Olivier Salvado

Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study

BACKGROUND Similar to most chronic diseases, Alzheimers disease (AD) develops slowly from a preclinical phase into a fully expressed clinical syndrome. We aimed to use longitudinal data to calculate the rates of amyloid β (Aβ) deposition, cerebral atrophy, and cognitive decline. METHODS In this prospective cohort study, healthy controls, patients with mild cognitive impairment (MCI), and patients with AD were assessed at enrolment and every 18 months. At every visit, participants underwent neuropsychological examination, MRI, and a carbon-11-labelled Pittsburgh compound B ((11)C-PiB) PET scan. We included participants with three or more (11)C-PiB PET follow-up assessments. Aβ burden was expressed as (11)C-PiB standardised uptake value ratio (SUVR) with the cerebellar cortex as reference region. An SUVR of 1·5 was used to discriminate high from low Aβ burdens. The slope of the regression plots over 3-5 years was used to estimate rates of change for Aβ deposition, MRI volumetrics, and cognition. We included those participants with a positive rate of Aβ deposition to calculate the trajectory of each variable over time. FINDINGS 200 participants (145 healthy controls, 36 participants with MCI, and 19 participants with AD) were assessed at enrolment and every 18 months for a mean follow-up of 3·8 (95% CI CI 3·6-3·9) years. At baseline, significantly higher Aβ burdens were noted in patients with AD (2·27, SD 0·43) and those with MCI (1·94, 0·64) than in healthy controls (1·38, 0·39). At follow-up, 163 (82%) of the 200 participants showed positive rates of Aβ accumulation. Aβ deposition was estimated to take 19·2 (95% CI 16·8-22·5) years in an almost linear fashion-with a mean increase of 0·043 (95% CI 0·037-0·049) SUVR per year-to go from the threshold of (11)C-PiB positivity (1·5 SUVR) to the levels observed in AD. It was estimated to take 12·0 (95% CI 10·1-14·9) years from the levels observed in healthy controls with low Aβ deposition (1·2 [SD 0·1] SUVR) to the threshold of (11)C-PiB positivity. As AD progressed, the rate of Aβ deposition slowed towards a plateau. Our projections suggest a prolonged preclinical phase of AD in which Aβ deposition reaches our threshold of positivity at 17·0 (95% CI 14·9-19·9) years, hippocampal atrophy at 4·2 (3·6-5·1) years, and memory impairment at 3·3 (2·5-4·5) years before the onset of dementia (clinical dementia rating score 1). INTERPRETATION Aβ deposition is slow and protracted, likely to extend for more than two decades. Such predictions of the rate of preclinical changes and the onset of the clinical phase of AD will facilitate the design and timing of therapeutic interventions aimed at modifying the course of this illness. FUNDING Science and Industry Endowment Fund (Australia), The Commonwealth Scientific and Industrial Research Organisation (Australia), The National Health and Medical Research Council of Australia Program and Project Grants, the Austin Hospital Medical Research Foundation, Victorian State Government, The Alzheimers Drug Discovery Foundation, and the Alzheimers Association.

Amyloid imaging results, from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging

The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, a participant of the worldwide Alzheimers Disease Neuroimaging Initiative (ADNI), performed (11)C-Pittsburgh Compound B (PiB) scans in 177 healthy controls (HC), 57 mild cognitive impairment (MCI) subjects, and 53 mild Alzheimers disease (AD) patients. High PiB binding was present in 33% of HC (49% in ApoE-epsilon4 carriers vs 21% in noncarriers) and increased with age, most strongly in epsilon4 carriers. 18% of HC aged 60-69 had high PiB binding rising to 65% in those over 80 years. Subjective memory complaint was only associated with elevated PiB binding in epsilon4 carriers. There was no correlation with cognition in HC or MCI. PiB binding in AD was unrelated to age, hippocampal volume or memory. Beta-amyloid (Abeta) deposition seems almost inevitable with advanced age, amyloid burden is similar at all ages in AD, and secondary factors or downstream events appear to play a more direct role than total beta amyloid burden in hippocampal atrophy and cognitive decline.

Longitudinal Assessment of Aβ and Cognition in Aging and Alzheimer Disease

Assess Aβ deposition longitudinally and explore its relationship with cognition and disease progression.

Relationship between atrophy and β‐amyloid deposition in Alzheimer disease

Elucidating the role of aggregated β‐amyloid in relation to gray matter atrophy is crucial to the understanding of the pathological mechanisms of Alzheimer disease and for the development of therapeutic trials. The present study aims to assess this relationship.

β-Amyloid burden in the temporal neocortex is related to hippocampal atrophy in elderly subjects without dementia

Objective: To investigate whether global and regional β-amyloid (Aβ) burden as measured with 11C Pittsburgh compound B (PIB) PET is associated with hippocampal atrophy characterized using MRI in healthy controls and patients with amnestic mild cognitive impairment (aMCI) or Alzheimer disease (AD). Methods: Ninety-two elderly healthy controls, 32 subjects with aMCI, and 35 patients with AD were imaged using 11C-PIB PET and MRI. Hippocampal volume was measured and PIB standardized uptake value ratio was extracted after partial volume correction within 41 regions of interest. Global, regional, and voxel-based correlations between PIB and hippocampal volume were computed for each group. Results: In healthy control participants with elevated neocortex PIB retention, significant correlation was found between PIB retention in the inferior temporal region and hippocampal volume using both region-based and voxel-based approaches. No correlation was found in any other group. Conclusions: The strong correlation between hippocampal atrophy and β-amyloid (Aβ) burden in the Pittsburgh compound B–positive healthy control group suggests that Aβ deposition in the inferior temporal neocortex is related to hippocampal synaptic and neuronal degeneration.

Apparent Fibre Density: a novel measure for the analysis of diffusion-weighted magnetic resonance images.

This article proposes a new measure called Apparent Fibre Density (AFD) for the analysis of high angular resolution diffusion-weighted images using higher-order information provided by fibre orientation distributions (FODs) computed using spherical deconvolution. AFD has the potential to provide specific information regarding differences between populations by identifying not only the location, but also the orientations along which differences exist. In this work, analytical and numerical Monte-Carlo simulations are used to support the use of the FOD amplitude as a quantitative measure (i.e. AFD) for population and longitudinal analysis. To perform robust voxel-based analysis of AFD, we present and evaluate a novel method to modulate the FOD to account for changes in fibre bundle cross-sectional area that occur during spatial normalisation. We then describe a novel approach for statistical analysis of AFD that uses cluster-based inference of differences extended throughout space and orientation. Finally, we demonstrate the capability of the proposed method by performing voxel-based AFD comparisons between a group of Motor Neurone Disease patients and healthy control subjects. A significant decrease in AFD was detected along voxels and orientations corresponding to both the corticospinal tract and corpus callosal fibres that connect the primary motor cortices. In addition to corroborating previous findings in MND, this study demonstrates the clear advantage of using this type of analysis by identifying differences along single fibre bundles in regions containing multiple fibre populations.

An Atlas-Based Electron Density Mapping Method for Magnetic Resonance Imaging (MRI)-Alone Treatment Planning and Adaptive MRI-Based Prostate Radiation Therapy

PURPOSE Prostate radiation therapy dose planning directly on magnetic resonance imaging (MRI) scans would reduce costs and uncertainties due to multimodality image registration. Adaptive planning using a combined MRI-linear accelerator approach will also require dose calculations to be performed using MRI data. The aim of this work was to develop an atlas-based method to map realistic electron densities to MRI scans for dose calculations and digitally reconstructed radiograph (DRR) generation. METHODS AND MATERIALS Whole-pelvis MRI and CT scan data were collected from 39 prostate patients. Scans from 2 patients showed significantly different anatomy from that of the remaining patient population, and these patients were excluded. A whole-pelvis MRI atlas was generated based on the manually delineated MRI scans. In addition, a conjugate electron-density atlas was generated from the coregistered computed tomography (CT)-MRI scans. Pseudo-CT scans for each patient were automatically generated by global and nonrigid registration of the MRI atlas to the patient MRI scan, followed by application of the same transformations to the electron-density atlas. Comparisons were made between organ segmentations by using the Dice similarity coefficient (DSC) and point dose calculations for 26 patients on planning CT and pseudo-CT scans. RESULTS The agreement between pseudo-CT and planning CT was quantified by differences in the point dose at isocenter and distance to agreement in corresponding voxels. Dose differences were found to be less than 2%. Chi-squared values indicated that the planning CT and pseudo-CT dose distributions were equivalent. No significant differences (p > 0.9) were found between CT and pseudo-CT Hounsfield units for organs of interest. Mean ± standard deviation DSC scores for the atlas-based segmentation of the pelvic bones were 0.79 ± 0.12, 0.70 ± 0.14 for the prostate, 0.64 ± 0.16 for the bladder, and 0.63 ± 0.16 for the rectum. CONCLUSIONS The electron-density atlas method provides the ability to automatically define organs and map realistic electron densities to MRI scans for radiotherapy dose planning and DRR generation. This method provides the necessary tools for MRI-alone treatment planning and adaptive MRI-based prostate radiation therapy.

Predicting Alzheimer disease with β-amyloid imaging: results from the Australian imaging, biomarkers, and lifestyle study of ageing

Biomarkers for Alzheimer disease (AD) can detect the disease pathology in asymptomatic subjects and individuals with mild cognitive impairment (MCI), but their cognitive prognosis remains uncertain. We aimed to determine the prognostic value of β‐amyloid imaging, alone and in combination with memory performance, hippocampal atrophy, and apolipoprotein E ε4 status in nondemented, older individuals.

Independent contribution of temporal β-amyloid deposition to memory decline in the pre-dementia phase of Alzheimer's disease

The relationship between β-amyloid deposition and memory deficits in early Alzheimers disease is unresolved, as past studies show conflicting findings. The present study aims to determine the relative contribution of regional β-amyloid deposition, hippocampal atrophy and white matter integrity to episodic memory deficits in non-demented older individuals harbouring one of the characteristic hallmarks of Alzheimers disease, i.e. with β-amyloid pathology. Understanding these relationships is critical for effective therapeutic development. Brain magnetic resonance imaging and [(11)C]Pittsburgh Compound B-positron emission tomography scans were obtained in 136 non-demented individuals aged over 60 years, including 93 healthy elderly and 43 patients with mild cognitive impairment. Voxel-based correlations were computed between a memory composite score and grey matter volume, white matter volume and β-amyloid deposition imaging datasets. Hierarchical linear regression analyses were then performed using values extracted in regions of most significant correlations to determine the relative contribution of each modality to memory deficits. All analyses were conducted pooling all groups together as well as within separate subgroups of cognitively normal elderly, patients with mild cognitive impairment and individuals with high versus low neocortical β-amyloid. Brain areas of highest correlation with episodic memory deficits were the hippocampi for grey matter volume, the perforant path for white matter volume and the temporal neocortex for β-amyloid deposition. When considering these three variables together, only hippocampal volume and temporal β-amyloid deposition provided independent contributions to memory deficits. In contrast to global β-amyloid deposition, temporal β-amyloid deposition was still related to memory independently from hippocampal atrophy within subgroups of cognitively normal elderly, patients with mild cognitive impairment or cases with high neocortical β-amyloid. In the pre-dementia stage of Alzheimers disease, subtle episodic memory impairment is related to β-amyloid deposition, especially in the temporal neocortex, and independently from hippocampal atrophy, suggesting that both factors should be independently targeted in therapeutic trials aimed at reducing cognitive decline.

MRI-guided prostate radiation therapy planning: Investigation of dosimetric accuracy of MRI-based dose planning

BACKGROUND AND PURPOSE Dose planning requires a CT scan which provides the electron density distribution for dose calculation. MR provides superior soft tissue contrast compared to CT and the use of MR-alone for prostate planning would provide further benefits such as lower cost to the patient. This study compares the accuracy of MR-alone based dose calculations with bulk electron density assignment to CT-based dose calculations for prostate radiotherapy. MATERIALS AND METHODS CT and whole pelvis MR images were contoured for 39 prostate patients. Plans with uniform density and plans with bulk density values assigned to bone and tissue were compared to the patients gold standard full density CT plan. The optimal bulk density for bone was calculated using effective depth measurements. The plans were evaluated using ICRU point doses, dose volume histograms, and Chi comparisons. Differences in spatial uniformity were investigated for the CT and MR scans. RESULTS The calculated dose for CT bulk bone and tissue density plans was 0.1±0.6% (mean±1 SD) higher than the corresponding full density CT plan. MR bulk bone and tissue density plans were 1.3±0.8% lower than the full density CT plan. CT uniform density plans and MR uniform density plans were 1.4±0.9% and 2.6±0.9% lower, respectively. Paired t-tests performed on specific points on the DVH graphs showed that points on DVHs for all bulk electron density plans were equivalent with two exceptions. There was no significant difference between doses calculated on Pinnacle and Eclipse. The dose distributions of six patients produced Chi values outside the acceptable range of values when MR-based plans were compared to the full density plan. CONCLUSIONS MR-alone bulk density planning is feasible provided bone is assigned a density, however, manual segmentation of bone on MR images will have to be replaced with automatic methods. The major dose differences for MR bulk density plans are due to differences in patient external contours introduced by the MR couch-top and pelvic coil.