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 |