Diagnostic tests for Alzheimer's disease: rationale, methodology, and challenges.

There has been a large increase in the amount of research seeking to define or diagnose Alzheimer's disease before patients develop dementia. If successful, this would principally have clinical benefits both in terms of treatment as well as risk modification. Moreover, a better method for diagnosing predementia disease would assist research which seeks to develop such treatments and risk modification strategies. The evidence-based definition of a diagnostic test's accuracy is fundamental to achieve the above goals and to address this, the Cochrane Collaboration has established a Diagnostic Test Accuracy group dedicated to examining the utility and accuracy of proposed tests in dementia and cognitive impairment. We present here the assumptions and observations underpinning the chosen methodology as well as the initial methodological approach decided upon.

Olfactory impairment is more marked in patients with mild dementia with Lewy bodies than those with mild Alzheimer disease.

BACKGROUND: Dementia patients with anosmia are more likely to have Lewy body pathology at postmortem, but clinicopathological studies have only assessed olfaction in moderate dementia or an average of 5 years before death. It is not known whether, in patients with mild dementia (MMSE score over 20), olfactory function is more impaired in Alzheimer disease (AD) than dementia with Lewy bodies (DLB). METHODS: Patients with mild DLB (n = 21), mild AD (n = 27), mild cognitive impairment (MCI) (n = 21) and controls (n = 47) were assessed using a 16-item olfactory identification test and an olfactory threshold test which used sticks impregnated with differing concentrations of butanol. RESULTS: Patients with mild DLB had impaired olfactory identification ability compared with those with mild AD or MCI, independent of age, cognitive function and sex. The sensitivity of a cutoff score of seven correct responses out of 16 was 0.81 for distinguishing mild DLB from mild AD (AUC 0.682). The specificity, positive predictive value and negative predictive value for the same cut-off score were 0.41, 0.48 and 0.73, respectively. The olfactory threshold was not different in the AD and DLB groups. CONCLUSIONS: Simple bedside tests of olfactory identification merit further examination for their potential to improve the identification of patients with DLB when used alongside existing criteria. They are insufficiently specific for use in screening.

Metal protein attenuating compounds for the treatment of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) may be caused by the formation of extracellular senile plaques comprised of beta-amyloid (Ass). In vitro and mouse model studies have demonstrated that metal protein attenuating compounds (MPACs) promote the solubilisation and clearance of Ass. OBJECTIVES: To evaluate the efficacy of metal protein attenuating compounds (MPACs) for the treatment of cognitive impairment due to Alzheimer's disease. SEARCH STRATEGY: The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched on 15 February 2007 using the terms clioquinol, PBT*, MPAC*. The Register contains records from major health care databases, many ongoing trial databases and grey literature and is updated regularly. The Internet was searched using the term: clioquinol, PBT*, MPAC* SELECTION CRITERIA: Randomised double-blind trials in which treatment with clioquinol was administered to participants with Alzheimer's disease in parallel group comparison with placebo are included. DATA COLLECTION AND ANALYSIS: Three reviewers (RM, LJ, ELS) independently assessed the quality of trials according to the Cochrane Collaboration Handbook. The primary outcome measures of interest were cognitive function (as measured by psychometric tests). The secondary outcome measures of interest were in the following areas: quality of life, functional performance, effect on carer, safety and adverse effects, and death. MAIN RESULTS: There was one included trial of clioquinol (PBT1) compared with placebo in 36 patients. There was no statistically significant difference in cognition (as measured on the ADAS-Cog scale) between active treatment and placebo groups at 36 weeks. One subject in the active treatment group developed neurological symptoms (impaired visual acuity and colour vision) which resolved on cessation of treatment and was thought to be possibly attributable to the drug. AUTHORS' CONCLUSIONS: There is an absence of evidence as to whether clioquinol (PBT1) has any positive clinical benefit for patients with AD, or whether the drug is safe. We have some concerns about the quality of the study methodology, particularly the randomisation (subjects in the active treatment group had higher mean pre-morbid IQ as measured by the NART and this may have biased the results), the secondary analyses of results stratified by baseline disease severity and whether the study was adequately powered for the analysis of the other data collected on Ass, zinc and copper levels.

Non-pharmacological interventions for wandering of people with dementia in the domestic setting.

BACKGROUND: A number of studies exist of interventions for wandering in the institutional setting, but much less work has been done on wandering in the domestic setting. The prevalence of wandering by people with dementia is difficult to assess; wandering is not a simple or static behaviour and the reasons why people wander remain unclear. In the absence of a theory of wandering and an agreed definition of wandering, it is difficult to discover effective strategies for managing wandering and difficult to design appropriate intervention strategies. Also, the same behaviour or type of wandering might occur for different reasons in different individuals; any theoretical formulation is going to have to allow for different triggers for the behaviour and so to get a 'one size fits all' kind of explanation is unlikely. Thus what we mostly encounter in this field is a 'trial and error' approach which does not always do justice to the complex interactions of personal and environmental factors that lead people with dementia to wander. While there seems to be a consensus in the literature that in the majority of cases non-pharmacological approaches may work as well as drug treatment and with fewer side effects, in practice clinicians often resort to drugs as the first line of treatment. This review reports the lack of evidence from RCTs and discusses the range of non-pharmacological interventions that have been carried out using other study designs. OBJECTIVES: To evaluate the effectiveness and safety of non-pharmacological interventions in reducing wandering in the domestic setting by people with dementia. The secondary objective is to highlight the quality and quantity of research evidence available and to set an agenda for future research. SEARCH STRATEGY: The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 11 May 2006 using the terms exit* or wander* or elopement or ambulat* or walk*. This Register contains records from all major healthcare databases and many ongoing trial databases and is updated regularly. SELECTION CRITERIA: Randomised clinical trials comparing intervention with no intervention or usual treatment ('standard care') or another intervention. DATA COLLECTION AND ANALYSIS: No suitable trials of non-pharmacological interventions for the prevention and management of wandering in the domestic setting were found. MAIN RESULTS: As no randomised controlled trials were found, no results can be reported. AUTHORS' CONCLUSIONS: There is an urgent need for randomised controlled trials of non-pharmacological interventions for wandering in the domestic setting.

Memantine for dementia.

BACKGROUND: Memantine, a low affinity antagonist to glutamate NMDA receptors, may prevent excitatory neurotoxicity in dementia. OBJECTIVES: To determine efficacy and safety of memantine for people with Alzheimer's disease (AD), vascular (VD) and mixed dementia. SEARCH STRATEGY: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group was searched on 8th February 2006. This register contains references from all major healthcare databases and many ongoing trial databases and is updated regularly. In addition, the search engines Copernic and Google were used to identify unpublished trials through inspection of the websites of licensing bodies like the FDA , EMEA and NICE and of companies' websites (Lundbeck, Merz, Forest, Suntori etc) and clinical trials registries. SELECTION CRITERIA: Double-blind, parallel group, placebo-controlled, randomized trials of memantine in people with dementia. DATA COLLECTION AND ANALYSIS: Data were pooled where possible. Intention-to-treat (ITT) and observed case (OC) analyses are reported. MAIN RESULTS: 1. Moderate to severe AD. Two out of three six month studies show a small beneficial effect of memantine. Pooled data indicate a beneficial effect at six months on cognition (2.97 points on the 100 point SIB, 95% CI 1.68 to 4.26, P < 0.00001), activities of daily living (1.27 points on the 54 point ADCS-ADLsev, 95% CI 0.44 to 2.09, P = 0.003) and behaviour (2.76 points on the 144 point NPI, 95% CI 0.88 to 4.63, P=0.004), supported by clinical impression of change (0.28 points on the 7 point CIBIC+, 95% CI 0.15 to 0.41, P < 0.0001).2. Mild to moderate AD. Pooled data from three unpublished studies indicate a marginal beneficial effect at six months on ITT cognition (0.99 points on the 70 point ADAS-Cog, 95% CI 0.21 to 1.78, P = 0.01) which was barely detectable clinically (0.13 CIBIC+ points, 95% CI 0.01 to 0.25, P = 0.03) but no effect on behaviour, activities of daily living or OC analysis of cognition.3. Mild to moderate vascular dementia. Pooled data from two six month studies indicated a small beneficial effect of memantine on cognition (1.85 ADAS-Cog points, 95% CI 0.88 to 2.83, P = 0.0002), and behaviour (0.84 95% CI 0.06 to 0.91, P = 0.03) but this was not supported by clinical global measures.4. Patients taking memantine were slightly less likely to develop agitation (134/1739, 7.7% versus 175/1873, 9.3% OR 0.78, 95% CI 0.61 to 0.99, P = 0.04). This effect was slightly larger, but still small, in moderate to severe AD (58/506 [12%] vs 88/499 [18%]; OR = 0.6, 95% CI 0.42 to 0.86, P = 0.005). There is no evidence either way about whether it has an effect on agitation which is already present.5. Memantine is well tolerated. AUTHORS' CONCLUSIONS: Memantine has a small beneficial effect at six months in moderate to severe AD. In patients with mild to moderate dementia, the small beneficial effect on cognition was not clinically detectable in those with vascular dementia and was detectable in those with AD. Memantine is well tolerated.

Clioquinol for the treatment of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) may result in senile plaques being formed outside the brain as accumulation of beta-amyloid (Ass). OBJECTIVES: To evaluate the efficacy of clioquinol for the treatment of cognitive impairment due to Alzheimer's disease. SEARCH STRATEGY: The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched on 20 May 2005 using the terms clioquinol and PBT1. The Register contains records from major health care databases and many ongoing trial databases and is updated regularly. The Internet was searched using the term: clioquinol PBT1 Alzheimer*. SELECTION CRITERIA: Randomised double-blind trials in which treatment with clioquinol was administered to participants with Alzheimer's disease in parallel group comparison with placebo are included. DATA COLLECTION AND ANALYSIS: Two reviewers (RM, LJ) independently assessed the quality of trials according to the Cochrane Collaboration Handbook. The primary outcome measures of interest were cognitive function (as measured by psychometric tests) and global impression. The secondary outcome measures of interest were in the following areas: quality of life, functional performance, effect on carer, safety and adverse effects, and death. MAIN RESULTS: There was one included trial of clioquinol compared with placebo in 36 patients. AUTHORS' CONCLUSIONS: It is not clear from the trial that clioquinol shows any positive clinical result on patients with AD. The two statistically significant positive results were seen for the more severely affected subgroup of patients. This effect was not maintained at the 36 week end-point. The sample size was small. Details of randomisation procedure or blinding were not reported. Further studies are needed to evaluate the potential for clioquinol as a treatment of AD. Trials of longer duration are also required, particularly because information about the side-effects of long-term use of clioquinol is limited.

Memantine for dementia.

BACKGROUND: Memantine, a low affinity antagonist to glutamate NMDA receptors, may prevent excitatory neurotoxicity in dementia. OBJECTIVES: To determine efficacy and safety of memantine for people with Alzheimer's disease (AD), vascular (VD) and mixed dementia. SEARCH STRATEGY: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group was searched on 20 May 2005. This register contains references from all major healthcare databases and many ongoing trial databases and is updated regularly. In addition the search engines Copernic and Google were used to identify unpublished trials through inspection of the websites of licensing bodies like the FDA , EMEA and NICE and of companies' websites (Lundbeck, Merz, Forest, Suntori etc) and clinical trials registries. SELECTION CRITERIA: Double-blind, parallel group, placebo-controlled, randomized trials of memantine in people with dementia. DATA COLLECTION AND ANALYSIS: Data were pooled where possible. Intention-to-treat (ITT) and observed case (OC) analyses are reported. MAIN RESULTS: 1. Moderate to severe AD. Two out of three six month studies show a small beneficial effect of memantine. Pooled data indicate a beneficial effect at six months on cognition (4.12 points on the 100 point SIB , 95% CI 2.14 to 5.74, P < 0.00001), activities of daily living (1.27 points on the 54 point ADCS-ADLsev, 95% CI 0.44 to 2.09, P = 0.003) and behaviour (2.76 points on the 144 NPI, 95% CI 0.88 to 4.63, P = 0.004), supported by clinical impression of change (0.28 points on the 7 point CIBIC+, 95% CI 0.15 to 0.41, P < 0.0001).2. Mild to moderate AD. In a single six month trial, memantine had a beneficial effect on ITT analysis of cognition, (1.9 ADAS-Cog points, 95% CI 0.35 to 3.45, P = 0.02) and behaviour (3.50 NPI points 95% CI 0.15 to 6.85, P = 0.04) supported by clinical global impression of change (0.30 CIBIC+ points, 95% CI 0.09 to 0.51, P = 0.005), but no effect on activities of daily living or OC analysis of cognition. The statistical significance of these benefits could be overturned by data from two unpublished studies which are known to show no significant effect. 3. Mild to moderate vascular dementia. In two six month studies, memantine improved cognition (1.85 ADAS-Cog points, 95% CI 0.88 to 2.83, P = 0.0002), and behaviour (0.84 95% CI 0.06 to 0.91, P = 0.03) but this was not supported by clinical global measures.4. Patients taking memantine appeared to be less likely to develop agitation (93/1167 [8%] versus 134/1141 [12%] (Peto odds ratio (OR): 0.65, 95% CI 0.49 to 0.86, P = 0.002). This was consistently seen in moderate to severe dementia. There were no data which suggested an effect on agitation which is already present.5. Memantine is well tolerated. AUTHORS' CONCLUSIONS: Published data suggest a small beneficial effect of memantine at six months in moderate to severe AD. The beneficial effect on cognition in patients with mild to moderate vascular dementia was not detectable on global assessment at six months. Whether memantine has any effect in mild to moderate AD is unknown.

Memantine for dementia.

BACKGROUND: Memantine, a low affinity antagonist to glutamate NMDA receptors, may prevent excitatory neurotoxicity in dementia. OBJECTIVES: To determine efficacy and safety of memantine for people with Alzheimer's disease (AD), vascular (VD) and mixed dementia. SEARCH STRATEGY: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group was searched on 28 October 2004. This register contains references from all major healthcare databases and many ongoing trial databases and is updated regularly. In addition the search engines Copernic and Google were used to identify unpublished trials through inspection of the websites of licensing bodies like the FDA , EMEA an Nice and of companies' websites (Lundbeck, Merz, Forest, Suntori etc). SELECTION CRITERIA: Double-blind, parallel group, placebo-controlled, randomized trials of memantine in people with dementia. DATA COLLECTION AND ANALYSIS: Data were pooled where possible. Intention-to-treat (ITT) and observed case (OC) analyses are reported. MAIN RESULTS: 1. Moderate to severe AD. A major study (MD-01) is unpublished. Published data from two six month studies show a small beneficial effect of memantine at six months on cognition (4.12 SIB points, 95% Confidence Interval (CI) 2.14 to 5.74, P < 0.00001), activities of daily living (1.70 ADCS-ADLsev19 points, 95% CI 0.63 to 2.76, p = 0.002) and behaviour (3.64 NPI points, 95% CI 1.38 to 5.90, p = 0.002), supported by clinical impression of change (0.27 CIBIC+ points, 95% CI 0.10 to 0.43, p = 0.002). The unpublished study would need to have found a detrimental effect of memantine to overturn the statistical significance of the benefits apparent in the two published studies. 2. Mild to moderate AD. In a single six month trial, memantine had a beneficial effect on ITT analysis of cognition, (1.9 ADAS-Cog points, 95% CI 0.35 to 3.43, p = 0.02) and behaviour (3.50 NPI points 95% CI 0.15 to 6.85, p = 0.04) supported by clinical global impression of change (0.30 CIBIC+ points, 95% CI 0.09 to 0.51, p = 0.005), but no effect on activities of daily living or OC analysis of cognition. The statistical significance of these benefits could be overturned by data from two unpublished studies which are known to show no significant effect. 3. Mild to moderate vascular dementia. In two six month studies, memantine improved cognition (1.85 ADAS-Cog points, 95% CI 0.88 to 2.83, p = 0.0002), and behaviour (Weighted Mean Difference (WMD) 0.84 95% CI 0.06 to 0.91, p = 0.03) but this was not supported by clinical global measures.4. Patients taking memantine were less likely to develop agitation (Odds Ratio (OR): 0.65, 95% CI 0.48 to 0.89, p = 0.007). The effect on agitation which is already present is unknown.5. Memantine is well tolerated. AUTHORS' CONCLUSIONS: Published data suggest a small beneficial effect of memantine at six months in moderate to severe AD. The beneficial effect on cognition in patients with mild to moderate vascular dementia was not clinically discernible at six months. Whether memantine has any effect in mild to moderate AD is unknown.

Cold perfluorochemical-induced hypothermia protects lung integrity in normal rabbits.

To test the hypothesis that intrapulmonary perfluorochemical (PFC) liquid may induce hypothermia, and to compare the effects of internal (IC), external (EC), and combined cooling techniques (EC + IC), 14 juvenile rabbits were randomized to EC by a cold blanket (4 degrees C, n = 5), IC by intrapulmonary cold PFC liquid lavage (4 degrees C, n = 5), or combined IC with PFC and EC (n = 4). Arterial blood gas, blood pressure, and lung mechanics were monitored, and lung histology was examined by light microscopy. The results showed that cooling rates and the time needed to be cooled down to 30 degrees C were significantly faster in EC and EC + IC than IC (p < 0.05). Blood gas analysis and cardiopulmonary function were within the normal range in all groups. Histological assessment revealed varied atelectasis in all lung regions in EC, whereas PFC-filled lungs (IC and EC + IC) demonstrated more homogenous expansion and no evidence of atelectasis. The results indicate that intrapulmonary PFC may be an effective technique to induce and/or augment hypothermia while supporting gas exchange, lung volume and pulmonary architecture.

Memantine for dementia.

BACKGROUND: Alzheimer's disease, vascular and mixed dementia are the three commonest forms of dementia affecting older people. There is evidence that the excitatory activity of L-glutamate plays a role in the pathogenesis of Alzheimer's disease and in the damage from an ischaemic stroke. A low affinity antagonist to N-Methyl-D-aspartate (NMDA) type receptors, such as memantine, may prevent excitatory amino acid neurotoxicity without interfering with the physiological actions of glutamate required for memory and learning. OBJECTIVES: To determine the clinical efficacy and safety of memantine for people with Alzheimer's disease, or vascular or mixed dementia. SEARCH STRATEGY: Trials were identified from a search of the Trial-based Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 7 April 2004 using the terms: memantin*, namenda*, ebixa*, axura*, D-145, DMAA, DRG-0267. All major health care databases and many ongoing trial databases are searched regularly to keep this Register up to date. SELECTION CRITERIA: Double-blind, parallel group, placebo-controlled, randomised and unconfounded trials in which memantine was administered to people with dementia. DATA COLLECTION AND ANALYSIS: Data were extracted, pooled where possible, and weighted mean differences, standardized mean differences or odds ratios were estimated. Intention-to-treat (ITT) and observed cases (OC) analyses are reported, where data were available. MAIN RESULTS: The evidence suggests that memantine has a positive effect on cognition, mood and behaviour and the ability to perform activities of daily living in patients with moderate to severe Alzheimer's disease. The results in patients with mild to moderate vascular dementia, suggest a beneficial effect of 20mg/day of memantine on cognitive function measured at 28 weeks. However, these results are neither supported by an effect on ability to perform activities of daily living nor by an effect on the clinical impression of change. This suggests that, in patients with mild to moderate vascular dementia, the effect on cognitive function is not translated into clinically detectable changes. REVIEWERS' CONCLUSIONS: :Memantine 20 mg/day caused a clinically noticeable reduction in deterioration over 28 weeks in patients with moderate to severe Alzheimer disease. This was supported by less functional and cognitive deterioration. Patients taking memantine were less likely to become agitated. The effect in mild to moderate AD is unknown. Patients with mild to moderate vascular dementia receiving memantine 20 mg/day had less cognitive deterioration at 28 weeks but the effects were not clinically discernible. There is an early beneficial effect on cognition, mood, behaviour and clinical impression for memantine at 6 weeks. The drug is well tolerated in general and the incidence of adverse effects is low.

Physical localization and order of genes in the class I region of the bovine MHC.

Fluorescence in situ hybridization (FISH) analyses were used to order 16 bacterial artificial chromosomes (BAC) clones containing loci from the bovine lymphocyte antigen (BoLA) class I and III regions of bovine chromosome 23 (BTA23). Fourteen of these BACs were assigned to chromosomal band locations of mitotic and pachytene chromosomes by single- and dual-colour FISH. Dual-colour FISH confirmed that class II DYA is proximal to and separated from BoLA class I genes by approximately three chromosome bands. The FISH results showed that tumour necrosis factor alpha (TNFA), heat shock protein 70 (HSP70.1) and 21 steroid dehydrogenase (CYP21) are closely linked in the region of BTA23 band 22 along with BoLA class I genes, and that male enhanced antigen (MEA) mapped between DYA and the CYP21/TNFA/HSP70.1 gene region. All BAC clones containing BoLA class I genes mapped distal to CYP21/TNFA/HSP70.1 and centromeric to prolactin (PRL). Myelin oligodendrocyte glycoprotein (MOG) was shown to be imbedded within the BoLA class I gene cluster. The cytogenetic data confirmed that the disrupted distribution of BoLA genes is most likely the result of a single large chromosomal inversion. Similar FISH results were obtained when BoLA DYA and class I BAC clones were mapped to discrete chromosomal locations on the BTA homologue in white-tailed deer, suggesting that this chromosomal inversion predates divergence of the advanced ruminant families from a common ancestor.

Wandering in dementia: a longitudinal study.

OBJECTIVE: This article analyzes the natural history of wandering behavior throughout the course of dementia. DESIGN: Prospective, 10-year, longitudinal study of wandering behavior in dementia, with autopsy follow-up. SETTING: Participants with dementia, living at home with a carer. All lived in Oxfordshire, UK. PARTICIPANTS: Eighty-six people with dementia who were living at home with a carer and who were able to walk unaided at entry to study. MEASURES: At 4-monthly intervals, the carers were interviewed using the Present Behavioural Examination to assess wandering behavior in detail; participants with dementia were assessed cognitively. Nine types of "wandering" behavior were distinguished. RESULTS: Changes in wandering behavior were not generally related to gender, age, or time since onset of dementia. Onset of different types of wandering behavior showed some relationship with cognitive state. Various forms of increased walking first appeared during moderate dementia, each type typically persisting for 1 to 2 years. Late dementia was characterized by decreased walking and immobility. CONCLUSIONS: Wandering behavior in dementia can cause great problems for carers. There are different causes for such changes, some of which are related to cognitive ability, for example increased confusion results in ineffectual "pottering" and getting lost. Increased walking at night corresponds with disruption of diurnal rhythm.

Anosmia in dementia is associated with Lewy bodies rather than Alzheimer's pathology.

OBJECTIVES: To assess olfactory function of patients with dementia. Odour detection ability is impaired in clinical Parkinson's disease. Evidence of impaired detection in patients with clinically diagnosed Alzheimer's disease is inconsistent. No studies of olfaction have been neuropathologically validated. METHODS: The olfactory function of 92 patients with dementia and 94 controls was assessed using a simple bedside test as part of the Oxford Project To Investigate Memory and Ageing (OPTIMA). Neuropathological assessment was made of cortical Lewy bodies and substantia nigra (SN) cell counts and of Alzheimer's disease in all 92 patients, 22 of whom had SN Lewy bodies and 43 of whom had only Alzheimer's disease. RESULTS: Patients with Lewy bodies were more likely to be anosmic than those with Alzheimer's disease or controls. Patients with Alzheimer's disease were not more likely to be anosmic than controls. Nor was anosmia associated with degree of neurofibrillary tangles, as assessed by Braak stage. Among subjects with Lewy bodies, overall cortical Lewy body scores and Lewy body density in the cingulate were higher in those who were anosmic. Consensus clinical criteria for dementia with Lewy bodies had a sensitivity of 64% and specificity of 89%. In the absence of definite Alzheimer's disease, the criteria had sensitivity of 100%. In patients with definite Alzheimer's disease, anosmia was slightly more sensitive (55%) than the consensus criteria (33%). However, the addition of anosmia to the consensus criteria did not improve their overall performance. CONCLUSION: Dementia with Lewy bodies is associated with impaired odour detection. Misdiagnosis may have accounted for some previous reports of impaired odour detection in Alzheimer's disease. Simple but more sensitive tests of anosmia are required if they are to be clinically useful in identifying patients with dementia with Lewy bodies.

Dementia with Lewy bodies: a pure case.

A pure case of autopsy-confirmed dementia with Lewy bodies (DLB) is described. The patient presented with distinctive verbal fluency deficits in the context of mild language impairment, intact recognition memory, and impaired paragraph recall. Neuroimaging (CT and SPECT) showed progressive medial temporal lobe atrophy. Neuropathology revealed Lewy bodies, degeneration in the substantia nigra, nucleus basalis of Meynert (Nakano & Hirano, 1984), and locus ceruleus, but no pathology characteristic of Alzheimer's disease. It is in this sense that the case is "pure" DLB. Early neuropsychological diagnosis of DLB is essential (Salmon et al., 1996) given the potentially fatal hazard of neuroleptics (McKeith et al., 1992) and the difficulties associated with clinical neurological diagnoses (Litvan et al., 1998).

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.

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.

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.