Alzheimer Disease: Barnes J

Ridha BH, Anderson VM, Barnes J, Boyes RG, Price SL, Rossor MN, Whitwell JL, Jenkins L, Black RS, Grundman M, Fox NC. · Dementia Research Centre, Institute of Neurology, University College London, 8-11 Queen Square, London, WC1N 3BG, UK. · J Neurol. · Pubmed #18274807 No free full text.

Abstract: BACKGROUND : Both cognitive tests and MRI-based measures have been suggested as outcomes in trials assessing disease-modifying therapies in Alzheimer's disease (AD). OBJECTIVE : To compare changes in longitudinal MRI measures with changes in performance on cognitive tests routinely used in AD clinical trials. METHOD : Fifty-two subjects from the placebo-arm of a clinical trial in mild-to-moderate AD had volumetric T(1)-weighted scans and cognitive tests including the Mini-Mental State Examination (MMSE), AD Assessment Scale-Cognitive Subscale, Disability Assessment for Dementia, AD Cooperative Study-Clinical Global Impression of Change and Clinical Dementia Rating at baseline and one-year later. Rates of brain atrophy and ventricular enlargement were measured using the boundary shift integral. Hippocampal (Hc) atrophy was calculated from manual volume measurements. The relationships between MRI and cognitive measures were investigated. RESULTS : Rates of brain atrophy and/or ventricular enlargement were correlated with declining performance on cognitive scales. The strongest association was between brain atrophy rate and MMSE decline (r = 0.59, p < 0.0001). Hc atrophy rate was not significantly correlated with any of the cognitive scales. CONCLUSION : The lack of correlation between Hc atrophy and cognitive scales may reflect a combination of: the extensive functional damage to the Hc by the time AD is clinically established, the greater influence of ongoing cortical degeneration, and errors in Hc outlining. The strong correlations between brain atrophy and ventricular enlargement, and cognitive scales probably reflect the correspondence between these measures of overall cerebral loss and global cognitive measures in the moderate stages of AD.

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.

Henneman WJ, Sluimer JD, Barnes J, van der Flier WM, Sluimer IC, Fox NC, Scheltens P, Vrenken H, Barkhof F. · Department of Radiology, VU University Medical Center, Amsterdam, The Netherlands. · Neurology. · Pubmed #19289740 No free full text.

Abstract: OBJECTIVE: To investigate the added value of hippocampal atrophy rates over whole brain volume measurements on MRI in patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI), and controls. METHODS: We included 64 patients with AD (67 +/- 9 years; F/M 38/26), 44 patients with MCI (71 +/- 6 years; 21/23), and 34 controls (67 +/- 9 years; 16/18). Two MR scans were performed (scan interval: 1.8 +/- 0.7 years; 1.0 T), using a coronal three-dimensional T1-weighted gradient echo sequence. At follow-up, 3 controls and 23 patients with MCI had progressed to AD. Hippocampi were manually delineated at baseline. Hippocampal atrophy rates were calculated using regional, nonlinear fluid registration. Whole brain baseline volumes and atrophy rates were determined using automated segmentation and registration tools. RESULTS: All MRI measures differed between groups (p < 0.005). For the distinction of MCI from controls, larger effect sizes of hippocampal measures were found compared to whole brain measures. Between MCI and AD, only whole brain atrophy rate differed significantly. Cox proportional hazards models (variables dichotomized by median) showed that within all patients without dementia, hippocampal baseline volume (hazard ratio [HR]: 5.7 [95% confidence interval: 1.5-22.2]), hippocampal atrophy rate (5.2 [1.9-14.3]), and whole brain atrophy rate (2.8 [1.1-7.2]) independently predicted progression to AD; the combination of low hippocampal volume and high atrophy rate yielded a HR of 61.1 (6.1-606.8). Within patients with MCI, only hippocampal baseline volume and atrophy rate predicted progression. CONCLUSION: Hippocampal measures, especially hippocampal atrophy rate, best discriminate mild cognitive impairment (MCI) from controls. Whole brain atrophy rate discriminates Alzheimer disease (AD) from MCI. Regional measures of hippocampal atrophy are the strongest predictors of progression to AD.

Klöppel S, Stonnington CM, Barnes J, Chen F, Chu C, Good CD, Mader I, Mitchell LA, Patel AC, Roberts CC, Fox NC, Jack CR, Ashburner J, Frackowiak RS. · Department of Psychiatry and Psychotherapy and Freiburg Brain Imaging, University Clinic Freiburg, Freiburg, Germany. · Brain. · Pubmed #18835868 links to  free full text

Abstract: There has been recent interest in the application of machine learning techniques to neuroimaging-based diagnosis. These methods promise fully automated, standard PC-based clinical decisions, unbiased by variable radiological expertise. We recently used support vector machines (SVMs) to separate sporadic Alzheimer's disease from normal ageing and from fronto-temporal lobar degeneration (FTLD). In this study, we compare the results to those obtained by radiologists. A binary diagnostic classification was made by six radiologists with different levels of experience on the same scans and information that had been previously analysed with SVM. SVMs correctly classified 95% (sensitivity/specificity: 95/95) of sporadic Alzheimer's disease and controls into their respective groups. Radiologists correctly classified 65-95% (median 89%; sensitivity/specificity: 88/90) of scans. SVM correctly classified another set of sporadic Alzheimer's disease in 93% (sensitivity/specificity: 100/86) of cases, whereas radiologists ranged between 80% and 90% (median 83%; sensitivity/specificity: 80/85). SVMs were better at separating patients with sporadic Alzheimer's disease from those with FTLD (SVM 89%; sensitivity/specificity: 83/95; compared to radiological range from 63% to 83%; median 71%; sensitivity/specificity: 64/76). Radiologists were always accurate when they reported a high degree of diagnostic confidence. The results show that well-trained neuroradiologists classify typical Alzheimer's disease-associated scans comparable to SVMs. However, SVMs require no expert knowledge and trained SVMs can readily be exchanged between centres for use in diagnostic classification. These results are encouraging and indicate a role for computerized diagnostic methods in clinical practice.

Hua X, Leow AD, Lee S, Klunder AD, Toga AW, Lepore N, Chou YY, Brun C, Chiang MC, Barysheva M, Jack CR, Bernstein MA, Britson PJ, Ward CP, Whitwell JL, Borowski B, Fleisher AS, Fox NC, Boyes RG, Barnes J, Harvey D, Kornak J, Schuff N, Boreta L, Alexander GE, Weiner MW, Thompson PM, Alzheimer's Disease Neuroimaging Initiative. · Laboratory of Neuro Imaging, Department of Neurology, UCLA School of Medicine, Neuroscience Research Building 225E, Los Angeles, CA 90095-1769, USA. · Neuroimage. · Pubmed #18378167 links to  free full text

Abstract: Tensor-based morphometry (TBM) creates three-dimensional maps of disease-related differences in brain structure, based on nonlinearly registering brain MRI scans to a common image template. Using two different TBM designs (averaging individual differences versus aligning group average templates), we compared the anatomical distribution of brain atrophy in 40 patients with Alzheimer's disease (AD), 40 healthy elderly controls, and 40 individuals with amnestic mild cognitive impairment (aMCI), a condition conferring increased risk for AD. We created an unbiased geometrical average image template for each of the three groups, which were matched for sex and age (mean age: 76.1 years+/-7.7 SD). We warped each individual brain image (N=120) to the control group average template to create Jacobian maps, which show the local expansion or compression factor at each point in the image, reflecting individual volumetric differences. Statistical maps of group differences revealed widespread medial temporal and limbic atrophy in AD, with a lesser, more restricted distribution in MCI. Atrophy and CSF space expansion both correlated strongly with Mini-Mental State Exam (MMSE) scores and Clinical Dementia Rating (CDR). Using cumulative p-value plots, we investigated how detection sensitivity was influenced by the sample size, the choice of search region (whole brain, temporal lobe, hippocampus), the initial linear registration method (9- versus 12-parameter), and the type of TBM design. In the future, TBM may help to (1) identify factors that resist or accelerate the disease process, and (2) measure disease burden in treatment trials.

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.

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.

Ridha BH, Barnes J, van de Pol LA, Schott JM, Boyes RG, Siddique MM, Rossor MN, Scheltens P, Fox NC. · Dementia Research Centre, Institute of Neurology, University College London, WC1N 3BG, England. · Arch Neurol. · Pubmed #17562933 links to  free full text

Abstract: OBJECTIVE: To compare an automated intensity-based measure of medial temporal atrophy in Alzheimer disease (AD) with existing volumetric and visually based methods. DESIGN: Longitudinal study comparing a medial temporal atrophy measure with 2 criterion standards: (1) total hippocampal (HC) volume adjusted for total intracranial volume and (2) standard visual rating scale of medial temporal atrophy. SETTING: Cognitive disorders specialist clinic. PARTICIPANTS: Forty-seven patients with AD and 26 age- and sex-matched controls. INTERVENTION: Subjects were scanned using volumetric T1-weighted magnetic resonance imaging at baseline and 1 year later. MAIN OUTCOME MEASURE: Automated Medial Temporal Lobe Atrophy Scale (ATLAS) score, derived from dividing mean intensity of a standardized perihippocampal volume by that of a standardized pontine volume. RESULTS: Patients with AD had significantly reduced ATLAS scores and HC volumes and increased visual rating scores at baseline and repeat scanning. Rates of HC atrophy and decline in the ATLAS score were significantly higher in patients with AD compared with controls. The ATLAS scores were significantly correlated with HC volumes and visual rating scores. With specificity set at 85%, the sensitivities of HC volume and visual rating scale score were similar (84% and 86%, respectively), whereas ATLAS score had a lower sensitivity (73%). At repeat scanning, all 3 measures had similar sensitivities (86%-87%). Rate of decline in the ATLAS score required a similar sample size to HC atrophy rate to provide statistical power to clinical trials, but being automated, it is less labor intensive. CONCLUSIONS: Like the visual rating scale, ATLAS is a simple medial temporal atrophy measure, which has the additional advantage of being able to track AD progression on serial imaging.

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.

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.

Barnes J, Whitwell JL, Frost C, Josephs KA, Rossor M, Fox NC. · Dementia Research Centre, University College London, Institute of Neurology, London, England. · Arch Neurol. · Pubmed #17030660 links to  free full text

Abstract: BACKGROUND: Differentiating between Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) can be difficult, particularly in the earliest stages of the diseases. Patterns of atrophy on magnetic resonance imaging may help distinguish these diseases and aid diagnosis. OBJECTIVE: To assess the diagnostic utility of magnetic resonance imaging-derived amygdala and hippocampal volumes from patients with pathologically proved AD and FTLD. DESIGN: Cross-sectional volumetric magnetic resonance imaging study of the hippocampus and amygdala. SETTING: Specialist cognitive disorders clinic.Subjects Thirty-seven subjects, including 10 patients with pathologically proved AD, 17 patients with pathologically proved FTLD, and 10 age-matched control subjects. MAIN OUTCOME MEASURES: Hippocampal and amygdala volumes. RESULTS: Geometric mean amygdala and hippocampal volumes were, respectively, 15.0% (95% confidence interval [CI], 4.2%-24.5%) and 16.4% (95% CI, 5.9%-25.6%) lower in the AD than in the control group. In FTLD, the equivalent differences were 43.1% (95% CI, 31.9%-52.6%) in the amygdala and 36.1% (95% CI, 27.5%-43.7%) in the hippocampus. Volumes were significantly lower in the FTLD than in the AD group (P<.01 in both regions). Within the FTLD clinical subgroups, there was evidence of a difference in pattern of atrophy with greater asymmetry (left smaller than right) in semantic dementia compared with frontal variant FTLD (P<.001). On average, the left hippocampus was 14% smaller in semantic dementia than in frontal variant FTLD, whereas the right hippocampus was 37% larger. On average, the left amygdala was 39% smaller in semantic dementia than in frontal variant FTLD, whereas the right amygdala was only 1% smaller. CONCLUSIONS: Hippocampal atrophy is not specific to AD or FTLD. However, severe or asymmetrical amygdala atrophy should suggest FTLD. Atrophy patterns follow clinical syndromes rather than pathology.

Ridha BH, Barnes J, Bartlett JW, Godbolt A, Pepple T, Rossor MN, Fox NC. · Dementia Research Centre, University College London, Institute of Neurology, London, UK. · Lancet Neurol. · Pubmed #16987729 No free full text.

Abstract: BACKGROUND: Serial MRI scanning of autosomal dominant mutation carriers for Alzheimer's disease provides an opportunity to track changes that could predate symptoms or clinical diagnosis of the disease. We used hierarchical modelling to assess how hippocampal and whole-brain volumes change as familial Alzheimer's disease progresses from the presymptomatic stage through to diagnosis. METHODS: Nine mutation carriers had serial clinical assessments and volumetric MRI scans (41 scans: range 3-8 per patient) at different clinical stages (presymptomatic, mild cognitive impairment, or clinical Alzheimer's disease). 25 healthy controls had serial scanning (54 scans: range 2-4 per patient) for comparison. We measured whole brain and total hippocampal volumes using semi-automated techniques, and adjusted for total intracranial volume. Hierarchical models were developed to estimate differences in volume and atrophy rate between mutation carriers and controls in relation to when the disease was clinically diagnosed. FINDINGS: Mutation carriers had significantly increased hippocampal and whole-brain atrophy rates compared with controls and these differences increased with time. Differences in hippocampal and whole-brain atrophy rates between controls and mutation carriers were evident 5.5 and 3.5 years, respectively, before diagnosis of Alzheimer's disease. At a cross-sectional level, differences in mean hippocampal volume between mutation carriers and controls became significant 3 years before clinical diagnosis, whereas differences in mean brain volumes became significant only 1 year before diagnosis. INTERPRETATION: Structural changes can be seen on MRI scans that predate the clinical onset of familial Alzheimer's disease. Longitudinal measures of atrophy rates can identify differences between mutation carriers and controls 2-3 years earlier than cross-sectional volumetric measures.

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.

Archer HA, Edison P, Brooks DJ, Barnes J, Frost C, Yeatman T, Fox NC, Rossor MN. · Institute of Neurology, Dementia Research Centre, National Hospital for Neurology and Neurosurgery, London, United Kingdom. · Ann Neurol. · Pubmed #16802294 No free full text.

Abstract: To determine the relationship between cerebral amyloid plaque load and rates of cerebral atrophy in Alzheimer's disease. (11)C-PIB((11)C-6-OH benzothiazole)PET (positron emission tomography) findings were correlated with volumetric magnetic resonance imaging (MRI) measurements in nine subjects with mild to moderate AD. Analysis revealed a positive correlation between rates of whole brain atrophy and whole brain (p = 0.019) and regional (11)C-PIB uptake. This provides support for the central role of amyloid deposition in the pathogenesis of AD.

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.

Jones BF, Barnes J, Uylings HB, Fox NC, Frost C, Witter MP, Scheltens P. · Department of Neurology, VU University Medical Centre, Amsterdam, The Netherlands. · Cereb Cortex. · Pubmed #16400164 links to  free full text

Abstract: Magnetic resonance imaging-based volumetric measurements provide a useful technique for quantifying in vivo regional cerebral atrophy in Alzheimer disease (AD). Histopathological studies have shown the cingulate cortex, a cytoarchitectonically heterogeneous region, to be severely affected in AD. In this study, we developed and validated a manual segmentation protocol, based on macroscopic characteristics such as gyri and sulci patterns, in order to assess volumetric changes in 4 cingulate regions of interest. Cingulate cortical volumes of 10 familial AD patients were compared with 10 age- and sex-matched controls. Inter- and intrarater reliability coefficients were high for all cingulate regions (91.9-99.4%). All 4 cingulate regions were significantly smaller (P < 0.05) in AD cases compared with controls: rostral anterior cingulate gyrus (22.5% smaller), caudal anterior cingulate gyrus (20.7% smaller), posterior cingulate gyrus (44.1% smaller), and retrosplenial cortex (21.5% smaller). The atrophy in the posterior cingulate region was significantly greater than that in other cingulate regions (P < 0.001), suggesting a higher vulnerability for this region in familial AD. Considering the functional and connectional differences of these 4 cingulate regions, detection and monitoring of their atrophy may provide insights into the natural history of AD and may help in the search for diagnostic markers for early AD.

Archer HA, Schott JM, Barnes J, Fox NC, Holton JL, Revesz T, Cipolotti L, Rossor MN. · The Dementia Research Centre, The National Hospital for Neurology and Neurosurgery, London, UK. · Neurocase. · Pubmed #15804921 No free full text.

Abstract: We report the case of a chess player with superior premorbid cognitive function who presented to the Cognitive Disorders clinic at the National Hospital for Neurology and Neurosurgery with a 2-year history of symptoms of possible memory loss. Initially the MRI scan appearance was within normal limits and his cognitive scores inside the normal range; subsequently his cognitive function deteriorated and he fulfilled criteria for Mild Cognitive Impairment (MCI) two years later. Unexpectedly he died of an unrelated illness seven months later and post mortem examination of the brain was carried out, revealing advanced Alzheimer's disease (CERAD definite and NIA-Regan Institute high likelihood). This case highlights the difficulties encountered in assessing patients with superior premorbid function in the early stages of Alzheimer's disease, and reveals the value of serial MRI and neuropsychological assessment in detecting and monitoring early neurodegenerative disease.

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.