Alzheimer Disease: Scahill RI

Scahill RI, Fox NC. · Dementia Research Centre, 8-11 Queen Square, London WC1N 3BG, UK. · Br J Radiol. · Pubmed #18445749 No free full text.

Abstract: Dementia represents one of the major public health problems facing ageing populations, with 20% of those over 80 years of age suffering from this disorder. The advent of therapeutic agents has brought about an increasing demand for a more accurate and earlier diagnosis, and the value of neuroimaging in improving the diagnostic process is becoming widely accepted. Neuroimaging assessments may add weight to a diagnosis of neurodegeneration as opposed to healthy ageing, improve the differential diagnosis, aid in the prediction of conversion to dementia in individuals at a higher risk of developing the disorder, track disease progression and provide an outcome measure for assessment of drug efficacy.

Barnes J, Scahill RI, Boyes RG, Frost C, Lewis EB, Rossor CL, Rossor MN, Fox NC. · Dementia Research Centre, Institute of Neurology, University College London, 8-11 Queen Square, WCIN 3BG, London, UK. · Neuroimage. · Pubmed #15488407 No free full text.

Abstract: Manual segmentation of the hippocampus is the gold standard in volumetric hippocampal magnetic resonance imaging (MRI) analysis; however, this is difficult to achieve reproducibly. This study explores whether application of local registration and calculation of the hippocampal boundary shift integral (HBSI) can reduce random variation compared with manual measures. Hippocampi were outlined on the baseline and registered-repeat MRIs of 32 clinically diagnosed Alzheimer's disease (AD) patients and 47 matched controls (37-86 years) with a wide range of scanning intervals (175-1173 days). The scans were globally registered using 9 degrees of freedom and subsequently locally registered using 6 degrees of freedom and HBSI was then calculated automatically. HBSI significantly reduced the mean rate (P < 0.01) and variation in controls (P < 0.001) and increased group separation between AD cases and controls. When comparing HBSI atrophy rates with manually derived atrophy rates at 90% sensitivity, specificities were 98% and 81%, respectively. From logistic regression models, a 1% increase in HBSI atrophy rates was associated with an 11-fold (CI 3, 36) increase in the odds of a diagnosis of AD. For manually derived atrophy rates, the equivalent odds ratio was 3 (CI 2,4). We conclude that HBSI-derived atrophy rates reduce operator time and error, and are at least as effective as the manual equivalent as a diagnostic marker and are a potential marker of progression in longitudinal studies and trials.

Good CD, Scahill RI, Fox NC, Ashburner J, Friston KJ, Chan D, Crum WR, Rossor MN, Frackowiak RS. · Wellcome Department of Cognitive Neurology, Institute of Neurology, University College London, 12 Queen Square, London WC1N 3BG, United Kingdom. · Neuroimage. · Pubmed #12482066 No free full text.

Abstract: We compared voxel-based morphometry (VBM) with independent accurate region-of-interest (ROI) measurements of temporal lobe structures in order to validate the usefulness of this fully automated and unbiased technique in Alzheimer's disease (AD) and semantic dementia (SD). In AD, ROI analyses appear more sensitive to volume loss in the amygdalae, whereas VBM analyses appear more sensitive to right middle temporal gyrus and regional hippocampal volume loss. In SD, ROI analyses appear more sensitive to left middle and inferior temporal gyrus volume loss, whereas VBM appears more sensitive to regional hippocampal volume loss. In addition the significance of volume reductions was generally less in VBM owing to more stringent corrections for multiple comparisons. In conclusion, the automated technique detects a general trend of atrophy similar to that of expertly labeled ROI measurements in AD and SD, although there are discrepancies in the ranking of severity and in the significance of volume reductions that are more marked in AD.

Camara O, Schnabel JA, Ridgway GR, Crum WR, Douiri A, Scahill RI, Hill DL, Fox NC. · Centre for Medical Image Computing, Department of Medical Physics and Bioengineering, University College London, WC1E 6BT, UK. · Neuroimage. · Pubmed #18571436 No free full text.

Abstract: The evaluation of atrophy quantification methods based on magnetic resonance imaging have been usually hindered by the lack of realistic gold standard data against which to judge these methods or to help refine them. Recently [Camara, O., Schweiger, M., Scahill, R., Crum, W., Sneller, B., Schnabel, J., Ridgway, G., Cash, D., Hill, D., Fox, N., 2006. Phenomenological model of diffuse global and regional atrophy using finite-element methods. IEEE Trans. Med.l Imaging 25, 1417-1430], we presented a technique in which atrophy is realistically simulated in different tissue compartments or neuroanatomical structures with a phenomenological model. In this study, we have generated a cohort of realistic simulated Alzheimer's disease (AD) images with known amounts of atrophy, mimicking a set of 19 real controls and 27 probable AD subjects, with an improved version of our atrophy simulation methodology. This database was then used to assess the accuracy of several well-known computational anatomy methods which provide global (BSI and SIENA) or local (Jacobian integration) estimates of longitudinal atrophy in brain structures using MR images. SIENA and BSI results correlated very well with gold standard data (Pearson coefficient of 0.962 and 0.969 respectively), achieving small mean absolute differences with respect to the gold standard (percentage change from baseline volume): BSI of 0.23%+/-0.26%; SIENA of 0.22%+/-0.28%. Jacobian integration was guided by both fluid and FFD-based registration techniques and resulting deformation fields and associated Jacobians were compared, region by region, with gold standard ones. The FFD-based technique outperformed the fluid one in all evaluated structures (mean absolute differences from the gold standard in percentage change from baseline volume): whole brain, FFD=0.31%, fluid=0.58%; lateral ventricles, FFD=0.79%; fluid=1.45%; left hippocampus, FFD=0.82%; fluid=1.42%; right hippocampus, FFD=0.95%; fluid=1.62%. The largest errors for both local techniques occurred in the sulcal CSF (FFD=2.27%; fluid=3.55%) regions. For large structures such as the whole brain, these mean absolute differences, relative to the applied atrophy, represented similar percentages for the BSI, SIENA and FFD techniques (controls/patients): BSI, 51.99%/16.36%; SIENA, 62.34%/21.59%; FFD, 41.02%/24.95%. For small structures such as the hippocampi, these percentages were larger, especially for controls where errors were approximately equal to the small applied changes (controls/patients): FFD, 92.82%/43.61%. However, these apparently large relative errors have not prevented the global or hippocampal measures from finding significant group separation in our study. The evaluation framework presented here will help in quantifying whether the accuracy of future methodological developments is sufficient for analysing change in smaller or less atrophied local brain regions. Results obtained in our experiments with realistic simulated data confirm previously published estimates of accuracy for both evaluated global techniques. Regarding Jacobian Integration methods, the FFD-based one demonstrated promising results and potential for being used in clinical studies alongside (or in place of) the more common global methods. The generated gold standard data has also allowed us to identify some stages and sets of parameters in the evaluated techniques--the brain extraction step in the global techniques and the number of multi-resolution levels and the stopping criteria in the registration-based methods--that are critical for their accuracy.

Barnes J, Foster J, Boyes RG, Pepple T, Moore EK, Schott JM, Frost C, Scahill RI, Fox NC. · Dementia Research Centre, UCL, Institute of Neurology, London, UK. · Neuroimage. · Pubmed #18353687 No free full text.

Abstract: Hippocampal atrophy rates have been used in a number of studies in Alzheimer's disease (AD) to assess disease progression and are being increasingly utilized as an outcome measure in clinical trials of new pharmaceutical agents. Owing to the labor-intensive nature of hippocampal segmentation, more automated approaches are required for such analysis. In this study we compared methods of automatically segmenting the hippocampus (single-person template and template library) on the baseline image in a group of probable AD (n=36) and control (n=19) subjects with serial images. Using the method that gave most similar results to manual, three automated methods of calculating change within the hippocampal region were compared: fluid change calculated using (1) Jacobian change or (2) region propagation and (3) boundary shift. Rates were compared with manual measures. We found that segmentation of baseline hippocampus was most accurate using a template library combined with morphological operations (intensity thresholding plus one conditional dilation). This gave a voxel similarity of 0.69 (0.05) and 0.72 (0.06) in controls and probable AD subjects respectively compared with manual measures. Atrophy rates within these regions were most similar to the manual rates using the boundary shift integral (mean difference from manual rate 0.03% (1.29) in controls and 0.48% (2.44) in AD). A template library segmentation approach, together with morphological operations, provides a segmentation accurate enough to quantify relative change over time. The change over time can then be calculated automatically using boundary shift or fluid measures, with boundary shift giving most similar results to manual.

Klöppel S, Stonnington CM, Chu C, Draganski B, Scahill RI, Rohrer JD, Fox NC, Jack CR, Ashburner J, Frackowiak RS. · Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, UK. · Brain. · Pubmed #18202106 links to  free full text

Abstract: To be diagnostically useful, structural MRI must reliably distinguish Alzheimer's disease (AD) from normal aging in individual scans. Recent advances in statistical learning theory have led to the application of support vector machines to MRI for detection of a variety of disease states. The aims of this study were to assess how successfully support vector machines assigned individual diagnoses and to determine whether data-sets combined from multiple scanners and different centres could be used to obtain effective classification of scans. We used linear support vector machines to classify the grey matter segment of T1-weighted MR scans from pathologically proven AD patients and cognitively normal elderly individuals obtained from two centres with different scanning equipment. Because the clinical diagnosis of mild AD is difficult we also tested the ability of support vector machines to differentiate control scans from patients without post-mortem confirmation. Finally we sought to use these methods to differentiate scans between patients suffering from AD from those with frontotemporal lobar degeneration. Up to 96% of pathologically verified AD patients were correctly classified using whole brain images. Data from different centres were successfully combined achieving comparable results from the separate analyses. Importantly, data from one centre could be used to train a support vector machine to accurately differentiate AD and normal ageing scans obtained from another centre with different subjects and different scanner equipment. Patients with mild, clinically probable AD and age/sex matched controls were correctly separated in 89% of cases which is compatible with published diagnosis rates in the best clinical centres. This method correctly assigned 89% of patients with post-mortem confirmed diagnosis of either AD or frontotemporal lobar degeneration to their respective group. Our study leads to three conclusions: Firstly, support vector machines successfully separate patients with AD from healthy aging subjects. Secondly, they perform well in the differential diagnosis of two different forms of dementia. Thirdly, the method is robust and can be generalized across different centres. This suggests an important role for computer based diagnostic image analysis for clinical practice.

Camara O, Scahill RI, Schnabel JA, Crum WR, Ridgway GR, Hill DL, Fox NC. · Centre for Medical Image Computing (CMIC), Department of Medical Physics and Bioengineering, University College London, London WC1E 6BT, UK. · Med Image Comput Comput Assist Interv Int Conf Med Image Comput Comput Assist Interv. · Pubmed #18044640 No free full text.

Abstract: The main goal of this work was to assess the accuracy of several well-known methods which provide global (BSI and SIENA) or local (Jacobian integration) estimates of longitudinal atrophy in brain structures using Magnetic Resonance images. For that purpose, we have generated realistic simulated images which mimic the patterns of change obtained from a cohort of 19 real controls and 27 probable Alzheimer's disease patients. SIENA and BSI results correlate very well with gold standard data (BSI mean absolute error < 0.29%; SIENA < 0.44%). Jacobian integration was guided by both fluid and FFD-based registration techniques and resulting deformation fields and associated Jacobians were compared, region by region, with gold standard ones. The FFD registration technique provided more satisfactory results than the fluid one. Mean absolute error differences between volume changes given by the FFD-based technique and the gold standard were: sulcal CSF < 2.49%; lateral ventricles < 2.25%; brain < 0.36%; hippocampi < 1.42%.

Barnes J, Lewis EB, Scahill RI, Bartlett JW, Frost C, Schott JM, Rossor MN, Fox NC. · Dementia Research Centre, University College London, Institute of Neurology, Queen Square, London, UK. · J Comput Assist Tomogr. · Pubmed #17882036 No free full text.

Abstract: OBJECTIVE: To assess hippocampal atrophy rates calculated from fluid registration methods. METHODS: Hippocampi were segmented on baseline and registered-repeat scans of 32 probable Alzheimer disease (AD) subjects and 55 controls. Fluid-based atrophy rates were calculated. RESULTS: In AD patients, the mean (SD) atrophy rates for manual, fluidly propagated, and Jacobian methods were 5.09 (3.59), 5.34 (3.43), and 3.55 (2.70) (percentage per year). In controls, atrophy rates were 1.31 (2.00), 0.89 (0.75), and 0.56 (1.12) (percentage per year). In AD, fluid propagation and manual rates were similar in means (P = 0.55) and variances (P = 0.71). Jacobian rates were smaller in mean (P = 0.002) and variance (P = 0.026) than in manual rates. In controls, fluid-propagated rates were similar in mean to manual rates (P = 0.12), but less variable (P < 0.0001). Jacobian rates were smaller in mean (P = 0.014) and less variable (P < 0.0001) than in manual rates. Both fluid methods were superior to manual measures in separating AD from controls (P < 0.0001). CONCLUSIONS: Fluid-based methods may be useful in large serial hippocampal studies.

Barnes J, Scahill RI, Frost C, Schott JM, Rossor MN, Fox NC. · Dementia Research Centre, UCL, Institute of Neurology, London, United Kingdom. · Neurobiol Aging. · Pubmed #17368654 No free full text.

Abstract: We measured hippocampi on baseline-, 6- and 12-month scans in a group of AD (n=36) and control subjects (n=20). We found that mean annualised atrophy rates using 6-month intervals were comparable at a group level to those generated from a 12-month interval. Higher variance was seen using shorter intervals, although this was only significant in the control group. This has implications where shorter inter-scan intervals may be advantageous, such as rapid diagnosis, and tracking of disease progression including in a clinical trial.

Camara-Rey O, Schweiger M, Scahill RI, Crum WR, Schnabell JA, Hill DL, Fox NC. · Center of Medical Image Computing, Unviersity College of London, UK. · Med Image Comput Comput Assist Interv Int Conf Med Image Comput Comput Assist Interv. · Pubmed #17354863 No free full text.

Abstract: We propose a method for atrophy simulation in structural MR images based on finite-element methods, providing data for objective evaluation of atrophy measurement techniques. The modelling of diffuse global and regional atrophy is based on volumetric measurements from patients with known disease and guided by clinical knowledge of the relative pathological involvement of regions. The consequent biomechanical readjustment of structures is modelled using conventional physics-based techniques based on tissue properties and simulating plausible deformations with finite-element methods. Tissue characterization is performed by means of the meshing of a labelled brain atlas, creating a reference volumetric mesh, and a partial volume tissue model is used to reduce the impact of the mesh discretization. An example of simulated data is shown and a visual evaluation protocol used by experts has been developed to assess the degree of realism of the simulated images. First results demonstrate the potential of the proposed methodology.

van de Pol LA, Barnes J, Scahill RI, Frost C, Lewis EB, Boyes RG, van Schijndel RA, Scheltens P, Fox NC, Barkhof F. · Department of Neurology, Alzheimer Centre, VU Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · Neuroimage. · Pubmed #17174572 No free full text.

Abstract: MRI-derived rates of hippocampal atrophy may serve as surrogate markers of disease progression in mild cognitive impairment (MCI). Manual delineation is the gold standard in hippocampal volumetry; however, this technique is time-consuming and subject to errors. We aimed to compare regional non-linear (fluid) registration measurement of hippocampal atrophy rates against manual delineation in MCI. Hippocampi of 18 subjects were manually outlined twice on MRI scan-pairs (interval+/-SD: 2.01+/-0.11 years), and volumes were subtracted to calculate change over time. Following global affine and local rigid registration, regional fluid registration was performed from which atrophy rates were derived from the Jacobian determinants over the hippocampal region. Atrophy rates as derived by fluid registration were computed using both forward (repeat onto baseline) and backward (baseline onto repeat) registration. Reliability for both methods and agreement between methods was assessed. Mean+/-SD hippocampal atrophy rates (%/year) derived by manual delineation were: left: 2.13+/-1.62; right: 2.36+/-1.78 and for regional fluid registration: forward: left: 2.39+/-1.68; right: 2.49+/-1.52 and backward: left: 2.21+/-1.51; right: 2.42+/-1.49. Mean hippocampal atrophy rates did not differ between both methods. Reliability for manual hippocampal volume measurements (cross-sectional) was high (intraclass correlation coefficient (ICC): baseline and follow-up, left and right, >0.99). However, the resulting ICC for manual measurements of hippocampal volume change (longitudinal) was considerably lower (left: 0.798; right: 0.850) compared with regional fluid registration (forward: left: 0.985; right: 0.988 and backward: left: 0.975; right: 0.989). We conclude that regional fluid registration is more reliable than manual delineation in assessing hippocampal atrophy rates, without sacrificing sensitivity to change. This method may be useful to quantify hippocampal volume change, given the reduction in operator time and improved precision.

Camara O, Schweiger M, Scahill RI, Crum WR, Sneller BI, Schnabel JA, Ridgway GR, Cash DM, Hill DL, Fox NC. · Centre for Medical Image Computing (CMIC), Department of Medical Physics and Bioengineering, Department of Computer Science, University College London, London WCEI 6BT, UK. · IEEE Trans Med Imaging. · Pubmed #17117771 No free full text.

Abstract: The main goal of this work is the generation of ground-truth data for the validation of atrophy measurement techniques, commonly used in the study of neurodegenerative diseases such as dementia. Several techniques have been used to measure atrophy in cross-sectional and longitudinal studies, but it is extremely difficult to compare their performance since they have been applied to different patient populations. Furthermore, assessment of performance based on phantom measurements or simple scaled images overestimates these techniques' ability to capture the complexity of neurodegeneration of the human brain. We propose a method for atrophy simulation in structural magnetic resonance (MR) images based on finite-element methods. The method produces cohorts of brain images with known change that is physically and clinically plausible, providing data for objective evaluation of atrophy measurement techniques. Atrophy is simulated in different tissue compartments or in different neuroanatomical structures with a phenomenological model. This model of diffuse global and regional atrophy is based on volumetric measurements such as the brain or the hippocampus, from patients with known disease and guided by clinical knowledge of the relative pathological involvement of regions and tissues. The consequent biomechanical readjustment of structures is modelled using conventional physics-based techniques based on biomechanical tissue properties and simulating plausible tissue deformations with finite-element methods. A thermoelastic model of tissue deformation is employed, controlling the rate of progression of atrophy by means of a set of thermal coefficients, each one corresponding to a different type of tissue. Tissue characterization is performed by means of the meshing of a labelled brain atlas, creating a reference volumetric mesh that will be introduced to a finite-element solver to create the simulated deformations. Preliminary work on the simulation of acquisition artefacts is also presented. Cross-sectional and longitudinal sets of simulated data are shown and a visual classification protocol has been used by experts to rate real and simulated scans according to their degree of atrophy. Results confirm the potential of the proposed methodology.

Barnes J, Boyes RG, Lewis EB, Schott JM, Frost C, Scahill RI, Fox NC. · Dementia Research Centre, UCL, Institute of Neurology, London, UK. · Neurobiol Aging. · Pubmed #16934913 No free full text.

Abstract: We describe a method of automatically calculating hippocampal atrophy rates on T1-weighted MR images without manual delineation of hippocampi. This method was applied to a group of Alzheimer's disease (AD) (n=36) and control (n=19) subjects and compared with manual methods (manual segmentation of baseline and repeat-image hippocampi) and semi-automated methods (manual segmentation of baseline hippocampi only). In controls, mean (S.D.) atrophy rates for manual, semi-automated, and automated methods were 18.1 (53.5), 15.3 (50.2) and 11.3 (50.4) mm3 loss per year, respectively. In AD patients these rates were 174.6 (106.5) 159.4 (101.2) and 172.1 (123.1) mm3 loss per year, respectively. The automated method was a significant predictor of disease (p=0.001) and gave similar group discrimination compared with both semi-automated and manual methods. The automated hippocampal analysis in this small study took approximately 20 min per hippocampal pair on a 3.4 GHz Intel Xeon server, whereas manual delineation of each hippocampal pair took approximately 90 min of operator-intensive labour. This method may be useful diagnostically or in studies where analysis of many scans may be required.

Barnes J, Godbolt AK, Frost C, Boyes RG, Jones BF, Scahill RI, Rossor MN, Fox NC. · Dementia Research Centre, University College London, Institute of Neurology, Queen Square, London, UK. · Neurobiol Aging. · Pubmed #16406154 No free full text.

Abstract: This study explores the diagnostic utility of atrophy rates of the cingulate gyrus, its subdivisions and the hippocampus in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Regions were manually outlined on MR images of a group of pathologically or genetically confirmed patients with AD (n=19), FTLD (n=8) and age-matched controls (n=11). Mean (S.D.) atrophy rates (%year(-1)) in the cingulate in controls, AD and FTLD were -0.3 (1.2), 5.9 (3.5), and 8.6 (4.1), respectively. Hippocampal atrophy rates in controls, AD and FTLD were -0.1 (0.8), 3.4 (2.2), and 5.2 (5.4), respectively. Atrophy rates were significantly higher in the cingulate and hippocampi in AD and FTLD compared with controls (p<0.01). There was evidence of a difference in trends of atrophy in the cingulate (more anterior in FTLD and more posterior in AD) between the disease groups (p=0.03). Cingulate atrophy rates discriminated perfectly between FTLD and controls. Significantly better discrimination between AD and controls was obtained by hippocampal rather than cingulate rates. In conclusion, cingulate atrophy is as significant a feature of AD and FTLD as hippocampal atrophy.

Barnes J, Scahill RI, Schott JM, Frost C, Rossor MN, Fox NC. · Dementia Research Centre, Department of Clinical Neurology, Institute of Neurology, University College London, London, UK. · Dement Geriatr Cogn Disord. · Pubmed #15785035 No free full text.

Abstract: OBJECTIVE: To determine whether Alzheimer's disease (AD) is associated with preferential atrophy of either the left or right hippocampus. METHODS: We examined right-left asymmetry in hippocampal volume and atrophy rates in 32 subjects with probable AD and 50 age-matched controls. Hippocampi were measured on two serial volumetric MRI scans using a technique that minimizes laterality bias. RESULTS: We found a non-significant trend for right > left (R > L) asymmetry in controls at both time points (R > L: 1.7%; CI: -0.3-3.7%; p = 0.1). AD subjects showed a similar non-significant trend for R > L asymmetry at baseline (R > L: 1.8%; CI: -1.9-5.5%; p = 0.32), but not at repeat (p = 0.739). Change in R/L ratio between visits in AD patients was significant (p = 0.02). The AD group had significantly higher variance in these ratios than the controls at baseline (p = 0.02), but not repeat (p = 0.06). AD patients had higher atrophy rates than controls (p < 0.001). Mean (CI) annualized atrophy rates for left and right hippocampi were 1.2% (0.5-1.8%) and 1.1% (0.5-1.8%) for the controls, and 4.6% (3.3-6.0%) and 6.3% (4.9-7.8%) for AD subjects. There was no significant asymmetry in atrophy rates in controls (p = 0.9), but borderline significantly higher atrophy rates in the right hippocampus of the AD group (p = 0.05) compared to the left. Presence of an APOEepsilon4 allele had no significant effect on the size, asymmetry or atrophy rates in AD (p > 0.20). CONCLUSIONS: We report minor R > L asymmetry in hippocampal volumes in controls and present some evidence to suggest that there is a change in the natural R > L asymmetry during the progression of AD.

Schott JM, Fox NC, Frost C, Scahill RI, Janssen JC, Chan D, Jenkins R, Rossor MN. · Dementia Research Group, Institute of Neurology, University College London, Queen Square, United Kingdom. · Ann Neurol. · Pubmed #12557284 No free full text.

Abstract: Regional and global cerebral atrophy are inevitable features of Alzheimer's disease (AD). We assessed volumes and atrophy rates of brain structures in patients with familial AD during the period that they developed symptoms. Five patients with presymptomatic AD and 20 controls had two or more annual volumetric MRI brain scans. Volumes of brain, ventricles, temporal lobes, hippocampi, and entorhinal cortices (ECs) were measured. Rates of volume change were calculated from serial scans. There were no significant differences in baseline measures of whole brain, temporal lobe, or ventricular volume between patients and controls; averaged volumes of medial temporal lobe structures (both hippocampi and ECs) were 16.6% (95% confidence interval [CI], 3.3-28.0%) lower in patients. Atrophy rates for brain, temporal lobe, hippocampus, and EC were significantly increased in patients compared with controls (p < 0.05). Averaged atrophy rates from both hippocampi and ECs were 5.1% (95% CI, 3.0-7.1%) greater in patients than controls. Linear extrapolation backward suggested medial temporal lobe atrophy commenced 3.5 years (95% CI, 0.7-7.5 years) before onset, when all patients were asymptomatic. We conclude that increased medial temporal lobe atrophy rates are an early and distinguishing feature of AD and that pathological atrophy probably is occurring several years before the onset of symptoms.

Scahill RI, Schott JM, Stevens JM, Rossor MN, Fox NC. · Dementia Research Group, Department of Clinical Neurology, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, United Kingdom. · Proc Natl Acad Sci U S A. · Pubmed #11930016 links to  free full text

Abstract: Alzheimer's disease (AD) is characterized by progressive cerebral atrophy, which may be assessed by using volumetric MRI. We describe a voxel-based analysis of nonlinear-registered serial MRI to demonstrate the most statistically significant (P < 0.001) regions of change at different stages of the disease. We compared presymptomatic (n = 4), mild (n = 10), and moderately affected (n = 12) patients with early- and late-onset AD, with age- and sex-matched controls, and demonstrated increasing global atrophy with advancing disease. Significantly increased rates of hippocampal atrophy were seen in presymptomatic and mildly affected patients. There was a shift in the distribution of temporal lobe atrophy with advancing disease; the inferolateral regions of the temporal lobes showed the most significantly increased rates of atrophy by the time the patients were mildly or moderately affected. Significantly increased rates of medial parietal lobe atrophy were seen at all stages, with frontal lobe involvement occurring later in the disease. Our results suggest that the sites showing the most significant rates of atrophy alter as the disease advances, and that regional atrophy is already occurring before the onset of symptoms. This technique provides insights into the natural history of AD, and may be a valuable tool in assessing the efficacy of disease-modifying treatments, especially if these treatments were to have region-specific effects.

Høgh P, Smith SJ, Scahill RI, Chan D, Harvey RJ, Fox NC, Rossor MN. · Dementia Research Group, Department of Clinical Neurology, Institute of Neurology, Queen Square, London, UK. · Neurology. · Pubmed #11805262 No free full text.

Abstract: Three patients with progressive memory impairment initially attributed to AD underwent serial neuropsychometry, MRI, and EEG. Registered serial MRI volumetric analysis showed no loss of whole or regional brain volume. EEG revealed temporal lobe spike activity and antiepileptic treatment was optimized. Memory functions improved with antiepileptic medication in all three patients. The demonstration of temporal lobe spike activity in patients with progressive memory impairment is an indication for a trial of antiepileptic medication.

Chan D, Fox NC, Jenkins R, Scahill RI, Crum WR, Rossor MN. · Dementia Research Group, Department of Clinical Neurology, Institute of Neurology, London, UK. · Neurology. · Pubmed #11723259 No free full text.

Abstract: OBJECTIVE: Serial registered MRI provides a reproducible technique for detecting progressive cerebral atrophy in vivo and was used to determine if there were differences between the rates of cerebral atrophy in AD and frontotemporal dementia (FTD). METHODS: Eighty-four patients with dementia (54 AD and 30 FTD) and 27 age-matched control subjects each had at least two volumetric MR scans. Serial scans were positionally matched (registered), and brain volume loss was determined by calculation of the brain boundary shift integral. RESULTS: There was a difference between the rates of whole-brain atrophy in patients (mean annual volume loss 2.7% of total brain volume) and in control subjects (mean annual volume loss 0.5%). AD and FTD were associated with different rates of atrophy (mean annual losses 2.4 and 3.2%). The range of atrophy rates in the FTD group (0.3 to 8.0%) greatly exceeded that in the AD group (0.5 to 4.7%). Frontal-variant FTD was associated with a wider range of atrophy rates than temporal-variant FTD. Analysis of regional brain atrophy rates revealed that there was widespread symmetrically distributed cerebral volume loss in AD, whereas in frontal FTD there was greater atrophy anteriorly and in temporal FTD the atrophy rate was greatest in the left anterior cerebral cortex. CONCLUSIONS: Both AD and FTD patients had increased rates of brain atrophy. Whereas the patients with AD were associated with a relatively restricted spread of atrophy rates, the greater spread of rates observed in the patients with FTD may reflect the heterogeneity of disease in FTD, with differences observed between frontal and temporal FTD. Increased rates of whole-brain atrophy did not discriminate AD from FTD, but analysis of regional atrophy rates revealed marked differences between patient groups.

Fox NC, Crum WR, Scahill RI, Stevens JM, Janssen JC, Rossor MN. · Dementia Research Group, Department of Clinical Neurology, Institute of Neurology, University College London, London, UK. · Lancet. · Pubmed #11476837 No free full text.

Abstract: BACKGROUND: Early diagnosis and monitoring of the progression of Alzheimer's disease is important for the development of therapeutic strategies. To detect the earliest structural brain changes, individuals need to be studied before symptom onset. We used an imaging technique known as voxel-compression mapping to localise progressive atrophy in patients with preclinical Alzheimer's disease. METHODS: Four symptom-free individuals from families with early-onset Alzheimer's disease with known autosomal dominant mutations underwent serial magnetic resonance imaging (MRI) over 5-8 years. All four became symptomatic during follow-up. 20 individuals with a clinical diagnosis of probable Alzheimer's disease and 20 control participants also underwent serial MR imaging. A non-linear fluid matching algorithm was applied to register repeat scans onto baseline imaging. Jacobian determinants were used to create the voxel-compression maps. FINDINGS: Progressive atrophy was revealed in presymptomatic individuals, with posterior cingulate and neocortical temporoparietal cortical losses, and medial temporal-lobe atrophy. In patients with known Alzheimer's disease, atrophy was widespread apart from in the primary motor and sensory cortices and cerebellum, reflecting the clinical phenomenology. INTERPRETATION: Voxel-compression maps confirmed early involvement of the medial temporal lobes, but also showed posterior cingulate and temporoparietal cortical losses at presymptomatic stage. This technique could be applied diagnostically and used to monitor the effects of therapeutic intervention.

Chan D, Fox NC, Scahill RI, Crum WR, Whitwell JL, Leschziner G, Rossor AM, Stevens JM, Cipolotti L, Rossor MN. · Department of Clinical Neurology, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, London, UK. · Ann Neurol. · Pubmed #11310620 No free full text.

Abstract: Volumetric magnetic resonance imaging analyses of 30 subjects were undertaken to quantify the global and temporal lobe atrophy in semantic dementia and Alzheimer's disease. Three groups of 10 subjects were studied: semantic dementia patients, Alzheimer's disease patients, and control subjects. The temporal lobe structures measured were the amygdala, hippocampus, entorhinal cortex, parahippocampal gyrus, fusiform gyrus, and superior, middle, and inferior temporal gyri. Semantic dementia and Alzheimer's disease groups did not differ significantly on global atrophy measures. In semantic dementia, there was asymmetrical temporal lobe atrophy, with greater left-sided damage. There was an anteroposterior gradient in the distribution of temporal lobe atrophy, with more marked atrophy anteriorly. All left anterior temporal lobe structures were affected in semantic dementia, with the entorhinal cortex, amygdala, middle and inferior temporal gyri, and fusiform gyrus the most severely damaged. Asymmetrical, predominantly anterior hippocampal atrophy was also present. In Alzheimer's disease, there was symmetrical atrophy of the entorhinal cortex, hippocampus, and amygdala, with no evidence of an anteroposterior gradient in the distribution of temporal lobe or hippocampal atrophy. These data demonstrate that there is a marked difference in the distribution of temporal lobe atrophy in semantic dementia and Alzheimer's disease. In addition, the pattern of atrophy in semantic dementia suggests that semantic memory is subserved by anterior temporal lobe structures, within which the middle and inferior temporal gyri may play a key role.

Crum WR, Scahill RI, Fox NC. · Dementia Research Group, Institute of Neurology, 8-11 Queen Square, London, WC1N 3BG, United Kingdom. · Neuroimage. · Pubmed #11304081 No free full text.

Abstract: The application of voxel-level three-dimensional registration to serial magnetic resonance imaging (MRI) is described. This fluid registration determines deformation fields modeling brain change, which are consistent with a model describing a viscous fluid. The objective was to validate the measurement of hippocampal volumetric change by fluid registration in Alzheimer's disease (AD) against current methodologies. The hippocampus was chosen for this study because it is difficult to measure reproducibly by manual segmentation and is widely studied; however, the technique is applicable to any structure which can be delineated on a scan. First, suitable values for the viscosity-body-force-ratio, alpha (0.01), and the number of iterations (300), were established and the convergence, repeatability, linearity, and accuracy investigated and compared with expert manual segmentation. A simple model of hippocampal atrophy was used to compare simulated volumetric change against that obtained by fluid registration. Finally the serial segmentation was compared with the current gold standard technique-expert human labeling with a volume repeatability of approximately 4%-in 27 subjects (15 normal controls, 12 clinically diagnosed with Alzheimer's disease). The scan-rescan volumetric consistency of serial segmentation by fluid-registration was shown to be superior to human serial segmentors ( approximately 2%). The mean absolute volume difference between fluid and manual segmentation was 0.7%. Fluid registration has potential importance for tracking longitudinal structural changes in brain particularly in the context of the clinical trial where large numbers of subjects may have multiple MR scans.

Fox NC, Scahill RI, Crum WR, Rossor MN. · Department of Clinical Neurology, Institute of Neurology, University College, London, UK. · Neurology. · Pubmed #10331700 No free full text.

Abstract: Twenty-nine untreated patients diagnosed with probable AD and 15 control patients underwent two or more clinical and volumetric MRI assessments with intervals ranging from 5 months to 6 years. The change in global cerebral volume for an individual was calculated by a novel method of registration and subtraction of serial scans. Rate of global cerebral volume loss correlated strongly with rate of change in Mini-Mental State Examination scores (r = 0.80, p < 0.001), implying clinical relevance to this marker of progression.