Neuroimaging within the Dominantly Inherited Alzheimer’s Network (DIAN): PET and MRI

Abstract

The Dominantly Inherited Alzheimer Network (DIAN) Observational Study is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). This rare form of Alzheimer disease (AD) is caused by mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. As individuals from these families have a 50% chance of inheriting the familial mutation, this provides researchers with a well-matched cohort of carriers vs non-carriers for case-control studies. An important trait of ADAD is that the age at symptom onset is highly predictable and consistent for each specific mutation, allowing researchers to estimate an individual's point in their disease time course prior to symptom onset. Although ADAD represents only a small proportion (approximately 0.1%) of all AD cases, studying this form of AD allows researchers to investigate preclinical AD and the progression of changes that occur within the brain prior to AD symptom onset. Furthermore, the young age at symptom onset (typically 30-60 years) means age-related comorbidities are much less prevalent than in sporadic AD, thereby allowing AD pathophysiology to be studied independent of these confounds. A major goal of the DIAN Observational Study is to create a global resource for AD researchers. To that end, the current manuscript provides an overview of the DIAN magnetic resonance imaging (MRI) and positron emission tomography (PET) protocols and highlights the key imaging results of this study to date.

Multimodal brain age estimates relate to Alzheimer disease biomarkers and cognition in early stages: a cross-sectional observational study

“…We formed a training sample of healthy controls spanning the adult lifespan by combining structural and FC-MRI data from three sources, as described previously ( Millar et al, 2022 ): the Charles F. and Joanne Knight AD Research Center (ADRC) at Washington University in St. Louis (WUSTL), healthy controls from studies in the Ances lab at WUSTL ( Thomas et al, 2013 ; Petersen et al, 2021 ), and mutation-negative controls from the Dominantly Inherited Alzheimer Network (DIAN) study of autosomal dominant AD at multiple international sites including WUSTL ( McKay et al, 2022 ). To minimize the likelihood of undetected AD pathology in our training set, participants over the age of 50 were only included in the training set if they were cognitively normal, as assessed by the Clinical Dementia Rating (CDR 0; Morris, 1993 ), and had at least one biomarker indicating the absence of amyloid pathology (CN/A−, see below).…”

“…As described previously ( Millar et al, 2022 ), participants in the Knight ADRC and Ances lab studies completed one of two comparable structural MRI protocols, varying by scanner (sagittal T1-weighted magnetization-prepared rapid gradient echo sequence [MPRAGE] with repetition time [TR] = 2400 or 2300 ms, echo time [TE] = 3.16 or 2.95 ms, flip angle = 8 or 9°, frames = 176, field of view = sagittal 256×256 or 240×256 mm, 1 mm isotropic or 1×1×1.2 mm voxels; oblique T2-weighted fast spin echo sequence [FSE] with TR = 3200 ms, TE = 455 ms, 256×256 acquisition matrix, 1 mm isotropic voxels) and an identical resting-state fMRI protocol (interleaved whole-brain echo planar imaging sequence [EPI] with TR = 2200 ms, TE = 27 ms, flip angle = 90°, field of view = 256 mm, 4 mm isotropic voxels for two 6 min runs [164 volumes each] of eyes open fixation). DIAN participants completed a similar MPRAGE protocol (TR = 2300ms, TE = 2.95ms, flip angle = 9°, field of view = 270 mm, 1.1×1.1×1.2 mm voxels; McKay et al, 2022 ). Resting-state EPI sequence parameters for the DIAN participants differed across sites and scanners with the most notable difference being shorter resting-state runs (one 5 min run of 120 volumes; see Supplementary file 1 for summary of structural and functional MRI parameters; McKay et al, 2022 ).…”

“…DIAN participants completed a similar MPRAGE protocol (TR = 2300ms, TE = 2.95ms, flip angle = 9°, field of view = 270 mm, 1.1×1.1×1.2 mm voxels; McKay et al, 2022 ). Resting-state EPI sequence parameters for the DIAN participants differed across sites and scanners with the most notable difference being shorter resting-state runs (one 5 min run of 120 volumes; see Supplementary file 1 for summary of structural and functional MRI parameters; McKay et al, 2022 ).…”

Multimodal brain age estimates relate to Alzheimer disease biomarkers and cognition in early stages: a cross-sectional observational study

“…Louis (WUSTL), healthy controls from studies in the Ances lab at WUSTL (31,32), and mutation-negative controls from the Dominantly Inherited Alzheimer Network (DIAN) study of autosomal dominant AD at multiple international sites including WUSTL (33). To minimize the likelihood of undetected AD pathology in our training set, participants over the age of 50 were only included in the training set if they were cognitively normal (CN), as assessed by the Clinical Dementia Rating ® (CDR ® 0) (34), and had at least one biomarker indicating the absence of amyloid pathology (A-, see below).…”

“…As described previously (29), participants in the Knight ADRC and Ances lab studies completed one of two comparable structural MRI protocols, varying by scanner (sagittal T1-weighted magnetization-prepared rapid gradient echo sequence [MPRAGE] with repetition time [TR] = 2400 or 2300 ms, echo time [TE] = 3.16 or 2.95 ms, flip angle = 8° or 9°, frames = 176, field of view = sagittal 256×256 or 240×256 mm, 1-mm isotropic or 1×1×1.2 mm voxels; oblique T2-weighted fast spin echo sequence [FSE] with TR = 3200 ms, TE = 455 ms, 256 x 256 acquisition matrix, 1-mm isotropic voxels) and an identical resting-state fMRI protocol (interleaved whole-brain echo planar imaging sequence [EPI] with TR = 2200 ms, TE = 27 ms, flip angle = 90°, field of view = 256 mm, 4-mm isotropic voxels for two 6-minute runs [164 volumes each] of eyes open fixation). There was variability in the MPRAGE and EPI sequence parameters for the DIAN participants (33) with the most notable difference being shorter resting-state runs (one 5-minute run of 120 volumes).…”