementia, but also Alzheimer's disease (AD). These phenotypes include prediabetes, diabetes, and the metabolic syndrome. Both types 1 and 2 diabetes are also important risk factors for decreased performance in several neuropsychological functions. Chronic hyperglycemia and hyperinsulinemia primarily stimulates the formation of Advanced Glucose Endproducts (AGEs), which leads to an overproduction of Reactive Oxygen Species (ROS). Protein glycation and increased oxidative stress are the two main mechanisms involved in biological aging, both being also probably related to the etiopathogeny of AD. AD patients were found to have lower than normal cerebrospinal fluid levels of insulin. Besides its traditional glucoregulatory importance, insulin has significant neurothrophic properties in the brain. How can clinical hyperinsulinism be a risk factor for AD whereas lab experiments evidence insulin to be an important neurothrophic factor? These two apparent paradoxal findings may be reconciliated by evoking the concept of insulin resistance. Whereas insulin is clearly neurothrophic at moderate concentrations, too much insulin in the brain may be associated with reduced amyloid-beta (Abeta) clearance due to competition for their common and main depurative mechanism - the Insulin-Degrading Enzyme (IDE). Since IDE is much more selective for insulin than for Abeta, brain hyperinsulinism may deprive Abeta of its main clearance mechanism. Hyperglycemia and hyperinsulinemia seems to accelerate brain aging also by inducing tau hyperphosphorylation and amyloid oligomerization, as well as by leading to widespread brain microangiopathy. In fact, diabetes subjects are more prone to develop extense and earlier-than-usual leukoaraiosis (White Matter High-Intensity Lesions - WMHL). WMHL are usually present at different degrees in brain scans of elderly people. People with more advanced WMHL are at increased risk for executive dysfunction, cognitive impairment and dementia. Clinical phenotypes associated with insulin resistance possibly represent true clinical models for brain and systemic aging.

The demands of family caregivers of elderly individuals with dementia.

The purpose of this cross-sectional observational study was to identify characteristics of caregivers of elderly people with dementia, types of care demands and to relate demands to the stage of dementia. The study was carried out in 2004 with 104 older adults and 90 caregivers in Ribeirão Preto, state of São Paulo. The OARS instrument was utilized and a questionnaire answered by caregivers. Among older adults, 66.3% were female, aged 75.5 years in average and 86.5% had caregivers. Eighty percent of the caregivers were women family members, aged 52.3 years in average. They spent 15.10 hours/day with care, without help. An important relationship was observed between caregiver's burden, physical and emotional effort and stage of dementia. Emotional overburden was higher at dementia early and late stages, this difference was statistically non-significant. Results reveal the urgent need to plan formal and informal support strategies to caregivers of Brazilian elderly people with dementia.

The specific impact of uremic toxins upon cognitive domains: a review.

One of the mechanisms proposed for chronic kidney disease (CKD)-related cognitive impairment is the accumulation of uremic toxins due to the deterioration of the renal clearance function. Cognition can be categorized into five major domains according to its information processing functions: memory, attention, language, visual-spatial, and executive. We performed a review using the terms 'uric acid', 'indoxyl sulfate', 'p-cresyl sulfate', 'homocysteine', 'interleukins' and 'parathyroid hormone'. These are the compounds that were found to be strongly associated with cognitive impairment in CKD in the literature. The 26 selected articles point towards an association between higher levels of uric acid, homocysteine, and interleukin 6 with lower cognitive performance in executive, attentional, and memory domains. We also reviewed the hemodialysis effects on cognition. Hemodialysis seems to contribute to an amelioration of CKD-related encephalopathic dysfunction, although this improvement occurs more in some cognitive domains than in others.

Sirtuin 1 and Alzheimer's disease: An up-to-date review.

Sirtuins are NAD+-dependent enzymes that regulate a large number of cellular pathways and are related to aging and age-associated diseases. In recent years, the role of sirtuins in Alzheimer's disease (AD) has become increasingly apparent. Growing evidence demonstrates that sirtuin 1 (SIRT1) regulates many processes that go amiss in AD, such as: APP processing, neuroinflammation, neurodegeneration, and mitochondrial dysfunction. Here we review how SIRT1 affects AD and cognition, the main mechanisms in which SIRT1 is related to AD pathology, and its importance for the prevention and possible diagnosis of AD.

CSF Aß1-42, but not p-Tau181, Predicted Progression from Amnestic MCI to Alzheimer's Disease Dementia.

The purpose of the study was to determine whether Aß1-42 and p-Tau181 cerebral spinal fluid (CSF) levels can predict progression from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease dementia (ADD) in a 3-year follow-up study. All participants were evaluated blindly by a behavioral neurologist and a neuropsychologist, and classified according to the Petersen criteria for aMCI and according to the Clinical Dementia Rating (CDR) scale. Individuals were also submitted to lumbar puncture at baseline. Levels of Aß1-42 and p-Tau181 were measured by immunoenzymatic assay. Values were adjusted for age and sex. Thirty-one of 33 (93.9%) participants completed follow-up. Approximately 39% of aMCI individuals progressed to ADD. The relative risk of developing ADD in those with Aß1-42 CSF levels lower than 618.5 pg/mL was 17.4 times higher than in those whose levels were higher than 618.5 pg/mL (P = 0.003). p-Tau181 alone did not predict progression to ADD (P = 0.101). The relative risk in those with a p-Tau181/Aß1-42 ratio higher than 0.135 was 5.7 times greater (P < 0.001). Aß1-42 and p-Tau181 explained 40.1% of the verbal memory test subscore of the Consortium to Establish a Registry for Alzheimer's Disease (ΔCERADs) variance (P = 0.008). Aß1-42 strongly predicted progression from aMCI to ADD. p-Tau181 alone, or its relation to Aß1-42, was inferior than Aß1-42 alone as a predictor of progression to ADD.

CSF Aß1-42, but not p-Tau181, differentiates aMCI from SCI.

AIM: Individuals with amnestic mild cognitive impairment (aMCI) are at a high risk to develop Alzheimer's disease (AD). We compared CSF levels of biomarkers of amyloidosis (Aß1-42) and neurodegeneration (p-Tau181) in individuals with aMCI and with subjective cognitive impairment (SCI) in order to ascertain diagnostic accuracy and predict the odds ratio associated with aMCI. METHODS: We collected CSF of individuals clinically diagnosed with aMCI (33) and SCI (12) of a memory clinic of Southern Brazil. Levels of Aß1-42 and p-Tau181 were measured by immunoenzymatic assay. Participants also underwent neuropsychological testing including the verbal memory test subscore of the Consortium to Establish a Registry for Alzheimer's Disease (VM-CERAD). RESULTS: CSF concentration of Aß1-42 was significantly lower (p: .007) and p-Tau181/Aß1-42 ratio higher (p: .014) in aMCI individuals than in SCI. However, isolate p-Tau181 levels were not associated with aMCI (p: .166). There was a statistically significant association between Aß1-42 and p-Tau181 (R2: 0.177; ß: -4.43; p: .017). ROC AUC of CSF Aß1-42 was 0.768 and of the p-Tau181/Aß1-42 ratio equals 0.742. Individuals with Aß1-42 < 823 pg/mL levels were 6.0 times more likely to be diagnosed with aMCI (p: .019), with a 68.9% accuracy. Those with p-Tau181/Aß1-42 ratio > 0.071 were at 4.6 increased odds to have aMCI (p: .043), with a 64.5% accuracy. VM-CERAD was significantly lower in aMCI than among SCI (p: .041). CONCLUSION: CSF Aß1-42, but not p-Tau181, level was significantly associated with aMCI.

Stroke-independent association between metabolic syndrome and functional dependence, depression, and low quality of life in elderly community-dwelling Brazilian people.

OBJECTIVES: Metabolic syndrome (Met.S) is a risk factor for stroke, dementia, and ischemic heart disease (IHD). It is unclear whether Met.S is an independent risk factor for functional dependence, depression, cognitive impairment, and low health-related quality of life (HRQoL) in a population free of clinical stroke. DESIGN: Cross-sectional. SETTING: Two communities in southern Brazil. PARTICIPANTS: Four hundred twenty people aged 60 and older. MEASUREMENTS: An adapted (body mass index > or =30 kg/m(2) and blood pressure > or =140/90) Adult Treatment Panel III definition was used in diagnosing Met.S. Depression (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Revised) and Mini-Mental State Examination were evaluated along with activities of daily living (ADLs) and instrumental activities of daily living (IADLs). HRQoL was measured using a visual analogue scale (0-10). All values were adjusted for age, sex, and presence of IHD. RESULTS: Forty (9.5%) subjects had a stroke and were excluded from the final analysis. Met.S was present in 37.4% of the stroke-free population. Met.S was significantly and independently associated with 2.24 times as much ADL dependence, 2.39 times as much IADL dependence, a 2.12 times higher risk of depression, a 2.27 times higher likelihood of cognitive impairment, and a 1.62 times higher chance of low self-perceived HRQoL (all P<0.05). Adjustment for its own components reduced the strength of the above associations but did not eliminate their statistical significance. If Met.S were removed from this population, dependence, depression, cognitive impairment, and low QoL would be reduced 15.0% to 21.4%. CONCLUSION: Met.S was significantly associated with functional dependence, depression, cognitive impairment, and low HRQoL, and its effects were independent of clinical stroke, IHD, and its own individual components.

Cerebrospinal fluid inflammatory markers in amnestic mild cognitive impairment.

AIMS: Inflammatory processes might play a significant role at the pathophysiology of Alzheimer's disease (AD). Neuroinflammation is characterized by activation of microglia and the release of inflammatory cytokines, such as interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α. Although, it is unknown what the real contribution of these inflammatory markers in the development of AD is. The purpose of the present study was to assess the possible relationship between inflammatory markers in the cerebrospinal fluid (CSF) of amnestic mild cognitive impairment patients (aMCI), aged 60 years or older, and compare with aged healthy controls. METHODS: We examined concentrations of IL-1ß, IL-6 and tumor necrosis factor-α in the CSF of aMCI patients and controls by enzyme immunoassay. aMCI diagnoses were based on anamnesis and Petersen criteria, corroborated by the Clinical Dementia Rating. Cognitive function was assessed by neuropsychological tests. RESULTS: CSF levels of IL-1ß (13.735 vs 22.932 pg/mL; P < 0.001) and tumor necrosis factor-α (1.913 vs 2.627 pg/mL; P = 0.002), but not IL-6 (4.178 vs 5.689 pg/mL; P = 0.106), were significantly reduced in the aMCI samples as compared with controls. Individuals with IL-1ß < 17 pg/mL were at a 7.2 (CI 1.5-36; P: 0.016) increased odds of aMCI. There was a positive correlation between IL-1ß levels and the Consortium to Establish a Registry for Alzheimer's Disease word list score (rs = 0.299; P = 0.046). Linear regression analysis showed that IL-1ß levels might explain 13.7% (ß = 24.545; P = 0.012) of the variance on this Consortium to Establish a Registry for Alzheimer's Disease subscore. CONCLUSION: The present results show a pattern of cytokines expression in the CSF of aMCI patients that might be relevant to the pathogeny of prodromal AD. Geriatr Gerontol Int 2017; 17: 239-245.

Global epidemiology of dementia: Alzheimer's and vascular types.

The prevalence of dementia varies substantially worldwide. This is partially attributed to the lack of methodological uniformity among studies, including diagnostic criteria and different mean population ages. However, even after considering these potential sources of bias, differences in age-adjusted dementia prevalence still exist among regions of the world. In Latin America, the prevalence of dementia is higher than expected for its level of population aging. This phenomenon occurs due to the combination of low average educational attainment and high vascular risk profile. Among developed countries, Japan seems to have the lowest prevalence of dementia. Studies that evaluated the immigration effect of the Japanese and blacks to USA evidenced that acculturation increases the relative proportion of AD cases compared to VaD. In the Middle East and Africa, the number of dementia cases will be expressive by 2040. In general, low educational background and other socioeconomic factors have been associated with high risk of obesity, sedentarism, diabetes, hypertension, dyslipidemia, and metabolic syndrome, all of which also raise the risk of VaD and AD. Regulating these factors is critical to generate the commitment to make dementia a public health priority.

The specific impact of uremic toxins upon cognitive domains: a review / O impacto específico de toxinas urêmicas em domínios cognitivos: uma revisão

ABSTRACT One of the mechanisms proposed for chronic kidney disease (CKD)-related cognitive impairment is the accumulation of uremic toxins due to the deterioration of the renal clearance function. Cognition can be categorized into five major domains according to its information processing functions: memory, attention, language, visual-spatial, and executive. We performed a review using the terms 'uric acid', 'indoxyl sulfate', 'p-cresyl sulfate', 'homocysteine', 'interleukins' and 'parathyroid hormone'. These are the compounds that were found to be strongly associated with cognitive impairment in CKD in the literature. The 26 selected articles point towards an association between higher levels of uric acid, homocysteine, and interleukin 6 with lower cognitive performance in executive, attentional, and memory domains. We also reviewed the hemodialysis effects on cognition. Hemodialysis seems to contribute to an amelioration of CKD-related encephalopathic dysfunction, although this improvement occurs more in some cognitive domains than in others.

RESUMO Um dos mecanismos propostos para explicar o comprometimento cognitivo relacionado à doença renal crônica (DRC) é o acúmulo de toxinas urêmicas devido à deterioração da função de depuração renal. A cognição pode ser categorizada em cinco domínios principais de acordo com suas funções de processamento de informações: memória, atenção, linguagem, visual-espacial e executiva. Realizamos uma revisão usando os termos "ácido úrico", "indoxil sulfato", "p-cresil sulfato", "homocisteína", "interleucinas" e "paratormônio". Estes são os compostos que se mostraram fortemente associados ao comprometimento cognitivo na DRC na literatura. Os 26 artigos selecionados apontam para uma associação entre níveis mais elevados de ácido úrico, homocisteína e interleucina-6 com menor desempenho cognitivo nos domínios executivo, atenção e de memória. Também revisamos os efeitos da hemodiálise na cognição. A hemodiálise parece contribuir para uma melhoria da disfunção encefalopática relacionada à DRC, embora essa melhora ocorra mais em alguns domínios cognitivos do que em outros.

Mechanisms of brain aging regulation by insulin: implications for neurodegeneration in late-onset Alzheimer's disease.

Insulin and IGF seem to be important players in modulating brain aging. Neurons share more similarities with islet cells than any other human cell type. Insulin and insulin receptors are diffusely found in the brain, especially so in the hippocampus. Caloric restriction decreases insulin resistance, and it is the only proven mechanism to expand lifespan. Conversely, insulin resistance increases with age, obesity, and sedentarism, all of which have been shown to be risk factors for late-onset Alzheimer's disease (AD). Hyperphagia and obesity potentiate the production of oxidative reactive species (ROS), and chronic hyperglycemia accelerates the formation of advanced glucose end products (AGEs) in (pre)diabetes-both mechanisms favoring a neurodegenerative milieu. Prolonged high cerebral insulin concentrations cause microvascular endothelium proliferation, chronic hypoperfusion, and energy deficit, triggering ß-amyloid oligomerization and tau hyperphosphorylation. Insulin-degrading enzyme (IDE) seems to be the main mechanism in clearing ß-amyloid from the brain. Hyperinsulinemic states may deviate IDE utilization towards insulin processing, decreasing ß-amyloid degradation.

Socioeconomic and health differentials between two community-dwelling oldest-old groups.

OBJECTIVE: To identify demographic and socioeconomic differentials associated with the health status of oldest-old individuals living in two cities of different Brazilian regions. METHODS: A comparative and cross-sectional epidemiological study was conducted with the oldest-old (> 80 years), living in the cities of Ribeirão Preto (RP, Southeastern Brazil) and Caxias do Sul (CS, Southern). The probabilistic sample included 117 individuals in CS and 155 in RP, and data were collected between 2007 and 2008. The instrument included demographic and socioeconomic data, Mini-Mental State Examination, Functional Independence Measure, number of self-reported comorbidities and Geriatric Depression Scale. RESULTS: Mean age was similar, with predominance of women (~70%) and widowed individuals (~60%) in both cities. Mean level of education did no differ statistically, although mean income was higher in RP than in CS (p = 0.05). RP showed a higher concentration of individuals in the extreme levels of education and income than that of CS. Mean score of the Mini-Mental State Examination was similar in both groups and higher among men, individuals aged between 80 and 84 years, married and with a higher level of education. Better functional performance was observed in elderly individuals aged between 80 and 84 years in both cities, in those with higher level of education in RP; and in males and married individuals in CS. Elderly individuals in CS showed higher number of comorbidities than those in RP (p < 0.001). Male elderly individuals, married and with -higher income level showed fewer depressive symptoms in both groups; and those in RP showed higher Geriatric Depression Scale score than the others in CS (p < 0.001). CONCLUSIONS: Although the oldest old in CS showed lower socioeconomic inequality and fewer depressive symptoms, they also had a higher mean number of comorbidities and lower level of functional independence, when compared to those in RP.