Alzheimer Disease: Burton EJ

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.

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.

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.

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.

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.

Burton EJ, McKeith IG, Burn DJ, Firbank MJ, O'Brien JT. · Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Newcastle upon Tyne, UK. · Am J Geriatr Psychiatry. · Pubmed #17001024 No free full text.

Abstract: OBJECTIVE: The objective of this study was to investigate cross-sectional and longitudinal white matter hyperintensity (WMH) changes in older subjects with clinically diagnosed dementia. METHODS: Fluid-attenuated inversion recovery images were acquired one year apart in subjects with dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), Alzheimer disease (AD), and also healthy elderly comparison subjects. WMH volume was quantified using an automated technique. RESULTS: Baseline WMH (as a percent of brain volume) was significantly greater compared with healthy subjects (N=33, geometric mean WMH: 0.4%) in subjects with AD (N=23 [1.3%], analysis of variance post hoc p <0.001) but not PDD (N=13 [0.6%]) or DLB (N=14 [0.4%]). Increase in WMH volume (as a percent of brain volume) was not significantly different (Kruskal-Wallis p=0.4) between groups (AD median change: 0.08%; DLB: 0.025%; PDD: 0.07%, healthy: 0.02%). Severity of baseline WMH, rather than diagnosis or severity of dementia, was a significant predictor of lesion progression. Rate of change of WMH had no association with change in global cognitive performance. CONCLUSIONS: Significant WMH progression occurs in degenerative dementias with rates influenced by severity of lesions at baseline rather than dementia type or cognitive decline.

Tam CW, Burton EJ, McKeith IG, Burn DJ, O'Brien JT. · Department of Psychiatry, Tai Po Hospital, Hong Kong. · Neurology. · Pubmed #15753423 No free full text.

Abstract: OBJECTIVE: To investigate the extent of medial temporal lobe atrophy (MTA) on MRI in Parkinson disease (PD) with and without dementia compared with Alzheimer disease (AD) and dementia with Lewy bodies (DLB) and to determine whether MTA correlates with cognitive impairment in PD and PD dementia (PDD). METHODS: Coronal T1-weighted MRI scans were acquired from control subjects (n = 39) and patients with PD (n = 33), PDD (n = 31), DLB (n = 25), and AD (n = 31), diagnosed according to standardized clinical diagnostic criteria. Cognitive function was assessed using the Cambridge Cognitive Examination (CAMCOG), and MTA was rated visually using a standardized (Scheltens) scale. RESULTS: More severe MTA was seen in PDD (p = 0.007), DLB (p < 0.001), and AD (p < 0.001) vs control subjects. PD subjects had greater hippocampal atrophy than control subjects (p = 0.015) but less than subjects with DLB and AD, though not with PDD. MTA correlated with CAMCOG score and memory scores in the DLB group and with age in control, PDD, and AD groups. There were no correlations between MTA and cognitive impairment in PD, PDD, and AD. PDD and DLB had a similar profile of cognitive impairment and MTA. CONCLUSIONS: Medial temporal lobe atrophy (MTA) was seen in cognitively intact older subjects with Parkinson disease (PD) and was not more pronounced in Parkinson disease dementia (PDD). Alzheimer disease (AD) and, to a lesser extent, dementia with Lewy bodies (DLB) showed more pronounced MTA. Results suggest early hippocampal involvement in PD and that when dementia develops in PD, anatomic structures apart from the hippocampus are predominantly implicated. Greater hippocampal involvement in AD vs PDD and DLB is consistent with clinical, cognitive, and pathologic differences between the disorders.

Ballmaier M, O'Brien JT, Burton EJ, Thompson PM, Rex DE, Narr KL, McKeith IG, DeLuca H, Toga AW. · Laboratory of NeuroImaging, Department of Neurology, David Geffen UCLA School of Medicine, Los Angeles, CA 90095-1769, USA. · Neuroimage. · Pubmed #15325380 No free full text.

Abstract: We used magnetic resonance imaging (MRI) and cortical pattern matching to map differences in cortical gray matter deficits between Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), and explored the possible influence of gender on these patterns. Twenty-nine patients with AD (age 77.9 +/- 5.5), 16 patients with DLB (76.4 +/- 6.7), and 38 controls (75.3 +/- 6.8) were included. Dementia groups were matched for illness severity. Detailed spatial analyses of gray matter were conducted across the entire cerebral cortex by measuring local proportions of gray matter at thousands of homologous cortical surface locations in each subject and between diagnostic groups. To visualize regional changes, statistical differences were mapped at each cortical surface location in 3D. Main effects of diagnosis demonstrated prominent gray matter differences in orbitofrontal and temporal cortices, where AD exhibited the greatest deficits relative to DLB. Main effects of sex showed less gray matter in men within all group comparisons. Exploratory findings for sex by diagnosis interactions suggest greater gray matter loss in the anterior cingulate for men with AD, relative to controls, AD females, and individuals with DLB. Relative preservation of orbitofrontal cortices in addition to temporal structures may contribute to distinguishing DLB from AD. Further investigation of the influence of gender might provide a more comprehensive understanding of the pathophysiological differences underlying the two forms of dementia.

Burton EJ, McKeith IG, Burn DJ, Williams ED, O'Brien JT. · The Institute for Ageing and Health, University of Newcastle upon Tyne, Newcastle General Hospital, Newcastle, UK. · Brain. · Pubmed #14749292 links to  free full text

Abstract: Parkinson's disease is a common neurodegenerative disorder primarily characterized by rigidity, tremor and bradykinesia. Cognitive impairment and neuropsychiatric symptoms are frequent in Parkinson's disease, with a 70% cumulative incidence of dementia. The aim of this cross-sectional study was to establish the pattern of cerebral atrophy on MRI in Parkinson's disease patients with dementia. We used voxel-based morphometry (VBM) to provide an unbiased means of investigating brain volume loss. Whole brain structural T1-weighted MRI scans from Parkinson's disease patients with dementia (PDD, n = 26), Parkinson's disease patients without dementia (n = 31), Alzheimer's disease patients (n = 28), patients with dementia with Lewy bodies (DLB, n = 17) and control subjects (n = 36) were acquired. Images were analysed using SPM99 and the optimized method of VBM. Reduced grey matter volume in PDD patients compared with controls was observed bilaterally in the temporal lobe, including the hippocampus and parahippocampal gyrus, and in the occipital lobe, the right frontal lobe and the left parietal lobe, as well as some subcortical regions. Parkinson's disease patients without dementia showed reduced grey matter volume in the frontal lobe compared with control subjects. There was significant grey matter atrophy bilaterally in the occipital lobe of PDD patients compared with Parkinson's disease patients. In addition, significant temporal lobe atrophy, including the hippocampus and parahippocampal gyrus was detected in Alzheimer's disease relative to PDD. No significant volumetric differences were observed in PDD compared with DLB. Thus, Parkinson's disease involves grey matter loss in frontal areas. In PDD, this extends to temporal, occipital and subcortical areas, with occipital atrophy in PDD being the only difference between the two groups. This provides important information about the pattern of cerebral atrophy in Parkinson's disease and PDD.

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.

Middelkoop HA, van der Flier WM, Burton EJ, Lloyd AJ, Paling S, Barber R, Ballard C, McKeith IG, O'Brien JT. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #11739838 No free full text.

Abstract: Dementia with Lewy bodies (DLB) is associated with occipital changes in blood flow and metabolism, but structural changes in this region have not previously been assessed. The authors performed volumetric MRI measurement of the occipital lobe blind to the diagnosis in 23 subjects with DLB, 25 with AD, and 24 age-matched control subjects. There were no significant differences between groups in occipital lobe volume. The authors conclude gross structural changes in the occipital lobe do not occur in patients with mild to moderate DLB or AD.