Showing papers by "John T. O'Brien published in 1999"
TL;DR: In common with Alzheimer’s disease and vascular dementia, PVHs and WMHs were significantly more extensive in dementia with Lewy bodies than in controls, and this overlap between different dementias may reflect shared pathological mechanisms.
Abstract: OBJECTIVES—Alzheimer's disease and vascular dementia are associated with an increase in changes in white matter on MRI. The aims were to investigate whether white matter changes also occur in dementia with Lewy bodies and to examine the relation between white matter lesions and the cognitive and non-cognitive features of dementia with Lewy bodies, Alzheimer's disease, and vascular dementia.
METHODS—Proton density and T2 weighted images were obtained on a 1.0 Tesla MRI scanner in patients with dementia with Lewy bodies (consensus criteria; n=27, mean age=75.9 years), Alzheimer's disease (NINCDS/ADRDA; n=28, mean age=77.4 years), vascular dementia (NINDS/AIREN; n=25, mean age=76.8 years), and normal controls (n=26, mean age=76.2 years). Cognitive function, depressive symptoms, and psychotic features were assessed using a standardised protocol. Periventricular hyperintensities (PVHs), white matter hyperintensities (WMHs) and basal ganglia hyperintensities (BGHs) were visually rated blind to diagnosis using a semiquantitative scale.
RESULTS—Periventricular hyperintensities were positively correlated with age and were more severe in all dementia groups than controls. Total deep hyperintensities scores (WMHs plus BGHs) were significantly higher in all dementia groups than controls and higher in patients with vascular dementia than those with dementia with Lewy bodies or Alzheimer's disease. In all patients with dementia, frontal WMHs were associated with higher depression scores and occipital WMHs were associated with an absence of visual hallucinations and delusions.
CONCLUSION—In common with Alzheimer's disease and vascular dementia, PVHs and WMHs were significantly more extensive in dementia with Lewy bodies than in controls. This overlap between different dementias may reflect shared pathological mechanisms. The link between frontal WMHs and depression and the absence of occipital WMHs and psychotic symptoms has important implications for understanding the neurobiological basis of these symptoms.
401 citations
TL;DR: Delusional misidentification and hallucinations in the early stages of dementia may improve differentiation between patients with dementia with Lewy bodies and those with Alzheimer's disease and have important treatment implications.
Abstract: Objective: The literature reports considerable variation in the rates of psychiatric morbidity for patients with dementia with Lewy bodies. The authors intended to clarify the frequency of psychiatric morbidity in dementia with Lewy bodies and how it differs from probable Alzheimer’s disease. Method: The study incorporated two groups—a clinical case register cohort (98 with dementia with Lewy bodies; 92 with Alzheimer’s disease) and 80 (40 with dementia with Lewy bodies; 40 with Alzheimer’s disease) prospectively studied, neuropathologically confirmed cases. Diagnoses were made by using the McKeith et al. consensus criteria for dementia with Lewy bodies and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria for Alzheimer’s disease. Neuropathological diagnoses were made by using the consensus criteria for dementia with Lewy bodies and the Mirra et al. protocol for Alzheimer’s disease. Results: The occurrence of psychiatric symptoms was reported over 1 month. Hallucinations, depression, delusions, and delusional misidentification were all significantly higher for patients with dementia with Lewy bodies. The differences in frequency between dementia with Lewy bodies and Alzheimer’s disease for auditory and visual hallucinations were especially pronounced for patients with mild cognitive impairment. The presence of psychiatric symptoms at presentation was a better discriminator between dementia with Lewy bodies and Alzheimer’s disease than occurrence over the course of dementia. Conclusions: Delusional misidentification and hallucinations in the early stages of dementia may improve differentiation between patients with dementia with Lewy bodies and those with Alzheimer’s disease and have important treatment implications. (Am J Psychiatry 1999; 156:1039‐1045)
294 citations
TL;DR: A pairwise similarity measure between two p-dimensional data points, x and y, is introduced that is superior to commonly used metric distances, for example, Euclidean distance and a modified version of mutual information is introduced as a novel method for validating clustering results when the true clustering is known.
Abstract: Clustering is one of the main mathematical challenges in large-scale gene expression analysis. We describe a clustering procedure based on a sequential k-means algorithm with additional refinements that is able to handle high-throughput data in the order of hundreds of thousands of data items measured on hundreds of variables. The practical motivation for our algorithm is oligonucleotide fingerprinting—a method for simultaneous determination of expression level for every active gene of a specific tissue—although the algorithm can be applied as well to other large-scale projects like EST clustering and qualitative clustering of DNA-chip data. As a pairwise similarity measure between two p-dimensional data points, x and y, we introduce mutual information that can be interpreted as the amount of information about x in y, and vice versa. We show that for our purposes this measure is superior to commonly used metric distances, for example, Euclidean distance. We also introduce a modified version of mutual information as a novel method for validating clustering results when the true clustering is known. The performance of our algorithm with respect to experimental noise is shown by extensive simulation studies. The algorithm is tested on a subset of 2029 cDNA clones coming from 15 different genes from a cDNA library derived from human dendritic cells. Furthermore, the clustering of these 2029 cDNA clones is demonstrated when the entire set of 76,032 cDNA clones is processed.
245 citations
TL;DR: It is confirmed that the presence of MTA is useful in detecting AD but less useful in differentiating between dementias, however, in the differentiation of DLB from AD and VaD, the absence of MTA are highly suggestive of a diagnosis ofDLB.
Abstract: Objective: To investigate whether medial temporal lobe atrophy (MTA) on MRI is less frequent in dementia with Lewy bodies (DLB) compared with AD and vascular dementia (VaD), and to determine the diagnostic utility of MTA in the differential diagnosis of dementia. Method:— Coronal T1-weighted 1.0-T MR images were acquired in patients with DLB (consensus criteria; n = 26; mean age, 75.9 years), AD (National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association; n = 28; mean age, 77.4 years), VaD (National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences; n = 24; mean age, 76.9 years), and normal control subjects (n = 26; mean age, 76.2 years). Cognitive function was assessed using the Cambridge Cognitive Examination (CAMCOG), and MTA was rated visually using a standardized scale. Results: MTA was more frequent and severe in all dementia groups compared with control subjects (AD, 100%; VaD, 88%; DLB, 62%; control subjects, 4%; p p = 0.002), with a trend toward less atrophy in DLB compared with VaD ( p = 0.07). The absence of MTA had a specificity of 100% and 88% for separating DLB from AD and VaD respectively, and a sensitivity of 38%. In patients with DLB, MTA increased with age ( r = 0.58, p = 0.002), and in all dementia patients MTA correlated with memory impairment (combined memory score, r = −0.34, p = 0.003) but not total CAMCOG score or other subscales. Conclusion: Patients with DLB have significantly greater MTA than control subjects but significantly less than those with AD. The authors confirmed that the presence of MTA is useful in detecting AD but less useful in differentiating between dementias. However, in the differentiation of DLB from AD and VaD, the absence of MTA is highly suggestive of a diagnosis of DLB.
194 citations
TL;DR: The chief medical officer has recommended judicious use of neuroleptic drugs in patients with dementia, although their use is justified largely on the basis of clinical anecdote, and they have many harmful side effects.
Abstract: Dementia is a prominent healthcare issue for primary care physicians and specialist services. Over 90% of patients with dementia experience a “behaviour disturbance,”1 often referred to as behavioural or psychological signs in dementia in accordance with the recommendation of the International Psychogeriatric Association. These symptoms are distressing to patients and troublesome to carers and often precipitate admission to residential facilities.1 What is the evidence that any of the several drugs that are currently used to treat these symptoms are effective?
Managing the behavioural and psychological signs of dementia is a major problem for healthcare professionals. Neuroleptic drugs are the mainstay of pharmacological treatment, although their use is justified largely on the basis of clinical anecdote, and they have many harmful side effects. These include parkinsonism, drowsiness, tardive dyskinesia, falls, accelerated cognitive decline,2 and severe neuroleptic sensitivity reactions.3 It is therefore not surprising that the chief medical officer has recommended judicious use of these agents in patients with dementia.4
In 1990 Schneider published a landmark study showing the paucity of large, placebo controlled, double …
80 citations
TL;DR: The APOE ϵ4 allele does not determine medial temporal lobe atrophy or white matter lesions, as measured by magnetic resonance imaging in patients with Alzheimer disease, vascular dementia, or dementia with Lewy bodies, providing further evidence that APOEπ4 does not influence pathological processes thereafter.
Abstract: Objective To examine the relationship between the apolipoprotein E ( APOE ) ϵ4 genotype, medial temporal lobe atrophy, and white matter hyperintensities on magnetic resonance imaging in late-life dementias. Design Structural magnetic resonance imaging study using T 2 -weighted and proton density–weighted axial scans and T 1 -weighted coronal scans. Setting Community-dwelling population of elderly patients prospectively chosen from a clinical case register of consecutive referrals to old age psychiatry services. Subjects Twenty-five subjects with Alzheimer disease (by criteria of the National Institute of Neurological and Communication Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association; mean age, 77.8 years), 22 subjects with dementia with Lewy bodies (consensus criteria; mean age, 77.2 years), and 24 subjects with vascular dementia (by criteria of the National Institute of Neurological Disorders and Stroke and the Association International pour la Recherche et l'Enseignement en Neurosciences; mean age, 76.9 years) were selected. Subjects were well matched for age, sex, duration of illness, and cognitive function. Main Outcome Measures The APOE genotype was determined using the polymerase chain reaction method, and medial temporal lobe atrophy and white matter hyperintensities (periventricular and deep white matter) were visually rated using standardized scales. Results In all subjects with dementia, no significant associations were noted between APOE ϵ4 status and medial temporal lobe atrophy (mean score: 0 ϵ4=4.5, 1 ϵ4=4.5, and 2 ϵ4=4.3; P =.90), periventricular hyperintensities (0 ϵ4=3.3, 1 ϵ4=3.1, and 2 ϵ4=2.9; P =.83), and white matter hyperintensities (0 ϵ4=5.3, 1 ϵ4=4.9, and 2 ϵ4=4.9; P =.79). Conclusions The APOE ϵ4 allele does not determine medial temporal lobe atrophy or white matter lesions, as measured by magnetic resonance imaging in patients with Alzheimer disease, vascular dementia, or dementia with Lewy bodies. Although APOE ϵ4 may modify the risk for acquiring dementia, this finding provides further evidence that APOE ϵ4 does not influence pathological processes thereafter.
76 citations
TL;DR: DLB patients had significantly better performance on recent memory than AD patients, but more impaired visuospatial praxis, andOptimal cut-off points for the recent memory:praxis ratio achieved good discrimination between DLB and both other dementias.
Abstract: Consecutive patients from a dementia case register received a standardised evaluation which incorporated a neuropsychological assessment with the Cambridge Assessment for disorders in the elderly (CAMCOG). Operationalised clinical diagnoses were made (consensus criteria for dementia with Lewy bodies, DLB; NINCDS- ADRDA for Alzheimer’s disease, AD, NINCDS AIRENS for vascular dementia, VaD). Two-hundred and twenty-eight patients were studied (DLB 54, AD102, VaD 72). DLB patients had significantly better performance on recent memory than AD patients, but more impaired visuospatial praxis. DLB patients also had significantly better recent memory than those with VaD. Optimal cut-off points for the recent memory:praxis ratio achieved good discrimination between DLB and both other dementias.
75 citations
TL;DR: In forthcoming protocols on CVD-associated cognitive impairment, the following brain imaging features should be specified: detailed characterization of brain changes, use of possible predefined subtypes based on brain imaging; use of rating of vascular burden, and technical harmonization of methods of scanning and analysis.
Abstract: Vascular dementia (VaD) relates to different vascular mechanisms and changes in the brain and has different causes and clinical manifestations, reflecting complex interactions between vascular etiologies, changes in the brain, host factors, and cognition. Critical elements to the concept and diagnosis of VaD are defining the vascular causes, the vascular etiologies, and changes in the brain. Verifying the relation between brain lesions and cognition (i.e., the extent to which brain changes cause, compound, or coexist with cognitive impairment) and establishing the types, extent, side, site, and tempo of brain lesions that relate to incident cognitive impairment are major diagnostic challenges. Previous work on interactions between brain lesion and cognition in to cerebrovascular disease (CVD) have shown variation in the definitions and measures of cognitive impairment, in the techniques and methods used to reveal different brain changes, and in the selection of patient populations. Furthermore, small sample sizes and the absence of multivariate statistics have been design limitations. Accordingly, the different sets of criteria used and methods applied identify different numbers and clusters of subjects and different distribution of brain changes. Furthermore, this heterogeneity is reflected in variation in natural history such as the rate of progression of decline in different cognitive domains over time. All these factors have hampered optimal designs of clinical drug trials. A summary of generalizations regarding lesion and cognition interaction in VaD can be made. (1) Not a single feature, but a combination of infarct features--extent and type of white matter lesions (WMLs), degree and site of atrophy, and host factor characteristics--constitues correlates of VaD. (2) Infarct features favoring VaD include bilaterality, multiplicity (>1), location in the dominant hemisphere, and location in the limbic structures (fronto- and mediolimbic). (3) WML features favoring VaD are extensive WMLs (extensive periventricular WMLs and confluent to extensive WMLs in the deep WM). (4) It is doubtful that only a single small lesion could provide imaging evidence for a diagnosis of VaD. (5) Absence of CVD lesions on computed tomography or magnetic resonance imaging is strong evidence against a diagnosis of VaD. In forthcoming protocols on CVD-associated cognitive impairment, the following brain imaging features should be specified: detailed characterization of brain changes; use of possible predefined subtypes based on brain imaging; use of rating of vascular burden; defining the type and extent of WMLs favoring a diagnosis of VaD; defining the extent of medial temporal lobe atrophy disfavoring a diagnosis of VaD; and technical harmonization of methods of scanning and analysis.
56 citations
TL;DR: This pilot study supports the hypothesis that a greater burden of pathology centres on the temporal lobes in AD compared with DLB, except in DLB cases with concurrent Alzheimer pathology.
Abstract: Background. Temporal lobe atrophy on magnetic resonance imaging (MRI) has been suggested as a specific diagnostic marker for Alzheimer's disease (AD). No previous comparison with dementia with Lewy bodies (DLB) has been reported.Method. T1-weighted MRI scans were performed on 11 subjects with AD (nine with NINCDS/ADRDA probable AD and two with neuropathologically proven AD) and nine subjects with DLB (four with probable DLB diagnosed by clinical criteria and five with neuropathologically proven DLB). Groups were matched for age, duration of illness and cognitive test score. Two raters, blind to diagnosis and neuropathological findings, measured the volumes of the frontal lobes, temporal lobes, hippocampi, parahippocampal gyri, amygdalae, and caudate nuclei using a computerized volumetric analysis system. Scans were also rated for medial temporal atrophy on a four-point scale by an experienced rater.Results. AD subjects had significantly smaller left temporal lobes and parahippocampal gyri than those with DLB. Medial temporal atrophy was present in 9/11 AD cases (82%) and absent in 6/9 (67%) of DLB cases. Two neuropathologically confirmed cases of DLB had severe medial temporal atrophy; both had concurrent AD-type pathology in the temporal lobe (Braak stage 4).Conclusions. This pilot study supports the hypothesis that a greater burden of pathology centres on the temporal lobes in AD compared with DLB, except in DLB cases with concurrent Alzheimer pathology. A larger study is needed to confirm these findings and to determine whether MRI has a role in assisting with the clinical differentiation between DLB and AD.
52 citations
TL;DR: Dementia with Lewy bodies is a common cause of cognitive impairment in late life which appears to be clinically and neuropathologically distinct from AD, but some show promise as potential markers to differentiate DLB from AD.
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 neuro-pathological 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 t...
TL;DR: A contiguous sequence-ready map was constructed in the Down syndrome congenital heart disease region in 21q22, as a framework for large-scale genomic sequencing and positional candidate gene approach.
Abstract: Progress in complete genomic sequencing of human chromosome 21 relies on the construction of high-quality bacterial clone maps spanning large chromosomal regions. To achieve this goal, we have applied a strategy based on nonradioactive hybridizations to contig building. A contiguous sequence-ready map was constructed in the Down syndrome congenital heart disease (DS-CHD) region in 21q22.2, as a framework for large-scale genomic sequencing and positional candidate gene approach. Contig assembly was performed essentially by high throughput nonisotopic screenings of genomic libraries, prior to clone validation by (1) restriction digest fingerprinting, (2) STS analysis, (3) Southern hybridizations, and (4) FISH analysis. The contig contains a total of 50 STSs, of which 13 were newly isolated. A minimum tiling path (MTP) was subsequently defined that consists of 20 PACs, 2 BACs, and 5 cosmids covering 3 Mb between D21S3 and MX1. Gene distribution in the region includes 9 known genes (c21-LRP, WRB, SH3BGR, HMG14, PCP4, DSCAM, MX2, MX1, and TMPRSS2) and 14 new additional gene signatures consisting of cDNA selection products and ESTs. Forthcoming genomic sequence information will unravel the structural organization of potential candidate genes involved in specific features of Down syndrome pathogenesis.
TL;DR: The nature, classification and clinical significance of age-related cognitive changes that fall short of dementia remain a most controversial and difficult area.
Abstract: Complaints of poor memory are common in the healthy elderly and to many it may seem unsurprising that cognitive function declines with ‘normal’ ageing. Virtually every biological system alters with age and, just as a 70-year-old cannot run as fast or hear as well as when he or she was 20, it is perhaps inevitable that cognitive function also becomes impaired. However, far from being straightforward, the nature, classification and clinical significance of age-related cognitive changes that fall short of dementia remain a most controversial and difficult area (see O'Brien & Beats, 1994; Dal Forno & Kawas, 1995). The recent emergence of new drugs for the treatment of Alzheimer's disease (donepezil and rivastigmine) and related disorders has emphasised the need to study groups with milder degrees of cognitive impairment. It is necessary to determine whether such conditions are benign and non-progressive, or harbingers of progressive dementia and so appropriate conditions to target for early therapeutic intervention. The presence of age-related cognitive changes raises other important issues including why such changes occur, how they should be classified and whether, even if ‘benign’, they can and should be treated.
21 Jan 1999-Nuclear Instruments & Methods in Physics Research Section A-accelerators Spectrometers Detectors and Associated Equipment
TL;DR: In this article, the authors describe the construction of a thin vacuum window, currently in use on the CLAS photon tagging system at the Thomas Jefferson National Accelerator Facility, which supports a much thinner membrane of aluminized Mylar.
Abstract: The construction of a thin vacuum window, currently in use on the CLAS photon tagging system at the Thomas Jefferson National Accelerator Facility, is described. A layer of woven Kevlar cloth supports a much thinner membrane of aluminized Mylar. Notable features of this particular window include its overall length (9.6 m), and the fact that the entire load is supported by the epoxy seal with no mechanical clamping around the edges. Results from a diverse program of materials testing, including a clear dependence of leak rate on relative humidity, are also reported.