Biomedical subjects
R Jacoby
Publications and source records attributed to R Jacoby.
MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability.
DNA mismatch repair is important because of its role in maintaining genomic integrity and its association with hereditary non-polyposis colon cancer (HNPCC). To identify new human mismatch repair proteins, we probed nuclear extracts with the conserved carboxy-terminal MLH1 interaction domain. Here we describe the cloning and complete genomic sequence of MLH3, which encodes a new DNA mismatch repair protein that interacts with MLH1. MLH3 is more similar to mismatch repair proteins from yeast, plants, worms and bacteria than to any known mammalian protein, suggesting that its conserved sequence may confer unique functions in mice and humans. Cells in culture stably expressing a dominant-negative MLH3 protein exhibit microsatellite instability. Mlh3 is highly expressed in gastrointestinal epithelium and physically maps to the mouse complex trait locus colon cancer susceptibility I (Ccs1). Although we were unable to identify a mutation in the protein-coding region of Mlh3 in the susceptible mouse strain, colon tumours from congenic Ccs1 mice exhibit microsatellite instability. Functional redundancy among Mlh3, Pms1 and Pms2 may explain why neither Pms1 nor Pms2 mutant mice develop colon cancer, and why PMS1 and PMS2 mutations are only rarely found in HNPCC families.
Effect of cognitive impairment and premorbid intelligence on treatment preferences for life-sustaining medical therapy.
OBJECTIVE: This study examines the influence of cognitive impairment, premorbid intelligence, and decision-making capacity to complete advance directives on the treatment preferences for life-sustaining medical therapy in the elderly. METHOD: One hundred elderly individuals were recruited. Fifty were first referrals to specialist services with a DSM-IV diagnosis of dementia, and 50 were volunteers. Each person was asked about treatment preferences in three clinical vignettes. RESULTS: Elderly individuals who had cognitive impairment and were incapable of completing advance directives were significantly more likely to opt for life-sustaining interventions. There was no association between premorbid intelligence and treatment preferences. CONCLUSIONS: Cognitive impairment appears to influence treatment preferences for life-sustaining medical therapy. With increasing cognitive impairment, elderly individuals tend to opt for treatment interventions.
Dementia, intelligence, and the competence to complete advance directives.
At referral, a fifth of patients with dementia were competent to complete advance directives. Competence was significantly related to higher premorbid IQ estimated by the National Adult Reading Test.
Assessment of competence to complete advance directives: validation of a patient centred approach.
OBJECTIVE: To develop a patient centred approach for the assessment of competence to complete advance directives ("living wills") of elderly people with cognitive impairment. DESIGN: Semistructured interviews. SETTING: Oxfordshire. SUBJECTS: 50 elderly volunteers living in the community, and 50 patients with dementia on first referral from primary care. MAIN OUTCOME MEASURES: Psychometric properties of competence assessment. RESULTS: This patient centred approach for assessing competence to complete advance directives can discriminate between elderly persons living in the community and elderly patients with dementia. The procedure has good interrater (r=0.95) and test-retest (r=0.97) reliability. Validity was examined by relating this approach with a global assessment of competence to complete an advance directive made by two of us (both specialising in old age psychiatry). The data were also used to determine the best threshold score for discriminating between those competent and those incompetent to complete an advance directive. CONCLUSION: A patient centred approach to assess competence to complete advance directives can be reliably and validly used in routine clinical practice.
Natural history of aggressive behaviour in dementia.
OBJECTIVE: This article analyses changes in aggressive behaviour throughout the course of dementia. DESIGN: Prospective, 10 year, longitudinal study of aggressive behaviour in dementia, with autopsy follow-up. SETTING: Subjects with dementia, living at home with a carer, Oxfordshire, UK. PARTICIPANTS: Ninety-nine people with dementia (Alzheimer's disease and/or vascular dementia) who were living at home with a carer. MEASURES: At 4-monthly intervals, the carers were interviewed about the subjects and the subjects were assessed cognitively. Subjects' behaviour was assessed using the Present Behavioural Examination. This is an investigator-based, semi-structured interview consisting of eight main sections monitoring behavioural and psychological change. Eight different aspects of aggressive behaviour were assessed in detail and comparison made with other relevant factors. RESULTS: Verbal aggression is the most common and longest lasting form of aggressive behaviour. Aggressive resistance and physical aggression are most likely to persist until death. Intimate care is the main factor precipitating aggressive behaviour. There are no correlations between any type of aggressive behaviour and age, gender or time since onset of dementia. CONCLUSIONS: Aggressive behaviour creates problems for carers. In general, the physical types of aggressive behaviour are most prevalent in people with more severe dementia.
Natural history of behavioural changes and psychiatric symptoms in Alzheimer's disease. A longitudinal study.
BACKGROUND: Alzheimer's disease and other types of dementia are characterised by numerous psychiatric and behavioural changes. Little is known of their natural history. AIMS: To investigate the sequence and pattern of these changes throughout the course of dementia. METHOD: One hundred people, initially living at home with carers, entered a prospective, longitudinal study. At four-monthly intervals, behavioural and psychiatric symptoms were assessed using the Present Behavioural Examination and Mini-Mental State Examination. Follow-up continued for up to nine years (mean 3.3 years; s.d. 2.4). Patterns of onset and disappearance of these symptoms, their sequence and association with time of death and cognitive decline were analysed. Autopsy confirmed a diagnosis of pure Alzheimer's disease in 48 subjects. Data for this subgroup are presented. RESULTS: Some changes tend to occur earlier than others but changes can occur at almost any time in the course of dementia. CONCLUSIONS: The natural history of behaviour changes in Alzheimer's disease shows great individual variation although some changes tend to follow a recognisable sequence.
Can an informant questionnaire be used to predict the development of dementia in medical inpatients?
OBJECTIVE: To determine whether elderly medical inpatients without dementia who score >3.31 on the short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) are at an increased risk of developing dementia. DESIGN/PARTICIPANTS: Twenty-nine patients with an IQCODE score of >3.31 without dementia and 29 age- and sex-matched controls, from an original sample of 201 medical inpatients over 65, were examined 17-24 months after initial assessment. SETTING: Interviews took place in patients' homes, but all subjects had been recruited while medical inpatients in a general hospital 17-24 months previously. MEASURES: The IQCODE and clinical interview to make DSM-III-R diagnosis of dementia. RESULTS: Ten of the study group and one control had developed dementia since the original assessment. CONCLUSIONS: Non-demented elderly medical inpatients with an admission IQCODE score of >3.31 are more likely to develop dementia than those with an IQCODE score of <3.31. The IQCODE is a sensitive tool for detecting early dementia.
Ways of assessing capacity to complete an advance directive should be developed.
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The feasibility of electronic tracking devices in dementia: a telephone survey and case series.
BACKGROUND: Patients with dementia who go out unaccompanied are at risk of accidents or getting lost. It is not known whether they could benefit from electronic tracking devices or whether such devices are practically feasible. METHOD: The likely demand for an electronic tracking device was assessed by means of a telephone survey of a convenience sample of 99 carers. The practical feasibility of a tracking system was assessed in 24 patients with dementia. RESULTS: The telephone survey suggested that 20% of patients were at continuing risk of traffic accidents and 45% were at continuing risk of getting lost. About 7% could have benefited from using the device at the time of survey and a further 11% could have benefited at an earlier point in their illness. In the feasibility study, only nine patients consistently used the device. In two patients, it was successfully used in a search. One patient was injured by a passing vehicle when he had got lost out of range of the device. A major barrier to using the device was recognizing the risk of getting lost before it happened. CONCLUSION: Significant numbers of patients are at risk. Electronic tracking devices may occasionally be useful in carefully selected cases.
Predictors of institutionalization for people with dementia living at home with a carer.
OBJECTIVE: This article examines the relationships between behaviour, psychological functioning, the caring environment and subsequent institutionalization in patients with dementia living at home with a carer. DESIGN: Longitudinal study of behaviour in dementia, with a nested case-control study to investigate predictors of institutionalization. SETTING: Subjects with dementia, known to service, living at home with a carer. All lived in Oxfordshire, UK. PARTICIPANTS: 100 people with dementia (Alzheimer's disease and/or vascular dementia) who were living at home with a carer at the start of the study. MEASURES: At 4-monthly intervals, the carers were interviewed and the subjects with dementia were assessed cognitively. Subjects' behaviour and psychological functioning were assessed using the Present Behavioural Examination. RESULTS: The characteristics which best predicted institutionalization 1 year later were: excessive night-time activity; immobility or difficulty in walking; incontinence; being away from a carer for more than 16 hours a week; and being cared for by a female. Aggressive behaviour was not associated with an increased chance of entry into an institution 1 year later, although it was more prevalent 4 months before entering an institution. CONCLUSIONS: Both behaviour and psychological functioning and the caring environment can help in predicting which patients with dementia currently living at home will enter an institution 1 year later. These predictors are not the same as those which are the immediate cause of institutionalization.
Psychiatric symptoms in patients with dementia predict the later development of behavioural abnormalities.
BACKGROUND: Cross-sectional studies of non-cognitive symptoms in dementia show that patients with psychotic symptoms tend to have more disturbed behaviour. However, it is not known whether individuals who experience psychiatric symptoms early in dementia are more prone to develop behavioural problems later in the illness. METHOD: The behaviour of 86 community-dwelling subjects with dementia was intensively studied for 4 years or until death, using an informant interview which was administered every 4 months on a median of eight occasions. The extent to which psychiatric symptoms, age, sex and cognitive function predicted clinically significant physical aggression or motor hyperactivity was assessed. RESULTS: Physical aggression was predicted by sad appearance and motor hyperactivity was predicted by persecutory ideas. These associations were robust, remaining significant over 2, 3 and 4 years of follow-up and were independent of cognitive function, age, sex and duration of illness. CONCLUSIONS: There may be two distinct longitudinal syndromes of non-cognitive symptoms in dementia. This suggests that important aberrant behaviours in late dementia may share pathophysiological mechanisms with psychiatric symptoms in early dementia.
Getting lost in dementia: a longitudinal study of a behavioral symptom.
The occurrence of episodes of getting lost was examined in 104 subjects with dementia who were assessed every 4 months over 5 years. All subjects were initially living at home with a caregiver who could give good information. Forty-three subjects needed to be brought back home at least once. Five subjects repeatedly got lost. Forty-six subjects were kept behind locked doors at some point. Subjects who got lost were more likely to become permanently resident in institutions (odds ratio = 7.3; 95% confidence interval: 3.0 to 17.8). Patients who performed better on a behavioral test of topographical memory were less likely to get lost over the subsequent 5 years (negative predictive value: 90%). The risk of patients with dementia getting lost is substantial and requires frequent intervention by caregivers. This risk is a major reason for institutionalization. A simple test may help in assessing the risk of getting lost in patients with dementia.
A randomized, placebo-controlled trial of low-dose alpha-difluoromethylornithine in individuals at risk for colorectal cancer.
DFMO is an irreversible inhibitor of ornithine decarboxylase (ODC), the key enzyme in mammalian polyamine biosynthesis. The goal of this study was to determine the effects of DFMO 0.5 g/m2/day as a single oral dose on polyamine and ODC levels in rectal, rectosigmoidal, and cecal colonic mucosae of individuals at risk for colon cancer because of a personal history of adenomatous polyps of the colon or a family history of colon cancer in at least one first-degree relative. A second goal was to determine toxicity of this treatment given over 1 year. Forty-five randomized subjects had a flexible sigmoidoscopy with no preparation and a colonoscopy after lavage preparation at baseline, a sigmoidoscopy with no preparation after 3 months, and both procedures (as at baseline) after 12 months, with mucosal biopsies taken from the rectosigmoid area (sigmoidoscopy) or rectal and cecal areas (colonoscopy) for evaluations of ODC and polyamine levels. Significantly decreased levels of putrescine and spermidine were found in rectosigmoid colonic mucosae of DFMO-treated (n = 24) compared with placebo (n = 21) subjects at 3 months (P = 0.03 and 0.04) and 12 months (P = 0.005, P = 0.004). Similar trends, none reaching statistical significance, were found for individual polyamine levels in rectal and cecal mucosae. No significant differences in ODC levels were detected marginally. There was evidence of global suppression of ODC and polyamine levels in the treatment group (P = 0.035). Three DFMO recipients (12.5%) developed clinically noticeable and audiologically demonstrated hearing loss, which was reversible and attributed to DFMO after 3 months (two subjects) and 12 months (one subject). The tissue polyamine changes demonstrated in this study are consistent with findings in other studies in colon and other tissues. The ototoxicity findings here suggest that investigation of other DFMO schedules, such as ones with a drug "holiday," will be a necessary step before Phase III chemoprevention studies can be pursued.
Issues in drug treatment for Alzheimer's disease.
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Do neuroleptic drugs hasten cognitive decline in dementia? Prospective study with necropsy follow up.
OBJECTIVE: To investigate the contribution of neuroleptic drugs to cognitive decline in dementia. DESIGN: Two year prospective, longitudinal study consisting of interviews every four months, with necropsy follow up. SETTING: Community settings in Oxfordshire. SUBJECTS: 71 subjects with dementia, initially living at home with informant. MAIN OUTCOME MEASURES: Cognitive function (score from expanded minimental state examination); behavioural problems (physical aggression, hallucinations, persecutory ideas, and disturbance of diurnal rhythm); and postmortem neuropathological assessment (cortical Lewy body pathology). RESULTS: The mean (SE) decline in cognitive score in the 16 patients who took neuroleptics was twice that in the patients who did not (20.7 (2.9) v 9.3 (1.3), P = 0.002). An increased rate of decline was also associated with aggression, disturbed diurnal rhythm, and persecutory ideas. However, only use of neuroleptics and severity of persecutory ideas were independently associated with more rapid cognitive decline when all other variables were adjusted for. The start of neuroleptic treatment coincided with more rapid cognitive decline: median rate of decline was 5 (interquartile range 8.5) points per year before treatment and 11 (12) points per year after treatment (P = 0.02). Cortical Lewy body pathology did not account for association between neuroleptic use and more rapid decline. CONCLUSIONS: Neuroleptic drugs that are sometimes used to treat behavioural complications of dementia may worsen already poor cognitive function. Randomised controlled trials are needed to confirm a causal relation.
Behaviour changes in dementia. 1: Point of entry data of a prospective study.
OBJECTIVE: This article analyses behaviour changes in dementia at the point of entry to a longitudinal study. DESIGN: Prospective, longitudinal study of behaviour in dementia, with autopsy follow-up. SETTING: Subjects with dementia, living at home with a carer. All lived in Oxfordshire, UK. PARTICIPANTS: Ninety-seven people with dementia (Alzheimer's disease and/or vascular dementia) who were living at home with a carer. MEASURES: At 4-monthly intervals, the carers were interviewed and the subjects with dementia were assessed cognitively. Subjects' behaviour was assessed using the Present Behavioural Examination. This is an investigator-based, semi-structured interview consisting of eight main sections covering many different aspects of behaviour. The 121 main questions, with 66 further 'nested' questions, have been shown to have high reliability. RESULTS: This article analyses the types of behaviour change reported by carers at the point of entry to this long-term study. Few correlations were found between behaviour and age, gender and time since onset of dementia. Some types of behaviour were significantly more prevalent in those with greater cognitive impairment. CONCLUSIONS: Many of these changes create problems for carers, for example increased aggressive behaviour, wandering, wakefulness at night, incontinence and persecutory ideas. In general, they are more prevalent in people with more severe dementia.
Behaviour changes in dementia. 2: Are there behavioural syndromes?
OBJECTIVE: To establish whether robust behavioural 'syndromes' can be identified from among the widely heterogeneous behavioural changes which occur in dementia. DESIGN: Longitudinal, prospective study with follow-up at 4 and 8 months. SETTING: Community settings in Oxfordshire, UK. PARTICIPANTS: 97 elderly people with a diagnosis of Alzheimer's disease or vascular dementia (in many cases confirmed by postmortem examination) and who were living at home with a carer. MEASURES: Each subject's behaviour was assessed in detail at each interview using the Present Behavioural Examination to assess subject's behaviour over the preceding 4 weeks. Seventeen key behaviour items which were both common and clinically important were selected for further analysis. RESULTS: Three syndromes were identified: (a) overactivity (walking more, walking aimlessly, trailing the carer or checking where the carer was); (b) aggressive behaviour (physical aggression, aggressive resistance, verbal aggression); (c) psychosis (anxiety, persecutory ideas and hallucinations). The same syndromes were found using data collected at three different time points and by using a variety of statistical techniques, confirming their robustness. CONCLUSIONS: Overactivity, aggressive behaviour and psychosis form three distinct behavioural syndromes in dementia.