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Abstract
Objective We sought to determine the underlying mechanism for altered white matter diffusion tensor imaging (DTI) measures at the histopathologic level in patients with cerebral amyloid angiopathy (CAA).
Methods Formalin-fixed intact hemispheres from 9 CAA cases and 2 elderly controls were scanned at 3-tesla MRI, including a diffusion-weighted sequence. DTI measures (i.e., fractional anisotropy [FA] and mean diffusivity [MD]) and histopathology measures were obtained from 2 tracts: the anterior thalamic radiation and inferior longitudinal fasciculus.
Results FA was reduced in both tracts and MD was increased in cases with CAA compared to controls. Regional FA was significantly correlated with tissue rarefaction, myelin density, axonal density, and white matter microinfarcts. MD correlated significantly with tissue rarefaction, myelin density, and white matter microinfarcts, but not axonal density. FA and MD did not correlate with oligodendrocytes, astrocytes, or gliosis. Multivariate analysis revealed that tissue rarefaction (β = −0.32 ± 0.12, p = 0.009) and axonal density (β = 0.25 ± 0.12, p = 0.04) were both independently associated with FA, whereas myelin density was independently associated with MD (β = −0.32 ± 0.12, p = 0.013). Finally, we found an association between increased MD in the frontal white matter and CAA severity in the frontal cortex (p = 0.035).
Conclusions These results suggest that overall tissue loss, and in particular axonal and myelin loss, are major components underlying CAA-related alterations in DTI properties observed in living patients. The findings allow for a more mechanistic interpretation of DTI parameters in small vessel disease and for mechanism-based selection of candidate treatments to prevent vascular cognitive impairment.
Glossary
- AD=
- axial diffusivity;
- ATR=
- anterior thalamic radiation;
- CAA=
- cerebral amyloid angiopathy;
- DTI=
- diffusion tensor imaging;
- FA=
- fractional anisotropy;
- GFAP=
- glial fibrillary acidic protein;
- H&E=
- hematoxylin & eosin;
- ILF=
- inferior longitudinal fasciculus;
- LFB&H=
- Luxol fast blue & hematoxylin;
- MBP=
- myelin basic protein;
- MD=
- mean diffusivity;
- MGH=
- Massachusetts General Hospital;
- NF200=
- neurofilament 200;
- RD=
- radial diffusivity;
- ROI=
- region of interest;
- SVD=
- small vessel disease;
- TBS=
- tris-buffered saline;
- TE=
- echo time;
- TR=
- repetition time;
- True FISP=
- true fast imaging with steady-state free precession
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally to this work.
- Received May 25, 2018.
- Accepted in final form October 23, 2018.
- © 2019 American Academy of Neurology
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