Tom Dening

Donepezil and Memantine for Moderate-to-Severe Alzheimer's Disease

BACKGROUND Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimers disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. METHODS We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimers disease (a score of 5 to 13 on the Standardized Mini-Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS. RESULTS Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P=0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone. CONCLUSIONS In patients with moderate or severe Alzheimers disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimers Society; Current Controlled Trials number, ISRCTN49545035.).

Perception, attention, and working memory are disproportionately impaired in dementia with Lewy bodies compared with Alzheimer's disease

OBJECTIVE To test the hypotheses that visuoperceptual and attentional ability are disproportionately impaired in patients having dementia with Lewy Bodies (DLB) compared with Alzheimers disease (AD). METHODS A comprehensive battery of neuropsychological tasks designed to assess working, episodic, and semantic memory, and visuoperceptual and attentional functions was given to groups of patients with DLB (n=10) and AD (n=9), matched for age, education, and mini mental state examination (MMSE), and to normal controls (n=17). RESULTS Both patient groups performed equally poorly on tests of episodic and semantic memory with the exception of immediate and delayed story recall, which was worse in the AD group. Digit span was by contrast spared in AD. The most striking differences were on tests of visuoperceptual/spatial ability and attention. Whereas patients with AD performed normally on several subtests of the visual object and space perception battery, the DLB group showed substantial impairments. In keeping with previous studies, the AD group showed deficits in selective attention and set shifting, but patients with DLB were more impaired on virtually every test of attention with deficits in sustained, selective, and divided attention. CONCLUSIONS Patients with DLB have substantially greater impairment of attention, working memory, and visuoperceptual ability than patients with AD matched for overall dementia severity. Semantic memory seems to be equally affected in DLB and AD, unlike episodic memory, which is worse in AD. These findings may have relevance for our understanding of the genesis of visual hallucinations, and the differential diagnosis of AD and DLB.

The Cambridge Neurological Inventory: A clinical instrument for assessment of soft neurological signs in psychiatric patients

A schedule (the Cambridge Neurological Inventory) has been constructed for standardized neurological assessment of psychiatric patients. Normative data and data resulting from its application to a group of patients with schizophrenia are reported. The instrument is comprehensive, reliable, and easy to administer. In conjunction with other forms of clinical assessment, it may be useful for identifying soft neurological signs and other patterns of neurological impairment relevant to neurobiological localization and prognosis in schizophrenia and other psychiatric disorders.

Neuropathological Correlates of Dementia in Over-80-Year-Old Brain Donors from the Population-Based Cambridge City over-75s Cohort (CC75C) Study

Key neuropathological changes associated with late-onset dementia are not fully understood. Population-based longitudinal studies offer an opportunity to step back and examine which pathological indices best link to clinical state. CC75C is a longitudinal study of the population aged 75 and over at baseline in Cambridge, UK. We report on the first 213 participants coming to autopsy with sufficient information for an end of life dementia diagnosis. Clinical diagnosis was ascertained by examining retrospective informant interviews, survey responses, and death certificates according to DSM-IV criteria. The neuropathological protocol was based on the Consortium to Establish a Registry of Alzheimers Disease (CERAD). Clinical dementia was present in 113 participants (53%): 67% with Alzheimers disease, 4% vascular dementia, 22% mixed dementia, and 1% dementia with Lewy bodies. As Alzheimer-type pathology was common, the mutually blinded clinical and neuropathological diagnoses were not strongly related. Multivariable analysis identified associations between dementia during life and entorhinal cortex neuritic plaques, hippocampal diffuse plaques, neocortical neurofibrillary tangles, white matter pallor, Lewy bodies, and hippocampal atrophy. These results were consistent in those with clinical Alzheimers disease. Vascular pathologies, especially microinfarcts, were more common in those with clinical diagnoses including vascular dementia. Alzheimer-type and cerebrovascular pathology are both common in the very old. A greater burden of these pathologies, Lewy bodies, and hippocampal atrophy, are associated with a higher risk of, but do not define, clinical dementia in old age.

Population norms for the MMSE in the very old Estimates based on longitudinal data

Objective To report the percentile distribution of Mini-Mental State Examination (MMSE) scores in older people by age, sex, and education level, estimated from longitudinal data, after correcting for loss due to dropout. Methods The Cambridge City over 75 Cohort is a population-based study of a cohort of 2106 subjects age 75 years and older at study entry followed up over 9 years. At each of the four waves, cognitive function was assessed using MMSE. Based on these data, the relationship between age and MMSE score was modeled. Percentile distributions by age, sex, and education level were provided using inverse probability weighting to correct for dropouts. Results Performance on MMSE was related to age in men and women. In women, at age 75, MMSE score ranged from 21 (10th percentile) to 29 (90th percentile). At age 95, the range was 10 (10th percentile) to 27 (90th percentile). The upper end of MMSE distribution was slightly modified with age, whereas the lower end of the distribution was very sensitive to age effect. A similar pattern was observed in both sexes. Conclusion These findings provide norms for MMSE scores in subjects age 75 years and older from longitudinal population-based data. Such norms can be used as reference values to determine where an individuals score lies in relation to his or her age, sex, and education level.

Analysis of the apo E/apo C-I, angiotensin converting enzyme and methylenetetrahydrofolate reductase genes as candidates affecting human longevity

Genetic factors are likely to affect human survival, since twin studies have shown greater concordance for age of death in monozygotic compared to dizygotic twins. Coronary artery disease is an important contributor to premature mortality in the UK. Accordingly, we have chosen genes associated with cardiovascular risk, apo E/apo C-I, angiotensin converting enzyme (ACE) and methylenetetrahydrofolate reductase (MTHFR), as candidates which may affect longevity/survival into old age. An association study was performed by comparing allele and genotype frequencies at polymorphic loci associated with these genes in 182 women and 100 men aged 84 years and older with 100 boys and 100 girls younger than 17 years. MTHFR allele and genotype frequencies were similar in the elderly and young populations. Apo C-I allele and genotype frequencies were significantly different in the elderly women compared to the younger sample (P < 0.05). No difference was observed in the elderly men. At the neighbouring apo E gene, we only observed a difference between genotypes in the elderly women and the young sample; however, this did not retain significance when the genotype frequencies of the young sample were adjusted to values expected from the allele frequencies on the basis of Hardy-Weinberg equilibrium and compared to observed genotypes in elderly men and women. In contrast to previous studies, apo E2 was not overrepresented in the elderly men or women. Thus, the proposition that apo E2, E3 and E4 protein isoforms are themselves functionally associated with increasing risks for early death, may be too simplistic. The I/I ACE was depleted in the elderly males but not the elderly females. Furthermore, significant differences were observed between ACE genotypes in elderly men and elderly women. These data suggest that the penetrance of loci which influence survival may vary according to sex. The depletion of the ACE I/I genotype in elderly men is generally consistent with a previous study which found decreased frequencies of the I allele in French centenarians compared to younger controls. However, these results are apparently paradoxical, since others have suggested that the I allele is associated with increased cardiovascular risk. Clarification of the overall effect of a genotype on survival will be vital if therapies are to be considered which target specific genetic variants.

Estimating the true extent of cognitive decline in the old old

OBJECTIVE: To measure cognitive change using a brief measure over a period of 9 years and to adjust for attrition in the sample.

Education and trajectories of cognitive decline over 9 years in very old people: methods and risk analysis

BACKGROUND the investigation of cognitive decline in the older population has been hampered by analytical considerations. Most studies of older people over prolonged periods suffer from loss to follow-up, yet this has seldom been investigated fully to date. Such considerations limit our understanding of how basic variables such as education can affect cognitive trajectories. METHODS we examined cognitive trajectories in a population-based cohort study in Cambridge, UK, of people aged 75 and over in whom multiple interviews were conducted over time. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Socio-demographic variables were measured, including educational level and social class. An age-based quadratic latent growth model was fitted to cognitive scores. The effect of socio-demographic variables was examined on all latent variables and the probability of death and dropout. RESULTS at baseline, age, education, social class and mobility were associated with cognitive performance. Education and social class were not related to decline or its rate of change. In contrast, poor mobility was associated with lower cognitive performance, increased cognitive decline and increased rate of change of cognitive decline. Gender, age, mobility and cognitive ability predicted death and dropout CONCLUSIONS contrary to much of the current literature, education was not related to rate of cognitive decline or change in this rate as measured by MMSE. Higher levels of education do not appear to protect against cognitive decline, though if the MMSE is used in the diagnostic process, individuals with less education may be diagnosed as having dementia somewhat earlier.

Determining the minimum clinically important differences for outcomes in the DOMINO trial

Although less likely to be reported in clinical trials than expressions of the statistical significance of differences in outcomes, whether or not a treatment has delivered a specified minimum clinically important difference (MCID) is also relevant to patients and their caregivers and doctors. Many dementia treatment randomised controlled trials (RCTs) have not reported MCIDs and, where they have been done, observed differences have not reached these.

Wilson's disease: A longitudinal study of psychiatric symptoms

One hundred and twenty-nine cases of Wilsons disease (WD) were assessed at index admission and two follow-ups (F1 and F2) on a range of clinical and biochemical variables. The commonest psychiatric symptoms throughout were incongruous behavior, irritability, depression, and cognitive impairment. Among psychiatric cases, most improvements occurred in the interval index-F1, with subsequent leveling off. Significant improvement occurred only with incongruous behavior and cognitive impairment. Psychiatric cases whose psychiatric symptoms persisted to F2 differed from those who responded, in particular showing more dysarthria, incongruous behavior, and hepatic symptoms. Neuropsychiatric cases displayed more dysarthria and incongruous behavior than patients with neurological symptoms alone. Further evidence for associations between dysarthria and abnormal behavior emerged from this study.