Showing papers by "John T. O'Brien published in 2008"

Association of gait and balance disorders with age-related white matter changes The LADIS Study

Abstract: Objective: In the Leukoaraiosis and Disability (LADIS) Study, 11 European centers are evaluating the role of age-related white matter changes (ARWMC) as an independent determinant of the transition to disability in the elderly (65 to 84 years). We aimed at determining the influence of ARWMC on different objective measures of gait and balance. Methods: Six hundred thirty-nine nondisabled individuals were prospectively enrolled and are being followed-up for 3 years. Subjects are graded in three standardized categories of ARWMC (mild, moderate, and severe) according to central MRI reading. Quantitative tests of gait and balance include the Short Physical Performance Battery (SPPB; range: 0 [poor] to 12 [normal]), a timed 8-m walk, and a timed single leg stance test. Results: In cross-sectional analysis, deficiencies in gait and balance performance were correlated with the severity of ARWMC (SPPB: 10.2 ± 2.1 in the mild, 9.9 ± 2.0 in the moderate, 8.9 ± 2.6 in the severe group; p Conclusions: Our findings support a strong association between the severity of age-related white matter changes and the severity of gait and motor compromise. Physical activity might have the potential to reduce the risk of limitations in mobility.

Depression and cognition in older adults.

Abstract: Purpose of reviewRecognition that depression is associated with neurocognitive impairment and renewed recent interest in milder forms of cognitive impairment in older people (typified by the concept of mild cognitive impairment) have stimulated researchers to investigate the relationship between dep

Urinary Complaints in Nondisabled Elderly People with Age-Related White Matter Changes: The Leukoaraiosis And DISability (LADIS) Study

Abstract: OBJECTIVES: To investigate, in a cohort of nondisabled elderly people, the association between urinary complaints and severity of age-related white matter changes (ARWMC). DESIGN: Cross-sectional data analysis from a longitudinal multinational study. SETTING: The Leukoaraiosis And DISability Study, assessing ARWMC as an independent predictor of the transition from functional autonomy to disability in elderly subjects. PARTICIPANTS: Six hundred thirty-nine subjects (288 men, 351 women, mean age 74.1±5.0) with magnetic resonance imaging (MRI)-detected ARWMC of different severity. MEASUREMENTS: ARWMC severity was graded on MRI as mild, moderate, and severe (Fazekas scale). MRI assessment also included ARWMC volumetric analysis and the count of infarcts. Urinary complaints (nocturia, urinary frequency, urgency, incontinence) were recorded based on subjects' answers to four questions. RESULTS: In comparing the three ARWMC severity groups, there was a significant difference only in prevalence of urgency, with 16% of subjects in the mild severity group, 17% in the moderate severity group, and 25% in the severe group (P=.03). Adjusting for age, sex, lacunar and nonlacunar infarcts, diabetes mellitus, and use of diuretics, severe ARWMC retained an independent effect in the association with urinary urgency (odds ratio=1.74, 95% confidence interval=1.04–2.90, severe vs mild group). Subjects with urinary urgency also had higher ARWMC volumes (25.2, vs 20.4 mm3 in those without urinary urgency; P<.001). Urgency was confirmed to be associated with the severe degree of ARWMC, irrespective of complaints of memory, gait disturbances, or history of depression. CONCLUSION: In a cohort of nondisabled elderly people, severe ARWMC were associated with urinary urgency, independent of other potential confounders and vascular lesions of the brain.

Poor attentional function predicts cognitive decline in patients with non-demented Parkinson’s disease independent of motor phenotype

Abstract: Background: Postural instability gait difficulty (PIGD) motor phenotype in Parkinson’s disease (PD) is associated with a faster rate of cognitive decline than in tremor dominant cases and may be a risk factor for incident dementia. People with PD display attentional deficits; however, it is not clear whether attentional deficits in patients with non-demented PD are associated with (i) PIGD phenotype and/or (ii) subsequent cognitive decline. Aims: (i) To examine rates of cognitive decline (Mini-Mental State Examination (MMSE) and Cambridge Cognitive Examination (CAMCOG)) over 3 years in subjects with non-demented PD aged over 65 years, (ii) using Cognitive Drug Research computerised assessment test battery, determine the rate of change in power of attention (PoA) scores over time (sum of mean choice reaction time, simple reaction time and digit vigilance reaction time scores), (iii) determine whether the PIGD phenotype is associated with changes in PoA and (iv) establish whether baseline PoA is associated with subsequent cognitive decline. Results: 14 subjects (38%) were classified as PIGD motor phenotype at baseline. Cognitive decline was greater in PIGD compared with non-PIGD subjects (p⩽0.02). PIGD phenotype was not associated with baseline PoA score although it was associated with subsequent worsening in PoA (mean PoA increase/year: non-PIGD subjects 11.4 ms; PIGD subjects 244.0 ms; p = 0.01). Higher baseline PoA scores were associated with greater cognitive decline (MMSE, p = 0.03; CAMCOG, p = 0.05) independent of PIGD status. Conclusion: PIGD phenotype and attention deficits are independently associated with a greater rate of cognitive decline in patients with non-demented PD. We propose that subtle attentional deficits in patients with non-demented PD predict subsequent cognitive impairment.

A comparison of 99mTc-exametazime and 123I-FP-CIT SPECT imaging in the differential diagnosis of Alzheimer's disease and dementia with Lewy bodies.

Abstract: Background: The aim of this study is to investigate the diagnostic value of perfusion 99mTc-exametazime single photon emission computed tomography (SPECT) in the diagnosis of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) in comparison with dopaminergic 123I-2β-carbomethoxy-3β-(4-iodophenyl)-n-(3-fluoropropyl) nortropane (FP-CIT) SPECT imaging.Methods: Subjects underwent 99mTc-exametazime scanning (39 controls, 36 AD, 30 DLB) and 123I-FP-CIT scanning (33 controls, 33 AD, 28 DLB). For each scan, five raters performed visual assessments blind to clinical diagnosis on selected transverse 99mTc-exametazime images in standard stereotactic space. Diagnostic accuracy of 99mTc-exametazime was compared to 123I-FP-CIT results for the clinically relevant subgroups AD and DLB using receiver operating characteristic (ROC) curve analysis.Results: Inter-rater agreement for categorizing uptake was “moderate” (mean κ = 0.53) for 99mTc-exametazime and “excellent” (mean κ = 0.88) for 123I-FP-CIT. For AD and DLB, consensus rating matched clinical diagnosis in 56% of cases using 99mTc-exametazime and 84% using 123I-FP-CIT. In distinguishing AD from DLB, ROC analysis revealed superior diagnostic accuracy with 123I-FP-CIT (ROC curve area 0.83, sensitivity 78.6%, specificity 87.9%) compared to occipital 99mTc-exametazime (ROC curve area 0.64, sensitivity 64.3%, specificity 63.6%) p = 0.03.Conclusion: Diagnostic accuracy was superior with 123I-FP-CIT compared to 99mTc-exametazime in the differentiation of DLB from AD.

A volumetric magnetic resonance imaging study of entorhinal cortex volume in dementia with lewy bodies. A comparison with Alzheimer's disease and Parkinson's disease with and without dementia.

Abstract: Aims: To investigate whether subjects with dementia with Lewy bodies (DLB), Alzheimer’s disease (AD) and Parkinson’s disease with dementia (PDD) have reduced entorhinal cortex (EC)

Vascular factors and depression.

Abstract: Objective This paper examines possible mechanisms that may explain the bi-directional relationship between vascular disease and depression. Design A literature review was carried out using Medline from 1996 to 2007, using relevant key words including vascular depression, and supplemented by key references to earlier work. Results Several mechanisms were considered including: autonomic dysfunction, platelet activation, hypothalamic pituitary axis activation, endothelial dysfunction, cytokines, omega 3 fatty acids, genetics, homocysteine and effects of treatment. Conclusions The relationship between vascular disease and depression cannot solely be explained by current established risk factors or the effects of treatment for depression. Other mechanisms must apply, and there is some evidence for common genetic factors. Promising future lines of investigation include homocysteine, cytokines and endothelial dysfunction. More longitudinal studies combined with measurements of these biomarkers are needed. Copyright © 2008 John Wiley & Sons, Ltd.

Self-perceived memory impairment and cognitive performance in an elderly independent population with age-related white matter changes

Abstract: Objectives: To determine whether self-perceived memory impairment is associated with the severity of white matter changes (WMC) and is related to cognitive impairment. Methods: Data were drawn from the multinational Leukoaraiosis and Disability Study (LADIS), which investigates the impact of WMC on global functioning. WMC severity was rated using the Fazekas scale. Medial temporal lobe atrophy (MTA) was scored visually and mean values were calculated. The neuropsychological battery consisted of the Mini-Mental State Examination, a modified version of the VADAS-Cog, Trail making and Stroop tests. A question about self-perceived memory impairment was used as a measure for presence of memory complaints. Cognitive performance was analysed test-by-test and in three main domains: memory, executive functions and speed/motor control. The Geriatric Depression Scale (GDS) was used as a measure of depressive symptoms. Results: Six hundred and thirty-eight subjects were included in this study. No association was found between memory complaints and the severity of WMC. Subjects with memory complaints (n = 399) had a higher GDS score [t (637) = −7.15; p 2 = 0.183; F = 17.09, β = −0.126; p Conclusion: In a sample of non-disabled elderly subjects with WMC, self-perceived memory impairment is significantly associated with objective memory impairment independently of the WMC severity, depressive symptoms and MTA.

Validation of a fully automated hippocampal segmentation method on patients with dementia.

Abstract: We describe a fully automated method for hippocampal segmentation. The method uses SPM5 (http://www.fil.ion.ucl.ac.uk/spm/) software to segment the brain into grey/white matter, and spatially normalize the images to standard space. Grey matter pixels within a predefined hippocampal region in standard space are identified to segment the hippocampi. The method was validated on 36 subjects (9 each of Alzheimer's disease, dementia with Lewy bodies, vascular dementia, and healthy controls). The mean absolute difference in volume compared with manual segmentation was 11% (SD 9%). Linear regression between manual and automated volume gave V(auto) = V(manual) × 0.83 + 401 ml. The method provides an acceptable automated alternative to manual segmentation which may be of value in large studies. Hum Brain Mapp 2008. © 2007 Wiley-Liss, Inc.

Antipsychotics for people with dementia

Abstract: More than 25 million people worldwide have dementia, with a new case developing every seven seconds.1 While putative disease modifying agents are being developed, we are limited to symptomatic treatments for cognitive and non-cognitive features. Non-cognitive symptoms—referred to as behavioural and psychological symptoms of dementia—including agitation, psychosis, depression, and aggression, occur in up to half of those with dementia in the community and an even higher proportion in residential care. Antipsychotics have been widely prescribed off licence for these symptoms, and 20-50% of people with dementia in institutional care receive them.2 What is the evidence for their efficacy? Several placebo controlled, randomised controlled trials (RCTs), especially of newer “atypical” antipsychotics like risperidone, show an improvement in agitation, aggression, and psychosis.3 But, even before current concerns over their side effects, the strength of the evidence supporting widespread prescribing in dementia was questioned. Efficacy is modest, and most studies have assessed behavioural and psychological symptoms of dementia as a general outcome rather than targeting specific symptoms. Side effects include extrapyramidal features, sedation, metabolic disturbances, increased cognitive impairment, and severe sensitivity reactions in dementia with Lewy bodies. In 2004 it emerged that the risk of cerebrovascular events and stroke was three times higher in people treated with the atypicals olanzapine and risperidone. A subsequent meta-analysis showed increased mortality in people treated with atypical antipsychotics compared with placebo, with a number needed to harm of around 100.4 These findings combined with high prescribing rates for people with dementia led to warnings about the use of these drugs in many countries. In the United Kingdom, the Committee on Safety of Medicines went further than most to advise that “risperidone or olanzapine should not be used for the treatment of behavioural symptoms of dementia.”5 Subsequently, patients had their drugs withdrawn or were switched to typical antipsychotics, often without considering individual circumstances. This led to further guidance from professional organisations supporting the continued use of atypical antipsychotics in some circumstances.6 So where are we now? Cohort studies suggest that typical antipsychotics have a similar cerebrovascular risk to atypical antipsychotics, and possibly even higher mortality.7 8 So switching from atypical antipsychotics to typical antipsychotics is unlikely to be a sensible strategy. Questions over efficacy remain. A large pragmatic double blind placebo controlled trial, using an outcome measure of “time to treatment discontinuation,” found that the benefits of atypical antipsychotics on efficacy were largely offset by discontinuation because of side effects.9 A recent RCT showed that antipsychotics can be safely withdrawn in many people with dementia who have taken them for prolonged periods, especially if symptoms have largely resolved.10 Staff and environmental factors are important, and targeted training and support reduced the use of antipsychotics from 42% to 23% over one year.2 What are the alternatives to antipsychotics? Non-pharmacological approaches are often rightly advocated. Indeed, careful assessment for comorbid conditions and exacerbating factors—including physical illness, pain, communication difficulties, and depression—are an essential part of assessment of behavioural and psychological symptoms of dementia. For milder symptoms, watchful waiting combined with simple explanation, advice, and support may be sufficient. Increased social stimulation or personalised music may help, and aromatherapy has some evidence base. However, all these non-pharmacological approaches are limited, not only by lack of studies but by the difficulties in undertaking truly placebo controlled trials, combined with an absence of studies in more severe behavioural disturbance.11 Cholinesterase inhibitors may be useful for symptoms such as apathy and psychosis, consistent with cholinergic deficit as a likely neurochemical cause. Initial reports that they may reduce agitation, a common and problematic symptom for which antipsychotics are often prescribed, were not confirmed by a large non-industry funded RCT, which showed no benefit of donepezil over placebo.12 Post hoc analysis of trials of memantine, an NMDA (N-methyl D-aspartate) antagonist, suggest possible benefits on agitation and aggression.13 Evidence for other drugs is limited; carbamazepine may help agitation and aggression, but no clear consensus exists on the role of antidepressants in managing behavioural and psychological symptoms of dementia. What conclusions can we draw? Evidence based alternatives to antipsychotics are relatively few and limited to people with mild to moderate symptoms. In more severe cases no treatment or non-evidence based treatment is often not a clinical option. Antipsychotics, especially atypical ones, have the best evidence base, although their efficacy is more modest than previously supposed and their side effects more serious. Prescribing rates of up to 50% for people in residential care cannot be justified. However, given the lack of suitable alternatives, it is not reasonable to stop prescribing completely. Current advice, such as that contained in the National Institute for Health and Clinical Excellence guidelines for dementia, is pragmatic and helpful. Management of the symptoms consists of a thorough assessment, to search for any modifiable causes. Non-pharmacological approaches should be used first, and possible alternatives—like carbamazepine for aggression, cholinesterase inhibitors for apathy and psychosis, and memantine for agitation—should be considered. Prescription of antipsychotics should be carefully targeted, time limited, and reserved for severe and distressing symptoms after careful assessment of risk and benefit. This is not easy. How, for example, can we weigh up a small but real increased risk of a stroke compared with the possible benefit of remaining in a less restricted environment (for example, at home)? These complex decisions have to involve the patient, where possible, together with the family and carers.

Cognitive effects of acute tryptophan depletion in the healthy elderly.

Abstract: Summary This analysis was able to examine effects of ATDand the interaction of this with dose of depletingdrink, age and gender in a large group of healthyelderly subjects. Results are largely negative apartfrom an interaction between ATD, gender anddose on some neuropsychological variables. Wesuggest that females receiving high-dose ATD havereduced encoding or registration. This effect is inkeeping with previous literature. Authors' contributions All authors were involved in analysis and writingof the paper. Richard Porter and John O’Brienproduced the protocol. Richard Porter and PeterGallagher were involved in the conduct of thestudies.Acknowledgements We would like to thank Mel Leitch for measurement of TRPand Lucy Walker, Andrew Phipps, Ailsa Scott, Brian Lunn,Alistair Gray and John Gray for contributing to design andcollection of the data. References 1. Y OUNG SN, E RVIN FR, P IHL RO, F INN P. Biochemicalaspects of tryptophan depletion in primates. Psychophar-macology 1989;98:508–511.2. N

The effects of donepezil on nicotinic receptor status in dementia: A 123 I-5IA-85380 SPECT study

Abstract: Disturbances in the cerebral cholinergic nervous system and subsequent reduction of acetylcholine (ACh) are neurochemical features of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB), and treatments with acetylcholinesterase inhibitors (AChEIs) offer symptomatic improvement in cognitive and non-cognitive symptoms. One important subclass of ACh receptors are nicotinic acetylcholine receptors (nAChRs), which have been shown to be implicated in memory and cognitive processes. The SPECT tracer 123I-5IA-85380 is a radioligand that can visualise in vivo the presynaptic nAChR (α4β2 subtype, the most common subtype in man).1 In the present study, we assessed the effects of the AChEI donepezil on nicotinic receptor status in AD and DLB using 123I-5IA-85380 SPECT imaging. We hypothesised that relative 123I-5IA-85380 uptake would increase after administration of donepezil in accordance with previous studies using non-selective nicotinic ligands.2 ### Subjects We recruited 9 non-smoking patients (for >10 years) with dementia (4 AD and 5 DLB). Patients with AD fulfilled NINCDS/ADRDA criteria for “probable” AD,3 whereas DLB subjects satisfied criteria for “probable” DLB.4 The study received ethical and ARSAC approval. All participants and their nearest relative gave informed written consent. ### Assessments and study design Prior to baseline 123I-5IA-85380 imaging, patients underwent physical, neurological and neuropsychiatric assessments. Tests included the Cambridge Cognitive Examination (CAMCOG), the Mini-Mental State Examination (MMSE) and the motor Unified Parkinson’s Disease Rating Scale (UPDRS III). Following …