Alzheimer Disease: McKeith I

McKeith I. · No affiliation provided · Int Psychogeriatr. · Pubmed #15318759 No free full text.

This publication has no abstract.

McKeith I. · Wolfson Research Centre, Newcastle General Hospital, Newcastle upon Tyne NE4 6BE, UK. · Pract Neurol. · Pubmed #18024777 No free full text.

Abstract: Parkinson's disease and dementia with Lewy bodies are two common presentations of a single, underlying disease process (Lewy body disease) which is thought to be related to dysregulation of the synaptic protein, alpha-synuclein. This article discusses the nature of the relations between Parkinson's disease and dementia with Lewy bodies, and what can be learned from them about the causes of dementia in patients with established Parkinson's disease. This is an area of clinical practice which is of increasing importance as greater numbers of ageing patients survive longer with good treatment of their motor symptoms. Precise use of terminology and a clear understanding of the biological substrates underlying symptom formation are particularly helpful to both clinicians and patients.

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.

Geser F, Wenning GK, Poewe W, McKeith I. · Clinical Department of Neurology, Medical University Innsbruck, Austria. · Mov Disord. · Pubmed #16092075 No free full text.

Abstract: Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia in older people that has only been recognized in the past decade and that remains widely underdiagnosed. At postmortem examination, affected patients show numerous alpha-synuclein-positive Lewy bodies (LB) in many parts of the cerebral cortex, particularly neocortical and limbic areas in addition to the nigral LB degeneration characteristic of Parkinson's disease (PD). Clinical presentation, unlike PD, is with progressive cognitive decline with particular deficits of visuospatial ability as well as frontal executive function accompanied by usually only mildly to moderately severe parkinsonism, which is often akineto-rigid without the classical parkinsonian rest-tremor. Further accompanying features include spontaneous recurrent visual hallucinations and conspicuous fluctuations in alertness and cognitive performance. The two main differential diagnoses are Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). To improve the differential diagnosis of DLB, consensus criteria have been developed that establish possible and probable levels of clinical diagnostic accuracy. Generally, their sensitivity is variable and low but their specificity is high. Current consensus is to restrict a diagnosis of DLB only to patients with parkinsonism who develop dementia within 12 months of the onset of motor symptoms. Using operationalized criteria, DLB can be diagnosed clinically with an accuracy similar to that achieved for AD or PD. Ancillary investigations, particularly neuroimaging, can aid in differential diagnosis. We review the present state of the best practice in the clinical diagnosis of DLB. Future modifications of diagnostic criteria would ideally include the full range of clinical presentations that can be associated with LB disease.

McKeith I, Mintzer J, Aarsland D, Burn D, Chiu H, Cohen-Mansfield J, Dickson D, Dubois B, Duda JE, Feldman H, Gauthier S, Halliday G, Lawlor B, Lippa C, Lopez OL, Carlos Machado J, O'Brien J, Playfer J, Reid W, Anonymous00116. · Institute for Ageing and Health, University of Newcastle, Newcastle upon Tyne, UK. · Lancet Neurol. · Pubmed #14693108 No free full text.

Abstract: Dementia with Lewy bodies (DLB) is the second commonest cause of neurodegenerative dementia in older people. It is part of the range of clinical presentations that share a neuritic pathology based on abnormal aggregation of the synaptic protein alpha-synuclein. DLB has many of the clinical and pathological characteristics of the dementia that occurs during the course of Parkinson's disease. Here we review the current state of scientific knowledge on DLB. Accurate identification of patients is important because they have specific symptoms, impairments, and functional disabilities that differ from those of other common types of dementia. Severe neuroleptic sensitivity reactions are associated with significantly increased morbidity and mortality. Treatment with cholinesterase inhibitors is well tolerated by most patients and substantially improves cognitive and neuropsychiatric symptoms. Clear guidance on the management of DLB is urgently needed. Virtually unrecognised 20 years ago, DLB could within this decade be one of the most treatable neurodegenerative disorders of late life.

McKeith I, O'Brien J. · Newcastle General Hospital, Newcastle upon Tyne, United Kingdom. · Aust N Z J Psychiatry. · Pubmed #10619205 No free full text.

Abstract: OBJECTIVE: The aim of this paper is to summarise recent clinical and research findings with regard to dementia with Lewy bodies (DLB). METHOD: A literature review (Medline) was carried out, as well as a review of reports of recent DLB symposia of international meetings and of other relevant papers and data known to the authors. RESULTS: Dementia with Lewy bodies, as the disorder should be known, is the second commonest form of degenerative dementia, accounting for up to 20% cases in the elderly. It is characterised by fluctuating cognitive impairment, spontaneous parkinsonism and recurrent visual hallucinations. Consensus clinical and neuropathological criteria have been published. The clinical criteria have been shown to have high specificity, but may still lack sensitivity. Recognition of DLB is clinically important in view of the high incidence (60%) of adverse and life-threatening reaction to antipsychotics, the difference in prognosis and, possibly, the differential treatment response to cholinergic therapy. Neuroimaging changes have not been well described in DLB but some show promise as potential markers to differentiate DLB from AD. These include relative preservation of temporal lobe structures on magnetic resonance imaging and loss of pre- and postsynaptic dopaminergic markers on single photon emission tomography. CONCLUSIONS: Dementia with Lewy bodies is a common cause of cognitive impairment in late life which appears to be clinically and neuropathologically distinct from AD. All clinicians should be aware of the typical triad of clinical features (fluctuating cognitive impairment, visual hallucinations and parkinsonism) which characterise the disorder and either avoid antipsychotics or prescribe them with extreme caution in such patients. Further research is likely to result in advances in diagnostic methods and therapeutics in the near future.

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.

Shikiar R, Shakespeare A, Sagnier PP, Wilkinson D, McKeith I, Dartigues JF, Dubois B. · MEDTAP International, Seattle, Washington, USA. · J Am Geriatr Soc. · Pubmed #10733052 No free full text.

Abstract: OBJECTIVE: To assess the impact on burden reported by caregivers of patients with mild to moderate Alzheimer's disease (AD) who were treated with metrifonate during a randomized double blind clinical trial. DESIGN: Randomized clinical trial, with a 2-week screening period and a 26-week double blind, placebo controlled, treatment phase. Caregivers were assessed at baseline, at 12 weeks, and at end of trial. SETTING: Caregivers were interviewed at clinics as part of the assessment of the patients. PARTICIPANTS: Six hundred and three caregivers of AD patients who were enrolled in the MALT trial; 591 (98%) provided data suitable for analysis at baseline, and 546 (91%) provided data allowing for inclusion in the analysis of change scores. MEASUREMENTS: The Caregiver Burden Assessment consisted of the Screen for Caregiver Burden, including both subjective (SCB-subj) and objective (SCB-obj) scores; the cognitive subscale of Poulshock and Deimling (PD); an abridged version of the Relatives Stress Scale (aRSS); assessments of time spent in providing care, including the Caregiver Activity Time Scale (CATS); and demographic and background variables on both the patient and caregiver. RESULTS: Treatment of mild to moderate AD patients with metrifonate for a duration of 26 weeks significantly reduced the psychological burden of care to the caregivers, as measured by the SCB-subj, the PD, and the aRSS. There were no statistically significant differences on the measures assessing the time spent in caregiving, except for the caregiver's subjective impression of the change in time spent providing care during the trial. When comparing individual dose groups, most of the measures of burden showed the largest benefits in burden for the 60/80 mg group, followed by the 40/50 mg group, and then the placebo group. However, there was no statistically significant dose effect. CONCLUSIONS: This study provides the first evidence from a randomized clinical trial of any acetylcholinesterase inhibitor used in the treatment of AD demonstrating a positive impact on the patient's caregiver as well as benefits to the patient. These results were shown consistently across several measurement scales and were observed after six months of treatment. These findings reinforce the clinical significance of research that has shown that metrifonate has beneficial impacts on the cognitive, behavioral, and functional abilities of AD patients. Because caregiver burden is a leading factor in the decision for institutional care placement, the ability to favorably impact that burden through pharmacological treatment of the patient is important.

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.

Dubois B, McKeith I, Orgogozo JM, Collins O, Meulien D. · Hôpital de la Pitié-Salpêtrière, Paris, France. · Int J Geriatr Psychiatry. · Pubmed #10556869 No free full text.

Abstract: BACKGROUND: Metrifonate is a long-lasting acetylcholinesterase inhibitor being developed for the symptomatic treatment of Alzheimer's disease (AD).OBJECTIVES: This study compared the efficacy, tolerability and safety of two doses of metrifonate in patients with mild-to-moderate AD, over a 26-week treatment period. METHODS: Six hundred and five patients were randomized to placebo (n=208), a 40/50 mg dose (40 or 50 mg by weight; n=200) or a 60/80 mg dose (60 or 80 mg by weight; n=197) metrifonate. Patients randomized to receive metrifonate were administered a once-daily loading dose of 80 or 120 mg based on weight for 2 weeks, followed by the relevant maintenance dose for 24 weeks. Four main clinical domains of AD were assessed: cognition (ADAS-cog and MMSE), psychiatric and behavioural symptoms (ADAS-noncog and NPI), instrumental and basic activities of daily living (DAD) and global functioning (CIBIC-plus, CIBIS-plus and GDS).RESULTS: ADAS-cog performance was significantly improved in the 60/80 mg and 40/50 mg dose groups, compared with placebo, in the intention-to-treat (ITT) population. In addition, statistically significant treatment differences were demonstrated between the 60/80 mg dose group and placebo on MMSE, ADAS-noncog, the NPI subitems of hallucinations and apathy, DAD, CIBIC-plus, CIBIS-plus and the GDS. The performance of the 40/50 mg dose group was also significantly superior to placebo on the CIBIS-plus and the NPI subitem aberrant motor behaviour. CONCLUSIONS: Metrifonate significantly improved a wide range of symptoms across all four clinical domains of AD in a dose-dependent manner, and was safe and well tolerated at both doses studied.

Moreira T, Hughes JC, Kirkwood T, May C, McKeith I, Bond J. · School of Applied Social Sciences, University of Durham, UK. · Int Psychogeriatr. · Pubmed #18377700 No free full text.

Abstract: BACKGROUND: Mild cognitive impairment (MCI) is proposed to describe the transitional stage between normal cognitive aging and dementia. It has had significant impact in the field of dementia research, but it remains controversial whether or not it should be used as a diagnostic category in clinical practice. METHODS: Semi-structured interviews were carried out with international experts (N = 37) in the field of dementia research and practice. These interviews explored the advantages and difficulties of using MCI as a clinical diagnosis. RESULTS: There is wide variation in the clinical use of MCI. This variation depends on institutional factors and two types of cultural factors: (a) clinical culture, and (b) the "evidential culture" -- how research and guidelines figure in clinical practice. CONCLUSION: The study shows the importance of combining values-based practice with evidence-based practice in the early diagnosis of dementia.

Zaccai J, Brayne C, McKeith I, Matthews F, Ince PG, Anonymous00354. · Neuropathology, E Floor, Royal Hallamshire Hospital, Sheffield UK. · Neurology. · Pubmed #18362284 No free full text.

Abstract: BACKGROUND: It is proposed that alpha-synucleinopathy (AS) initially affects the medulla oblongata and progresses to more rostral brain areas in a hierarchical sequence ("Braak hypothesis"). Predominant involvement of the amygdala is also described. This study examines the applicability of these patterns, and their relationship to Alzheimer disease (AD) pathology, in brains of a population-based donor cohort. METHODS: Brains donated in two of six Cognitive Function and Ageing Study cohorts (Cambridgeshire and Nottingham) were examined. More than 80% were older than 80 years at death. The respondents were evaluated prospectively in life for cognitive decline and dementia. Immunocytochemistry for tau and alpha-synuclein was carried out in 208 brains to establish Braak stage and the pattern and severity of AS. RESULTS: Seventy-six brains showed Lewy bodies. Half (51%) conformed to the Braak hypothesis while 17% had pathology in a higher region which was absent in a lower region. A further 29% showed amygdala-predominant pathology. Six brains showed predominant neocortical pathology with minimal pathology in amygdala or substantia nigra. The stage of AD pathology was not associated with particular patterns of AS. CONCLUSION: alpha-Synucleinopathy (AS) is common in older people, and frequently associated with Alzheimer disease-type pathology. Although half of brains corresponded to the Braak hypothesis, and 29% to amygdala-predominant AS, there were a high proportion of cases which did not fit a staging system. An unexpectedly high proportion with a cortical form of Lewy body disease was identified.

Walker Z, Jaros E, Walker RW, Lee L, Costa DC, Livingston G, Ince PG, Perry R, McKeith I, Katona CL. · University College London and Royal Free Hospitals, London, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #17353255 links to  free full text

Abstract: BACKGROUND: Dementia with Lewy bodies (DLB) is a common form of dementia. The presence of Alzheimer's disease (AD) pathology modifies the clinical features of DLB, making it harder to distinguish DLB from AD clinically during life. Clinical diagnostic criteria for DLB applied at presentation can fail to identify up to 50% of cases. Our aim was to determine, in a series of patients with dementia in whom autopsy confirmation of diagnosis was available, whether functional imaging of the nigrostriatal pathway improves the accuracy of diagnosis compared with diagnosis by means of clinical criteria alone. METHODS: A single photon emission computed tomography (SPECT) scan was carried out with a dopaminergic presynaptic ligand [123I]-2beta-carbometoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (FP-CIT; ioflupane) on a group of patients with a clinical diagnosis of DLB or other dementia. An abnormal scan was defined as one in which right and left posterior putamen binding, measured semiquantitatively, was more than 2 SDs below the mean of the controls. RESULTS: Over a 10 year period it was possible to collect 20 patients who had been followed from the time of first assessment and time of scan through to death and subsequent detailed neuropathological autopsy. Eight patients fulfilled neuropathological diagnostic criteria for DLB. Nine patients had AD, mostly with coexisting cerebrovascular disease. Three patients had other diagnoses. The sensitivity of an initial clinical diagnosis of DLB was 75% and specificity was 42%. The sensitivity of the FP-CIT scan for the diagnosis of DLB was 88% and specificity was 100%. CONCLUSION: FP-CIT SPECT scans substantially enhanced the accuracy of diagnosis of DLB by comparison with clinical criteria alone.

Matthews FE, McKeith I, Bond J, Brayne C, Anonymous00232. · MRC Biostatistics Unit, Institute of Public Health, Cambridge, UK. · Int J Geriatr Psychiatry. · Pubmed #17136710 No free full text.

Abstract: BACKGROUND: Systematic evidence became available in the late 1990s on efficacy of cholinesterase inhibitors (CHEIs) for patients with mild to moderate Alzheimer's disease (AD) and they began to be used sporadically. Since January 2001 UK based guidelines indicated that one of three cholinesterase inhibitors (CHEIs) could be prescribed for these patients. Since then the cost of prescription in England and Wales has risen. There has been little investigation of uptake at the population level. OBJECTIVE: To estimate the population uptake of CHEIs in a population based study of dementia spanning this period. DESIGN: Using data from a 10-year follow up and a later 12 year interview of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS), a UK population based longitudinal cohort study of people originally aged 65 years and above, we investigated who was taking CHEIs during the period 2001-2004. We sought information from respondents taking part in the study what medication they were taking on a regular basis. RESULTS: Only 12, of the 219 individuals who received a study diagnosis of dementia were prescribed CHEIs [5%, 95% Confidence Intervals (CI) 3%-9%]) in 2001/2003 and none of the 28 individuals with a study diagnosis of dementia (0%, 95% CI 0-18%) in 2004 were prescribed CHEIs. Uptake was biased towards individuals with more education and higher social class. CONCLUSIONS: These data suggest that any impact on AD progression at the population level will be negligible as prescription of CHEIs and uptake in the age group at highest risk is so limited. There is little evidence that this has changed over time.

Maurer K, McKeith I, Cummings J, Ames D, Burns A. · Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt on Main, Frankfurt, Germany. · Lancet. · Pubmed #17084762 No free full text.

This publication has no abstract.

Ballard C, Morris C, Kalaria R, McKeith I, Perry R, Perry E. · Wolfson Centre for Age-Related Diseases, Guys Campus, Kings College London, London, UK. · Dement Geriatr Cogn Disord. · Pubmed #15802910 No free full text.

Abstract: Accumulating evidence suggests that butyrylcholinesterase (BuChE) plays an important role in the progression of cognitive deficits and Alzheimer-type pathology in dementia patients. We examined the relationship between the K variant of BuChE and the severity of deposits of amyloid (Abeta(1-42)) and phosphorylated tau in the temporal cortex (BA36) of 30 prospectively studied autopsy-diagnosed dementia (Alzheimer's disease and dementia with Lewy bodies) patients. There was 42% less phosphorylated tau in BA36 in cases with > or =1 K compared with those with wild-type BuChE alleles (t = 2.2, p = 0.039), but no difference in the extent of Abeta(1-42) deposition. BuChE may play this role in the phosphorylation of tau, relevant to therapeutic inhibition of the enzyme.

Almeida OP, Burton EJ, McKeith I, Gholkar A, Burn D, O'Brien JT. · School of Psychiatry and Clinical Neurosciences, University of Western Australia, Nedlands, Australia. · Dement Geriatr Cogn Disord. · Pubmed #12784028 No free full text.

Abstract: OBJECTIVE: To compare whole brain and caudate volume on MRI in subjects with Parkinson's disease without cognitive impairment (PD), Parkinson's disease with dementia with Lewy bodies (PD + DLB), Alzheimer's disease (AD) and normal control subjects. To examine the relationship between caudate volume and cognitive impairment, depression and movement disorder. METHOD: Whole brain and caudate volumes were segmented from volumetric 1.5-tesla magnetic resonance imaging (MRI) scans of older subjects with PD (n = 28; mean age 75.5 years), PD + DLB (n = 20; 73.0 years), AD (n = 27; 77.5 years) and normal controls (n = 35; 74.9 years). RESULTS: Subjects with AD had significantly reduced whole brain and caudate volume compared to controls and those with PD. Caudate atrophy in AD was proportionate to whole brain atrophy. There were no significant differences in whole brain or caudate volume between controls, PD and PD + DLB. There were no significant correlations between caudate volume and either global cognitive function, executive performance or processing speed. CONCLUSIONS: Caudate atrophy occurs in AD but not PD without dementia. Caudate atrophy is not regionally specific but part of generalised brain volume loss. Structural changes in the caudate, as assessed by in vivo MRI, do not appear to contribute to the cognitive impairment observed amongst patients with PD, PD + DLB or AD. Results indicate that the executive and attentional dysfunctions associated with PD and DLB are unlikely to be a direct and specific consequence of caudate atrophy as assessed on MRI.

Barber R, McKeith I, Ballard C, O'Brien J. · Institute for the Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, NE4 6BE, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #11861709 links to  free full text

Abstract: OBJECTIVES: To determine whether parkinsonian symptoms in dementia with Lewy bodies (DLB) are associated with greater atrophy of the caudate nucleus in comparison with patients with Alzheimer's disease (AD) and vascular dementia (VaD). METHODS: T1weighted MR scans were acquired in elderly patients with DLB, AD, VaD, and healthy controls. Normalised volumetric measurements of the caudate nucleus were obtained and parkinsonian symptoms rated using Hoehn and Yahr staging. RESULTS: There were no significant differences in the volume of the caudate nucleus between patients with dementia. However, the left caudate volume was significantly reduced in AD and DLB compared with controls. Parkinsonian symptoms did not correlate with caudate nucleus volume. CONCLUSIONS: Parkinsonian symptoms in DLB may be more closely coupled to neurochemical rather than structural changes in the caudate nucleus, and volumetric MRI analysis of caudate nucleus does not discriminate between patients with DLB, AD, and VaD.

Ballard C, O'Brien J, Gray A, Cormack F, Ayre G, Rowan E, Thompson P, Bucks R, McKeith I, Walker M, Tovee M. · Institute for the Health of the Elderly, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle, England NE4 6BE. · Arch Neurol. · Pubmed #11405813 links to  free full text

Abstract: BACKGROUND: Attentional deficits are described in the consensus clinical criteria for the operationalized diagnosis of dementia with Lewy bodies (DLB) as characteristic of the condition. In addition, preliminary studies have indicated that both attentional impairments and fluctuation of attentional impairments are more marked in patients with DLB than in patients with Alzheimer disease (AD), although neuropsychological function has not previously been examined in a large prospective cohort with confirmed diagnostic accuracy against postmortem diagnosis. METHODS: A detailed evaluation of attention and fluctuating attention was undertaken in 155 patients with dementia (85 with DLB and 80 with AD) from a representative hospital dementia case register and 35 elderly controls using the Cognitive Drug Research Computerized Assessment System for Dementia Patients computerized neuropsychological battery. Operationalized clinical diagnosis was made using the consensus criteria for DLB and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD. High levels of sensitivity and specificity have been achieved for the first 50 cases undergoing postmortem examination. RESULTS: The groups were well matched for severity of cognitive impairments, but the AD patients were older (mean age, 80 vs 78 years) and more likely to be female (55% vs 40%). Patients with DLB were significantly more impaired than patients with AD on all measures of attention and fluctuating attention (for all comparisons, t > or = 2.5, P<.001), and patients from both dementia groups were significantly more impaired than elderly controls for all comparisons other than cognitive reaction time, which was significantly more impaired in DLB patients than controls but was comparable in controls and AD patients. There were, however, significant associations between the severity of cognitive impairment and the severity of both attentional deficits and fluctuations in attention. CONCLUSIONS: This large prospective study confirms that slowing of cognitive processing, attention, and fluctuations of attention are significantly more pronounced in DLB and AD patients, although fluctuating attention is common in patients with moderate-to-severe AD. Deficits of cognitive reaction time appear to be specific to DLB, except in severe dementia. A detailed evaluation of attentional performance could make an important contribution to differential diagnosis, although the results need to be interpreted within the context of the overall severity of cognitive deficits.

Ballard C, O'Brien J, Morris CM, Barber R, Swann A, Neill D, McKeith I. · Reader in Old Age Psychiatry, University of Newcastle, Newcastle General Hospital, Newcastle upon Tyne, UK. · Int J Geriatr Psychiatry. · Pubmed #11376466 No free full text.

Abstract: BACKGROUND: Little is known about the rate of progression or associations of cognitive impairment in dementia with Lewy bodies (DLB), or the associations of accelerated decline. METHOD: Dementia patients from a case register were evaluated at baseline and 1 year follow-up using the Cambridge Assessment for Mental Disorders in the Elderly, section B (CAMCOG) and the Mini-Mental State Examination (MMSE) to determine the rate of cognitive decline. Operationalized clinical diagnoses were applied (NINCDS ADRDA for Alzheimer's disease (AD), NINCDS AIRENS for vascular dementia (VaD) and consensus criteria for DLB). RESULTS: One hundred and ninety-three patients completed annual MMSE schedules (AD, 101; DLB, 64; VaD, 38), of whom 154 completed the CAMCOG. The magnitude of cognitive decline (MMSE, 4-5 points; CAMCOG, 12-14 points) was similar in each of the dementias. The strongest predictor of accelerated cognitive decline in DLB was the apolipoprotein E4 allele (17.5 vs 8.3 points decline on the CAMCOG). CONCLUSION: Over 1 year, DLB, VaD and AD patients had similar rates of cognitive decline overall. Apolipoprotein E4 may be an important predictor of more rapid decline in DLB.

Ballard C, Walker M, O'Brien J, Rowan E, McKeith I. · Institute of Health for the Elderly, Newcastle General Hospital, Newcastle upon Tyne, UK. · Int J Geriatr Psychiatry. · Pubmed #11376465 No free full text.

Abstract: BACKGROUND: Case reports and clinical observations suggest that fluctuating cognition (FC) is common in all the major dementias, particularly dementia with Lewy bodies (DLB) where it is one of three core clinical diagnostic features. The purpose of this study was to characterise FC and determine its impact upon activities of daily living. METHODS: Forty matched subjects (15 DLB, 15 AD, 10 elderly controls) were assessed using the activities of daily living scale (ADLD), the cognitive drug research (CDR) computerised neuropsychological test battery and a semi-standardised assessment of FC. The CDR battery was completed three times across a 1-week period, to evaluate variability in attention, visuospatial ability, working memory and delayed recall. RESULTS: There was a strong positive correlation between clinical FC scores and total mean ADLD. Measures of cognitive variability also demonstrated strong significant correlations with independent clinical severity ratings of FC across several cognitive domains. These associations were most powerful between attentional measures and clinical FC ratings. CONCLUSIONS: Although attention is the cognitive domain which fluctuates most markedly, other cognitive domains are also affected. FC also has a significant independent impact on activities of daily living.

Ballard C, O'Brien J, Swann A, Neill D, Lantos P, Holmes C, Burn D, Ince P, Perry R, McKeith I. · MRC Neurochemical Pathology Unit, Newcastle General Hospital, Newcastle upon Tyne, UK. · Dement Geriatr Cogn Disord. · Pubmed #10867448 No free full text.

Abstract: The progression of parkinsonism over 1 year was evaluated in a prospective cohort of patients (n = 338), suffering from dementia with Lewy bodies (DLB), Alzheimer's disease (AD) or vascular dementia (VaD). Parkinsonism was assessed using the modified Unified Parkinson's Disease Rating Scale. Significant parkinsonism was significantly commoner in DLB sufferers (71%) than amongst patients with AD (7%) or VaD (10%). DLB patients with established parkinsonism had an annual increase in severity of 9%, but progression was more rapid (49% in 1 year) in patients with early parkinsonism. Parkinsonism was frequent at all severities in DLB patients, but usually only present in other dementias when MMSE <10.

Ballard C, O'Brien J, Barber B, Scheltens P, Shaw F, McKeith I, Kenny RA. · Institute for the Health of the Elderly, Wolfson Research Centre, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom. · Ann N Y Acad Sci. · Pubmed #10818535 No free full text.

Abstract: We investigated whether carotid sinus hypersensitivity (CSH) and orthostatic hypotension (OH) were associated with a greater severity of hyperintensities on MRI scan in 30 patients with neurodegenerative dementia (17 dementia with Lewy bodies, 13 Alzheimer's disease), who had a detailed evaluation of OH and CSH during active standing and head-up tilt. Patients also underwent a 1.0 Tesla MRI scan, from which hyperintensities were rated on a standardized scale. A blood pressure (BP) drop > 30 mm Hg during carotid sinus massage or active standing was significantly associated with the severity of MRI hyperintensities in the deep white matter (OR 10.0, 95%; CI 1.8-55.7) and in the basal ganglia (OR 11.0, 95%; CI 1.2-99.5) but not in periventricular areas (OR 1.4, 95%; CI 0.3-1.8). Patients with the cardio-inhibitory form of CSH with the largest BP drops were the most at risk. Further longitudinal studies need to investigate the direction of causality to determine whether CSH or OH predispose to MRI hyperintensities and accelerate cognitive decline.

Perry E, Martin-Ruiz C, Lee M, Griffiths M, Johnson M, Piggott M, Haroutunian V, Buxbaum JD, Nãsland J, Davis K, Gotti C, Clementi F, Tzartos S, Cohen O, Soreq H, Jaros E, Perry R, Ballard C, McKeith I, Court J. · Department of Neuropathology, MRC Neurochemical Pathology Unit, Newcastle General Hospital, Westgate Road, Newcastle, UK. · Eur J Pharmacol. · Pubmed #10771016 No free full text.

Abstract: Human brain ageing is associated with reductions in a variety of nicotinic receptors subtypes, whereas changes in age-related disorders including Alzheimer's disease or Parkinson's disease are more selective. In Alzheimer's disease, in the cortex there is a selective loss of the alpha4 (but not alpha3 or 7) subunit immunoreactivity and of nicotine or epibatidine binding but not alpha-bungarotoxin binding. Epibatidine binding is inversely correlated with clinical dementia ratings and with the level of Abeta1-42, but not related to plaque or tangle densities. In contrast, alpha-bungarotoxin binding is positively correlated with plaque densities in the entorhinal cortex. In human temporal cortex loss of acetylcholinesterase catalytic activity is positively correlated with decreased epibatidine binding and in a transgenic mouse model over expressing acetylcholinesterase, epibatidine binding is elevated. In Parkinson's disease, loss of striatal nicotine binding appears to occur early but is not associated with a loss of alpha4 subunit immunoreactivity. Tobacco use in normal elderly individuals is associated with increased alpha4 immunoreactivity in the cortex and lower densities of amyloid-beta plaques, and with greater numbers of dopaminergic neurons in the substantia nigra pars compacta. These findings indicate an early involvement of the alpha4 subunit in beta-amyloidosis but not in nigro-striatal dopaminergic degeneration.