Incidence of dementia in very elderly individuals: a clinical, neuropathological and molecular genetic study.
ABSTRACT To evaluate the effect of medical record use on figures for the incidence of dementia and the effect of apolipoprotein E (APOE) polymorphism on this incidence and neuropathologically defined Alzheimer's disease (AD) in very elderly individuals.
Cognitive functions were examined in a cohort of 328 (92% of the very elderly people of a town participated in this study) nondemented Finnish elderly individuals 85 years of age or more in 1991. The examination was repeated in survivors in 1994, 1996, 1999 and 2001. Medical notes and social work records were evaluated. All these individuals were genotyped for APOE. Neuropathological analysis of AD-type pathology was performed on 159 of 303 subjects who died during the follow-up.
Age group, gender or APOE did not significantly affect the incidence of dementia, which was over 20% higher (85 vs. 69 per 1,000 person-years) if the cognitive status at death was ascertained by medical and social work records than without this evaluation. The APOE upsilon4 allele was highly significantly (p=0.002) and age almost significantly (p=0.06) associated with neuropathological AD in nondemented individuals.
Medical records should be analyzed in studies on the incidence of dementia in very elderly individuals. APOE polymorphism does not affect the incidence of dementia in this age group. However, clinical dementia diagnosis in very elderly individuals does not necessarily correlate well with the presence of neuropathological AD which, even in this age group, is significantly associated with the APOE upsilon4 allele.
SourceAvailable from: Daniel H.j. Davis[Show abstract] [Hide abstract]
ABSTRACT: Background Delirium is a profound neuropsychiatric disturbance precipitated by acute illness. Although dementia is the major risk factor this has typically been considered a binary quantity (i.e. cognitively impaired versus cognitively normal) with respect to delirium risk. We used humans and mice to address the hypothesis that the severity of underlying neurodegenerative changes and/or cognitive impairment progressively alters delirium risk. Methods Humans in a population-based longitudinal study, Vantaa 85+, were followed for incident delirium. Odds for reporting delirium at follow-up (outcome) were modeled using random-effects logistic regression, where prior cognitive impairment measured by MMSE (exposure) was considered. To address whether underlying neurodegenerative pathology increased susceptibility to acute cognitive change, mice at three stages of neurodegenerative disease progression (ME7 model of neurodegeneration: controls, 12 and 16 weeks) were assessed for acute cognitive dysfunction upon systemic inflammation induced by bacterial lipopolysaccharide (LPS; 100μg/kg). Synaptic and axonal correlates of susceptibility to acute dysfunction were assessed using immunohistochemistry. Results In the Vantaa cohort, 465 persons (88.4±2.8 years) completed MMSE at baseline. For every MMSE point lost, risk of incident delirium increased by 5% (p=0.02). LPS precipitated severe and fluctuating cognitive deficits in 16w ME7 mice but lower incidence or no deficits in 12w ME7 and controls respectively. This was associated with progressive thalamic synaptic loss and axonal pathology. Conclusions A human population-based cohort with graded severity of existing cognitive impairment and a mouse model with progressing neurodegeneration both indicate that the risk of delirium increases with greater severity of pre-existing cognitive impairment and neuropathology.American Journal of Geriatric Psychiatry 08/2014; 23(4). DOI:10.1016/j.jagp.2014.08.005 · 3.52 Impact Factor
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ABSTRACT: Acute hospitals have seen unprecedented demographic changes, where older age, frailty and cognitive impairment now characterise the majority of health service users. Delirium is very common in this setting, and adverse outcomes are well described. However, studies investigating cognitive outcomes after delirium in unselected samples have been lacking. This thesis had four objectives: (1) To estimate the prevalence of delirium in the general population (2) To assess the association of delirium with cognitive outcomes (3) To investigate how these associations relate to underlying dementia pathology (4) To develop novel methods for retrospectively ascertaining delirium. Methods: Data from three population-based neuropathology cohort studies were used: Vantaa 85+; Cambridge City over-75s Cohort (CC75C); MRC Cognitive Function and Ageing Study (CFAS). (1) To ascertain the prevalence of delirium in the general population, a measure of delirium was developed using data recorded in standardised interview schedules, with criterion validity evaluated through the association with mortality and dementia risk. (2) The association with cognitive outcomes was tested in a series of logistic regression models, where delirium was the exposure and dementia (or worsening dementia severity) was the outcome. In addition, the association with change in Mini-Mental Status Examination (MMSE) score was assessed using random-effects linear regression. (3) In brain donors from all three cohorts, the independent effects of delirium, dementia pathology, and their interaction, were investigated using the same approach. (4) A chart-based method for deriving a retrospective diagnosis for delirium was developed, validated against bedside psychiatrist diagnosis. Vignettes from the medical record were abstracted and delirium status decided by expert consensus panel. Results: (1) Age-specific prevalence in CFAS increased with age from 1.8% in the 65-69 year age group to 13.5% in the ≥90 age group (p<0.01 for trend). (2) Delirium was consistently associated with adverse cognitive outcomes: new dementia (OR 8.7, 95% CI 2.1 to 35); worsening dementia severity (OR 3.1, 95% CI 1.5 to 6.3); faster change in Mini-Mental Status Examination (MMSE) score (1.0 additional points/year, p<0.01) (3) In the neuropathology analyses, decline attributable to delirium was -0.37 MMSE points/year (p<0.01). Decline attributable to dementia pathology was -0.39 MMSE points/year (p<0.01). However, the combination of delirium and dementia pathology resulted in the greatest decline, where the interaction contributed a further -0.16 MMSE points/year (p=0.01), suggesting that delirium worsened cognitive trajectories in dementia, but through distinct pathophysiological pathways not accounted for by Alzheimer’s, vascular or Lewy body pathology. (4) The chart abstraction method yielded a sensitivity of 0.88 and specificity 0.75 for ‘possible delirium’, with lower sensitivity (0.58) and higher specificity (0.93) for ‘probable delirium’ (AUC 0.86, 95% CI 0.82 to 0.89). This thesis adds to the small body of work on delirium in prospective studies, with the first ever analyses conducted in whole populations. The findings suggest new possibilities regarding the pathology of cognitive impairment, positioning delirium and/or its precipitants as a critically inter-related mechanism.10/2013, Degree: PhD, Supervisor: Carol Brayne
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ABSTRACT: Existing reports on the frequencies of neurodegenerative diseases are typically based on clinical diagnoses. We sought to determine these frequencies in a prospectively assessed, community-based autopsy series. Included subjects had normal cognitive and movement disorder assessments at study entry. Of the 119 cases meeting these criteria, 52% were women; the median age of study entry was 83.5 years (range, 67-99 years), and the median duration from the first visit until death was 4.3 years (range, 0-10 years). At autopsy, clinicopathological diagnoses were made in 30 cases (25%). These diagnoses included 20 with Alzheimer disease (AD) (17%), 7 with vascular dementia (6%), 4 with progressive supranuclear palsy (3%), 3 with Parkinson disease and 1 each with dementia with Lewy bodies, corticobasal degeneration, or multiple system atrophy (0.8% each). Of the 87 subjects still clinically normal at death (73%), 33 had extensive AD pathology (preclinical AD) (38%), 17 had incidental Lewy bodies (20%), and 4 had incidental pathology consistent with progressive supranuclear palsy (5%). The diagnoses were not mutually exclusive. Although limited by a relatively small sample size, the neuropathological outcome of these initially normal elderly subjects represents a rough estimate of the incidence of these neurodegenerative conditions over a defined time period.01/2014; 9(4). DOI:10.1097/NEN.0000000000000046