Clinical judgment of GPs for the diagnosis of dementia: a diagnostic test accuracy study.

BACKGROUND: GPs often report using clinical judgment to diagnose dementia. AIM: To investigate the accuracy of GPs' clinical judgment for the diagnosis of dementia. DESIGN & SETTING: Diagnostic test accuracy study, recruiting from 21 practices around Bristol, UK. METHOD: The clinical judgment of the treating GP (index test) was based on the information immediately available at their initial consultation with a person aged ≥70 years who had cognitive symptoms. The reference standard was an assessment by a specialist clinician, based on a standardised clinical examination and made according to the 10th revision of the International Classification of Diseases (ICD-10) criteria for dementia. RESULTS: A total of 240 people were recruited, with a median age of 80 years (interquartile range [IQR] 75-84 years), of whom 126 (53%) were men and 132 (55%) had dementia. The median duration of symptoms was 24 months (IQR 12-36 months) and the median Addenbrooke's Cognitive Examination III (ACE-III) score was 75 (IQR 65-87). GP clinical judgment had sensitivity 56% (95% confidence interval [CI] = 47% to 65%) and specificity 89% (95% CI = 81% to 94%). Positive likelihood ratio was higher in people aged 70-79 years (6.5, 95% CI = 2.9 to 15) compared with people aged ≥80 years (3.6, 95% CI = 1.7 to 7.6), and in women (10.4, 95% CI = 3.4 to 31.7) compared with men (3.2, 95% CI = 1.7 to 6.2), whereas the negative likelihood ratio was similar in all groups. CONCLUSION: A GP clinical judgment of dementia is specific, but confirmatory testing is needed to exclude dementia in symptomatic people whom GPs judge as not having dementia.

Different trajectories of decline for global form and global motion processing in aging, mild cognitive impairment and Alzheimer's disease.

The visual processing of complex motion is impaired in Alzheimer's disease (AD). However, it is unclear whether these impairments are biased toward the motion stream or part of a general disruption of global visual processing, given some reports of impaired static form processing in AD. Here, for the first time, we directly compared the relative preservation of motion and form systems in AD, mild cognitive impairment, and healthy aging, by measuring coherence thresholds for well-established global rotational motion and static form stimuli known to be of equivalent complexity. Our data confirm a marked motion-processing deficit specific to some AD patients, and greater than any form-processing deficit for this group. In parallel, we identified a more gradual decline in static form recognition, with thresholds raised in mild cognitive impairment patients and slightly further in the AD group compared with controls. We conclude that complex motion processing is more vulnerable to decline in dementia than complex form processing, perhaps owing to greater reliance on long-range neural connections heavily targeted by AD pathology.

Towards improving diagnosis of memory loss in general practice: TIMeLi diagnostic test accuracy study protocol.

BACKGROUND: People with cognitive problems, and their families, report distress and uncertainty whilst undergoing evaluation for dementia and perceive that traditional diagnostic evaluation in secondary care is insufficiently patient centred. The James Lind Alliance has prioritised research to investigate the role of primary care in supporting a more effective diagnostic pathway, and the topic is also of interest to health commissioners. However, there are very few studies that investigate the accuracy of diagnostic tests for dementia in primary care. METHODS: We will conduct a prospective diagnostic test accuracy study to evaluate the accuracy of a range of simple tests for diagnosing all-cause-dementia in symptomatic people aged over 70 years who have consulted with their general practitioner (GP). We will invite eligible people to attend a research clinic where they will undergo a range of index tests that a GP could perform in the surgery and also be assessed by a specialist in memory disorders at the same appointment. Participating GPs will request neuroimaging and blood tests and otherwise manage patients in line with their usual clinical practice. The reference standard will be the consensus judgement of three experts (neurologist, psychiatrist and geriatrician) based on information from the specialist assessment, GP records and investigations, but not including items in the index test battery. The target condition will be all-cause dementia but we will also investigate diagnostic accuracy for sub-types where possible. We will use qualitative interviews with patients and focus groups with clinicians to help us understand the acceptability and feasibility of diagnosing dementia in primary care using the tests that we are investigating. DISCUSSION: Our results will help clinicians decide on which tests to perform in someone where there is concern about possible dementia and inform commissioning of diagnostic pathways.

Measuring Information Processing Speed in Mild Cognitive Impairment: Clinical Versus Research Dichotomy.

A substantial body of research evidence is indicative of disproportionately slowed information processing speed in a wide range of multi-trial, computer-based, neuroimaging- and electroencephalography-based reaction time (RT) tests in Alzheimer's disease and mild cognitive impairment (MCI). However, in what is arguably a dichotomy between research evidence and clinical practice, RT associated with different brain functions is rarely assessed as part of their diagnosis. Indeed, often only the time taken to perform a single, specific task, commonly the Trail making test (TMT), is measured. In clinical practice therefore, there can be a failure to assess adequately the integrity of the rapid, serial information processing and response, necessary for efficient, appropriate, and safe interaction with the environment. We examined whether a typical research-based RT task could at least match the TMT in differentiating amnestic MCI (aMCI) from cognitively healthy aging at group level. As aMCI is a heterogeneous group, typically containing only a proportion of individuals for whom aMCI represents the early stages of dementia, we examined the ability of each test to provide intra-group performance variation. The results indicate that as well as significant slowing in performance of the operations involved in TMT part B (but not part A), individuals with aMCI also experience significant slowing in RT compared to controls. The results also suggest that research-typical RT tests may be superior to the TMT in differentiating between cognitively healthy aging and aMCI at group level and in revealing the performance variability one would expect from an etiologically heterogeneous disorder such as aMCI.

Early visual evoked potentials and mismatch negativity in Alzheimer's disease and mild cognitive impairment.

BACKGROUND: Cortical visual association areas are highly vulnerable to Alzheimer's disease (AD) microscopic pathology. Visual evoked potentials (VEPs) provide the tools to examine the functional integrity of these areas and may provide useful indicators of early disease progression. OBJECTIVE: To assess the functional integrity of visual association area processing in AD and amnestic mild cognitive impairment (aMCI) using VEPs. METHODS: We investigated the visual processing of healthy older adults (n = 26), AD (n = 20), and aMCI (n = 25) patients in a visual oddball paradigm designed to elicit the visual P1, N1, and visual mismatch negativity (vMMN). RESULTS: AD patients showed a significant reduction of P1 and N1 VEP amplitudes and aMCI patients showed a reduction in N1 amplitude compared to healthy older adults. P1 amplitude in response to deviant stimuli and vMMN amplitude were found to be associated with the degree of cognitive impairment as measured by the Mini-Mental State Examination. CONCLUSIONS: Changes in VEPs in AD may be a consequence of the microscopic AD pathology typically found in the extrastriate cortex. Neural measures of visual processing may help to better characterize subgroups of aMCI patients likely to develop AD. Additionally, VEPs and vMMN may provide objective markers of cognitive decline.

Intra-individual reaction time variability in mild cognitive impairment and Alzheimer's disease: gender, processing load and speed factors.

Compared to cognitively healthy ageing (CH), intra-individual variability in reaction time (IIV(RT)), a behavioural marker of neurological integrity, is commonly reported to increase in both Alzheimer's disease (AD) and mild cognitive impairment (MCI). It varies in MCI with respect to whether it represents the pro-dromal stages of dementia or not; being greatest in those most likely to convert. Abnormal IIV(RT) in MCI therefore represents a potential measure of underlying functional integrity that may serve to differentiate MCI from CH and to help identify those patients for whom MCI is the result of a progressive pathological process. As the clinical approach to MCI is increasingly stratified with respect to gender, we investigated whether this factor could influence study outcome. The influence of RTSPEED and processing load upon IIV(RT) was also examined. Under low processing load conditions, IIV(RT) was significantly increased in both MCI and AD compared to CH. However, correcting for an individual's processing speed abolished this effect in MCI but not in AD, indicating that the increased IIV(RT) in MCI and AD may result from different factors. In MCI but not in CH, IIV(RT) was significantly greater for females. Increasing task processing load by adding distracting information, although increasing overall IIV(RT), failed to improve the differentiation between CH and both MCI and AD, and in MCI resulted in a reduction in the influence of gender upon study outcome. The outcome of studies investigating IIV(RT) in MCI and AD compared to CH therefore appear influenced by the gender of the participants, by task-related processing load and processing speed.

Dealing with illumination in visual scenes: effects of ageing and Alzheimer's disease.

Various visual functions decline in ageing and even more so in patients with Alzheimer's disease (AD). Here we investigated whether the complex visual processes involved in ignoring illumination-related variability (specifically, cast shadows) in visual scenes may also be compromised. Participants searched for a discrepant target among items which appeared as posts with shadows cast by light-from-above when upright, but as angled objects when inverted. As in earlier reports, young participants gave slower responses with upright than inverted displays when the shadow-like part was dark but not white (control condition). This is consistent with visual processing mechanisms making shadows difficult to perceive, presumably to assist object recognition under varied illumination. Contrary to predictions, this interaction of "shadow" colour with item orientation was maintained in healthy older and AD groups. Thus, the processing mechanisms which assist complex light-independent object identification appear to be robust to the effects of both ageing and AD. Importantly, this means that the complexity of a function does not necessarily determine its vulnerability to age- or AD-related decline.We also report slower responses to dark than light "shadows" of either orientation in both ageing and AD, in keeping with increasing light scatter in the ageing eye. Rather curiously, AD patients showed further slowed responses to "shadows" of either colour at the bottom than the top of items as if they applied shadow-specific rules to non-shadow conditions. This suggests that in AD, shadow-processing mechanisms, while preserved, might be applied in a less selective way.

Intra-individual reaction time variability in amnestic mild cognitive impairment: a precursor to dementia?

We used an exogenous target detection cueing paradigm to examine whether intra-individual reaction time variability (IIV) or phasic alerting varied significantly between patients with amnestic mild cognitive impairment (aMCI) (n = 45) and healthy older adult controls (n = 31) or between those with aMCI who, within a 2.5 year follow-up period, developed dementia (n = 13) and those who did not (n = 26). Neither IIV, nor simple reaction time, differentiated aMCI from healthy aging, indicating that raised IIV and overall response slowing are not general characteristics of aMCI. However, within the aMCI group, IIV did differentiate between those who converted to dementia and those who remained with a diagnosis of aMCI (non-converters), being significantly more variable in those who later developed dementia. Furthermore, there was no difference in IIV between non-converters and healthy controls. High IIV appears related to an increased probability that an individual with aMCI will become demented within 2.5 years, rather than to amnestic dysfunction per se. In contrast, phasic alerting performance significantly differentiated aMCI from healthy aging, but failed to discriminate those with aMCI who developed dementia from those who did not. In addition, those patients with aMCI who did not develop dementia still showed a significantly poorer phasic alerting effect compared to healthy aging. The phasic alerting abnormality in aMCI compared to healthy aging does not appear specifically related to the performance of those patients for whom aMCI represents the prodromal stages of dementia.

Do memory-impaired individuals report stable attitudes?

This research explored whether individuals diagnosed with probable Alzheimer's disease report stable attitudes. Two groups of participants (16 memory-impaired individuals with dementia and 16 matched controls without memory impairment) were presented with photos of various common objects and asked to indicate their attitude towards each object. Participants completed this task on two occasions, separated by 1 week. The results of the experiment revealed that memory-impaired individuals showed significant stability across time in their attitudes, although their level of attitude stability was less pronounced than that demonstrated by the matched controls. Theoretical and applied implications of the results are discussed.

Exogenous phasic alerting and spatial orienting in mild cognitive impairment compared to healthy ageing: Study outcome is related to target response.

Whether or not attentional mechanisms such as phasic alerting, spatial cueing and inhibition of return (IOR) remain intact in adults with Alzheimer's disease (AD) and mild cognitive impairment (MCI) remains a matter of debate. This is possibly the result of inter-study outcome variation caused by the adoption of different methodological components by different research groups. Here we investigated the influence of methodological factors upon study outcome, using a Posner-type exogenous cueing paradigm with amnestic MCI patients and healthy older controls. Specifically, we compared results when the required response involved target discrimination with results for a simple target detection response, using cue-to-target intervals (CTIs) of 200msec and 800msec in each case and with the same participants completing all conditions. For both groups, the presence or absence of both alerting and spatial cue-related effects depended upon the combination of target response requirement and CTI. Moreover, differences between the groups were specific to certain task conditions. The MCI group showed the same alerting effects as healthy people with a discrimination response, but the alerting effect shown by controls with a 200msec CTI and target detection was absent in MCI. Patients and controls showed similar spatial cue validity effects at 200msec CTI, but group differences emerged at 800msec CTI: target discrimination evoked a validity effect in the MCI group only, while target detection evoked an IOR effect in the healthy group only. These data indicate that detection and discrimination responses may each activate different attentional mechanisms, which are themselves differentially vulnerable in MCI. Thus a seemingly arbitrary choice of response may directly influence whether attentional processing appears preserved or disrupted in MCI. Furthermore, these data provide further evidence in support of the existence of significant visual attention-related functional abnormalities in amnestic MCI.

Visual search in mild cognitive impairment: a longitudinal study.

In the study of Alzheimer's disease, a multidisciplinary research approach has identified significant abnormality in several areas of visual and visual attention-related brain function in addition to those typically measured as part of clinical diagnosis. This raises the possibility that a similar approach applied to amnestic mild cognitive impairment (aMCI) will increase our understanding of its theoretical and clinical constructs, particularly if functions whose integrity is heterogeneous with respect to etiological outcome can be found. In this study we examined visual search performance (the brain's ability to search effectively throughout the environment for a particular object) in aMCI compared to healthy aging. Cross-sectionally, visual search performance in aMCI was significantly poorer than in healthy aging, with greater intra-group performance heterogeneity in the aMCI compared to the healthy older adult group. This outcome illustrates that although individuals within an aMCI group ostensibly have the same condition they can differ substantially with respect to the integrity of aspects of brain function. Such findings may have implications for the clinical management of the individual patient. The results from the longitudinal aspect of this study also illustrate how heterogeneity in the performance of brain operations other than memory in aMCI may help to inform the likelihood of their developing dementia, as those patients who were diagnosed with dementia within 2.5 years of baseline measurement showed significantly poorer visual search performance compared to those who did not.

New insights into feature and conjunction search: I. Evidence from pupil size, eye movements and ageing.

Differences in the processing mechanisms underlying visual feature and conjunction search are still under debate, one problem being a common emphasis on performance measures (speed and accuracy) which do not necessarily provide insights to the underlying processing principles. Here, eye movements and pupil dilation were used to investigate sampling strategy and processing load during performance of a conjunction and two feature-search tasks, with younger (18-27 years) and healthy older (61-83 years) age groups compared for evidence of differential age-related changes. The tasks involved equivalent processing time per item, were controlled in terms of target-distractor similarity, and did not allow perceptual grouping. Close matching of the key tasks was confirmed by patterns of fixation duration and an equal number of saccades required to find a target. Moreover, moment-to-moment pupillary dilation was indistinguishable across the tasks for both age groups, suggesting that all required the same total amount of effort or resources. Despite matching, subtle differences in eye movement patterns occurred between tasks: the conjunction task required more saccades to reach a target-absent decision and involved shorter saccade amplitudes than the feature tasks. General age-related changes were manifested in an increased number of saccades and longer fixation durations in older than younger participants. In addition, older people showed disproportionately longer and more variable fixation durations for the conjunction task specifically. These results suggest a fundamental difference between conjunction and feature search: accurate target identification in the conjunction context requires more conservative eye movement patterns, with these further adjusted in healthy ageing. The data also highlight the independence of eye movement and pupillometry measures and stress the importance of saccades and strategy for understanding the processing mechanisms driving different types of visual search.

New insights into feature and conjunction search: II. Evidence from Alzheimer's disease.

Deficits in inefficient visual search task performance in Alzheimer's disease (AD) have been linked both to a general depletion of attentional resources and to a specific difficulty in performing conjunction discriminations. It has been difficult to examine the latter proposal because the uniqueness of conjunction search as compared to other visual search tasks has remained a matter of debate. We explored both these claims by measuring pupil dilation, as a measure of resource application, while patients with AD performed a conjunction search task and two single-feature search tasks of similar difficulty in healthy individuals. Maximum pupil dilation in the AD group was greater during performance of the conjunction than the feature search tasks, although pupil response was indistinguishable for the three tasks in healthy controls. This, together with patients' false positive errors for the conjunction task, indicates an AD-specific deficit impacting upon the ability to combine information on multiple dimensions. In addition, maximum pupil dilation was no less for patients than the control group during task performance, which tends to oppose the concept of general resource depletion in AD. However, eye movement patterns in the patient group indicated that they were less able than controls to use organised strategies to assist with task performance. The data are therefore in keeping with a loss of access to resource-saving strategies, rather than a loss of resources per se, in AD. Moreover they demonstrate an additional processing mechanism in performing conjunction search compared with inefficient single-feature search.

Visual mismatch negativity highlights abnormal pre-attentive visual processing in mild cognitive impairment and Alzheimer's disease.

Alzheimer's disease (AD) and mild cognitive impairment (MCI) are traditionally characterised in relation to abnormalities in higher-level brain function, particularly memory. However, in the study presented here we report significant abnormality in pre-attentive visual processing in both MCI and AD compared to healthy ageing. The functional integrity of the automatic change detection system was determined by measuring the visual mismatch negativity (vMMN) component of the N2 visual event-related potential (ERP) in 8 individuals with amnestic MCI, 10 individuals with AD and 10 healthy older adult controls. Compared to healthy ageing, both the MCI and AD groups displayed a significant abnormally increased vMMN over the 140-250 ms measurement epoch although such effects were not apparent over the later 250-400 ms epoch. These novel findings support the view that deficits in brain function in both AD and MCI are not exclusively high-level and indeed that abnormal output from 'low level' or pre-attentive processes (as evinced by the abnormal vMMN) is likely to contribute to the high-level processing deficits so characteristic of these clinical disorders.

Abnormal visual search in mild cognitive impairment and Alzheimer's disease.

Our aim was to further characterize the clinical concept of mild cognitive impairment (MCI). We examined the status of visual attention-related processing in such patients in relation to healthy older adults and patients with Alzheimer's disease (AD) by measuring performance on a computer-based visual search task. We tested 20 older adult control participants, 13 patients with amnestic mild cognitive impairment and 12 patients with AD. Patients with AD and with MCI exhibited a significant detriment in visual search performance compared to the older adult controls. The deficit in visual search was greater for the patients with AD than the patients with MCI. The pattern of results displayed by the MCI group indicates that patients who appear clinically to suffer only from a deficit in memory also display a deficit in visual attention-related processing, which although not as severe as those with AD, represents a significant detriment in such performance compared to that seen in healthy ageing.

Abnormal spatial and non-spatial cueing effects in mild cognitive impairment and Alzheimer's disease.

Our aim was to further characterize the clinical concept of mild cognitive impairment (MCI). We examined visual attention-related processing in 12 patients with amnestic MCI, 16 healthy older adults and 16 patients with Alzheimer's disease (AD) by measuring performance on computer-based tests of attentional disengagement, alerting ability, and inhibition of return. Unlike the healthy older controls, the patients with AD and the patients with amnestic MCI exhibited a significant detriment in both the ability to disengage attention from an incorrectly cued location and the ability to use a visual cue to produce an alerting effect. The pattern of results displayed by the MCI group indicates that patients who only appear clinically to suffer from a deficit in memory also display a deficit in specific aspects of visual attention-related processing, which closely resemble the magnitude seen in AD.

Patterns of clinically detectable treatment effects with galantamine: a qualitative analysis.

The Clinician's Interview Based Impression of Change, plus carer interview (CIBIC-Plus) is widely used in anti-dementia drug trials. It includes clinicians' notes about patients' behaviour, function, and cognition, and a 7-point clinical global impression of change scale that summarizes patients' changes during treatment. We analyzed the narrative content of clinicians' notes from a randomized, controlled trial of galantamine, an anti-Alzheimer's disease drug, and identified varying degrees of improvement and decline. In general, while most patients were rated as showing 'no change', considerable changes were seen in such patients, but were judged by clinicians to have been offset by decline in other areas. Most patients rated as 'improved' showed combinations of cognitive, functional and/or behavioural improvement or stability. While patients with signs of cognitive improvement could be found across the scale from 'very much improved' to 'minimally worse', patients with functional improvement were rated as having improved or not having changed. Cognitive declines in several domains or any cognitive decline seen with functional declines were the chief drivers of worsening ratings. The CIBIC-Plus notes have potential value in identifying reproducible patterns of clinically relevant treatment effects provided that data are consistent and specific, and that seemingly contradictory information is carefully explored. Clinicians appear to be skeptical of cognitive changes not supported by like changes in function or behaviour.

Bristol Activities of Daily Living Scale: a critical evaluation.

This article discusses the role of scales to measure activities of daily living, in particular in Alzheimer's disease, in the assessment and management of dementia. It explains the principles of activities of daily living measurement before introducing the reader to the Bristol Activities of Daily Living Scale. Many scales have been developed for measuring activities of daily living, but few were specifically designed for individuals with mild dementia living in the community for completion by caregivers. Fewer still were designed with the assistance of caregivers themselves. The article considers the use of the Bristol Activities of Daily Living Scale since its development and potential future changes. It also takes a longer look forwards at possible, more general advances in activities of daily living measurement.