Cerebral atrophy in mild cognitive impairment and Alzheimer disease: rates and acceleration.

OBJECTIVE: To quantify the regional and global cerebral atrophy rates and assess acceleration rates in healthy controls, subjects with mild cognitive impairment (MCI), and subjects with mild Alzheimer disease (AD). METHODS: Using 0-, 6-, 12-, 18-, 24-, and 36-month MRI scans of controls and subjects with MCI and AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, we calculated volume change of whole brain, hippocampus, and ventricles between all pairs of scans using the boundary shift integral. RESULTS: We found no evidence of acceleration in whole-brain atrophy rates in any group. There was evidence that hippocampal atrophy rates in MCI subjects accelerate by 0.22%/year2 on average (p = 0.037). There was evidence of acceleration in rates of ventricular enlargement in subjects with MCI (p = 0.001) and AD (p < 0.001), with rates estimated to increase by 0.27 mL/year2 (95% confidence interval 0.12, 0.43) and 0.88 mL/year2 (95% confidence interval 0.47, 1.29), respectively. A post hoc analysis suggested that the acceleration of hippocampal loss in MCI subjects was mainly driven by the MCI subjects that were observed to progress to clinical AD within 3 years of baseline, with this group showing hippocampal atrophy rate acceleration of 0.50%/year2 (p = 0.003). CONCLUSIONS: The small acceleration rates suggest a long period of transition to the pathologic losses seen in clinical AD. The acceleration in hippocampal atrophy rates in MCI subjects in the ADNI seems to be driven by those MCI subjects who concurrently progressed to a clinical diagnosis of AD

Measuring brain atrophy with a generalized formulation of the boundary shift integral

AbstractBrain atrophy measured using structural magnetic resonance imaging (MRI) has been widely used as an imaging biomarker for disease diagnosis and tracking of pathologic progression in neurodegenerative diseases. In this work, we present a generalized and extended formulation of the boundary shift integral (gBSI) using probabilistic segmentations to estimate anatomic changes between 2 time points. This method adaptively estimates a non-binary exclusive OR region of interest from probabilistic brain segmentations of the baseline and repeat scans to better localize and capture the brain atrophy. We evaluate the proposed method by comparing the sample size requirements for a hypothetical clinical trial of Alzheimer's disease to that needed for the current implementation of BSI as well as a fuzzy implementation of BSI. The gBSI method results in a modest but reduced sample size, providing increased sensitivity to disease changes through the use of the probabilistic exclusive OR region

The value of hippocampal and temporal horn volumes and rates of change in predicting future conversion to AD.

Hippocampal pathology occurs early in Alzheimer disease (AD), and atrophy, measured by volumes and volume changes, may predict which subjects will develop AD. Measures of the temporal horn (TH), which is situated adjacent to the hippocampus, may also indicate early changes in AD. Previous studies suggest that these metrics can predict conversion from amnestic mild cognitive impairment (MCI) to AD with conversion and volume change measured concurrently. However, the ability of these metrics to predict future conversion has not been investigated. We compared the abilities of hippocampal, TH, and global measures to predict future conversion from MCI to AD. TH, hippocampi, whole brain, and ventricles were measured using baseline and 12-month scans. Boundary shift integral was used to measure the rate of change. We investigated the prediction of conversion between 12 and 24 months in subjects classified as MCI from baseline to 12 months. All measures were predictive of future conversion. Local and global rates of change were similarly predictive of conversion. There was evidence that the TH expansion rate is more predictive than the hippocampal atrophy rate (P=0.023) and that the TH expansion rate is more predictive than the TH volume (P=0.036). Prodromal atrophy rates may be useful predictors of future conversion to sporadic AD from amnestic MCI

Generalised boundary shift integral for longitudinal assessment of spinal cord atrophy

Spinal cord atrophy measurements obtained from structural magnetic resonance imaging (MRI) are associated with disability in many neurological diseases and serve as in vivo biomarkers of neurodegeneration. Longitudinal spinal cord atrophy rate is commonly determined from the numerical difference between two volumes (based on 3D surface fitting) or two cross-sectional areas (CSA, based on 2D edge detection) obtained at different time-points. Being an indirect measure, atrophy rates are susceptible to variable segmentation errors at the edge of the spinal cord. To overcome those limitations, we developed a new registration-based pipeline that measures atrophy rates directly. We based our approach on the generalised boundary shift integral (GBSI) method, which registers 2 scans and uses a probabilistic XOR mask over the edge of the spinal cord, thereby measuring atrophy more accurately than segmentation-based techniques. Using a large cohort of longitudinal spinal cord images (610 subjects with multiple sclerosis from a multi-centre trial and 52 healthy controls), we demonstrated that GBSI is a sensitive, quantitative and objective measure of longitudinal spinal cord volume change. The GBSI pipeline is repeatable, reproducible, and provides more precise measurements of longitudinal spinal cord atrophy than segmentation-based methods in longitudinal spinal cord atrophy studies

Phenomenological model of diffuse global and regional atrophy using finite-element methods

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 artefa- - cts is also presented. Cross-sectional and

Visual ratings of atrophy in MCI: prediction of conversion and relationship with CSF biomarkers.

Medial temporal lobe atrophy (MTA) and cerebrospinal fluid (CSF) markers of Alzheimer's disease (AD) pathology may aid the early detection of AD in mild cognitive impairment (MCI). However, the relationship between structural and pathological markers is not well understood. Furthermore, while posterior atrophy (PA) is well recognized in AD, its value in predicting conversion from late-onset amnestic MCI to AD is unclear. In this study we used visual ratings of MTA and PA to assess their value in predicting conversion to AD in 394 MCI patients. The relationship of atrophy patterns with CSF Aβ1-42, tau, and p-tau(181) was further investigated in 114 controls, 192 MCI, and 99 AD patients. There was a strong association of MTA ratings with conversion to AD (p < 0.001), with a weaker association for PA ratings (p = 0.047). Specific associations between visual ratings and CSF biomarkers were found; MTA was associated with lower levels of Aβ1-42 in MCI, while PA was associated with elevated levels of tau in MCI and AD, which may reflect widespread neuronal loss including posterior regions. These findings suggest both that posterior atrophy may predict conversion to AD in late-onset MCI, and that there may be differential relationships between CSF biomarkers and regional atrophy patterns

Associations of β-Amyloid and Vascular Burden With Rates of Neurodegeneration in Cognitively Normal Members of the 1946 British Birth Cohort

OBJECTIVE: To quantify the independent and interactive associations of amyloid-β (Aβ) and white matter hyperintensity volume (WMHV) - a marker of presumed cerebrovascular disease (CVD) - with rates of neurodegeneration, and to examine the contributions of APOE ε4 and vascular risk measured at different stages of adulthood in cognitively normal members of the 1946 British birth cohort. METHODS: Participants underwent brain MRI and florbetapir-Aβ positron emission tomography as part of Insight 46, an observational population-based study. Changes in whole brain, ventricular and hippocampal volume were directly measured from baseline and repeat volumetric T1 MRI using the Boundary Shift Integral. Linear regression was used to test associations with: baseline Aβ deposition; baseline WMHV; APOE ε4; and office-based Framingham heart study-cardiovascular risk scores (FHS-CVS) and systolic blood pressure (BP) at ages 36, 53 and 69 years. RESULTS: 346 cognitively normal participants (mean [SD] age at baseline scan 70.5 [0.6] years; 48% female) had high-quality T1 MRI data from both time-points (mean [SD] scan interval 2.4 [0.2] years). Being Aβ positive at baseline was associated with 0.87 ml/year faster whole brain atrophy (95% CI 0.03, 1.72), 0.39 ml/year greater ventricular expansion (95% CI 0.16, 0.64) and 0.016 ml/year faster hippocampal atrophy (95% CI 0.004, 0.027), while each 10 ml additional WMHV at baseline was associated with 1.07 ml/year faster whole brain atrophy (95% CI 0.47, 1.67), 0.31 ml/year greater ventricular expansion (95% CI 0.13, 0.60) and 0.014 ml/year faster hippocampal atrophy (95% CI 0.006, 0.022). These contributions were independent and there was no evidence that Aβ and WMHV interacted in their effects. There were no independent associations of APOE ε4 with rates of neurodegeneration after adjusting for Aβ status and WMHV, and no clear relationships between FHS-CVS or systolic BP and rates of neurodegeneration when assessed across the whole sample, nor any evidence that they acted synergistically with Aβ. CONCLUSIONS: Aβ and presumed CVD have distinct and additive effects on rates of neurodegeneration in cognitively normal elderly. These findings have implications for the use of MRI measures as biomarkers of neurodegeneration and emphasize the importance of risk management and early intervention targeting both pathways

Longitudinal neuroimaging measures of volumetric change across the frontotemporal dementia spectrum

Frontotemporal dementia (FTD) is a common cause of young onset dementia, encompassing several clinical, genetic and pathological subgroups. Currently there are no treatments, but there are promising candidates in development. However, proven biomarkers of disease progression in FTD are lacking and urgently needed to facilitate these trials. Investigating large sporadic and genetic FTD cohorts, this thesis provides a comprehensive comparison of longitudinal neuroimaging measures of structural change within the clinical, genetic and pathological FTD subgroups. Effect size and sample size estimates are computed to explore the feasibility of these brain measures as surrogate markers of disease progression in order to detect disease-modifying treatment effects. The first project compares 17 automated techniques for extracting whole-brain atrophy measures. Many of the techniques showed great promise, producing sample sizes of substantially less than 100 patients required to detect a disease-modifying effect. Significant differences in performance were found between both techniques and patient subgroups, highlighting the importance of informed biomarker choice in matching the optimal marker to the patient group to be enrolled in a trial. In the following chapters, I explored lobar and subcortical change across the disease spectrum. The different patient subgroups presented with unique profiles of change but, interestingly, automated measures of temporal lobe, caudate and thalamic atrophy proved to be particularly sensitive markers of change, producing low sample size estimates across the FTD subgroups. Importantly, I found significantly increased rates of amygdala, hippocampus, caudate and thalamic atrophy in differing patterns across presymptomatic mutation carriers, providing the first comprehensive assessment of the utility of such markers for early therapeutic intervention at this ideal stage before symptoms develop. In summary, this work expands current knowledge and builds on the limited longitudinal investigations currently available in FTD, as well as providing valuable information about the potential of non-invasive biomarkers for sporadic and genetic FTD trials

Patterns of progressive atrophy vary with age in Alzheimer's disease patients.

Age is not only the greatest risk factor for Alzheimer's disease (AD) but also a key modifier of disease presentation and progression. Here, we investigate how longitudinal atrophy patterns vary with age in mild cognitive impairment (MCI) and AD. Data comprised serial longitudinal 1.5-T magnetic resonance imaging scans from 153 AD, 339 MCI, and 191 control subjects. Voxel-wise maps of longitudinal volume change were obtained and aligned across subjects. Local volume change was then modeled in terms of diagnostic group and an interaction between group and age, adjusted for total intracranial volume, white-matter hyperintensity volume, and apolipoprotein E genotype. Results were significant at p < 0.05 with family-wise error correction for multiple comparisons. An age-by-group interaction revealed that younger AD patients had significantly faster atrophy rates in the bilateral precuneus, parietal, and superior temporal lobes. These results suggest younger AD patients have predominantly posterior progressive atrophy, unexplained by white-matter hyperintensity, apolipoprotein E, or total intracranial volume. Clinical trials may benefit from adapting outcome measures for patient groups with lower average ages, to capture progressive atrophy in posterior cortices

Spinal cord atrophy in a primary progressive multiple sclerosis trial: Improved sample size using GBSI

Background: We aimed to evaluate the implications for clinical trial design of the generalised boundary-shift integral (GBSI) for spinal cord atrophy measurement. / Methods: We included 220 primary-progressive multiple sclerosis patients from a phase 2 clinical trial, with baseline and week-48 3DT1-weighted MRI of the brain and spinal cord (1 × 1 × 1 mm3), acquired separately. We obtained segmentation-based cross-sectional spinal cord area (CSA) at C1-2 (from both brain and spinal cord MRI) and C2-5 levels (from spinal cord MRI) using DeepSeg, and, then, we computed corresponding GBSI. / Results: Depending on the spinal cord segment, we included 67.4–98.1% patients for CSA measurements, and 66.9–84.2% for GBSI. Spinal cord atrophy measurements obtained with GBSI had lower measurement variability, than corresponding CSA. Looking at the image noise floor, the lowest median standard deviation of the MRI signal within the cerebrospinal fluid surrounding the spinal cord was found on brain MRI at the C1-2 level. Spinal cord atrophy derived from brain MRI was related to the corresponding measures from dedicated spinal cord MRI, more strongly for GBSI than CSA. Spinal cord atrophy measurements using GBSI, but not CSA, were associated with upper and lower limb motor progression. / Discussion: Notwithstanding the reduced measurement variability, the clinical correlates, and the possibility of using brain acquisitions, spinal cord atrophy using GBSI should remain a secondary outcome measure in MS studies, until further advancements increase the quality of acquisition and reliability of processing