Magnetic resonance imaging in Alzheimer's Disease Neuroimaging Initiative 2.

INTRODUCTION: Alzheimer's Disease Neuroimaging Initiative (ADNI) is now in its 10th year. The primary objective of the magnetic resonance imaging (MRI) core of ADNI has been to improve methods for clinical trials in Alzheimer's disease (AD) and related disorders. METHODS: We review the contributions of the MRI core from present and past cycles of ADNI (ADNI-1, -Grand Opportunity and -2). We also review plans for the future-ADNI-3. RESULTS: Contributions of the MRI core include creating standardized acquisition protocols and quality control methods; examining the effect of technical features of image acquisition and analysis on outcome metrics; deriving sample size estimates for future trials based on those outcomes; and piloting the potential utility of MR perfusion, diffusion, and functional connectivity measures in multicenter clinical trials. DISCUSSION: Over the past decade the MRI core of ADNI has fulfilled its mandate of improving methods for clinical trials in AD and will continue to do so in the future.

Riemannian frameworks for the harmonization of resting-state functional MRI scans.

Magnetic Resonance Imaging provides unprecedented images of the brain. Unfortunately, scanners and acquisition protocols can significantly impact MRI scans. The development of statistical methods able to reduce this variability without altering the relevant information in the scans, often coined harmonization methods, has been the topic of an increasing research effort supported by the recent growth of publicly available neuroimaging data sets and new possibilities for combining them to achieve greater statistical power. In this work, we focus on the challenges specifically raised by the harmonization of resting-state functional MRI scans. We propose to harmonize resting-state fMRI scans by reducing the impact of covariates such as scanner differences and scanning protocols on their associated functional connectomes and then propagating the changes back to the rs-fMRI time series. We use Riemannian geometric frameworks to preserve the mathematical properties of functional connectomes during their harmonization, and we demonstrate how state-of-the-art harmonization methods can be embedded within these frameworks to reduce covariates effects while preserving the relevant clinical information associated with aging or brain disorders. During our experiments, a large set of synthetic data was generated and processed to compare eighty variants of the proposed approach. The framework achieving the best harmonization was then applied to three low-dimensional data sets made of 712 sets of fMRI time series provided by the ABIDE consortium and two high-dimensional data sets obtained by processing 1527 rs-fMRI scans provided by the Human Connectome Project, the Framingham Heart Study and the Genetics of Brain Structure and Function study. These experiments established that our new framework could successfully harmonize low-dimensional connectomes and voxelwise functional time series and confirmed the need for preserving connectomes properties during their harmonization.

Associations Between Brainstem Volume and Alzheimer's Disease Pathology in Middle-Aged Individuals of the Framingham Heart Study.

The brainstem is among the first regions to accumulate Alzheimer's disease (AD)-related hyperphosphorylated tau pathology during aging. We aimed to examine associations between brainstem volume and neocortical amyloid-ß or tau pathology in 271 middle-aged clinically normal individuals of the Framingham Heart Study who underwent MRI and PET imaging. Lower volume of the medulla, pons, or midbrain was associated with greater neocortical amyloid burden. No associations were detected between brainstem volumes and tau deposition. Our results support the hypothesis that lower brainstem volumes are associated with initial AD-related processes and may signal preclinical AD pathology.

Association of Midlife Depressive Symptoms with Regional Amyloid-ß and Tau in the Framingham Heart Study.

BACKGROUND: Depressive symptoms predict increased risk for dementia decades before the emergence of cognitive symptoms. Studies in older adults provide preliminary evidence for an association between depressive symptoms and amyloid-ß (Aß) and tau accumulation. It is unknown if similar alterations are observed in midlife when preventive strategies may be most effective. OBJECTIVE: The study aim was to evaluate the association between depressive symptoms and cerebral Aß and tau in a predominately middle-aged cohort with examination of the apolipoprotein (APOE) ɛ4 allele as a moderator. METHODS: Participants included 201 adults (mean age 53±8 years) who underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging, as well as eight years prior. Associations between depressive symptoms at both timepoints, as well as depression (CES-D≥16), with regional Aß and tau PET retention were evaluated with linear regression adjusting for age and sex. Interactions with the APOE ɛ4 allele were explored. RESULTS: Depressive symptoms and depression were not associated with PET outcomes in the overall sample. However, among APOE ɛ4 allele carriers, there was a significant cross-sectional association between depressive symptoms and increased tau PET uptake in the entorhinal cortex (ß= 0.446, SE = 0.155, p = 0.006) and amygdala (ß= 0.350, SE = 0.133, p = 0.012). CONCLUSION: Although longitudinal studies are necessary, the results suggest that APOE ɛ4 carriers with depressive symptoms may present with higher susceptibility to early tau accumulation in regions integral to affective regulation and memory consolidation.

The cortical origin and initial spread of medial temporal tauopathy in Alzheimer's disease assessed with positron emission tomography.

Advances in molecular positron emission tomography (PET) have enabled anatomic tracking of brain pathology in longitudinal studies of normal aging and dementia, including assessment of the central model of Alzheimer's disease (AD) pathogenesis, according to which TAU pathology begins focally but expands catastrophically under the influence of amyloid-ß (Aß) pathology to mediate neurodegeneration and cognitive decline. Initial TAU deposition occurs many years before Aß in a specific area of the medial temporal lobe. Building on recent work that enabled focus of molecular PET measurements on specific TAU-vulnerable convolutional temporal lobe anatomy, we applied an automated anatomic sampling method to quantify TAU PET signal in 443 adult participants from several observational studies of aging and AD, spanning a wide range of ages, Aß burdens, and degrees of clinical impairment. We detected initial cortical emergence of tauopathy near the rhinal sulcus in clinically normal people and, in a subset with longitudinal 2-year follow-up data (n = 104), tracked Aß-associated spread of TAU from this site first to nearby neocortex of the temporal lobe and then to extratemporal regions. Greater rate of TAU spread was associated with baseline measures of both global Aß burden and medial temporal lobe TAU. These findings are consistent with clinicopathological correlation studies of Alzheimer's tauopathy and enable precise tracking of AD-related TAU progression for natural history studies and prevention therapeutic trials.

Whole brain quantitative T2 MRI across multiple scanners with dual echo FSE: applications to AD, MCI, and normal aging.

The ability to pool data from multiple MRI scanners is becoming increasingly important with the influx in multi-site research studies. Fast spin echo (FSE) dual spin echo sequences are often chosen for such studies based principally on their short acquisition time and the clinically useful contrasts they provide for assessing gross pathology. The practicality of measuring FSE-T2 relaxation properties has rarely been assessed. Here, FSE-T2 relaxation properties are examined across the three main scanner vendors (General Electric (GE), Philips, and Siemens). The American College of Radiology (ACR) phantom was scanned on four 1.5T platforms (two GE, one Philips, and one Siemens) to determine if the dual echo pulse sequence is susceptible to vendor-based variance. In addition, data from 85 subjects spanning the spectrum of normal aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD) was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to affirm the presence of any phantom based between vendor variance and determine the relationship between this variance and disease. FSE-T2 relaxation properties, including peak FSE-T2 and histogram width, were calculated for each phantom and human subject. Direct correspondence was found between the phantom and human subject data. Peak FSE-T2 of Siemens scanners was consistently at least 20ms prolonged compared to GE and Philips. Siemens scanners showed broader FSE-T2 histograms than the other scanners. Greater variance was observed across GE scanners than either Philips or Siemens. FSE-T2 differences were much greater with scanner vendor than between diagnostic groups, as no significant changes in peak FSE-T2 or histogram width between normal aged, MCI, and AD subject groups were observed. These results indicate that whole brain histogram measures are not sensitive enough to detect FSE-T2 changes between normal aging, MCI, and AD and that FSE-T2 is highly variable across scanner vendors.

Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain.

We present a technique for automatically assigning a neuroanatomical label to each voxel in an MRI volume based on probabilistic information automatically estimated from a manually labeled training set. In contrast to existing segmentation procedures that only label a small number of tissue classes, the current method assigns one of 37 labels to each voxel, including left and right caudate, putamen, pallidum, thalamus, lateral ventricles, hippocampus, and amygdala. The classification technique employs a registration procedure that is robust to anatomical variability, including the ventricular enlargement typically associated with neurological diseases and aging. The technique is shown to be comparable in accuracy to manual labeling, and of sufficient sensitivity to robustly detect changes in the volume of noncortical structures that presage the onset of probable Alzheimer's disease.

Feasibility of multi-site clinical structural neuroimaging studies of aging using legacy data.

The application of advances in biomedical computing to medical imaging research is enabling scientists to conduct quantitative clinical imaging studies using data collected across multiple sites to test new hypotheses on larger cohorts, increasing the power to detect subtle effects. Given that many research groups have valuable existing (legacy) data, one goal of the Morphometry Biomedical Informatics Research Network (BIRN) Testbed is to assess the feasibility of pooled analyses of legacy structural neuroimaging data in normal aging and Alzheimer's disease. The present study examined whether such data could be meaningfully reanalyzed as a larger combined data set by using rigorous data curation, image analysis, and statistical modeling methods; in this case, to test the hypothesis that hippocampal volume decreases with age and to investigate findings of hippocampal asymmetry. This report describes our work with legacy T1-weighted magnetic resonance (MR) and demographic data related to normal aging that have been shared through the BIRN by three research sites. Results suggest that, in the present application, legacy MR data from multiple sites can be pooled to investigate questions of scientific interest. In particular, statistical analyses suggested that a mixed-effects model employing site as a random effect best fits the data, accounting for site-specific effects while taking advantage of expected comparability of age-related effects. In the combined sample from three sites, significant age-related decline of hippocampal volume and right-dominant hippocampal asymmetry were detected in healthy elderly controls. These expected findings support the feasibility of combining legacy data to investigate novel scientific questions.

Seed Location Impacts Whole-Brain Structural Network Comparisons between Healthy Elderly and Individuals with Alzheimer's Disease.

Whole-brain networks derived from diffusion tensor imaging (DTI) data require the identification of seed and target regions of interest (ROIs) to assess connectivity patterns. This study investigated how initiating tracts from gray matter (GM) or white matter (WM) seed ROIs impacts (1) structural networks constructed from DTI data from healthy elderly (control) and individuals with Alzheimer's disease (AD) and (2) between-group comparisons using these networks. DTI datasets were obtained from the Alzheimer's disease Neuroimaging Initiative database. Deterministic tractography was used to build two whole-brain networks for each subject; one in which tracts were initiated from WM ROIs and another in which they were initiated from GM ROIs. With respect to the first goal, in both groups, WM-seeded networks had approximately 400 more connections and stronger connections (as measured by number of streamlines per connection) than GM-seeded networks, but shared 94% of the connections found in the GM-seed networks. With respect to the second goal, between-group comparisons revealed a stronger subnetwork (as measured by number of streamlines per connection) in controls compared to AD using both WM-seeded and GM-seeded networks. The comparison using WM-seeded networks produced a larger (i.e., a greater number of connections) and more significant subnetwork in controls versus AD. Global, local, and nodal efficiency were greater in controls compared to AD, and between-group comparisons of these measures using WM-seeded networks had larger effect sizes than those using GM-seeded networks. These findings affirm that seed location significantly affects the ability to detect between-group differences in structural networks.

Pre-clinical testing of a phased array ultrasound system for MRI-guided noninvasive surgery of the brain--a primate study.

MRI-guided and monitored focused ultrasound thermal surgery of brain through intact skull was tested in three rhesus monkeys. The aim of this study was to determine the amount of skull heating in an animal model with a head shape similar to that of a human. The ultrasound beam was generated by a 512 channel phased array system (Exablate 3000, InSightec, Haifa, Israel) that was integrated within a 1.5-T MR-scanner. The skin was pre-cooled by degassed temperature controlled water circulating between the array surface and the skin. Skull surface temperature was measured with invasive thermocouple probes. The results showed that by applying surface cooling the skin and skull surface can be protected, and that the brain surface temperature becomes the limiting factor. The MRI thermometry was shown to be useful in detecting the tissue temperature distribution next to the bone, and it should be used to monitor the brain surface temperature. The acoustic intensity values during the 20 s sonications were adequate for thermal ablation in the human brain provided that surface cooling is used.

The Alzheimer's Disease Neuroimaging Initiative (ADNI): MRI methods.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a longitudinal multisite observational study of healthy elders, mild cognitive impairment (MCI), and Alzheimer's disease. Magnetic resonance imaging (MRI), (18F)-fluorodeoxyglucose positron emission tomography (FDG PET), urine serum, and cerebrospinal fluid (CSF) biomarkers, as well as clinical/psychometric assessments are acquired at multiple time points. All data will be cross-linked and made available to the general scientific community. The purpose of this report is to describe the MRI methods employed in ADNI. The ADNI MRI core established specifications that guided protocol development. A major effort was devoted to evaluating 3D T(1)-weighted sequences for morphometric analyses. Several options for this sequence were optimized for the relevant manufacturer platforms and then compared in a reduced-scale clinical trial. The protocol selected for the ADNI study includes: back-to-back 3D magnetization prepared rapid gradient echo (MP-RAGE) scans; B(1)-calibration scans when applicable; and an axial proton density-T(2) dual contrast (i.e., echo) fast spin echo/turbo spin echo (FSE/TSE) for pathology detection. ADNI MRI methods seek to maximize scientific utility while minimizing the burden placed on participants. The approach taken in ADNI to standardization across sites and platforms of the MRI protocol, postacquisition corrections, and phantom-based monitoring of all scanners could be used as a model for other multisite trials.

The effects of consecutive night shifts on neuropsychological performance of interns in the emergency department: a pilot study.

STUDY OBJECTIVE: We obtain preliminary information on the neuropsychological performance of house officers at the beginning and end of a shift while they worked consecutive night shifts in the emergency department. METHODS: We prospectively studied interns working 12-hour consecutive night shifts in an urban Level I trauma center ED. All consecutive non-emergency medicine interns rotating for 1 month were eligible except those older than 40 years and those with sleep disorders or depression (identified by using the Profile of Mood Scale, Sleep Diagnostic Questionnaire). We tested research subjects at the beginning of a day shift and at the beginning and end of night shifts 1 and 3 of 4 consecutive night shifts at times of estimated baseline wakefulness (10 PM) and maximum fatigue (3 AM). We used 3 standardized neuropsychological tests: (1) Delayed Recognition Span Test (visual memory capacity); (2) Continuous Performance Test (attentional function, vigilance); and (3) Santa Ana Form Board Test (psychomotor speed, coordination). We analyzed data with mixed-model analysis, with research subject as a random effect. RESULTS: Thirteen interns were eligible, and 1 declined. Twelve interns (6 men and 6 women; age range 25 to 35 years) were enrolled. The Delayed Recognition Span Test (number correct before first error) revealed significant deterioration from the beginning of the shift to the end of the shift (mean difference -2.2; 95% confidence interval -3.1 to -1.3). This represents an 18.5% decrease in visual memory capacity. There were no significant differences found for the other tests. CONCLUSION: Interns working nights demonstrated a significant reduction in visual memory capacity across the night shift. Research involving neuropsychological performance during night shifts in the ED is important. It might provide valuable insights into ways to improve our performance during night shifts.

MRI-guided focused ultrasound surgery in the brain: tests in a primate model.

MRI-guided focused ultrasound was tested in the brains of rhesus monkeys. Locations up to 4.8 cm deep were targeted. Focal heating was observed in all cases with MRI-derived temperature imaging. Subthreshold heating was observed at the focus when the ultrasound beam was targeted with low power sonications, and in the ultrasound beam path during high-power exposures. Lethal temperature values and histologically confirmed tissue damage were confined to the focal zone (e.g., not in the ultrasound beam path), except when the focus was close to the bone. In that case, damage to the neighboring brain tissue was observed. Focal lesions were observed on histological examination and, in some cases, in MR images acquired immediately after the ultrasound exposures. The capabilities demonstrated in this study will be of benefit for clinical ultrasound therapies in the brain.