Duygu Tosun

Update on the magnetic resonance imaging core of the Alzheimer's disease neuroimaging initiative.

Functions of the Alzheimers Disease Neuroimaging Initiative (ADNI) magnetic resonance imaging (MRI) core fall into three categories: (1) those of the central MRI core laboratory at Mayo Clinic, Rochester, Minnesota, needed to generate high quality MRI data in all subjects at each time point; (2) those of the funded ADNI MRI core imaging analysis groups responsible for analyzing the MRI data; and (3) the joint function of the entire MRI core in designing and problem solving MR image acquisition, pre‐processing, and analyses methods. The primary objective of ADNI was and continues to be improving methods for clinical trials in Alzheimers disease. Our approach to the present (“ADNI‐GO”) and future (“ADNI‐2,” if funded) MRI protocol will be to maintain MRI methodological consistency in the previously enrolled “ADNI‐1” subjects who are followed up longitudinally in ADNI‐GO and ADNI‐2. We will modernize and expand the MRI protocol for all newly enrolled ADNI‐GO and ADNI‐2 subjects. All newly enrolled subjects will be scanned at 3T with a core set of three sequence types: 3D T1‐weighted volume, FLAIR, and a long TE gradient echo volumetric acquisition for micro hemorrhage detection. In addition to this core ADNI‐GO and ADNI‐2 protocol, we will perform vendor‐specific pilot sub‐studies of arterial spin‐labeling perfusion, resting state functional connectivity, and diffusion tensor imaging. One of these sequences will be added to the core protocol on systems from each MRI vendor. These experimental sub‐studies are designed to demonstrate the feasibility of acquiring useful data in a multicenter (but single vendor) setting for these three emerging MRI applications.

CRUISE: Cortical reconstruction using implicit surface evolution

Segmentation and representation of the human cerebral cortex from magnetic resonance (MR) images play an important role in neuroscience and medicine. A successful segmentation method must be robust to various imaging artifacts and produce anatomically meaningful and consistent cortical representations. A method for the automatic reconstruction of the inner, central, and outer surfaces of the cerebral cortex from T1-weighted MR brain images is presented. The method combines a fuzzy tissue classification method, an efficient topology correction algorithm, and a topology-preserving geometric deformable surface model (TGDM). The algorithm is fast and numerically stable, and yields accurate brain surface reconstructions that are guaranteed to be topologically correct and free from self-intersections. Validation results on real MR data are presented to demonstrate the performance of the method.

Mapping techniques for aligning sulci across multiple brains.

Visualization and mapping of function on the cortical surface is difficult because of its sulcal and gyral convolutions. Methods to unfold and flatten the cortical surface for visualization and measurement have been described in the literature. This makes visualization and measurement possible, but comparison across multiple subjects is still difficult because of the lack of a standard mapping technique. In this paper, we describe two methods that map each hemisphere of the cortex to a portion of a sphere in a standard way. To quantify how accurately the geometric features of the cortex – i.e., sulci and gyri – are mapped into the same location, sulcal alignment across multiple brains is analyzed, and probabilistic maps for different sulcal regions are generated to be used in automatic labelling of segmented sulcal regions.

Relations between brain tissue loss, CSF biomarkers, and the ApoE genetic profile: a longitudinal MRI study

Previously it was reported that Alzheimers disease (AD) patients have reduced beta amyloid (Abeta(1-42)) and elevated total tau (t-tau) and phosphorylated tau (p-tau(181p)) in the cerebrospinal fluid (CSF), suggesting that these same measures could be used to detect early AD pathology in healthy elderly individuals and those with mild cognitive impairment (MCI). In this study, we tested the hypothesis that there would be an association among rates of regional brain atrophy, the CSF biomarkers Abeta(1-42), t-tau, and p-tau(181p) and apolipoprotein E (ApoE) epsilon4 status, and that the pattern of this association would be diagnosis-specific. Our findings primarily showed that lower CSF Abeta(1-42) and higher tau concentrations were associated with increased rates of regional brain tissue loss and the patterns varied across the clinical groups. Taken together, these findings demonstrate that CSF biomarker concentrations are associated with the characteristic patterns of structural brain changes in healthy elderly and mild cognitive impairment subjects that resemble to a large extent the pathology seen in AD. Therefore, the finding of faster progression of brain atrophy in the presence of lower Abeta(1-42) levels and higher tau levels supports the hypothesis that CSF Abeta(1-42) and tau are measures of early AD pathology. Moreover, the relationship among CSF biomarkers, ApoE epsilon4 status, and brain atrophy rates are regionally varying, supporting the view that the genetic predisposition of the brain to beta amyloid and tau mediated pathology is regional and disease stage specific.

Spatial patterns of brain amyloid-β burden and atrophy rate associations in mild cognitive impairment

Amyloid-β accumulation in the brain is thought to be one of the earliest events in Alzheimers disease, possibly leading to synaptic dysfunction, neurodegeneration and cognitive/functional decline. The earliest detectable changes seen with neuroimaging appear to be amyloid-β accumulation detected by (11)C-labelled Pittsburgh compound B positron emission tomography imaging. However, some individuals tolerate high brain amyloid-β loads without developing symptoms, while others progressively decline, suggesting that events in the brain downstream from amyloid-β deposition, such as regional brain atrophy rates, play an important role. The main purpose of this study was to understand the relationship between the regional distributions of increased amyloid-β and the regional distribution of increased brain atrophy rates in patients with mild cognitive impairment. To simultaneously capture the spatial distributions of amyloid-β and brain atrophy rates, we employed the statistical concept of parallel independent component analysis, an effective method for joint analysis of multimodal imaging data. Parallel independent component analysis identified significant relationships between two patterns of amyloid-β deposition and atrophy rates: (i) increased amyloid-β burden in the left precuneus/cuneus and medial-temporal regions was associated with increased brain atrophy rates in the left medial-temporal and parietal regions; and (ii) in contrast, increased amyloid-β burden in bilateral precuneus/cuneus and parietal regions was associated with increased brain atrophy rates in the right medial temporal regions. The spatial distribution of increased amyloid-β and the associated spatial distribution of increased brain atrophy rates embrace a characteristic pattern of brain structures known for a high vulnerability to Alzheimers disease pathology, encouraging for the use of (11)C-labelled Pittsburgh compound B positron emission tomography measures as early indicators of Alzheimers disease. These results may begin to shed light on the mechanisms by which amyloid-β deposition leads to neurodegeneration and cognitive decline and the development of a more specific Alzheimers disease-specific imaging signature for diagnosis and use of this knowledge in the development of new anti-therapies for Alzheimers disease.

Cortical surface segmentation and mapping

Segmentation and mapping of the human cerebral cortex from magnetic resonance (MR) images plays an important role in neuroscience and medicine. This paper describes a comprehensive approach for cortical reconstruction, flattening, and sulcal segmentation. Robustness to imaging artifacts and anatomical consistency are key achievements in an overall approach that is nearly fully automatic and computationally fast. Results demonstrating the application of this approach to a study of cortical thickness changes in aging are presented.

Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer’s disease and mild cognitive impairment

Patients with Alzheimers disease have reduced cerebral blood flow measured by arterial spin labelling magnetic resonance imaging, but it is unclear how this is related to amyloid-β pathology. Using 182 subjects from the Alzheimers Disease Neuroimaging Initiative we tested associations of amyloid-β with regional cerebral blood flow in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimers disease with dementia (n = 24). Based on the theory that Alzheimers disease starts with amyloid-β accumulation and progresses with symptoms and secondary pathologies in different trajectories, we tested if cerebral blood flow differed between amyloid-β-negative controls and -positive subjects in different diagnostic groups, and if amyloid-β had different associations with cerebral blood flow and grey matter volume. Global amyloid-β load was measured by florbetapir positron emission tomography, and regional blood flow and volume were measured in eight a priori defined regions of interest. Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-β load was related to lower cerebral blood flow in several regions, independent of diagnostic group. When comparing amyloid-β-positive subjects with -negative controls, we found reductions of cerebral blood flow in several diagnostic groups, including in precuneus, entorhinal cortex and hippocampus (dementia), inferior parietal cortex (late mild cognitive impairment and dementia), and inferior temporal cortex (early and late mild cognitive impairment and dementia). The associations of amyloid-β with cerebral blood flow and volume differed across the disease spectrum, with high amyloid-β being associated with greater cerebral blood flow reduction in controls and greater volume reduction in late mild cognitive impairment and dementia. In addition to disease stage, amyloid-β pathology affects cerebral blood flow across the span from controls to dementia patients. Amyloid-β pathology has different associations with cerebral blood flow and volume, and may cause more loss of blood flow in early stages, whereas volume loss dominates in late disease stages.

Nonlinear time course of brain volume loss in cognitively normal and impaired elders

The goal was to elucidate the time course of regional brain atrophy rates relative to age in cognitively normal (CN) aging, mild cognitively impairment (MCI), and Alzheimers disease (AD), without a priori models for atrophy progression. Regional brain volumes from 147 cognitively normal subjects, 164 stable MCI, 93 MCI-to-AD converters and 111 ad patients, between 51 and 91 years old and who had repeated 1.5 T magnetic resonance imaging (MRI) scans over 30 months, were analyzed. Relations between regional brain volume change and age were determined using generalized additive models, an established nonparametric concept for approximating nonlinear relations. Brain atrophy rates varied nonlinearly with age, predominantly in regions of the temporal lobe. Moreover, the atrophy rates of some regions leveled off with increasing age in control and stable MCI subjects whereas those rates progressed further in MCI-to-AD converters and AD patients. The approach has potential uses for early detection of AD and differentiation between stable and progressing MCI.

Hippocampal atrophy rates and CSF biomarkers in elderly APOE2 normal subjects

Objective: To determine whether elderly normal APOE E2 (APOE2) carriers exhibit slower rates of hippocampal atrophy and memory decline compared to APOE3/3 carriers. We also determined whether APOE2 carriers have less Alzheimer pathology as reflected by CSF biomarkers. Methods: We included longitudinal data from 134 cognitively normal individuals (27 APOE2/2 or E2/3, 107 APOE3/3) from the Alzheimers Disease Neuroimaging Initiative, a prospective cohort study. A linear mixed-effects model was used to determine how APOE2 affected rates of hippocampal atrophy and cognitive change over time. In a subsample of 72 individuals who also underwent CSF analysis, an ordinary least-squares regression was used to determine whether CSF β-amyloid (Aβ), total tau, and phosphorylated tau-181 (p-tau) differed by APOE2 status. Results: APOE2 carriers demonstrated slower rates of hippocampal atrophy (p = 0.004). The mean rate of hippocampal atrophy among APOE2 carriers was −33 mm3/year (95% confidence interval −65 to +0.4), or −0.5%/year, compared to −86 mm3/year (95% confidence interval −102 to −71), or −1.3%/year, in the APOE3/3 group. No differences in the rates of episodic memory (p = 0.23) or overall cognitive change (p = 0.90) were detected. In the CSF subsample, APOE2 carriers had higher levels of CSF Aβ (p = 0.01), lower p-tau (p = 0.02), and marginally lower tau (p = 0.12). Conclusion: A slower rate of hippocampal atrophy in normal APOE2 carriers is consistent with the lower risk of Alzheimer disease in these individuals. We hypothesize that the slower atrophy rate is related to decreased preclinical Alzheimer pathology.

Joint Assessment of Structural, Perfusion, and Diffusion MRI in Alzheimer's Disease and Frontotemporal Dementia

Most MRI studies of Alzheimers disease (AD) and frontotemporal dementia (FTD) have assessed structural, perfusion and diffusion abnormalities separately while ignoring the relationships across imaging modalities. This paper aimed to assess brain gray (GM) and white matter (WM) abnormalities jointly to elucidate differences in abnormal MRI patterns between the diseases. Twenty AD, 20 FTD patients, and 21 healthy control subjects were imaged using a 4 Tesla MRI. GM loss and GM hypoperfusion were measured using high-resolution T1 and arterial spin labeling MRI (ASL-MRI). WM degradation was measured with diffusion tensor imaging (DTI). Using a new analytical approach, the study found greater WM degenerations in FTD than AD at mild abnormality levels. Furthermore, the GM loss and WM degeneration exceeded the reduced perfusion in FTD whereas, in AD, structural and functional damages were similar. Joint assessments of multimodal MRI have potential value to provide new imaging markers for improved differential diagnoses between FTD and AD.