Cerebral amyloid is associated with poorer integrity of white matter lesions, penumbra, and healthy white matter in the elderly

Cerebral amyloid is associated with poorer integrity of white matter lesions, penumbra, and healthy white matter in the elderly

Poster Presentations: IC-P observable in cognitively normal elderly, though these effects are greater in individuals harboring brain Ab pathology. I...

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Poster Presentations: IC-P

observable in cognitively normal elderly, though these effects are greater in individuals harboring brain Ab pathology.



Jill N. Barnes, Ronee E. Harvey, Samantha M. Zuk, Emily S. Lundt, Timothy G. Lesnick, Jeffrey L. Gunter, Matthew L. Senjem, Virginia M. Miller, Clifford R. Jack, Jr., Michael J. Joyner, Kejal Kantarci, Mayo Clinic, Rochester, MN, USA. Contact e-mail: [email protected] Background: White matter hyperintensity (WMH) load on T2weighted MRI associates with cognitive decline and cardiovascular risk factors, such as hypertension. Early changes in arterial structure often occur in the intimal layer of the central elastic arteries, affecting central hemodynamics and arterial stiffness before the appearance of clinically-diagnosed hypertension. Therefore, evaluating central hemodynamics and arterial stiffness may identify normotensive individuals who have a higher risk of WMH. In this context, the hormonal shifts during menopause accelerate arterial stiffness in women, putting postmenopausal women at increased risk for both hypertension and WMH. This study determined the association between central hemodynamics and WMH in healthy, postmenopausal women with normal blood pressure. Methods: Brachial blood pressure (BP) was determined using an arm cuff in 53 non-hypertensive postmenopausal women (age 6062 yrs; body mass index 2764 kg/m2). Central hemodynamics (aortic augmentation index, AIx; and aortic round trip transit time, Aortic TR) were estimated using beat-by-beat tonometry (Sphygmocor). AIx is related to arterial stiffness, such that higher arterial stiffness results in greater augmentation of the pressure waveform (higher AIx). Aortic TR is also related to arterial stiffness because higher arterial stiffness results in faster velocity of pulse wave travel. Therefore, the time it takes for the pressure wave to reach the reflection point and return is shorter (lower Aortic TR). WMH load was calculated from fluid-attenuated inversion recovery MRI using a semi-automated segmentation algorithm. WMH volume was divided by the total white matter volume at risk to calculate WMH fraction in each subject. Results: Blood pressure was within normative ranges (systolic: 121610 mmHg; diastolic: 7367 mmHg). Central hemodynamics were 2768 % for AIx and 140613 ms for Aortic TR. WMH fraction positively associated with AIx (r¼0.29;p<0.05) and inversely associated with Aortic TR(r¼-0.28;p<0.05) after adjusting for age. Conclusions: In postmenopausal women with blood pressure within normative ranges, higher AIx and lower Aortic TR were associated with greater WMH load. Alterations in central hemodynamics and arterial stiffness precede changes in brachial blood pressure, and our results suggest that monitoring these variables may identify individuals at accelerated risk for WMH and cognitive decline.



Julia A. Scott1, Pauline Maillard1, Meredith N. Braskie2, Duygu Tosun3, Paul Thompson2, Michael W. Weiner3, Charles DeCarli1, Owen T. Carmichael4, 1University of California Davis, Davis, CA, USA; 2 University of Southern California, Los Angeles, CA, USA; 3University of


California San Francisco, San Francisco, CA, USA; 4Pennington Biomedical Research Center, Baton Rouge, LA, USA. Contact e-mail: [email protected] Background: White matter hyperintensities (WMH) in the elderly are highly prevalent and presumed to be vascular in origin. However, a recent study (Scott, AAN2015) suggests that individuals with cerebral amyloid have greater WMH burden independent of vascular risks. Here we extend this analysis to determine whether cerebral amyloid is associated with more widespread white matter problems than increased WMH burden. We used diffusion MRI to determine whether elderly individuals with elevated cerebral amyloid had poorer white matter integrity within WMH (lesion core) as well as WMH-proximal (penumbra) and WMH-distal (healthy) white matter. Methods:We used FLAIR to identify WMHs and diffusion MRI to calculate fractional anisotropy (FA) in 178 baseline MRI from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) ADNI-GO and ADNI-2 studies. Lesion-level mixed effects regression models within specific tissue types (lesion core, penumbra) had age, gender, hypertension history, intracranial volume, lesion size, and CSF amyloid as predictors, and mean FA as the outcome measure. Similar voxel-level regression had the same predictors (except lesion size) and the same outcome. Analyses were also conducted by diagnostic group and by lobe. Results: In lesion-level models, lower CSF amyloid (i.e. higher cerebral amyloid) was associated with lower FA in all tissue types. In voxellevel analysis, lower CSF amyloid was associated with lower FA in bilateral periventricular occipital white matter (Fig. 1A). Lesion-level effects were present in subgroups with and without hypertension. Hypertension had its own independent effect on lower FA in lesion core and penumbra. Diagnostic group specific models suggested that these effects were driven by cognitively normal individuals, in whom amyloid associations with white matter FA extended into the corpus callosum and frontal lobe (Fig. 1B). Lobe specific models suggested that the lesion core and penumbra findings were due to amyloid-associated lesions in occipital and parietal white matter. Conclusions: Elderly individuals with elevated cerebral amyloid have poorer white matter integrity in all tissue types–WMH lesions, penumbra and healthy white matter—independent of hypertension history. The possibility that amyloid burden may independently contribute to widespread white matter degeneration independent of vascular risks should be further examined, especially in cognitively healthy elderly individuals.

Figure 1. Voxel-wise models for FA with covariates of CSF amyloid, age, sex, intracranial volume, and vascular risk factors. Display of axial sections of significance maps are thresholded at p<0.05, corrected for multiple comparisons using threshold-free cluster enhancement permutation testing (Smith and Nichols, 2009). (A) In all subjects, significant associations (3,000-11,184) with greater amyloid burden were constrained to periventricular white matter of the occipital lobe. (B) In cognitively normal, the significant associations (3,134-6,985) with amyloid were more widespread and not influenced by vascular risk factors. Early MCI, Late MCI and Alzheimer’s Disease groups did not have any significant associations with amyloid burden that survived multiple comparisons correction.