The preclinical phase of Alzheimer's disease (AD), as defined by beta-amyloid deposition in the brain, precedes the development of cognitive alterations by several years (1). A recent study by Benitez et al. (2) specifically assessed the amyloid-related changes in the white matter of 153 cognitively unimpaired older adults aged 45 to 85 years, recruited from a US community-dwelling sample. Diffusional kurtosis imaging (DKI) and biophysical modeling were used to test whether beta-amyloid-negative (AB-) and -positive (AB+) participants differed on DKI-based metrics, and to assess the relationship of any alterations with other biomarkers.
The authors described a significantly greater diffusion restriction in the white matter of AB+, compared with AB-, with medium-to-large effect sizes (partial η2 = 0.08–0.19). These alterations were mostly evident in the extra-axonal space within primarily late myelinating tracts (e.g., the genu of the corpus callosum). Diffusion metrics predicted amyloid status incrementally over age (area under the curve = 0.84). Axonal water fraction (a marker of axonal density) correlated with speed/executive functions and neurodegeneration, whereas extra-axonal radial diffusivity (a marker of gliosis/myelin repair) correlated with amyloid deposition and white matter hyperintensity volume.
The results of this study support the hypothesis that, in the AD continuum, an early increase in diffusion restriction may occur due to inflammation and myelin repair, prior to an ensuing decrease in diffusion restriction, indicating glial and neuronal degeneration.
Key Points:
- Greater diffusion restriction occurs in the white matter of amyloid-beta positive cognitively unimpaired individuals, compared with A-beta negative.
- Diffusion metrics can be used to predict amyloid status.
- In early preclinical AD, an increase in diffusion restriction may derive from inflammation and myelin repair.
References:
Dubois B, et al.; Proceedings of the Meeting of the International Working Group (IWG) and the American Alzheimer's Association on “The Preclinical State of AD”; July 23, 2015; Washington DC, USA. Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria. Alzheimers Dement. 2016 Mar;12(3):292-323. doi: 10.1016/j.jalz.2016.02.002. PMID: 27012484; PMCID: PMC6417794. https://pubmed.ncbi.nlm.nih.gov/27012484/
Benitez A, et al. Greater Diffusion Restriction in White Matter in Preclinical Alzheimer Disease. Ann Neurol. 2022 Jun;91(6):864-877. doi: 10.1002/ana.26353. PMID: 35285067; PMCID: PMC9106903. https://pubmed.ncbi.nlm.nih.gov/35285067/