Alzheimer Disease: O'Brien JT

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

O'Brien JT, Ballard CG. · No affiliation provided · BMJ. · Pubmed #11463665 links to  free full text

This publication has no abstract.

O'Brien JT. · Newcastle University, Institute for Ageing and Health, Wolfson Research Centre, Newcastle upon Tyne, UK. j.t.o' · Br J Radiol. · Pubmed #18445747 No free full text.

Abstract: Dementia is a common and growing problem, affecting 5% of the over 65 s and 20% of the over 80s. The recent availability of new treatments for dementia, as well as the importance of subtype-specific management, has renewed interest in the use of brain imaging techniques that can assist in the accurate recognition of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), vascular dementia (VaD) and frontotemporal dementia (FTD). Structural imaging, historically used to exclude an intracerebral lesion as a cause for dementia, is increasingly playing a role in "ruling in" diagnoses, with atrophy of the hippocampus and entorhinal cortex an early and sensitive marker for AD, and cortical and subcortical infarcts and white matter lesions characteristic of VaD. Regionally distinct patterns of hypoperfusion on single-photon emission computed tomography (SPECT) or hypometabolism on positron emission tomography (PET) can help differentiate FTD, AD and VaD, and dopaminergic loss in the basal ganglia can differentiate DLB from AD. Newer techniques show great promise to detect specific neuroreceptor changes as well as pathological underpinnings of dementia, such as amyloid and tau pathology.

O'Brien JT. · Institute for Ageing and Health, Wolfson Research Centre, Newcastle-upon-Tyne, UK. j.t.o' · Am J Geriatr Psychiatry. · Pubmed #16943169 No free full text.

Abstract: Cerebrovascular disease is increasingly recognized as a common cause of cognitive impairment and dementia in later life either alone or in conjunction with other pathologies, most often Alzheimer disease (AD). Progress in the field has been limited by difficulties in terminology; for example, use of the term dementia necessitates the presence of memory impairment, which is the norm in AD, but not in cognitive disorders associated with cerebrovascular disease. The term vascular cognitive impairment (VCI) has been proposed as an umbrella term to recognize the broad spectrum of cognitive, and indeed behavioral, changes associated with vascular pathology. It is characterized by a specific cognitive profile with predominantly attentional and executive impairments together with particular noncognitive features (especially depression) and a relatively stable course, at least in clinical trial populations. Subtypes of VCI have been proposed based on clinical and pathologic differences, including cortical, subcortical, strategic infarct, hypoperfusion, hemorrhagic, and mixed (with AD) type. Diagnostic criteria are emerging but require refinement and validation, especially for mixed dementias. There remain fundamental gaps in our understanding of pathophysiology, predicting prognosis and outcome, and in therapeutics. Clinical trials to date, mainly in populations selected using currently accepted criteria for vascular dementia, have generally been disappointing. A relatively modest cognitive benefit of agents such as nimodipine, memantine, and cholinesterase inhibitors has been reported, although the clinical significance of these improvements remains to be established. Further studies, focusing on particular subtypes of VCI and involving subjects at earlier stages of the disease, are required. The aim of this article is to review the concept of VCI in terms of the evidence base surrounding diagnosis, clinical features, pathophysiology, and management and to make some recommendations regarding further research in the area. It begins with a discussion on the historical background, which is important to understand the different and somewhat confusing terminology that currently exists in the field.

McKeith IG, Burn DJ, Ballard CG, Collerton D, Jaros E, Morris CM, McLaren A, Perry EK, Perry R, Piggott MA, O'Brien JT. · Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Newcastle, UK. · Semin Clin Neuropsychiatry. · Pubmed #12567332 No free full text.

Abstract: The objective was to summarize recent findings about the clinical features, diagnosis and investigation of dementia with Lewy (DLB) bodies, together with its neuropathology, neurochemistry and genetics. Dementia with Lewy bodies (DLB) is a primary, neurodegenerative dementia sharing clinical and pathological characteristics with both Parkinson's disease (PD) and Alzheimer's disease (AD). Antiubiquitin immunocytochemical staining, developed in the early 1990s, allowed the frequency and distribution of cortical LBs to be defined. More recently, alpha-synuclein antibodies have revealed extensive neuritic pathology in DLB demonstrating a neurobiological link with other "synucleinopathies" including PD and multiple system atrophy (MSA). The most significant correlates of cognitive failure in DLB appear to be with cortical LB and Lewy neurites (LNs) rather than Alzheimer type pathology. Clinical diagnostic criteria for DLB, published in 1996, have been subjected to several validation studies against autopsy findings. These conclude that although diagnostic specificity is high (range 79- 100%, mean 92%), sensitivity is lower (range 0- 83 %, mean, 49%). Improved methods of case detection are therefore required. Fluctuating impairments in attention, visual recognition and construction are more indicative of DLB than AD. Relative preservation of medial temporal lobe volume on structural MRI and the use of SPECT tracers for regional blood flow and the dopamine transporter are the most reliable current biomarkers for DLB. There are no genetic or CSF tests recommended for the diagnosis of DLB at present. Between 15 and 20% of all elderly demented cases reaching autopsy have DLB, making it the most common cause of degenerative dementia after AD. Exquisite, not infrequently fatal, sensitivity to neuroleptic drugs and encouraging reports of the effects of cholinesterase inhibitors on cognitive, psychiatric and neurological features, mean that an accurate diagnosis of DLB is more than merely of academic interest. Dementia developing late in the course of PD shares many of the same clinical and pathological characteristics.

Firbank MJ, Harrison RM, O'Brien JT. · Institute for Ageing and Health, Newcastle General Hospital, Newcastle upon Tyne, UK. · Dement Geriatr Cogn Disord. · Pubmed #12145453 No free full text.

Abstract: We reviewed the literature of proton magnetic resonance spectroscopy (MRS) in dementia and Parkinson's disease (PD) and quantitatively compared the reported values of the markers N-acetyl aspartate (NAA), choline, and myo-Inositol between control and disease groups. We analysed a total of 27 reports in dementia. Combining the quantitative data from these showed a relative decrease of 15% in NAA level in the temporal lobe tissue in patients with Alzheimer's disease (AD) compared with controls. The rest of the brain showed a seemingly uniform 10% decrease in NAA levels in AD compared with controls. myo-Inositol was raised by about 15%, again uniformly throughout the brain, but there was no evidence for changed levels of choline. We found 15 reports of MRS in PD, which show a small decrease (5%) in the NAA level in the lentiform nucleus compared with controls. In progressive supranuclear palsy (PSP), there is a greater decrease in NAA levels in the frontal region and the lentiform nucleus. This may aid in the diagnosis of PSP. Further research is needed to determine spectroscopic changes in other dementias, to monitor how markers change with disease progression and to establish clinical utility.

Kalaria RN, Ballard CG, Ince PG, Kenny RA, McKeith IG, Morris CM, O'Brien JT, Perry EK, Perry RH, Edwardson JA. · MRC-Newcastle University Centre Development in Clinical Brian Ageing, Wolfson Research Centre, Institute for Health of the Elderly, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK. · Novartis Found Symp. · Pubmed #11280033 No free full text.

Abstract: Age is the single most important risk factor for progressive dementia in populations worldwide. In developed countries the prevalence of dementia is estimated to be 3-5% at age 65 years and expected to double every decade thereafter. Although there is ageing-related attrition of neural tissue accompanied by profound changes in brain glia, marked neuronal loss and severe cognitive impairment are associated with pathological changes. Accelerated somatic ageing of the vasculature comprising endothelial and smooth muscle cells and slowed glial replacement are also likely to pre-dispose to degenerative processes. Approximately 90% of patients with late-onset dementia have neuropathological features of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or vascular dementia (VaD), alone or in combination. Both AD and DLB reveal extensive amyloid beta deposition within senile plaques. Neurofibrillary tangles evident as tau pathology are much reduced in DLB where symptoms may be more related to cholinergic transmitter abnormalities than structural pathology. Depletion of brain acetylcholine is also encountered in VaD, which like AD and DLB may respond to cholinergic therapy. Cerebrovascular pathology, ischaemic brain damage and neurovascular instability resulting in cerebral hypoperfusion appears fundamental in the pathogenesis of late-onset dementia. The apolipoprotein E epsilon 4 allele, a major genetic susceptibility factor for AD also associated with cardiovascular pathology, may contribute to neurodegenerative changes through vascular mechanisms. The interrelationships of these multiple substrates of late-onset dementia have major implications for neuroprotective and disease slowing therapies. Measures that improve cardiovascular function and increase brain perfusion would be useful to attenuate cognitive decline.

Colloby SJ, O'Brien JT, Fenwick JD, Firbank MJ, Burn DJ, McKeith IG, Williams ED. · Institute for Ageing and Health, Newcastle University, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle- upon-Tyne NE4 6BE, UK. · Neuroimage. · Pubmed #15528096 No free full text.

Abstract: Dopaminergic loss can be visualised using (123)I-FP-CIT single photon emission computed tomography (SPECT) in several disorders including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Most previous SPECT studies have adopted region of interest (ROI) methods for analysis, which are subjective and operator-dependent. The purpose of this study was to investigate differences in striatal binding of (123)I-FP-CIT SPECT using the automated technique of statistical parametric mapping (SPM99) in subjects with DLB, Alzheimer's disease (AD), PD and healthy age-matched controls. This involved spatial normalisation of each subject's image to a customised template, followed by smoothing and intensity normalisation of each image to its corresponding mean occipital count per voxel. Group differences were assessed using a two-sample t test. Applying a height threshold of P <or= 0.05 corrected, the SPM[t] maps showed a significant bilateral reduced uptake in caudate, anterior and posterior putamen in DLB and PD subjects compared to AD subjects and controls. Significant reduction in binding was also observed bilaterally in the caudate nucleus in AD compared to controls. Striatal binding was indistinguishable between patients with DLB and PD. To investigate the usefulness of SPM as a decision aid in the evaluation of visually rated normal and abnormal patterns of uptake, receiver operator characteristic (ROC) curve analysis was performed using data from single-subject SPMs. The areas under the ROC curves were greater than 0.92, demonstrating comparable discriminatory power with visual rating. The automated voxel-based approach is a viable alternative to the subjective and often time-consuming method of ROI and, in addition, may have the potential to differentiate between normal and abnormal patterns of uptake in a manner similar to visual inspection.

Paling SM, Williams ED, Barber R, Burton EJ, Crum WR, Fox NC, O'Brien JT. · Institute for Ageing and Health, Newcastle General Hospital, Newcastle upon Tyne, UK. · Med Image Anal. · Pubmed #14644147 No free full text.

Abstract: We have used a serial MR image analysis technique previously developed for studies of cerebral atrophy in early-onset dementia and applied it to a study of late-onset dementia patients with images acquired using a different scanner and scan sequence. Validation and optimisation tests showed that with only small changes to key analysis parameters the technique can successfully be applied to previously untested data with dissimilar image characteristics. The overall accuracy in estimation of cerebral atrophy using the technique was determined to be between 2 and 4 ml (1sigma) depending on the conditions during image acquisition. By comparing the results of alternative registration techniques we demonstrate the potential of using of fully automated 9 DOF image registration as an effective and efficient means of correcting for scanner pixel size variations, even in the presence of significant cerebral atrophy. Applied to the late-onset dementia study, patients were found to have significantly increased mean atrophy rates (p<0.001) compared to controls. In general the analysis technique is shown to be a robust, accurate and transferable tool of potential value for future studies of dementia and related neuro-degenerative disorders.

Cousins DA, Burton EJ, Burn D, Gholkar A, McKeith IG, O'Brien JT. · Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Newcastle upon Tyne, UK. · Neurology. · Pubmed #14610119 No free full text.

Abstract: OBJECTIVE: To compare the volume of the putamen on MRI in subjects with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) and age-matched normal control subjects, along with the relationship between putamen volume and severity of both extrapyramidal signs and cognitive impairment. METHODS: MRI-based volumetric measurements at 1.5 T of total intracranial volume, total brain volume, and putamen volume were acquired in elderly patients with AD (n = 27; 77.6 years) and DLB (n = 14; 76.2 years) and normal control subjects (n = 37; 75.4 years). Patients and control subjects also underwent a standardized neuropsychiatric examination including the motor subsection of the Unified Parkinson's Disease Rating Scale (UPDRS III) and the Cambridge Cognitive Examination (CAMCOG) with Mini-Mental State Examination (MMSE). RESULTS: Patients with DLB had smaller raw putamen volumes than control subjects (right 12.5% reduction, p = 0.007; left 13.7% reduction, p = 0.003). When putamen volume was normalized to total intracranial volume, patients with DLB had significantly smaller volume ratios than both controls and patients with AD. Patients with AD did not differ from control subjects on any measure of putamen volume. Putamen volume did not correlate with age or with scores on UPDRS III, CAMCOG, or MMSE in any of the groups. CONCLUSIONS: Atrophy of the putamen is a feature of DLB. This may be important in understanding the etiology of parkinsonian features seen in DLB, though in this study, no direct correlation was found between degree of volume loss and severity of parkinsonism.

Firbank MJ, Colloby SJ, Burn DJ, McKeith IG, O'Brien JT. · Institute for Ageing and Health, Newcastle University, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, NE4 6BE, UK. · Neuroimage. · Pubmed #14568499 No free full text.

Abstract: Tc99 HMPAO SPECT and T1 weighted 3D MRI scans were acquired in cognitively intact subjects with Parkinson's disease (PD) (n = 31), and in PD subjects with dementia (PDD) (n = 34), healthy controls (n = 37), those with Alzheimer's disease (AD) (n = 32), and those with dementia with Lewy bodies (DLB) (n = 15). We used SPM99 to look for regions which showed a reduction in perfusion on SPECT not related to associated structural brain changes assessed by a MRI scan. The precuneus and inferior lateral parietal regions showed a perfusion deficit in Parkinson's disease with dementia, similar to the pattern observed in DLB. In comparison, AD showed a perfusion deficit in the midline parietal region, in a more anterior and inferior location than in PDD, involving the posterior cingulate as well as the precuneus. The perfusion deficits in PDD are similar those in DLB, and in a location associated with visual processing, and may be associated with the visuospatial perception deficits which are present in persons with DLB and PDD.

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.

Porter RJ, Lunn BS, O'Brien JT. · Department of Psychological Medicine, Christchurch School of Medicine, Christchurch, New Zealand. · Psychol Med. · Pubmed #12537035 No free full text.

Abstract: BACKGROUND: The cholinergic system is profoundly impaired in senile dementia of Alzheimer type (SDAT) and replacement therapy produces only modest clinical benefits. The serotonergic system is also impaired and may contribute both to cognitive and non-cognitive symptoms in SDAT. To investigate this further we assessed the effects of lowering brain serotonin using the technique of acute tryptophan depletion on cognitive function in patients with SDAT and in age matched control subjects. METHOD: Sixteen patients with probable SDAT and 17 healthy elderly subjects received two amino acid drinks in a within subject, double-blind, placebo-controlled, counterbalanced, crossover design. One of the drinks was nutritionally balanced and contained tryptophan (placebo), the other was identical but contained no tryptophan. A battery of detailed neuropsychological tests was performed between 4 and 6 h after the drink. Mood rating scales and other ratings of behavioural and emotional symptoms were also performed on both occasions. RESULTS: Acute tryptophan depletion resulted in impairment on tasks of working memory in both groups. There was no group specific effect. Female SDAT subjects performed better on a task of pattern recognition during acute tryptophan depletion compared with placebo. There were no changes in behavioural symptoms during acute tryptophan depletion in either group. CONCLUSION: Compromised serotonergic function may be an important contributor to cognitive decline in SDAT and in ageing. Strategies targeting specific 5HT receptors may be helpful in SDAT.

Burton EJ, Karas G, Paling SM, Barber R, Williams ED, Ballard CG, McKeith IG, Scheltens P, Barkhof F, O'Brien JT. · Institute for Ageing and Health, University of Newcastle upon Tyne, United Kingdom. · Neuroimage. · Pubmed #12377138 No free full text.

Abstract: Previous cross-sectional MRI studies based on region-of-interest analyses have shown that increased cerebral atrophy is a feature of both Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Relative preservation of the hippocampus and temporal lobe structures in DLB compared to AD has been reported in region-of-interest-based studies. Recently, image processing techniques such as voxel-based morphometry (VBM) have been developed to provide an unbiased, visually informative, and comprehensive means of studying patterns of cerebral atrophy. We report the first study to use the voxel-based approach to assess patterns of cerebral atrophy in DLB compared to control subjects and AD. Regional gray matter volume loss was observed bilaterally in the temporal and frontal lobes and insular cortex of patients with DLB compared to control subjects. Comparison of dementia groups showed preservation of the medial temporal lobe, hippocampus, and amygdala in DLB relative to AD. Significant gray matter loss was also observed in the thalamus of AD patients compared to DLB.

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.

Porter RJ, Marshall EF, O'Brien JT. · Department of Psychological Medicine, Christchurch School of Medicine, University of Otago, New Zealand. · J Psychopharmacol. · Pubmed #11949775 No free full text.

Abstract: Serotonergic function is reduced in dementia of Alzheimer type (DAT) and abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are also common. There is considerable interaction between the two systems. Effects of lowering brain serotonin on salivary and plasma cortisol were assessed in patients with DAT and in control subjects. A double-blind, cross-over design involving administration of two nutritionally balanced amino acid mixtures with or without tryptophan was used. Salivary and plasma cortisol were measured at intervals before and after the drink. DAT patients had higher salivary cortisol than controls. Despite a reduction of approximately 70% in plasma free tryptophan after 4 h in both groups, there was no effect on salivary or plasma cortisol. We conclude that, in subjects with DAT and healthy elderly subjects, acute tryptophan depletion had no effect on cortisol secretion.

Walker MP, Ayre GA, Cummings JL, Wesnes K, McKeith IG, O'Brien JT, Ballard CG. · Medical Research Council Neurochemical Pathology Unit, Institute for the Health of the Elderly, Newcastle, UK. · Neurology. · Pubmed #10762503 No free full text.

Abstract: BACKGROUND: Case reports and clinical observations suggest that fluctuating cognition (FC) is common in the major dementias, particularly dementia with Lewy bodies (DLB), where it is one of three core clinical diagnostic features. OBJECTIVES: To examine the frequency, characteristics, and diagnostic utility of FC in dementia using clinical, attentional, and EEG markers. Method:- A total of 155 subjects (61 with AD, 37 with DLB, 22 with vascular dementia [VaD], 35 elderly controls) received clinical evaluation for FC using a semiquantified measure applied by experienced clinicians and 90-second cognitive choice reaction time (CRT) and vigilance reaction time (VIGRT) trials. Forty subjects also received an evaluation of mean EEG frequency across 90 seconds. RESULTS: Patients with DLB had a greater prevalence and severity of FC than did patients with AD or VaD rated using clinical, attentional, and EEG measures. The 90-second cognitive and EEG trials demonstrated that FC occurs on a second-to-second basis in patients with DLB. Patients with VaD had a higher prevalence of FC than did those with AD, although the profile of FC was different from that expressed by DLB cases. Optimal cutoff values on the clinical scale achieved good discrimination between the dementia groups (sensitivity 81%, specificity 92%, DLB versus AD; sensitivity 81%, specificity 82%, DLB versus VaD; sensitivity 64%, specificity 77%, VaD versus AD). CONCLUSION: Standardized assessment methods demonstrate that FC is significantly more common and severe in DLB than in other major dementias. The periodicity of FC is different in DLB and VaD cases, with important implications for the underlying causal mechanisms and for differential diagnosis.

Porter RJ, Lunn BS, Walker LL, Gray JM, Ballard CG, O'Brien JT. · Academic Department of Psychiatry, University of Newcastle upon Tyne, England. · Am J Psychiatry. · Pubmed #10739429 links to  free full text

Abstract: OBJECTIVE: The study assessed the effects on global cognitive function and mood of a reduction of brain serotonin by means of acute tryptophan depletion in 16 patients with dementia of the Alzheimer type and in 16 cognitively intact comparison subjects. METHOD: In a double-blind, crossover design, subjects received a tryptophan-free amino acid drink to induce acute tryptophan depletion and, on a separate occasion, a placebo drink containing a balanced mixture of amino acids. On each occasion, ratings of depressed mood were made at baseline and 4 and 7 hours later, and the Modified Mini-Mental State was administered at baseline and 4 hours later. RESULTS: Patients with dementia of the Alzheimer type had a significantly lower mean score on the Modified Mini-Mental State after acute tryptophan depletion than after receiving placebo. The comparison group showed no difference in mean score on the Modified Mini-Mental State after acute tryptophan depletion and after receiving placebo. No significant changes in mood were found in either group. CONCLUSIONS: Acute tryptophan depletion significantly impaired cognitive function in patients with dementia of the Alzheimer type. Compromised serotonergic function, in combination with cholinergic deficit, may make an important contribution to cognitive decline in dementia of the Alzheimer type.

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.

Burton EJ, Barber R, Mukaetova-Ladinska EB, Robson J, Perry RH, Jaros E, Kalaria RN, O'Brien JT. · Wolfson Research Centre, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK. · Brain. · Pubmed #19022858 No free full text.

Abstract: The purpose of this study was to determine the diagnostic accuracy of medial temporal lobe atrophy (MTA) on MRI for distinguishing Alzheimer's disease from other dementias in autopsy confirmed cases, and to determine pathological correlates of MTA in Alzheimer's disease, dementia with Lewy bodies (DLB) and vascular cognitive impairment (VCI). We studied 46 individuals who had both antemortem MRI and an autopsy. Subjects were clinicopathologically classified as having Alzheimer's disease (n = 11), DLB (n = 23) or VCI (n = 12). MTA was rated visually using a standardized (Scheltens) scale blind to clinical or autopsy diagnosis. Neuropathological analysis included Braak staging as well as quantitative analysis of plaques, tangles and alpha-synuclein Lewy body-associated pathology in the hippocampus. Correlations between MTA and pathological measures were carried out using Spearman's rho, linear regression to assess the contributions of local pathologic changes to MTA. Receiver operator curve analysis was used to assess the diagnostic specificity of MTA for Alzheimer's disease among individuals with Alzheimer's disease, DLB and VCI. MTA was a highly accurate diagnostic marker for autopsy confirmed Alzheimer's disease (sensitivity of 91% and specificity of 94%) compared with DLB and VCI. Across the entire sample, correlations were observed between MTA and Braak stage (rho = 0.50, P < 0.001), per cent area of plaques in the hippocampus (rho = 0.37, P = 0.014) and per cent area of tangles in the hippocampus (rho = 0.49, P = 0.001). Linear regression showed Braak stage (P = 0.022) to be a significant predictor of MTA but not percent area of plaques (P = 0.375), percent area of tangles (P = 0.330) or percent area of Lewy bodies (P = 0.086). MTA on MRI had robust discriminatory power for distinguishing Alzheimer's disease from DLB and VCI in pathologically confirmed cases. Pathologically, it is more strongly related to tangle rather than plaque or Lewy body pathology in the temporal lobe. It may have utility as a means for stratifying samples in vivo on the basis of putative differences in pathology.

Kenny ER, Burton EJ, O'Brien JT. · Institute for Ageing and Health, Newcastle University, Wolfson Research Centre, Campus for Ageing and Vitality, Newcastle upon Tyne, UK. · Dement Geriatr Cogn Disord. · Pubmed #18781072 No free full text.

Abstract: AIMS: To investigate whether subjects with dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and Parkinson's disease with dementia (PDD) have reduced entorhinal cortex (EC) volumes compared to controls and cognitively intact Parkinson's disease (PD) subjects. METHODS: Volumes of the EC were measured on magnetic resonance imaging (MRI) scans of 144 individuals (aged over 65 years): 20 with DLB, 26 with AD, 30 with PDD, 31 with PD and 37 normal age-matched controls. RESULTS: Total normalised EC volumes were significantly smaller in DLB, AD and PDD patients compared to controls, and in DLB and AD patients compared to PD patients (p < 0.001). The percentage volume reduction in EC volume in the dementia groups relative to controls was 19.9% in DLB, 21.9% in AD and 14.7% in PDD. CONCLUSIONS: MRI measurements of the EC have shown that volumes are smaller in dementia subjects compared to controls and patients with non-dementia disorders. Further research is required to recognise those at risk of dementia and to differentiate between the dementias.

Colloby SJ, Firbank MJ, Pakrasi S, Lloyd JJ, Driver I, McKeith IG, Williams ED, O'Brien JT. · Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK. · Int Psychogeriatr. · Pubmed #18752700 No free full text.

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

Thomas AJ, Gallagher P, Robinson LJ, Porter RJ, Young AH, Ferrier IN, O'Brien JT. · Institute for Ageing and Health, Newcastle University, UK. · Psychol Med. · Pubmed #18667097 No free full text.

Abstract: BACKGROUND: Neurocognitive impairment is a well-recognized feature of depression that has been reported in younger and older adults. Similar deficits occur with ageing and it is unclear whether the greater deficits in late-life depression are an ageing-related phenomenon or due to a difference in the nature of late-life depression itself. We hypothesized that ageing alone would not fully explain the increased neurocognitive impairment in late-life depression but that differences in the illness explain the greater decrements in memory and executive function. METHOD: Comparison of the neuropsychological performance of younger (<60 years) and older (60 years) adults with major depressive disorder (MDD) and healthy comparison subjects. Scores for each depression group were normalized against their respective age-matched control group and the primary comparisons were on four neurocognitive domains: (i) attention and executive function; (ii) verbal learning and memory; (iii) visuospatial learning and memory; and (iv) motor speed. RESULTS: We recruited 75 subjects with MDD [<60 years (n=44), 60 years (n=31)] and 82 psychiatrically healthy comparison subjects [<60 years (n=42), 60 years (n=40)]. The late-life depression group had greater impairment in verbal learning and memory and motor speed but not in executive function. The two depressed groups did not differ in depression severity, global cognitive function, intelligence or education. CONCLUSIONS: Late-life depression is associated with more severe impairment in verbal learning and memory and motor speed than depression in earlier adult life and this is not due to ageing alone.

Firbank MJ, Barber R, Burton EJ, O'Brien JT. · Institute for Ageing and Health, Newcastle University, Wolfson Research Centre, Westgate Road, Newcastle upon Tyne NE4 6BE, United Kingdom. · Hum Brain Mapp. · Pubmed #17979118 No free full text.

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

Howard RJ, Juszczak E, Ballard CG, Bentham P, Brown RG, Bullock R, Burns AS, Holmes C, Jacoby R, Johnson T, Knapp M, Lindesay J, O'Brien JT, Wilcock G, Katona C, Jones RW, DeCesare J, Rodger M, Anonymous00016. · Medical Research Council Neurogeneration Research Centre, Institute of Psychiatry, King's College London, London, United Kingdom. · N Engl J Med. · Pubmed #17914039 links to  free full text

Abstract: BACKGROUND: Agitation is a common and distressing symptom in patients with Alzheimer's disease. Cholinesterase inhibitors improve cognitive outcomes in such patients, but the benefits of these drugs for behavioral disturbances are unclear. METHODS: We randomly assigned 272 patients with Alzheimer's disease who had clinically significant agitation and no response to a brief psychosocial treatment program to receive 10 mg of donepezil per day (128 patients) or placebo (131 patients) for 12 weeks. The primary outcome was a change in the score on the Cohen-Mansfield Agitation Inventory (CMAI) (on a scale of 29 to 203, with higher scores indicating more agitation) at 12 weeks. RESULTS: There was no significant difference between the effects of donepezil and those of placebo on the basis of the change in CMAI scores from baseline to 12 weeks (estimated mean difference in change [the value for donepezil minus that for placebo], -0.06; 95% confidence interval [CI], -4.35 to 4.22). Twenty-two of 108 patients (20.4%) in the placebo group and 22 of 113 (19.5%) in the donepezil group had a reduction of 30% or greater in the CMAI score (the value for donepezil minus that for placebo, -0.9 percentage point; 95% CI, -11.4 to 9.6). There were also no significant differences between the placebo and donepezil groups in scores for the Neuropsychiatric Inventory, the Neuropsychiatric Inventory Caregiver Distress Scale, or the Clinician's Global Impression of Change. CONCLUSIONS: In this 12-week trial, donepezil was not more effective than placebo in treating agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number, NCT00142324 [ClinicalTrials.gov].).