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Associations in Alzheimer’s disease between Intracranial Vascular Metrics from 4D-Flow MRI and β-Amyloid and Tau PET
Leonardo A Rivera-Rivera1,2, Karly A Cody1, Tobey Betthauser1, Robert V Cadman1, Thomas Reher3, Howard A Rowley3, Cynthia M Carlsson1, Laura Eisenmenger3, Sterling C Johnson1, and Kevin M Johnson2,3
1Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States, 2Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, United States, 3Department of Radiology, University of Wisconsin-Madison, Madison, WI, United States

Synopsis

Cerebrovascular disease (CVD), has been linked with mild cognitive impairment and dementia stages of Alzheimer’s disease (AD); however, the question of whether CVD is associated with underlying AD pathophysiology remains unresolved. There remain many questions regarding CVD/AD pathophysiology interactions and whether related clinical AD dementia is enhanced by CVD. In this study, we investigated the relationship between cardiac and low frequency flow oscillations from 4D-Flow, white matter hyperintensities (WMHs) from T2 FLAIR MRI, and AD pathology assessed using β-amyloid (Aβ) and tau PET imaging data.

Introduction:

Recent data suggests a potential compounding influence of cerebrovascular disease (CVD) on the pathologic trajectory of Alzheimer’s disease (AD).1 For example, animal studies have shown cardiac pulsations and vasomotion play a key role in brain clearance of AD related metabolites.2,3,4,5 A barrier to understanding AD and concomitant CV pathology is the lack of precise methods to measure vascular degeneration. MRI is currently used to aid in the characterization of CVD in AD typically based on the quantification of white matter hyperintensities (WMHs) seen on T2-FLAIR and cerebral perfusion from arterial spin labeling; however, WMHs and hypo-perfusion occur in other diseases and in normal aging. Intracranial 4D-Flow MRI is a technique with the ability to provide complementary vessel information to these measures. Using newly developed acquisition and reconstruction strategies, 4D-Flow MRI hemodynamic alterations have been observed in subjects diagnosed with AD clinical syndrome6; however, a syndrome is not an etiology.7 Clinical AD diagnoses often differ significantly (>35%) from final neuropathological diagnoses.8 Therefore, to study the relationship between CVD and AD, AD biomarker data are necessary. In this study we investigated the relationship between 4D-Flow and T2-FLAIR vascular markers including high frequency cardiac pulsations and low frequency oscillations (LFOs) and WMHs with AD biomarkers of β-amyloid deposition and neurofibrillary tau tangles using 11C-PiB and 18F-MK-6240 PET in both preclinical and clinical AD.

Methods:

Subjects: A total of 115 subjects participated in this study (fig1). Subjects were clinically cognitively normal, except those in the impaired group A+/T+/IM (IM; impaired, n=9 MCI, n=5 AD). MRI: Whole brain 4D-Flow data were acquired on a 3.0T system (MR750, GE Healthcare) using a 32-channel head coil with a 3D radially undersampled sequence and the following imaging parameters Venc=80cm/s, imaging volume=22x22x16cm3, TR/TE=7.7/2.5ms, scantime~6.35min.9 To characterize LFOs 4D-Flow data were retrospectively reconstructed to absolute time using GPU accelerated (SigPy)10 iterative SENSE with JSENSE11 sensitivity maps and a local-low rank temporal constraint12. Reconstructions were performed with block shifting of a 16x16x16 block and an empirically tuned regularization parameter (λ=0.0001). Velocity data time series were reconstructed into 100 frames (temporal res ~3.8s, spatial res ~1.72mm3) and rigidly registered. In addition, 4D-Flow MRI data were also reconstructed with gating to the cardiac cycle (temporal res ~50ms, spatial res ~0.7mm3). This was done to characterize high frequency cardiac pulsations. Background phase and velocity aliasing corrections were performed.13 Intracranial arteries including internal carotid arteries (ICAs) and veins (superior sagittal sinus (SSS)) were segmented automatically in MATLAB (Mathworks, Natick, MA).14 Quantified flow parameters included: total cerebral blood flow, trans-capillary pulse wave delay, low frequency flow range and standard deviations, and LFOs from power spectral analysis. Trans-capillary pulse wave delay was defined as the time shift between arterial and venous cardiac waveforms measured from time-to-upstroke (maximum acceleration).15 Intracranial volumes (ICVs), CSF and hippocampal volume were segmented using T1-weighted data, SPM1216 and FSL FIRST17. WMHs lesion volumes were segmented from 3D T2-FLAIR images using a lesion segmentation tool for SPM12.18 PET: Amyloid and tau burden were assessed using 11C-PiB and 18F-MK-6240 PET, respectively.19 Three biomarker groups were established (A-T-, A+T-, A+T+) based on PET biomarker positivity, where amyloid positivity was determined using a previously established global PiB distribution volume ratio (DVR) threshold >1.19 and tau positivity was determined using a previously established entorhinal cortex MK-6240 standard uptake value ratio (SUVR) threshold >1.27.19,20 Pairwise statistical differences were assessed using ANOVA followed by post hoc analysis using the Tukey‐Kramer method (P<0.05 significance).

Results:

Demographics, cardiovascular and AD biomarkers are summarized in figure 1. No significant AT biomarker group differences were observed across traditional cardiovascular and cerebrovascular metrics, including WMH lesion volumes. Cerebral blood flow was similar between AT groups (fig2 a); however, ICA trans-capillary pulse wave delay was significantly longer in controls when compared with AD biomarker confirmed groups (fig2 b) including cognitively normal and impaired amyloid and tau positive groups (P<0.001, P<0.001, P<0.001). Low frequency flow range and standard deviations in the ICA were significantly lower in AT positive groups both cognitively normal and impaired (fig3 a, b) (P=0.024, P=0.034). ICA and SSS LFOs were diminished in groups both amyloid and tau positive when compared to controls and amyloid positive only groups (fig 4). Overall, linear regression analysis showed a relatively weak correlation between ICA trans-capillary pulse wave delay and PiB and MK-6240 (R2=0.12, R2=0.03), and low frequency blood flow standard deviation and PiB and MK-6240 (R2=0.06, R2=0.04) (fig5.).

Discussion and Conclusions:

Although more traditional measures of CVD were not related to biomarker groups, high frequency cardiac-resolved MRI suggests alterations in the cerebrovasculature are occurring in AD biomarker positive subjects during preclinical stage (e.g. A+/T-/CN, A+/T+/CN). The significantly shorter trans-capillary pulse wave delay might be an indicator of underlying AD pathology related artery and capillary stiffening and diminished caliber changes.21 In addition, low frequency time-resolved MRI showed decreased LFO content in amyloid+tau positive subjects, but not in A+ only. This result suggests compounding cerebrovascular modifications in amyloid+tau positive subjects related to changes in vessel smooth muscle cell, vasomotion and decreased autoregulation.22 4D-Flow measures were noisy and thus require acquisition and reconstruction improvements. Studies investigating interactions between vascular measures and AD biomarkers on cognitive trajectories are ongoing.

Acknowledgements

We gratefully acknowledge research support from GE Healthcare, and funding support from the Alzheimer's Association (AARFD-20-678095) and from NIH grants R01NS066982, P50-AG033514, and R01AG021155.

References

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Figures

Figure 1. A+/− and T+/− represent amyloid-β and tau tangle positivity groups determined by 11C-PiB and 18F-MK-6240 PET respectively. Pairwise differences were assessed using ANOVA followed by post hoc analysis using the Tukey‐Kramer method (P<0.05 significance). Abbreviations: CN, cognitively normal; IM, impaired; APOE, apolipoprotein E; WMH, white matter hyperintensity; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; ICV, intracranial volume; PiB, 11C-Pittsburgh compound B; DVR, distribution volume ratio; SUVR, standard uptake value ratio.

Figure 2. Cardiac-resolved 4D-Flow MRI data are summarized for controls and AD biomarker confirmed groups (amyloid positive (A+), tau positive (T+), cognitively normal (CN), cognitively impaired (IM)). (a) Cerebral blood flow (basilar (BA) + internal carotid artery (ICA)) was normalized to brain volume and was similar between groups. (b) ICA trans-capillary pulse wave delay time was significantly longer in the control group (A-/T-/CN) when compared to A+/T-/CN (P<0.001), A+/T+/CN (P<0.001) and (A+/T+/IM) (P<0.001). AD biomarker confirmed subjects showed similar delay times.

Figure 3. Low frequency time-resolved 4D-Flow MRI data are summarized for controls and AD biomarker confirmed groups (amyloid positive (A+), tau positive (T+), cognitively normal (CN), cognitively impaired (IM)). Brain volume normalized low frequency flow range and standard deviation (σ) were significantly lower in the arterial circulation (internal carotid artery (ICA)) in amyloid and tau positive cognitively normal and impaired groups (A+/T+/CN, A+/T+/IM) when compared to controls (A-/T-/CN) (P=0.024, P=0.034). Relationships were not observed in the venous circulation.

Figure 4. Power spectrum density shows average low frequency content derived from time-resolved 4D-Flow data in the internal carotid artery (ICA) (a, c) and superior sagittal sinus (SSS) (b, d) for tau negative (A-/T-/CN, A+/T-/CN) (a, b) and tau positive groups (A+/T+/CN, A+/T+/IM) (cognitively normal (CN), cognitively impaired (IM)) (c, d). Diminished frequency content was measured in both A+/T+/CN and A+/T+/IM groups when compared to tau negative groups. ICA frequency content was significantly diminished in A+/T+/CN vs A-/T-/CN (P=0.049) (A+/T+/IM vs A-/T-/CN, P=0.063).

Figure 5. Linear regressions with 95% confidence intervals showing internal carotid artery (ICA) trans-capillary pulse wave delay (a, b) and low frequency blood flow standard deviation (c, d) as a function of global PiB distribution volume ratio (DVR) and enthorinal cortex MK-6240 standard uptake value ratio (SUVR) in all participants (n=115). Linear correlations were relatively weak with coefficients of R2=0.12 (trans-capillary pulse wave delay vs PiB DVR), R2=0.03 (MK-6240 SUVR) and R2=0.06 (low frequency blood flow standard deviation vs PiB DVR), R2=0.04 (MK-6240 SUVR).

Proc. Intl. Soc. Mag. Reson. Med. 29 (2021)
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