George M. Savva

Age, Neuropathology, and Dementia

BACKGROUND Research in Alzheimers disease is focused mainly on younger old persons, whereas studies involving very old persons report attenuated relationships between the pathological features of Alzheimers disease and dementia. METHODS We assessed 456 brains donated to the population-based Medical Research Council Cognitive Function and Ageing Study from persons 69 to 103 years of age at death. We used a standard neuropathological protocol that included measures of the pathological features of Alzheimers disease, cerebral atrophy, and cerebrovascular disease. Neuropathological variables were dichotomized to represent no burden or a mild burden of pathological lesions as compared with a moderate or severe burden. Logistic regression was used to estimate the effect of age on the relationship between neuropathological features and dementia. RESULTS The difference in the prevalence of moderate and severe Alzheimers-type pathological changes between persons with and those without dementia decreased with increasing age. The association between neocortical neuritic plaques and dementia was strong at 75 years of age (odds ratio, 8.63; 95% confidence interval [CI], 3.81 to 19.60) and reduced at 95 years of age (odds ratio, 2.48; 95% CI, 0.92 to 4.14), and similar attenuations with advancing age were observed in the association between other pathological changes related to Alzheimers disease and dementia in all brain areas. In contrast, neocortical cerebral atrophy maintained a relationship with age in persons with dementia at both 75 years of age (odds ratio, 5.11; 95% CI, 1.94 to 13.46) and 95 years of age (odds ratio, 6.10; 95% CI, 2.80 to 13.28) and thus distinguished the cohort with dementia from the cohort without dementia. CONCLUSIONS The association between the pathological features of Alzheimers disease and dementia is stronger in younger old persons than in older old persons. Age must be taken into account when assessing the likely effect of interventions against dementia on the population.

Anticholinergic medication use and cognitive impairment in the older population:the medical research council cognitive function and ageing study

OBJECTIVES: To determine whether the use of medications with possible and definite anticholinergic activity increases the risk of cognitive impairment and mortality in older people and whether risk is cumulative.

The presence of sodium dodecyl sulphate-stable Aβ dimers is strongly associated with Alzheimer-type dementia

The molecular pathways leading to Alzheimer-type dementia are not well understood, but the amyloid beta-protein is believed to be centrally involved. The quantity of amyloid beta-protein containing plaques does not correlate well with clinical status, suggesting that if amyloid beta-protein is pathogenic it involves soluble non-plaque material. Using 43 brains from the Newcastle cohort of the population-representative Medical Research Council Cognitive Function and Ageing Study, we examined the relationship between biochemically distinct forms of amyloid beta-protein and the presence of Alzheimer-type dementia. Cortical samples were serially extracted with Tris-buffered saline, Tris-buffered saline containing 1% TX-100 and with 88% formic acid and extracts analysed for amyloid beta-protein by immunoprecipitation/western blotting. The cohort was divisible into those with dementia at death with (n = 14) or without (n = 10) significant Alzheimer-type pathology, and those who were not demented (n = 19). Amyloid beta-protein monomer in extracts produced using Tris-buffered saline and Tris-buffered saline containing 1% TX-100 were strongly associated with Alzheimer type dementia (P < 0.001) and sodium dodecyl sulphate-stable amyloid beta-protein dimer was detected specifically and sensitively in Tris-buffered saline, Tris-buffered saline containing 1% TX-100 and formic acid extracts of Alzheimer brain. Amyloid beta-protein monomer in the formic acid fraction closely correlated with diffuse and neuritic plaque burden, but was not specific for dementia. These findings support the hypothesis that soluble amyloid beta-protein is a major correlate of dementia associated with Alzheimer-type pathology and is likely to be intimately involved in the pathogenesis of cognitive failure.

Prevalence, correlates and course of behavioural and psychological symptoms of dementia in the population.

BACKGROUND Behavioural and psychological symptoms of dementia (BPSD) are major contributors to the burden of dementia. AIMS To describe the prevalence, correlates and course of BPSD in the population of England and Wales. METHOD The prevalence of 12 symptoms was estimated in 587 participants with dementia and 2050 participants without dementia as part of a population-based longitudinal study of ageing. The effect of risk factors and the factor structure were estimated using 1782 interviews provided by participants with dementia throughout the study. RESULTS Each symptom apart from sleeping problems was more common in the population with dementia. The co-occurrence of the symptoms was explained by a four-factor solution, corresponding to psychosis/apathy, depression/anxiety, irritability/persecution and wandering/sleep problems. Psychosis occurred more frequently with declining cognition. Anxiety and depression were more common in younger individuals and in those with poor self-reported health. Persistence varied between symptoms. CONCLUSIONS Behavioural and psychological symptoms of dementia affect nearly all people with dementia. Symptoms co-occur, and the symptoms that affected individuals experience are related to their socio-demographic and clinical characteristics.

Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain.

Astrocyte pathology occurs in association with Alzheimers disease (AD) and in brain ageing, but is poorly characterised. We sought to define the detailed cellular pathology of astrocytes, the extent of population variation and the relationship to Alzheimer-type changes in a population-based cohort. Three staining patterns were associated with GFAP and excitatory amino acid transporter 2 (EAAT2): minimal, moderate or extensive immunoreactivity. GFAP and EAAT2 expression were inversely related (p=0.015), with trends to increased expression of GFAP (p=0.019) and decreased expression of EAAT2 (p=ns) with increasing Braak stage. GFAP and EAAT2 correlated incompletely with beta-amyloid and tau immunoreactivity. However, gliosis increased with increasing burden of neuritic (p=0.011), but not diffuse (p=ns), plaques. Double-staining revealed distinct subsets of astrocytes; GFAP(+)EAAT(-), GFAP(-)EAAT(+), or GFAP(+)EAAT(+). In contrast to the variation in GFAP and EAAT2, levels of EAAT1 and S100B showed consistent staining patterns. Alzheimer-type pathology only partially explains the variation in gliosis and astrocyte functional markers, suggesting that other factors contribute to the population variance in astrocyte pathology.

Frailty and cognitive impairment--a review of the evidence and causal mechanisms.

Incidence rates of cognitive impairment and dementia are rising with the ageing population. Meanwhile, the limited success of current treatments has led to a search for early markers of dementia which could predict future progression or improve quality of life for those already suffering from the disease. One focus has been on the correlation between physical and cognitive measures with an increasing interest in the association between frailty and cognitive decline. Frailty is an age-related syndrome described as the decreased ability of an organism to respond to stressors. A number of epidemiological studies have reported that frailty increases the risk of future cognitive decline and that cognitive impairment increases the risk of frailty suggesting that cognition and frailty interact within a cycle of decline associated with ageing. This paper reviews the evidence for an association between frailty and cognitive impairment and outlines some of the mechanisms that potentially underpin this relationship from brain neuropathology and hormonal dysregulation to cardiovascular risk and psychological factors.

Cohort Profile: The Irish Longitudinal Study on Ageing

Ireland shares with other developed countries the prospect of rapid and sustained population ageing. The age distribution of the Irish population is undergoing a dramatic change at present and this trend is predicted to continue into the future. People are living longer, and older persons represent a larger proportion of the population. In Ireland, the proportion of the population aged 565 years has remained steady at 11% for the past 40 years. However, it is projected that this proportion will rise to 14% by 2021 and to 19% by 2031. The greatest increase will be in the oldest old, aged 480 years, which is expected to more than treble by 2036. This change in the demographic profile of the Irish population poses a major public health challenge. Unlike the situation in the USA, the UK and many other developed countries, there have been no large population-based cohort studies in Ireland to inform research on healthy ageing. Whereas a number of studies have provided population-based data on the health status of older people living in Ireland, many questions remain unanswered. The Irish Longitudinal Study on Ageing (TILDA) is a large prospective cohort study of ageing, which includes an assessment of the social, economic and health circumstances of community-resident older people living in Ireland. The study has been harmonized with leading international research so as to ensure adoption of best practice and comparability of results. The Irish government, The Atlantic Philanthropies and Irish Life plc have provided funding for the study. Ethical approval has been obtained from the Trinity College Dublin Research Ethics Committee. Who is in the sample?

Inflammation and frailty measures in older people

Inflammation in patients defined as frail by Fried’s phenotypic definition may be related to sarcopenia. This study aimed to investigate inflammation in older patients across different frailty criteria. Frailty status was determined in 110 patients aged over 75 years (mean 83.9 years) according to function (dependent, intermediate, independent); Fried (three or more items of exhaustion, weight loss, slow walking speed, low handgrip strength, low physical activity) and Frailty Index (a measure of accumulated deficits). With increasing patient frailty as defined by function and by Fried phenotype, tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6) and C‐reactive protein (CRP) increased significantly. Albumin was lowest in the frailest subjects by each definition. The greatest differences were seen between intermediate and dependent groups and between the pre‐frail and frail. Adjustment for multiple covariates (age, sex, BMI category, smoking status, number of co‐morbidities and number of prescribed medications) did not account for any of the observed differences in levels of inflammatory markers. The Frailty Index correlated significantly with log‐transformed CRP (r= 0.221, P < 0.05), log‐transformed IL‐6 (r= 0.369, P < 0.01), TNF‐α (r= 0.379, P < 0.01) and inversely with albumin (r=– 0.545, P < 0.01). This study provides further evidence linking inflammation and frailty in older people, an association that seems consistent across different frailty measures.

Epidemiological Studies of the Effect of Stroke on Incident Dementia A Systematic Review

Background and Purpose— Stroke is implicated in the incidence of dementia, and the risk of poststroke dementia is well characterized, but the excess risk of dementia in those with stroke compared with those without stroke is not well known. Methods— We conducted a systematic review of the excess risk of incident dementia conferred by stroke. Studies of the risk of incident dementia in the population with stroke compared with the population without stroke were identified and compared. Results— Sixteen studies were identified with all but one conducted in a community setting. A history of stroke doubles the risk of incident dementia in the older population. This increase is not explained by demographic or cardiovascular risk factors or by prestroke cognitive decline. The excess risk of incident dementia diminishes with time after stroke and may be higher in those without an APOE &egr;4 allele. There is no excess risk of incident dementia in those aged >85 years with a history of stroke compared to those aged >85 years without stroke. Conclusions— The effect of stroke on dementia incidence in the population is not explained by common risk factors. At this time of population aging and increased stroke survival, more research is needed to determine to what extent efforts to reduce the incidence of stroke will affect the incidence of dementia.

Design and Methodology of The Irish Longitudinal Study on Ageing

To provide comprehensive data on older people in Ireland and new insights into the causal processes underlying the aging transformation.