Alzheimer Disease: Ballard C

Ballard C. · No affiliation provided · Am J Geriatr Psychiatry. · Pubmed #17974863 No free full text.

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Ballard C, O'Brien J, Tovee M. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #11971037 links to  free full text

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Ballard C, O'Brien J. · No affiliation provided · BMJ. · Pubmed #10406732 links to  free full text

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Aarsland D, Londos E, Ballard C. · The Norwegian Centre for Parkinson's Disease, Stavanger University Hospital, Norway and Institute of Clinical Medicine, University of Bergen, Norway. · Int Psychogeriatr. · Pubmed #19173762 No free full text.

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Ballard C, Day S, Sharp S, Wing G, Sorensen S. · Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London. · Int Rev Psychiatry. · Pubmed #18925489 No free full text.

Abstract: Neuropsychiatric symptoms are frequent in people with dementia, result in distress for the people experiencing them and their caregivers, and are a common precipitant of institutional care. The safe and effective treatment of these symptoms is a key clinical priority, but is a long way from being achieved. Psychological interventions are recommended as the first line treatment strategy in most good practice guidelines, and there is emerging evidence of efficacy for agitation and depression. Neuroleptics remain the mainstay of pharmacological treatment, although meta-analyses indicate that they are mainly of benefit for the short-term (up to 12 weeks) treatment of aggression in people with Alzheimer's disease, and there have been increasing concerns about serious adverse effects including mortality. The evidence is limited for other pharmacological approaches for the treatment of agitation, and psychosis in people with Alzheimer's disease is limited, but post-hoc analyses do indicate that memantine may be a promising therapy and aromatherapy may be a useful alternative. Autopsy studies indicate that the adrenergic system may be an important therapeutic target. Clinical experience suggests that antidepressants are effective in people with severe depression in the context of dementia, but the evidence base regarding the broader value of antidepressants is far from clear. There are very few trials specifically focusing upon the treatment of neuropsychiatric symptoms in common non-Alzheimer dementias, which is a major limitation and urgently needs to be addressed to provide an evidence base to enable the safe and effective treatment of these individuals.

Aarsland D, Kurz M, Beyer M, Bronnick K, Piepenstock Nore S, Ballard C. · Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway. · Dement Geriatr Cogn Disord. · Pubmed #18204253 No free full text.

Abstract: BACKGROUND: The clinical diagnostic criteria for dementia with Lewy bodies (DLB) have a low sensitivity, and there are no generally accepted biomarkers to distinguish DLB from other dementias. Our aim was to identify biomarkers that may differentiate DLB from Alzheimer's disease (AD). METHOD: We performed a systematic literature search for studies of EEG, imaging techniques and genetic and CSF markers that provide sensitivity and specificity in the identification of DLB. RESULTS: The best evidence was for scintigraphy of the striatal dopamine transporter system using FP-CIT SPECT. Several small scintigraphy studies of cardiovascular autonomic function using metaiodobenzylguanidine SPECT have reported promising results. Studies exploring innovative techniques based on CSF have reported interesting findings for the combination of amyloid beta (abeta) isoforms as well as alpha-synuclein, and there are interesting results emerging from preliminary studies applying proteomic techniques. Data from studies using structural MRI, perfusion SPECT, genetics and EEG studies show differences between DLB and AD but only at a group level. CONCLUSION: Several potential biomarkers for the differential diagnosis of probable DLB and AD have shown good diagnostic accuracy in the research setting. Data from large multicentre studies and from studies with autopsy confirmation exist for scintigraphy of the dopamine transporter system. Future studies should explore its value in possible DLB and for clinical management and health economics.

Ballard C, Sorensen S, Sharp S. · Alzheimer's Society, UK. · J Alzheimers Dis. · Pubmed #17851194 No free full text.

Abstract: The drive for evidence based practice and cost-effective use of pharmacological therapies has advantages, but can also be problematic. These difficulties are particularly challenging in the context of long-term conditions, such as Alzheimer's disease. The complexity of the illness, the variable and complex pattern of service use and the difficulty of conducting long term clinical trials are extremely difficult to factor into a meaningful cost effectiveness model. In Alzheimer's disease, the additional impact on caregivers as well as the person with dementia should be considered. In the current article we give a brief overview of the clinical effectiveness of cholinesterase inhibitors for the treatment of Alzheimer's disease, discuss in detail the NICE appraisal of these treatments in the UK as an example of an attempt at a standardised evaluation of cost-effectiveness and discuss a proposed way forward to achieve a unified and consistent approach to the assessment of cost-effectiveness for anti-dementia therapies.

Burns A, O'Brien J, Anonymous00334, Auriacombe S, Ballard C, Broich K, Bullock R, Feldman H, Ford G, Knapp M, McCaddon A, Iliffe S, Jacova C, Jones R, Lennon S, McKeith I, Orgogozo JM, Purandare N, Richardson M, Ritchie C, Thomas A, Warner J, Wilcock G, Wilkinson D, Anonymous00335. · University of Manchester, Manchester, UK. · J Psychopharmacol. · Pubmed #17060346 No free full text.

Abstract: The British Association for Psychopharmacology (BAP) coordinated a meeting of experts to review the evidence on the drug treatment for dementia. The level of evidence (types) was rated using a standard system: Types 1a and 1b (evidence from meta-analysis of randomised controlled trials or at least one controlled trial respectively); types 2a and 2b (one well-designed study or one other type of quasi experimental study respectively); type 3 (non-experimental descriptive studies); and type 4 (expert opinion). There is type 1a evidence for cholinesterase inhibitors (donepezil, rivastigmine and galantamine) for mild to moderate Alzheimer's disease; memantine for moderate to severe Alzheimer's disease; and for the use of bright light therapy and aromatherapy. There is type 1a evidence of no effect of anti inflammatory drugs or statins. There is conflicting evidence regarding oestrogens, with type 2a evidence of a protective effect of oestrogens but 1b evidence of a harmful effect. Type 1a evidence for any effect of B12 and folate will be forthcoming when current trials report. There is type 1b evidence for gingko biloba in producing a modest benefit of cognitive function; cholinesterase inhibitors for the treatment of people with Lewy body disease (particularly neuropsychiatric symptoms); cholinesterase inhibitors and memantine in treatment cognitive impairment associated with vascular dementia; and the effect of metal collating agents (although these should not be prescribed until more data on safety and efficacy are available). There is type 1b evidence to show that neither cholinesterase inhibitors nor vitamin E reduce the risk of developing Alzheimer's disease in people with mild cognitive impairment; and there is no evidence that there is any intervention that can prevent the onset of dementia. There is type 1b evidence for the beneficial effects of adding memantine to cholinesterase inhibitors, and type 2b evidence of positive switching outcomes from one cholinesterase inhibitor to another. There is type 2a evidence for a positive effect of reminiscence therapy, and type 2a evidence that cognitive training does not work. There is type 3 evidence to support the use of psychological interventions in dementia. There is type 2 evidence that a clinical diagnosis of dementia can be made accurately and that brain imaging increases that accuracy.Although the consensus statement dealt largely with medication, the role of dementia care in secondary services (geriatric medicine and old age psychiatry) and primary care, along with health economics, was discussed. There is ample evidence that there are effective treatments for people with dementia, and Alzheimer's disease in particular. Patients, their carers, and clinicians deserve to be optimistic in a field which often attracts therapeutic nihilism.

Ballard C, Howard R. · Medical Research Council Centre for Neurodegeneration Research, King's College London, De Crespigny Park, London SE5 8AF, UK. · Nat Rev Neurosci. · Pubmed #16715057 No free full text.

Abstract: Neuroleptic (antipsychotic) drugs are often used to treat psychiatric symptoms frequently seen in dementia, but their use is controversial. We present a new meta-analysis to assess the efficacy of these drugs for the treatment of psychiatric symptoms in Alzheimer's disease, and discuss the more limited evidence for their potential benefits in other dementias. We recommend that these treatments be limited to the short-term treatment of psychiatric symptoms associated with serious distress or risk.

Ballard C, Waite J. · Kings College London, Wolfson Centre for Age-Related Diseases, Wolfson Wing, Hodgkin Building, Guy's Campus, London, UK, SE1 1UL. · Cochrane Database Syst Rev. · Pubmed #16437455 No free full text.

Abstract: BACKGROUND: Aggression, agitation or psychosis occur in the majority of people with dementia at some point in the illness. There have been a number of trials of atypical antipsychotics to treat these symptoms over the last five years, and a systematic review is needed to evaluate the evidence in a balanced way. OBJECTIVES: To determine whether evidence supports the use of atypical antipsychotics for the treatment of aggression, agitation and psychosis in people with Alzheimer's disease. SEARCH STRATEGY: The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 7 December 2004 using the terms olanzapine, quetiapine, risperidone, clozapine, amisulpride, sertindole, zotepine, aripiprazole, ziprasidone. This Register contains articles from all major healthcare databases and many ongoing trials databases and is updated regularly. SELECTION CRITERIA: Randomised, placebo-controlled trials, with concealed allocation, where dementia and psychosis and/or aggression were assessed. DATA COLLECTION AND ANALYSIS: 1. Two reviewers extracted data from included trials2. Data were pooled where possible, and analysed using appropriate statistical methods3. Analysis included patients treated with an atypical antipsychotic, compared with placebo MAIN RESULTS: Sixteen placebo controlled trials have been completed with atypical antipsychotics although only nine had sufficient data to contribute to a meta-analysis and only five have been published in full in peer reviewed journals. No trials of amisulpiride, sertindole or zotepine were identified which met the criteria for inclusion. The included trials led to the following results:1. There was a significant improvement in aggression with risperidone and olanzapine treatment compared to placebo.2. There was a significant improvement in psychosis amongst risperidone treated patients.3. Risperidone and olanzpaine treated patients had a significantly higher incidence of serious adverse cerebrovascular events (including stroke), extra-pyramidal side effects and other important adverse outcomes.4. There was a significant increase in drop-outs in risperidone (2 mg) and olanzapine (5-10 mg) treated patients.5. The data were insufficient to examine impact upon cognitive function. AUTHORS' CONCLUSIONS: Evidence suggests that risperidone and olanzapine are useful in reducing aggression and risperidone reduces psychosis, but both are associated with serious adverse cerebrovascular events and extra-pyramidal symptoms. Despite the modest efficacy, the significant increase in adverse events confirms that neither risperidone nor olanzapine should be used routinely to treat dementia patients with aggression or psychosis unless there is marked risk or severe distress. Although insufficient data were available from the considered trials, a meta-analysis of seventeen placebo controlled trials of atypical neuroleptics for the treatment of behavioural symptoms in people with dementia conducted by the Food and Drug Administration (using data not in the public domain) suggested a significant increase in mortality (OR 1.7).

Aarsland D, Sharp S, Ballard C. · Centre for Clinical Neuroscience Research, Stavanger University Hospital, PO Box 1163, 4095 Stavanger, Norway. · Curr Neurol Neurosci Rep. · Pubmed #16131417 No free full text.

Abstract: Psychiatric and behavioral symptoms are common in all types of dementia and have important consequences for patients, caregivers, and society. This paper reviews recent studies of the etiology and management of these symptoms. Genetic and neurochemical studies indicate that cholinergic, serotonergic, and dopaminergic systems may influence the risk of psychiatric symptoms in patients with dementia. There is still no consensus regarding the management of such symptoms. Controlled studies of psychosocial interventions, usually performed in the nursing home setting, report encouraging results. Atypical antipsychotics may be effective in some cases but have a high risk of adverse events. There is emerging evidence that cholinesterase inhibitors may reduce and prevent such symptoms. More studies are needed to clarify the role of cholinergic and other psychotropic agents as well as nonpharmacologic interventions for psychiatric and behavioral symptoms in patients with dementia.

Perry NS, Bollen C, Perry EK, Ballard C. · Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand. · Pharmacol Biochem Behav. · Pubmed #12895683 No free full text.

Abstract: S. lavandulaefolia Vahl. (Spanish sage) extracts and constituents have demonstrated anticholinesterase, antioxidant, anti-inflammatory, oestrogenic and CNS depressant (sedative) effects all of which are currently relevant to the treatment of Alzheimer's disease (AD). The essential oil inhibits the enzyme acetylcholinesterase (AChE) from human brain tissue and bovine erythrocyte and individual monoterpenoid constituents inhibit AChE with varying degrees of potency. In vivo AChE inhibition of select brain (striatal and hippocampal over cortical) AChE was obtained following oral administration of the essential oil to rats. In a study in healthy volunteers essential oil administration produced significant effects on cognition. In a pilot open-label study involving oral administration of the essential oil to patients with AD, a significant increase in diastolic and systolic blood pressure was observed in two patients, however this may have been due primarily to preexisting hypertension and there were no abnormalities in other vital signs or blood samples during the trial period. Although an open label trial is not free from practice effects or rater-caregiver expectations, statistically significant differences between baseline and 6 weeks treatment were a reduction in neuropsychiatric symptoms and an improvement in attention.

Kenny RA, Kalaria R, Ballard C. · MRC Development Centre for Clinical Brain Ageing, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom. · Ann N Y Acad Sci. · Pubmed #12480751 No free full text.

Abstract: Neurocardiovascular instability (NCVI, neurally mediated disorders causing hypotension with or without bradycardia) represents abnormal neural control of the cardiovascular system and presents as dizziness, syncope, or falls. The mechanisms underpinning NCVI are incompletely understood. The three most common disorders are carotid sinus syndrome (CSS), orthostatic hypotension (OH), and vasovagal syndrome (VVS): CSS, cardioinhibition > 3 s and/or vasodepressor response > or = 50 mmHg drop in systolic pressure during carotid sinus stimulation; OH: fall in systolic blood pressure > 20 mmHg during standing; VVS: cardioinhibition > 3 s and/or vasodepressor response > 50 mmHg during prolonged head-up tilting. In fallers with cognitive impairment or dementia, the prevalence of NCVI is 70%. Multifactorial interventions, including treatment of NCVI, significantly reduce falls and syncope. The predominant components of NCVI in fallers with cognitive impairment and dementia are CSS and OH. In Lewy body and Alzheimer's dementia, the prevalence of NCVI is up to 60%, again predominantly CSS and OH. The prevalence of cardioinhibitory carotid sinus hypersensitivity is particularly high in Lewy body dementia-41% compared with 12% in Alzheimer's disease and 3% in case controls. In addition, patients with Lewy body dementia have greater heart rate slowing (>2 s) and falls in systolic blood pressure (>20 mmHg) than those with Alzheimer's disease or controls during carotid sinus stimulation. The extent of deep white matter hyperintensities on MRI correlates with systolic fall during carotid sinus stimulation (R = 0.58; p < 0.005), suggesting a possible causal association between bradyarrhythmia-induced hypotension and microvascular pathology. NCVI is common in patients with dementia and may be a reversible cause of falls and syncope. Repeated hypotensive episodes may exaggerate cognitive decline in these patients.

Ballard C, Walker M. · MRC Neurochemical Pathology Unit, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, NE4 6BE, UK. · Curr Psychiatry Rep. · Pubmed #11122905 No free full text.

Abstract: The increase in research studies focusing on neuropsychiatric symptoms over the last decade has greatly increased our knowledge base, particularly with regard to the frequency of these symptoms and their impact on both patients and carers. We still have a poor understanding of the natural course of these symptoms and their biologic correlates, however, and more specific treatment studies are needed to inform clinical management.

Cormack FK, Tovee M, Ballard C. · Department of Psychology, University of Newcastle upon Tyne, UK. · Int J Geriatr Psychiatry. · Pubmed #10918342 No free full text.

Abstract: Alzheimer's disease is a disorder which is typified by a deterioration in cognition and a range of behavioural problems which result in a loss of functional ability and often necessitate transfer to residential care. This article looks at a growing body of research which is revealing the presence of changes in vision, particularly contrast sensitivity and acuity. We discuss the possible pathological basis for such deficits, and examine the possibility that such changes in vision may impact on the behavioural and functional outcomes of the demented individual.

Ballard C, Gray A, Ayre G. · MRC Neurochemical Pathology Unit, Newcastle General Hospital, Newcastle upon Tyne, U.K. · Rev Neurol (Paris). · Pubmed #10637938 No free full text.

Abstract: The current article reviews the literature pertaining to psychosis, aggression and restlessness in dementia sufferers examining frequency, course and associations as well as treatment considerations. All of these problems are highly prevalent, with a high impact upon dementia sufferers and their carers. Although there has been an expansion in this literature over the last few years there are still very few studies describing the natural course of behavioural and psychological symptoms in dementia (BPSD) and a paucity of data relating to non-Alzheimer dementias. Several large treatment studies have recently been completed, but there are still very few double blind controlled trials focusing upon BPSD in particular respect to non-pharmacological interventions.

Kalaria RN, Ballard C. · Department of Psychiatry, Institute for Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom. · Alzheimer Dis Assoc Disord. · Pubmed #10609690 No free full text.

Abstract: There is overwhelming evidence to suggest that the neuropathology of Alzheimer disease (AD) extends beyond amyloid plaques and neurofibrillary tangles. Review of various consortium data shows that more than 30% of AD cases exhibit cerebrovascular pathology. However, certain vascular lesions such as cerebral amyloid angiopathy, microvascular degeneration, and periventricular white matter lesions are evident in almost all cases of AD. Whether these vascular lesions are coincidental or causal in the pathogenetic processes of AD remains to be defined. Although systemic vascular influences such as hypertension, coronary artery disease, and other cardiovascular disturbances may be responsible for such pathology in AD, it is equally intriguing that about one third of patients diagnosed with vascular dementia (VaD) will have AD-type pathology at autopsy. Moreover, previous studies have revealed that deficits in cholinergic indices related to the basal forebrain neurones are apparent in multi-infarct dementia. In this short review, we evaluate cerebrovascular pathology of AD in light of peripheral vascular pathophysiology implicated in the etiopathogenesis of the dementia. We also consider pathological findings in relation to genetic influences such as apolipoprotein E that may shed light on the link between AD and VaD. In view of these commonalties, it is reasonable to consider the same treatment strategies for both AD and VaD.

Ballard C, Margallo-Lana M, Juszczak E, Douglas S, Swann A, Thomas A, O'Brien J, Everratt A, Sadler S, Maddison C, Lee L, Bannister C, Elvish R, Jacoby R. · Institute of Psychiatry, King's College, London SE5 8AF. · BMJ. · Pubmed #15722369 links to  free full text

Abstract: OBJECTIVES: To determine the respective efficacy of quetiapine and rivastigmine for agitation in people with dementia in institutional care and to evaluate these treatments with respect to change in cognitive performance. DESIGN: Randomised double blind (clinician, patient, outcomes assessor) placebo controlled trial. SETTING: Care facilities in the north east of England. PARTICIPANTS: 93 patients with Alzheimer's disease, dementia, and clinically significant agitation. INTERVENTION: Atypical antipsychotic (quetiapine), cholinesterase inhibitor (rivastigmine), or placebo (double dummy). MAIN OUTCOME MEASURES: Agitation (Cohen-Mansfield agitation inventory) and cognition (severe impairment battery) at baseline and at six weeks and 26 weeks. The primary outcome was agitation inventory at six weeks. RESULTS: 31 patients were randomised to each group, and 80 (86%) started treatment (25 rivastigmine, 26 quetiapine, 29 placebo), of whom 71 (89%) tolerated the maximum protocol dose (22 rivastigmine, 23 quetiapine, 26 placebo). Compared with placebo, neither group showed significant differences in improvement on the agitation inventory either at six weeks or 26 weeks. Fifty six patients scored > 10 on the severe impairment battery at baseline, 46 (82%) of whom were included in the analysis at six week follow up (14 rivastigmine, 14 quetiapine, 18 placebo). For quetiapine the change in severe impairment battery score from baseline was estimated as an average of -14.6 points (95% confidence interval -25.3 to -4.0) lower (that is, worse) than in the placebo group at six weeks (P = 0.009) and -15.4 points (-27.0 to -3.8) lower at 26 weeks (P = 0.01). The corresponding changes with rivastigmine were -3.5 points (-13.1 to 6.2) lower at six weeks (P = 0.5) and -7.5 points (-21.0 to 6.0) lower at 26 weeks (P = 0.3). CONCLUSIONS: Neither quetiapine nor rivastigmine are effective in the treatment of agitation in people with dementia in institutional care. Compared with placebo, quetiapine is associated with significantly greater cognitive decline.

Karas GB, Burton EJ, Rombouts SA, van Schijndel RA, O'Brien JT, Scheltens P, McKeith IG, Williams D, Ballard C, Barkhof F. · Department of Diagnostic Radiology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. · Neuroimage. · Pubmed #12725765 No free full text.

Abstract: Voxel-based morphometry (VBM) has already been applied to MRI scans of patients with Alzheimer's disease (AD). The results of these studies demonstrated atrophy of the hippocampus, temporal pole, and insula, but did not describe any global brain changes or atrophy of deep cerebral structures. We propose an optimized VBM method, which accounts for these shortcomings. Additional processing steps are incorporated in the method, to ensure that the whole spectrum of brain atrophy is visualized. A local group template was created to avoid registration bias, morphological opening was performed to eliminate cerebrospinal fluid voxel misclassifications, and volume preserving modulation was used to correct for local volume changes. Group differences were assessed and thresholded at P < 0.05 (corrected). Our results confirm earlier findings, but additionally we demonstrate global cortical atrophy with sparing of the sensorimotor cortex, occipital poles, and cerebellum. Moreover, we show atrophy of the caudate head nuclei and medial thalami. Our findings are in full agreement with the established neuropathological descriptions, offering a comprehensive view of atrophy patterns in AD.

Colloby SJ, Fenwick JD, Williams ED, Paling SM, Lobotesis K, Ballard C, McKeith I, O'Brien JT. · Wolfson Research Centre, The Institute for Ageing and Health, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, NE4 6BE, UK. · Eur J Nucl Med Mol Imaging. · Pubmed #11976799 No free full text.

Abstract: Differences in regional cerebral blood flow (rCBF) between subjects with Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and healthy volunteers were investigated using statistical parametric mapping (SPM99). Forty-eight AD, 23 DLB and 20 age-matched control subjects participated. Technetium-99m hexamethylpropylene amine oxime (HMPAO) brain single-photon emission tomography (SPET) scans were acquired for each subject using a single-headed rotating gamma camera (IGE CamStar XR/T). The SPET images were spatially normalised and group comparison was performed by SPM99. In addition, covariate analysis was undertaken on the standardised images taking the Mini Mental State Examination (MMSE) scores as a variable. Applying a height threshold of P < or = 0.001 uncorrected, significant perfusion deficits in the parietal and frontal regions of the brain were observed in both AD and DLB groups compared with the control subjects. In addition, significant temporoparietal perfusion deficits were identified in the AD subjects, whereas the DLB patients had deficits in the occipital region. Comparison of dementia groups (height threshold of P < or = 0.01 uncorrected) yielded hypoperfusion in both the parietal [Brodmann area (BA) 7] and occipital (BA 17, 18) regions of the brain in DLB compared with AD. Abnormalities in these areas, which included visual cortex and several areas involved in higher visual processing and visuospatial function, may be important in understanding the visual hallucinations and visuospatial deficits which are characteristic of DLB. Covariate analysis indicated group differences between AD and DLB in terms of a positive correlation between cognitive test score and temporoparietal blood flow. In conclusion, we found evidence of frontal and parietal hypoperfusion in both AD and DLB, while temporal perfusion deficits were observed exclusively in AD and parieto-occipital deficits in DLB.

O'Brien JT, Metcalfe S, Swann A, Hobson J, Jobst K, Ballard C, McKeith I, Gholkar A. · Institute for the Health of the Elderly, University of Newcastle-upon-Tyne, Glasgow, UK. j.t.o' · Dement Geriatr Cogn Disord. · Pubmed #10705169 No free full text.

Abstract: A simple linear measurement of the minimum width of the medial temporal lobe (MTL) on angled CT scans has been suggested as an accurate ante-mortem marker for Alzheimer's disease (AD). To determine the clinical utility and specificity of this finding, we performed angled CT scans with 5-mm slices in 116 subjects referred to a geographically based Old Age Psychiatry service in Newcastle. Diagnoses were of NINCDS/ADRDA AD (n = 69, 36 probable and 33 possible). NINDS/AIREN vascular dementia (VaD, n = 25), consensus criteria for dementia with Lewy bodies (DLB, n = 9) and DSM-IV criteria for major depression (n = 13). Subjects were well matched for age. Minimum MTL width was significantly greater in depressed subjects (13.7 mm) compared to those with dementia, though no differences were seen within the dementia groups (AD 10.8, VaD 10.4, and DLB 10.9 mm). An MTL width below 11.5 mm had a sensitivity of 54% (56/103) and a specificity of 77% (10/13) for distinguishing dementia from depression. We conclude that a single cross-sectional measurement of MTL width on CT does not help differentiate between different types of dementia, though it may provide some supportive evidence when distinguishing depression from dementia.

Ballard C, McKeith I, O'Brien J, Kalaria R, Jaros E, Ince P, Perry R. · MRC Neurochemical Pathology Unit, Newcastle General Hospital, UK. · Dement Geriatr Cogn Disord. · Pubmed #10705161 No free full text.

Abstract: The neuropathological substrates of dementia and depression were evaluated in 30 patients with cerebrovascular disease and significant cognitive impairment (VaD), with a particular focus on patients with small infarct volumes (<15 ml). VaD patients with small infarct volumes had a similar degree of cognitive impairment to those with larger infarct volumes (>15 ml) but were significantly more likely to be depressed and to have areas of microinfarction. A review of individual cases with small infarct volumes suggested that the combination of microinfarction, diffuse white matter disease and perivascular changes, or the overlap of neurodegenerative pathologies and microvascular changes were particularly important. Microinfarction was also significantly associated with major depression.

Ballard C, Hanney ML, Theodoulou M, Douglas S, McShane R, Kossakowski K, Gill R, Juszczak E, Yu LM, Jacoby R, Anonymous00015. · Wolfson Centre for Age-Related Diseases, King's College London, London, UK. · Lancet Neurol. · Pubmed #19138567 No free full text.

Abstract: BACKGROUND: Data from 12-week placebo-controlled trials have led to mounting concerns about increased mortality in patients with Alzheimer's disease (AD) who are prescribed antipsychotics; however, there are no mortality data from long-term placebo-controlled trials. We aimed to assess whether continued treatment with antipsychotics in people with AD is associated with an increased risk of mortality. METHODS: Between October, 2001, and December, 2004, patients with AD who resided in care facilities in the UK were enrolled into a randomised, placebo-controlled, parallel, two-group treatment discontinuation trial. Participants were randomly assigned to continue with their antipsychotic treatment (thioridazine, chlorpromazine, haloperidol, trifluoperazine, or risperidone) for 12 months or to switch their medication to an oral placebo. The primary outcome was mortality at 12 months. An additional follow-up telephone assessment was done to establish whether each participant was still alive 24 months after the enrollment of the last participant (range 24-54 months). Causes of death were obtained from death certificates. Analysis was by intention to treat (ITT) and modified intention to treat (mITT). This trial is registered with the Cochrane Central Registry of Controlled Trials/National Research Register, number ISRCTN33368770. FINDINGS: 165 patients were randomised (83 to continue antipsychotic treatment and 82 to placebo), of whom 128 (78%) started treatment (64 continued with their treatment and 64 received placebo). There was a reduction in survival in the patients who continued to receive antipsychotics compared with those who received placebo. Cumulative probability of survival during the 12 months was 70% (95% CI 58-80%) in the continue treatment group versus 77% (64-85%) in the placebo group for the mITT population. Kaplan-Meier estimates of mortality for the whole study period showed a significantly increased risk of mortality for patients who were allocated to continue antipsychotic treatment compared with those allocated to placebo (mITT log rank p=0.03; ITT p=0.02). The hazard ratio for the mITT group was 0.58 (95% CI 0.35 to 0.95) and 0.58 (0.36 to 0.92) for the ITT population. The more pronounced differences between groups during periods of follow up longer than 12 months were evident at specific timepoints (24-month survival 46%vs 71%; 36-month survival 30%vs 59%). INTERPRETATION: There is an increased long-term risk of mortality in patients with AD who are prescribed antipsychotic medication; these results further highlight the need to seek less harmful alternatives for the long-term treatment of neuropsychiatric symptoms in these patients. FUNDING: UK Alzheimer's Research Trust.

Aarsland D, Rongve A, Nore SP, Skogseth R, Skulstad S, Ehrt U, Hoprekstad D, Ballard C. · Department of Old Age Psychiatry, Stavanger University Hospital, Bergen, Norway. · Dement Geriatr Cogn Disord. · Pubmed #18974647 No free full text.

Abstract: OBJECTIVE: To find the proportion of dementia with Lewy bodies (DLB) in a referral cohort of patients with a first-time diagnosis of mild dementia. BACKGROUND: The proportion of DLB among the dementia sufferers is not known and the clinical consensus criteria have low sensitivity. We employed the revised DLB criteria to study the proportion with DLB in a community sample of patients with mild dementia. METHODS: From March 2005 to March 2007, we included 196 patients from referrals to all geriatric medicine, old age psychiatry and neurology outpatient clinics in Rogaland and Hordaland counties in Western Norway. Standardized clinical instruments and diagnostic criteria were employed. RESULTS: 65% had Alzheimer dementia, 20% DLB (16% probable DLB), 5.6% vascular dementia, 5.6% Parkinson disease with dementia, 2.0% frontotemporal dementia and 1.5% alcoholic dementia. There were no significant differences in the proportion with DLB according to age bands and dementia severity groups. The revised criteria for a clinical diagnosis of DLB increased the proportion of probable DLB by 25% compared to the previous criteria. CONCLUSION: DLB is common in patients with mild dementia, and is the second most common type of dementia. The introduction of new clinical criteria for DLB leads to an increase in the proportion diagnosed with probable DLB.

Ballard C, Sauter M, Scheltens P, He Y, Barkhof F, van Straaten EC, van der Flier WM, Hsu C, Wu S, Lane R. · Wolfson Centre for Age-Related Diseases, King's College, London, UK. · Curr Med Res Opin. · Pubmed #18674411 No free full text.

Abstract: OBJECTIVE: The aim was to evaluate the efficacy, safety and tolerability of rivastigmine capsules in patients diagnosed with probable vascular dementia (VaD). METHODS: VantagE (Vascular Dementia trial studying Exelon) was a 24-week, multicentre, double-blind study. VaD patients aged 50-85 years were randomized to rivastigmine capsules (3-12 mg/day) or placebo. Efficacy assessments included global and cognitive performances, activities of daily living and neuropsychiatric symptoms. Adverse events were recorded. Additional exploratory analyses determined whether heterogeneity in pathologies and symptoms extended to differential treatment effects. TRIAL REGISTRATION: NCT00099216. RESULTS: 710 patients were randomized. Rivastigmine demonstrated superiority over placebo on three measures of cognitive performance (Vascular Dementia Assessment Scale, Alzheimer's Disease Assessment Scale cognitive subscale, Mini-Mental State Examination; all p< or = 0.05, intent-to-treat population [ITT]), but not other outcomes. Predominant adverse events were nausea and vomiting. Exploratory analyses indicated that older patients (> or =75 years old), assumed more likely to also have Alzheimer's disease (AD) pathology, demonstrated significant cognitive responses to rivastigmine and a safety profile similar to that seen in AD patients. Younger patients, assumed less likely to have concomitant AD pathology, showed no efficacy response and were associated with slight elevations of blood pressure, cerebrovascular accidents and mortality. Rivastigmine-placebo differences in patients with, versus those without, medial temporal atrophy (also suggestive of concomitant AD) showed a numerical difference similar to that seen between the older versus younger patients, but did not attain statistical significance. CONCLUSION: Consistent with trials evaluating other cholinesterase inhibitors, rivastigmine did not provide consistent efficacy in probable VaD. The efficacy apparent on cognitive outcomes was derived from effects in older patients likely to have concomitant Alzheimer pathology. This is supportive of an existing argument that the putative cholinergic deficit in VaD reflects the presence of concomitant Alzheimer pathology.