It is well recognized that mild cognitive impairment (MCI) is often the prodromal stage of Alzheimer’s disease (AD), but is a heterogeneous condition, suggesting that such classification may not be sufficient in identification of appropriate candidates for therapeutic intervention studies. Developing measurements that predict AD progression in MCI patients is of clinical significance because they can be used to identify candidates at early stage of disease who are likely to display more significant neurodegenerative change and clinical change in the near future. In this study, we investigated the value of regional cerebral blood flow (CBF), measured by arterial spin labeled perfusion MRI (ASL-MRI) during a memory encoding task, in predicting the rate of hippocampal atrophy, which has been shown to be a useful marker of AD progression ^1,2. Further, we compared these CBF measurements to baseline hippocampal volume, the most commonly used structural biomarker of AD research.

Participants: 22 amnestic MCI patients (a-MCI) and 39 normal controls (NC) were recruited from Penn Memory Center with a baseline and at least one follow-up visit. Diagnosis of a-MCI was made following the criteria outlined by Petersen and others ^3–5. Table 1 shows the demographic and neuropsychological data of this cohort.

MRI protocol: All imaging was performed on a 3T Siemens Trio MRI scanner. Structural images were acquired with 3D-MPRAGE at 1 mm³ isotropic resolution (TI=950ms, TE=3ms, TR=1620ms). A pCASL sequence was acquired using 2D gradient-echo echo planar imaging (TR/TE/FA=4s/19ms/90°, 16 slices, 3.5x3.5x7 mm³). A visual scene-encoding task was administrated during ASL-MRI, as has been previously described ^6,7.

Structural Image Processing: Unbiased annualized hippocampal atrophy rate was estimated using a previously described technique ⁸. Average atrophy rate and average hippocampal volume of each subject were computed by averaging the values of left and right hemispheres (similar for CBF measurements below). Brain mask, grey matter (GM) and white matter (WM) masks were generated using ANTS cortical thickness analysis pipeline ⁹. Baseline hippocampal volume (HV) was normalized using intracranial volume (derived from brain mask). Due to structural MRI distortion, two subjects (1 NC, 1 a-MCI) were excluded.

CBF Quantification: For each subject, baseline ASL time series data were motion corrected, co-registered with the anatomical image and smoothed in space using a 4mm FWHM isotropic Gaussian kernel. The perfusion-weighted image series were then generated by pair-wise subtraction of the label and control images, followed by conversion to an absolute CBF (aCBF) image series using the model in ¹⁰. Subsequently, CBF image series were de-noised using SCORE ¹¹ before being normalized to MNI template. Relative CBF (rCBF) maps were generated by dividing aCBF maps by the mean aCBF within GM and WM voxels in the subject space. Mean aCBF and rCBF in bilateral posterior cingulate cortex (PCC), precuneus, fusiform gyrus, hippocampus and parahippocampal gyrus were computed, using ROIs extracted from the AAL template ¹². Two control subjects were excluded because of ASL artifact. Due to technical issues or subject fatigue, four subjects (3 NC, 1 a-MCI) did not have task ASL data available.

Two-sample t-test (Figure 1) demonstrates that a-MCI patients’ average hippocampal atrophy rate was significantly higher (t₅₁=3.6, p=0.00069) than that of NC. As shown in Table 2, partial correlation analyses, with age as covariate, show that both baseline HV and multiple CBF measurements are significantly correlated with average hippocampal atrophy rate in the whole cohort, but only CBF measurements are significant in the a-MCI patients. Figure 2 shows plots of the most correlated measurements in the two groups, i.e. left PCC aCBF and left hippocampal aCBF vs. average hippocampal atrophy rate. To further investigate whether different measurements provide complementary information, stepwise regression analyses were performed with age entered in the first step and all other measurements entered in a step-wise manner as the second step. Only left PCC aCBF and left hippocampal aCBF, and no structural measurements, were included in the most predictive models for a-MCI and the whole cohort respectively (Table 3), which indicates the stronger power of CBF measurements in predicting AD progression. The significant association between CBF measurements and longitudinal hippocampal atrophy in a-MCI demonstrates their potential in predicting disease progression.The current study compared functional measurements from ASL-MRI with hippocampal volume from structural MRI in predicting AD progression measured by longitudinal hippocampal atrophy. Our results indicate that, compared to structural measurements, functional ones are stronger predictors of likely AD-related progressive neurodegeneration. Further, only functional measurements showed predictive value in a-MCI patients. As such, ASL-MRI could have important utility in identifying candidates for AD treatment clinical trials likely to display significant progression.