Alzheimer Disease: Williams ED

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.

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.

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.

Pakrasi S, Colloby SJ, Firbank MJ, Perry EK, Wyper DJ, Owens J, McKeith IG, Williams ED, O'Brien JT. · Institute for Ageing and Health, Newcastle University, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, NE4 6BE, UK. · J Neurol. · Pubmed #17361343 No free full text.

Abstract: BACKGROUND : One of the most characteristic changes in Alzheimer's disease (AD) is a deficit in cortical cholinergic neurotransmission and associated receptor changes. OBJECTIVE : To investigate differences in the distribution of M1/M4 receptors using (R, R) (123)I-iodo-quinuclidinyl-benzilate (QNB) and single photon emission computed tomography (SPECT) in patients with mild/moderate AD and age-matched controls. Also, to compare (123)I-QNB uptake to the corresponding changes in regional cerebral blood flow (rCBF) in the same subjects. METHODS : Forty two subjects (18 AD and 24 healthy elderly controls) underwent (123)IQNB and perfusion (99m)Tc-exametazime SPECT scanning. Image analysis was performed using statistical parametric mapping (SPM99) following intensity normalisation of each image to its corresponding mean whole brain uptake. Group differences and correlations were assessed using two sample t-tests and linear regression respectively. RESULTS : Significant reductions in (123)I-QNB uptake were observed in regions of the frontal rectal gyrus, right parahippocampal gyrus, left hippocampus and areas of the left temporal lobe in AD compared to controls (height threshold of p < or = 0.001 uncorrected). Such regions were also associated with marked deficits in rCBF. No significant correlations were identified between imaging data and clinical variables. CONCLUSION : Functional impairment as measured by rCBF is more widespread than changes in M1/M4 receptor density in mild/moderate AD, where there was little or no selective loss of M1/M4 receptors in these patients that was greater than the general functional deficits shown on rCBF scans.

O'Brien JT, Colloby SJ, Pakrasi S, Perry EK, Pimlott SL, Wyper 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. · J Neurol Neurosurg Psychiatry. · Pubmed #17135460 No free full text.

Abstract: BACKGROUND: Loss of the alpha4beta2 nicotinic receptor subtype is found at autopsy in Alzheimer's disease. OBJECTIVE: To investigate in vivo changes in this receptor using single-photon-emission CT (SPECT) with 123I-5-iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380), a novel nicotinic acetylcholine receptor ligand which binds predominantly to the alpha4beta2 receptor. METHODS: 32 non-smoking subjects (16 with Alzheimer's disease and 16 normal elderly controls) underwent 123I-5IA-85380 and perfusion (99mTc-hexamethylenepropyleneamine oxime (HMPAO)) SPECT scanning. Region of interest analysis was performed with cerebellar normalisation. RESULTS: Significant bilateral reductions in nicotinic receptor binding were identified in frontal (left, p = 0.004; right, p = 0.002), striatal (left, p = 0.004; right, p = 0.003), right medial temporal (p = 0.04) and pons (p<0.001) in patients with AD compared to controls. There were no significant correlations with clinical or cognitive measures. The pattern of nicotinic binding significantly differed from that of perfusion in both patients with AD and controls. Both 123I-5IA-85380 and 99mTc-HMPAO SPECT imaging demonstrated similar diagnostic performance in correctly classifying controls and patients with AD. CONCLUSION: Using 123I-5IA-85380 SPECT we found changes consistent with significant reductions in the nicotinic alpha4beta2 receptor in cortical and striatal brain regions. This method could facilitate diagnosis and may be useful for monitoring progression of the disease and response to treatment in patients with AD and related diseases.

O'Brien JT, Colloby S, Fenwick J, Williams ED, Firbank M, Burn D, Aarsland D, McKeith IG. · Institute for Ageing and Health, Newcastle University, Wolfson Research Centre, Newcastle General Hospital, Newcastle upon Tyne, England. j.t.o' · Arch Neurol. · Pubmed #15210531 links to  free full text

Abstract: BACKGROUND: Dementia with Lewy bodies (DLB) is a common form of late-life dementia that can be difficult to differentiate from other disorders, especially Alzheimer disease (AD), during life. At autopsy the striatal dopaminergic transporter is reduced. OBJECTIVES: To examine the extent and pattern of dopamine transporter loss using iodine I 123-radiolabeled 2beta-carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (FP-CIT) with single-photon emission computed tomography (SPECT) in DLBs compared with other dementias and to assess its potential to enhance a differential diagnosis. DESIGN: Cohort study comparing FP-CIT with criterion standard of consensus clinical diagnosis. SETTING: General hospital. PARTICIPANTS: One hundred sixty-four older subjects (33 healthy older control subjects, 34 with NINCDS/ADRDA [National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association]-confirmed AD, 23 with consensus guideline-confirmed DLB, 38 with United Kingdom's Parkinson Disease Society Brain Bank-confirmed Parkinson disease [PD], and 36 with PD and dementia). INTERVENTIONS: Injection of (123)I-2beta-carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane with SPECT scan performed at 4 hours. MAIN OUTCOME MEASURES: Visual ratings of scans and region of interest analysis. RESULTS: Significant reductions (P<.001) in FP-CIT binding occurred in the caudate and anterior and posterior putamens in subjects with DLB compared with subjects with AD and controls. Transporter loss in DLBs was of similar magnitude to that seen in PD, but with a flatter rostrocaudal (caudate-putamen) gradient (P =.001), while the greatest loss in all 3 areas was seen in those who had PD and dementia. Both region of interest analysis and visual ratings provided good separation between DLBs and AD (region of interest: sensitivity, 78%; specificity, 94%; positive predictive value, 90%) but not among subjects with DLB, PD, and PD with dementia. CONCLUSIONS: Dopamine transporter loss can be detected in vivo using FP-CIT SPECT in DLB. Further studies, especially of subjects with DLB without PD, are required to fully establish use in clinical practice.

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.

O'Brien JT, Paling S, Barber R, Williams ED, Ballard C, McKeith IG, Gholkar A, Crum WR, Rossor MN, Fox NC. · Institute for the Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom. j.t.o' · Neurology. · Pubmed #11376193 No free full text.

Abstract: The authors determined rates of brain atrophy, as assessed by the boundary shift integral on serial MRI, in patients with dementia with Lewy Bodies (DLB, n = 10), AD (n = 9), vascular dementia (VaD, n = 9), and age-matched controls (n = 20). Mean % +/- SD atrophy rates per year were as follows: DLB, 1.4 +/- 1.1; AD, 2.0 +/- 0.9; VaD, 1.9 +/- 1.1; and controls, 0.5 +/- 0.7. Dementia subjects had higher rates than controls (p < 0.001), but there were no significant differences between the three dementia groups. The authors found accelerating atrophy with increasing severity of cognitive impairment, further emphasizing the need for early diagnosis and intervention in dementia.