Imaging markers for Alzheimer disease: which vs how

Abstract

Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, ¹⁸F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured ("metric": visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR-), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR- between 0.25 and 0.08, whereas prognostic LR+ and LR- were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR- from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR-. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR-. Within markers, the largest proportion of diagnostic LR+ and LR- variability was within ¹⁸F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.

Figure 1. Markers, submarkers, and metrics reviewed in the current study

3D-SSP = 3-dimensional stereotactic surface projection; ¹¹C-PiB = ¹¹C-labeled Pittsburgh compound B; ^99mTc-ECD = technetium-99m bicisate; ^99mTc-HMPAO = technetium-99m hexamethylpropylene amine oxime; ¹²³I-IMP = 123I-N-isopropyl-iodoamphetamine; FDG = fluorodeoxyglucose; HCI = hypometabolic convergence; sc-SPM = single-case statistical parametric mapping; t-sum = PMOD Alzheimer discrimination analysis tool; TP = temporoparietal.

Figure 2. Diagnostic (A) positive and (B) negative likelihood ratio (LR+ and LR−) for correct classification between patients with Alzheimer disease and healthy subjects broken down by markers by metrics and by markers by submarkers

Only metrics with at least 3 studies are shown. Boxplots denote median, first, and third quartiles, and whiskers denote minimum and maximum values (excluding outliers). Dashed lines indicate the conventional thresholds of clinical relevance (5 for LR+ and 0.2 for LR−). DVR = distribution volume ratio; FDG = fluorodeoxyglucose; sc-SPM = single-case statistical parametric mapping; SUVR = standardized uptake value ratio; 3D-SSP = 3-dimensional stereotactic surface projection.

Figure 3. Prognostic (A) positive and (B) negative likelihood ratio (LR+ and LR−) for correct classification of patients with progressed vs nonprogressed mild cognitive impairment, broken down by markers by metrics and by markers by submarkers

Only metrics with at least 3 studies are shown. Boxplots denote median, first, and third quartiles, and whiskers denote minimum and maximum values (excluding outliers). Dashed lines indicate the conventional thresholds of clinical relevance (5 for LR+ and 0.2 for LR−). FDG = fluorodeoxyglucose; HCI = hypometabolic convergence index; sc-SPM = single-case statistical parametric mapping; SUVR = standardized uptake value ratio.

Figure 4. Proportion of explained variance and significance of positive and negative likelihood ratio (LR+ and LR−) for correct classification between (A) patients with Alzheimer disease and healthy subjects, and (B) patients with progressed and nonprogressed mild cognitive impairment

Analysis included only values for metrics with at least 3 studies. Rectangles denote the markers or metrics whose LR variance is computed. DVR = distribution volume ratio; FDG = fluorodeoxyglucose; sc-SPM = single-case statistical parametric mapping; SUVR = standardized uptake value ratio; 3D-SSP = 3-dimensional stereotactic surface projection.