Thompson, Paul M.

Abstract Introduction Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. Methods Serial T1‐weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed‐effects models estimated the change‐points when atrophy rates deviate from normal and the rates of change before and after this point. Results Atrophy increased after the change‐point, which occurred 1–1.5 years (assuming a single step change in atrophy rate) or 3–8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change‐point. Discussion Atrophy rates are pathologically increased up to seven years before “expected onset”. During this period, atrophy rates may be useful for inclusion and tracking of disease progression.

PurposeIn diffusion MRI (dMRI), fractional anisotropy derived from the single‐tensor model (FADTI) is the most widely used metric to characterize white matter (WM) microarchitecture, despite known limitations in regions with crossing fibers. Due to time constraints when scanning patients in clinical settings, high angular resolution diffusion imaging acquisition protocols, often used to overcome these limitations, are still rare in clinical population studies. However, the tensor distribution function (TDF) may be used to model multiple underlying fibers by representing the diffusion profile as a probabilistic mixture of tensors.MethodsWe compared the ability of standard FADTIand TDF‐derived FA (FATDF), calculated from a range of dMRI angular resolutions (41, 30, 15, and 7 gradient directions), to profile WM deficits in 251 individuals from the Alzheimer's Disease Neuroimaging Initiative and to detect associations with 1) Alzheimer's disease diagnosis, 2) Clinical Dementia Rating scores, and 3) average hippocampal volume.ResultsAcross angular resolutions and statistical tests, FATDFshowed larger effect sizes than FADTI, particularly in regions preferentially affected by Alzheimer's disease, and was less susceptible to crossing fiber anomalies.ConclusionThe TDF “corrected” form of FA may be a more sensitive and accurate alternative to the commonly used FADTI, even in clinical quality dMRI data. Magn Reson Med 78:2322–2333, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

AbstractAlzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive decline in memory and other aspects of cognitive function. Diffusion‐weighted imaging (DWI) offers a non‐invasive approach to delineate the effects of AD on white matter (WM) integrity. Previous studies calculated either some summary statistics over regions of interest (ROI analysis) or some statistics along mean skeleton lines (Tract Based Spatial Statistic [TBSS]), so they cannot quantify subtle local WM alterations along major tracts. Here, a comprehensive WM analysis framework to map disease effects on 3D tracts both locally and globally, based on a study of 200 subjects: 49 healthy elderly normal controls, 110 with mild cognitive impairment, and 41 AD patients has been presented. 18 major WM tracts were extracted with our automated clustering algorithm—autoMATE (automated Multi‐Atlas Tract Extraction); we then extracted multiple DWI‐derived parameters of WM integrity along the WM tracts across all subjects. A novel statistical functional analysis method—FADTTS (Functional Analysis for Diffusion Tensor Tract Statistics) was applied to quantify degenerative patterns along WM tracts across different stages of AD. Gradually increasing WM alterations were found in all tracts in successive stages of AD. Among all 18 WM tracts, the fornix was most adversely affected. Among all the parameters, mean diffusivity (MD) was the most sensitive to WM alterations in AD. This study provides a systematic workflow to examine WM integrity across automatically computed 3D tracts in AD and may be useful in studying other neurological and psychiatric disorders. Hum Brain Mapp 38:1191–1207, 2017. © 2016 Wiley Periodicals, Inc.

AbstractIntroductionAlzheimer'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.MethodsWe 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.ResultsContributions 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.DiscussionOver 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.

Abstract Introduction The Alzheimer's Disease Neuroimaging Initiative (ADNI) was established in 2004 to facilitate the development of effective treatments for Alzheimer's disease (AD) by validating biomarkers for AD clinical trials. Methods We searched for ADNI publications using established methods. Results ADNI has (1) developed standardized biomarkers for use in clinical trial subject selection and as surrogate outcome measures; (2) standardized protocols for use across multiple centers; (3) initiated worldwide ADNI; (4) inspired initiatives investigating traumatic brain injury and post‐traumatic stress disorder in military populations, and depression, respectively, as an AD risk factor; (5) acted as a data‐sharing model; (6) generated data used in over 600 publications, leading to the identification of novel AD risk alleles, and an understanding of the relationship between biomarkers and AD progression; and (7) inspired other public‐private partnerships developing biomarkers for Parkinson's disease and multiple sclerosis. Discussion ADNI has made myriad impacts in its first decade. A competitive renewal of the project in 2015 would see the use of newly developed tau imaging ligands, and the continued development of recruitment strategies and outcome measures for clinical trials.