Shashank Shekhar, MD, MS

van Leijsen EMC, Kuiperij HB, Kersten I, Bergkamp MI, van Uden IWM, Vanderstichele H, et al. Plasma Aβ (Amyloid-β) Levels and Severity and Progression of Small Vessel Disease. Stroke. 2018

Leukoaraiosis, along with microbleeds and lacunes, are one of the most commonly encountered findings after a brain imaging in patients with multiple vascular risk factors. These changes are a result of small vessel disease (SVD). White matter disease is considered as a potential imaging marker for the development of dementia. Apart from traditional risk factors, e.g., hypertension, diabetes, etc., Aβ (amyloid β) has been proposed as an additional contributor to SVD. To investigate the association of plasma Aβ levels with severity and progression of SVD, the authors studied 487 participants in a prospective cohort RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort).

There were 503 participants initially selected for study; however, after exclusion, only 487 matched the quality for participation. Baseline plasma sample was collected and was analyzed for Aβ38, Aβ40, and Aβ42 levels using ELISA. Patients were longitudinally assessed for volume changes of white matter over the course of 9 years using three subsequent MRI assessments.

For statistical association, levels of Aβ38, Aβ40, and Aβ42 and SVD markers on MRI were tested using 1-way ANOVA, followed by a Bonferroni correction to correct for multiple comparisons. They used four models to investigate the associations between plasma Aβ levels and SVD markers:

  • Model 1, unadjusted
  • Model 2, adjusted for age and sex
  • Model 3, adjusted for hypertension
  • Model 4, total brain volume or atrophy

Additionally, the ratio of plasma Aβ38/Aβ40, Aβ38/Aβ42, and Aβ42/Aβ40 and SVD markers were assessed. To quantify the strength of association between plasma Aβ levels and SVD markers, Aβ levels in quintiles of their distribution were tested in continuous linear trend. They also analyzed the relationship between Aβ levels and microbleeds.

Results suggested plasma Aβ40 levels were elevated in participants with microbleeds (mean, 205.4 versus 186.4 pg/mL; P<0.01) and lacunes (mean, 194.8 versus 181.2 pg/mL; P<0.05).

Both Aβ38 and Aβ40 were elevated in participants with severe white matter hyperintensities (Aβ38, 25.3 versus 22.7 pg/mL; P<0.01; Aβ40, 201.8 versus 183.3 pg/mL; P<0.05). Longitudinally, plasma Aβ40 levels were elevated in participants with white matter hyperintensity progression (mean, 194.6 versus 182.9 pg/mL; P<0.05).

Both Aβ38 and Aβ40 were elevated in participants with incident lacunes (Aβ38, 24.5 versus 22.5 pg/mL; P<0.05; Aβ40, 194.9 versus 181.2 pg/mL; P<0.01) and Aβ42 in participants with incident microbleeds (62.8 versus 60.4 pg/mL; P<0.05).

Figure: Pathogenetic mechanisms (1-4) of plasma Aβ levels associated with development of small vessel disease.

Figure: Pathogenetic mechanisms (1-4) of plasma Aβ levels associated with development of small vessel disease.

The authors discussed some interesting mechanistic pathways, which could explain the association between Aβ levels and SVD (Figure) and concluded by suggesting Aβ pathology might contribute to the presence and progression of SVD. To this date, there is no reliable biomarker available to predict the future risk of progression of SVD and measuring plasma levels of Aβ types 38, 40, 42 could be an inexpensive way to answer the questions. However, the results could be concluded with some reservation because the study only collected plasma Aβ levels at baseline and not serial measurement. APOE was not measured on all subjects, and some subjects might have lost follow up because of the severity of symptoms.

This paper, in line with other papers, suggests the importance of measuring Aβ, which could be a potential biomarker for SVD when combined with imaging modality and will help to predict the development of degenerative disease. It would be interesting to see if Aβ changes longitudinally in patients who are at higher risk for developing white matter disease and dementia.