Alzheimer Disease: Matthews FE

Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C, Anonymous00023. · Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, United Kingdom. · N Engl J Med. · Pubmed #19474427 No free full text.

Abstract: BACKGROUND: Research in Alzheimer's disease is focused mainly on younger old persons, whereas studies involving very old persons report attenuated relationships between the pathological features of Alzheimer's 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 Alzheimer's 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 Alzheimer's-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 Alzheimer's 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 Alzheimer's 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.

Lace G, Savva GM, Forster G, de Silva R, Brayne C, Matthews FE, Barclay JJ, Dakin L, Ince PG, Wharton SB, Anonymous00038. · Academic Unit of Pathology, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK. · Brain. · Pubmed #19321462 No free full text.

Abstract: Deposits of abnormally phosphorylated tau protein are found in numerous neurodegenerative disorders; the 'tauopathies', which include Alzheimer's and Pick's diseases, but tau pathology is also found in the ageing brain. Variation in tau pathology in brain ageing and its relationship to development of tauopathies and cognitive impairment remains unclear. We aimed to determine the extent and pattern of spread of tau pathology in the hippocampus, a susceptible region important in dementia and milder states of memory impairment, using hippocampal samples from the elderly population-based Medical Research Council Cognitive Function and Ageing Study neuropathology cohort. Tau deposition was assessed in hippocampal anatomical sub-regions using the AT8 antibody to phosphorylated tau and isoform-specific antibodies to 3 and 4-repeat tau (RD3 and RD4). Abeta pathology was also assessed. In this population sample, which includes the full ageing spectrum from individuals with no cognitive impairment to those with dementia satisfying clinico-pathology criteria for Alzheimer's disease, we have demonstrated a high prevalence at death of tau pathology. AT8, Abeta, RD3 and RD4 showed similar regional distribution and increased RD3 was noted in late-stage ghost tangles. Abeta was shown to be a poor explanatory variable for tau pathology. Tau deposition progressed in a hierarchical manner. Hippocampal input regions and projection zones (such as lateral entorhinal cortex, CA1/subiculum border and outer molecular layer of dentate) were initially affected, with anterograde progression though the hippocampal circuitry. Six hippocampal tau anatomical stages were defined, each linking projectionally to their adjacent stages, suggesting spread of tau malfunction through neuroanatomical pathways in hippocampal ageing. These stages were significantly associated with dementia, and may provide a clinically useful tool in the clinico-pathological assessment of dementia and mild cognitive impairment.

Matthews FE, Stephan BC, McKeith IG, Bond J, Brayne C, Anonymous00158. · Medical Resarch Council Biostatistics Unit, Institute of Public Health, Cambridge, United Kindom. · J Am Geriatr Soc. · Pubmed #18662209 No free full text.

Abstract: OBJECTIVES: To determine the 2-year outcome from 16 different current classifications of mild cognitive impairment (MCI) in a population-based sample. DESIGN: Prospective cohort study: baseline and 2-year follow-up phases. SETTING: Large-scale multicenter study, United Kingdom. PARTICIPANTS:: Thirteen thousand four individuals aged 65 and older from the Medical Research Council Cognitive Function and Ageing Study. From this, a subsample of 2,640 individuals was selected and completed a more-detailed cognitive assessment. Individuals who underwent further assessment were asked to complete annual or 2-year follow-ups. MEASUREMENTS: Information on sociodemographic status, general health, cognitive impairment and functional ability were collected using a structured interview. Individuals were classified according to 16 different definitions of MCI. These were applied retrospectively. RESULTS: The dominant outcome across definitions was an impairment that was not classifiable or reversion to normality. Progression to dementia was variable and generally poor. Overall progression was highest in classifications in which impairment extended to memory and nonmemory domains. Predictability was age dependent in some but not all classifications. CONCLUSION: Current classifications of MCI have variable outcomes in population-based samples. Progression to dementia is relatively rare and is dependent on age and definition. Selection criteria developed for the clinic are based on a "high risk" approach that leads to exclusion of a large percentage of the impaired population who are neither normal nor demented and for whom no intervention options are currently available. A refined definition of this construct is urgently needed if MCI is to be used to predict dementia in population-based studies.

Matthews FE, McKeith I, Bond J, Brayne C, Anonymous00232. · MRC Biostatistics Unit, Institute of Public Health, Cambridge, UK. · Int J Geriatr Psychiatry. · Pubmed #17136710 No free full text.

Abstract: BACKGROUND: Systematic evidence became available in the late 1990s on efficacy of cholinesterase inhibitors (CHEIs) for patients with mild to moderate Alzheimer's disease (AD) and they began to be used sporadically. Since January 2001 UK based guidelines indicated that one of three cholinesterase inhibitors (CHEIs) could be prescribed for these patients. Since then the cost of prescription in England and Wales has risen. There has been little investigation of uptake at the population level. OBJECTIVE: To estimate the population uptake of CHEIs in a population based study of dementia spanning this period. DESIGN: Using data from a 10-year follow up and a later 12 year interview of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS), a UK population based longitudinal cohort study of people originally aged 65 years and above, we investigated who was taking CHEIs during the period 2001-2004. We sought information from respondents taking part in the study what medication they were taking on a regular basis. RESULTS: Only 12, of the 219 individuals who received a study diagnosis of dementia were prescribed CHEIs [5%, 95% Confidence Intervals (CI) 3%-9%]) in 2001/2003 and none of the 28 individuals with a study diagnosis of dementia (0%, 95% CI 0-18%) in 2004 were prescribed CHEIs. Uptake was biased towards individuals with more education and higher social class. CONCLUSIONS: These data suggest that any impact on AD progression at the population level will be negligible as prescription of CHEIs and uptake in the age group at highest risk is so limited. There is little evidence that this has changed over time.