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Table 1 Evidentiary table showing different imaging modalities implemented in AD research with relevant information

From: Imaging as a biomarker in drug discovery for Alzheimer’s disease: is MRI a suitable technology?

  Patient population Current use. (Potential clinical use) Cost; feasibility. Burden Biological and multi-center validation Limitation Regulatory status
FDG PET MCI, AD, and other dementias Diagnostic; stratification [10]; provide support to therapeutic clinic effects [11]. (Disease progression.) High cost; - Feasible. - IV infusion radioactive agent needed. Biological post-mortem data. Guidelines for single- and multi-site use, vendor-specific protocols. Standardized for multi-center trials. High validity [12]. Signal affected by inflammation and ischemia or behavior state [9, 13]; misdiagnosis reported [14]. Indicated for differential diagnosis of dementia (FDA and EMA) in 2004. No regulatory qualification for use in early AD at this time.
Amyloid-β PET MCI, AD, and other dementias Diagnostic: AD exclusion; stratification; target engagement [15]. High cost; - Difficult. - IV infusion radioactive agent needed. Biological post-mortem data [16]. Guidelines for single- and multi-site use, vendor-specific protocols. Standardization for multi-center trials partially achieved [12]. Cases of normal subjects with high amyloid-β and cases of subjects with dementia with low amyloid-β. Detection threshold to be validated [8]. Indicated for differential diagnosis of dementia in 2012 (FDA and EMA). Qualified as baseline measure for selecting patients for trials in pre-dementia and mild-moderate AD (EMA). Regulatory guidance for use in research and drug development.
Volumetric MRI MCI, AD Diagnostic [10]; stratification using hippocampal volume [17, 18]. (Disease progression; provide support to therapeutic clinic effects.) Low cost; - Easy. Burden: no pacemaker carriers; claustrophobic reaction. SOPs for single and multi-site; vendor-specific protocols. Standardization for multi-center trials partially achieved [6, 9]. Lack molecular specificity. Direct data on hippocampal histopathology. Loss of volume as non-specific atrophy [9]. Patterns overlap with non-AD disease or in advanced aging. Hippocampal volume qualified as baseline measure for selecting patients for trials in pre-dementia AD/MCI through EMA. Hippocampal volume qualification for patient stratification in MCI/AD through CAMD/FDA in progress.
ARIA MRI MCI, AD Safety signal; vascular integrity; inflammation [14]. Low cost; - Easy. Burden: no pacemaker carriers; claustrophobic reaction. SOPs for single and multi-site; vendor-specific protocols. Standardization for multi-center trials achieved [19]. Occurrence of spontaneous ARIA in elderly unknown. False positive in untreated APP duplication case. Requirement of monitoring (several MRI scans) during trials with amyloid-β-lowering agents (FDA and EMA).
DTI tracto-graphy MCI, AD, non-clinical at genetic risk subject Diagnostic [20]; stratification; disease progression. (Provide support to therapeutic clinic effects.) Low cost; - Easy. Burden: no pacemaker carriers; claustrophobic reaction. Biological validation in progress [21]. SOPs for single and multi-site; vendor-specific test protocols; standardization for multi-center trials in progress [22, 23]. Head motion artifacts; partial volume effects. Limited direct data on histopathology. Few multimodal relationships established. No regulatory guidelines
Resting-state fMRI MCI, AD, non-clinical at genetic risk subject (Provide support to therapeutic clinic effect [24, 25]. Stratification [26]; disease progression [7].) Low cost; - Easy. Burden: no pacemaker carriers; claustrophobic reaction. Various SOPs for BOLD in single- [27] and multi-center; ASL in single center [20, 28]. Test-retest done [7, 29]. Standardization for multi-center trials in progress [26]. Head motion artifacts; unclear biology; few data in histopathology. Preliminary data longitudinal and multimodal data available [7]. No regulatory guidelines
Memory task - fMRI MCI, AD, non-clinical at genetic risk subject (Provide support to therapeutic clinic effect. Stratification [24]; disease progression [30].) Middle cost; - Complex. Burden: no pacemaker; claustrophobic reaction. Various SOPs for single center [31, 32]. Vendor-specific test protocols. No standard for multi-center trials. Test-retest not always available [33]. Head motion artifacts; difficult implementation in cognitively impaired subject Longitudinal data available in part; incomplete reliability data [9, 34]. No regulatory guidelines
  1. AD, Alzheimer’s disease; APP, amyloid precursor protein; ARIA, amyloid-related imaging abnormality; ASL, arterial spin labeling; BOLD, brain oxygen level-dependent; CAMD, coalition against major diseases; DTI, diffusion tensor imaging; EMA, European Medicines Agency; FDA, US Food and Drug Administration; FDG, fluoro-2-deoxy-D-glucose; fMRI, functional magnetic resonance imaging; IV, intravenous; MCI, mild cognitive impairment; MRI, magnetic resonance imaging; PET, positron emission tomography; SOP, standard operating procedure.