[Study] Relations between white matter hyperintensity (WMH) feature and amyloid-beta (β-amyloid) and tau burden

31 Jan 2024     #bio #brainImaging #demensia #atn

WMH: A form of cerebrovascular degeneration in which the white matter, the medulla, which acts as a pathway between the cortex and gray matter, is dilated and damaged. Usually seen with MR FLAIR imaging

References

Alban, Sierra L., et al. “The association between white matter hyperintensities and amyloid and tau deposition.” NeuroImage: Clinical 38 (2023): 103383. link

Graff-Radford, Jonathan, et al. “White matter hyperintensities: relationship to amyloid and tau burden.” Brain 142.8 (2019): 2483-2491. link

Hedden, Trey, et al. “Cognitive profile of amyloid burden and white matter hyperintensities in cognitively normal older adults.” Journal of Neuroscience 32.46 (2012): 16233-16242. link

Keys

• The relationship between WMH and amyloid beta accumulation remains unclear: From whether they are related to each other to how they are related if they are related.

• A growing number of studies are attempting to elucidate the relationship between WMH and Ab.

• There is no relationship between WMH and tau accumulation.

The association between white matter hyperintensities and amyloid and tau deposition (2023)

Abstract

… Finally, the regions where β-amyloid and WMH count were most positively associated were the middle temporal region in the right hemisphere (r = 0.18, p = 0.002) and the fusiform region in the left hemisphere (r = 0.017, p = 0.005). β-amyloid and WMH have a clear association, though the mechanism facilitating this association is still not fully understood. The associations found between β-amyloid and WMH burden emphasize the relationship between β-amyloid and vascular lesion formation while factors like CVRFs, age, and sex affect AD development through various mechanisms

Data

The subset of ADNI-3 participants who had all the T1-weighted, 3D FLAIR, Amyloid, and Tau PET modalities available

Snippets

• The percentage of white matter volume occupied by WMH was significantly and positively correlated with β-amyloid PET SUVR (Fig. 1; r = 0.28, p < 0.001). We observed WMH volume to significantly predict global amyloid accumulation when controlling for age, sex, years of education, and scanner manufacturer (F(1, 309) = 13.9, p = 0.0002).
• The correlational analyses were repeated after the log transformation of WMH volume and outcomes remained the same, resulting in a significant positive correlation between WMH volume and β-amyloid (r = 0.24, p = 4.9e-5), and a nonsignificant positive correlation between WMH volume and meta-temporal tau (r = 0.09, p = 0.12).
• The inclusion of MOCA, MMSE, and Global CDR, as covariates, did not change the significant relationship between WMH volume and β-amyloid. We observed a significant effect of hippocampal volume fraction on WMH volume (F(1, 580) = 16.9, p = 4.5e-5) and β-amyloid (F(1, 309) = 32.5, p = 2.8e-8).
• WMH volume percent of participants with either amyloid (A+) or tau (T+) pathology was higher than controls (A-/T-) (Fig. 2). We observed a significantly higher WMH percent in AD pathology participants (A+/T+) compared to controls (A-/T-) (p = 0.007, Cohen’s d = 0.4, t = -2.5). … No significant association was found in the A-/T- group (r = 0.06, p = 0.45). A significant positive correlation was observed between β-amyloid SUVR and WMH count in the A+/T+ group only.
• WMH count was used as another method of measuring WMH burden. … Both statistical tests on the WMH volume and the WMH count showed similar results, confirming that WMH count is an accurate measure to use alongside WMH volume. Correlations of WMH count with β-amyloid within A/T pathological groups also paralleled the WMH volume analysis result.
• Our regional analysis showed that β-amyloid and WMH accumulation in the precentral, cuneus, fusiform, isthmus cingulate, lateral occipital, lingual, superior parietal, and supramarginal regions were most significantly associated across all pathological groups when averaged across hemispheres. Variations in the locations of increased WMHs are indicative of AD and its phase of progression, some of these regions being more implicated in cognitive decline than others.

• We observed neither a correlation nor an association between WMH and Tau uptake in the entire cohort (Fig. 4: correlation p = 0.25; association p = 0.4, controlling for age, sex, years of education, and scanner manufacturer).

• Additionally, WMH volume was only predicted by CN and MCI diagnoses, not AD. The relationship between WMH volume often predicts AD in the preclinical stages, likely accounting for the relationship we observed.

• The inclusion of cognitive scores MMSE, MOCA, and Global CDR had no effect on the associations found between β-amyloid and WMH volume, therefore not significantly impacting this relationship. In the literature, worse performance on these cognitive tests has been associated with increased WMH volume (Wang et al., 2020).

• The relationship between higher MMSE scores and increased WMH volume showed significance with multiple comparison corrections while controlling for age and sex in the isthmus cingulate region

• For Global CDR scores, this spatial distribution was significant in the isthmus cingulate, temporal pole, and pars triangularis

• Lastly, the MOCA scores showed significant positive spatial relationships in the isthmus cingulate, linguistic, and temporal pole regions

• We also did not observe any significant effect of APOE-ε4 presence on the established relationship between β-amyloid and WMH volume or WMH count. … Although, we did have a small sample size of individuals with the homozygous APOE-ε4 genotype.

White matter hyperintensities: relationship to amyloid and tau burden (2019)

Abstract

White matter hyperintense volumes in the detected topographic pattern correlated strongly with lobar cerebral microbleeds (P < 0.001, age and sex-adjusted Cohen’s d = 0.703). In contrast, there were no white matter hyperintense regions significantly associated with increased tau burden using voxel-based analysis or region-specific analysis, among non-demented elderly, amyloid load correlated with a topographic pattern of white matter hyperintensities. Further, the amyloid-associated, white matter hyperintense regions strongly correlated with lobar cerebral microbleeds suggesting that cerebral amyloid angiopathy contributes to the relationship between amyloid and white matter hyperintensities.

Data

• Participants, aged 50 to 89, were enrolled in the Mayo Clinic Study of Aging (MCSA), a population-based study of Olmsted County, Minnesota residents.
• 434 non-demented participants with FLAIR-MRI, tau-PET (AV-1451), and Pittsburgh compound B (PiB)-PET (amyloid) scans to assess the relationship between FLAIR WMH and Alzheimer’s disease pathologies.

Snippets

• In the study of non-demented individuals, we found that amyloid burden measured by PET was associated with a topographic pattern of WMH. These amyloid-related WMH regions were associated with lobar CMBs suggesting that regional changes correlate with CAA. We found no evidence to support an association between tau burden and WMH burden.

• We did not detect an association between tau burden and WMH in either the voxel-level analyses or region-level analyses.

Cognitive Profile of Amyloid Burden and White Matter Hyperintensities in Cognitively Normal Older Adults (2012)

Abstract

Amyloid burden and WMH were not correlated with one another. Age was associated with lower performance in all cognitive domains, while higher estimated verbal intelligence was associated with higher performance in all domains. Hypothesis-driven tests revealed that amyloid burden and WMH had distinct cognitive profiles, with amyloid burden having a specific influence on episodic memory and WMH primarily associated with executive function but having broad (but lesser) effects on the other domains. These findings suggest that even before clinical impairment, amyloid burden, and WMH likely represent neuropathological cascades with distinct etiologies and dissociable influences on cognition.

Data

• 168 (95 female) cognitively normal, community-dwelling older adults (aged 65–86, M=73.24, SD=5.80).

• Participants in the Harvard Aging Brain Study, an ongoing longitudinal study currently in the baseline assessment phase

• Because of the staged nature of the visits (all baseline visits must be completed within 6 months), positron emission tomography (PET) amyloid imaging and magnetic resonance imaging (MRI) estimates of WMH were currently available for 109 of the older adults.