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Cerebral Microhemorrhages Predict Faster Worsening on CDR-SB Score

Researchers compared CMH rates in PSEN1, PSEN2, and APP mutation carriers and noncarriers of dominantly inherited Alzheimer disease.

Data from a recent study suggest that cerebral microhemorrhages (CMHs), or cerebral microbleeds, are a part of the underlying disease process in dominantly inherited Alzheimer disease (DIAD) and are significantly associated with dementia.

Researchers from the Washington University School of Medicine found that prevalent or incident CMHs predicted faster changes in clinical dementia rating, with participants with CMHs at baseline exhibiting faster increases on Clinical Dementia Rating scale –Sum of Boxes (CDR-SB) score (0.67 per year; P = .001; 95% CI, 0.27-1.07) compared to those without CMHs. Having 2 or more CMHs was found to be associated with a significant risk of developing additional CMHs in the future (odds ratios [OR], 8.95; standard deviation [SD], 10.04 per year).

“In this cross-sectional and longitudinal study, we describe microhemorrhage prevalence, location, severity, and inherent increase in a population with DIAD, allowing study of AD pathology with reduced influence from confounders of age-related vascular risk factors,” first author Nelly Joseph-Mathurin, PhD, research associate, neurodegenerative disease, Benzinger research group, University of Washington School of Medicine, and colleagues wrote.

“We found that CMH were associated with worsening of clinical symptoms, occurred primarily after the expected age of symptom onset, and that, once present, they are likely to increase in number over time. These findings have important implications for participant selection and monitoring in clinical trials involving the DIAD population,” they added.

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Joseph-Mathurin and colleagues analyzed data from 201 noncarriers, 284 mutation carriers without CMH (212 with a mutation in PSEN1, 23 with a mutation in PSEN2, and 49 with a mutation in APP) and 26 carriers with CMH (20 with a mutation in PSEN1, 1 in PSEN2, and 5 in APP). Noncarriers were an average age of 37.5 years old (SD, 11.2), carriers without CMH were an average age of 37.1 years (SD, 10.6), and carriers with CMH 46.7 years (SD, 10.5; P <.0001). 

Of 310 carriers, 26 (8.4%) had CMHs, while 6 of the 201 (3.0%) noncarriers had CMHs (OR, 3.575; 95% CI, 1.499-9.904). Age (OR, 1.071; 95% CI, 1.034-1.110) and diastolic blood pressure (OR, 1.068; 95% CI, 1.030-1.108) were also significantly associated with the odds of having CMHs. APOE-ε4 status was not associated with CMH.

Joseph-Mathurin and colleagues found that participants with CMHs at baseline exhibited faster increases on CDR-SB score (0.67 per year; P = .001; 95% CI, 0.27-1.07) and a large, but non-significant, annual decline in the cognitive composite score (–0.07 per year; P = .14; 95% CI, –0.16 to 0.02) compared to participants without CMH at baseline. Carriers that had increased CMHs at follow-up also had a faster annual increase in CDR-SB (0.75 per year; P = .048; 95% CI, 0.01-1.49) and a large, but non-significant, annual decline in the cognitive composite score (–0.07 per year; P = .38; 95% CI, 0.01-1.49) compared to participants that did not increase in CMHs. 

Researchers determined that CMH severity in mutation carriers was associated with increased white matter lesion volume (P <.0001; F(3208) = 26.2) and with greater volume increases at follow-up (P = .001; F(3244) = 5.4). This association was especially pronounced in carriers that presented with 5 or more CMHs at baseline (14847.1 mm3 per year; P <.0001; 95% CI, 7555.6-22138.6).

Joseph-Mathurin and colleagues found that the rate of CMH accumulation per year was associated with the number of CMHs observed at baseline in carriers (P <.0001; F(3,252) = 57.5). The presence of 2-4 CMHs (5.9 CMH per year, P <.0001; 95% CI, 4.0-7.7) and more than 4 CMHs (11.2 CMH/year; P <.0001; 95% CI, 9.4-13.1) at baseline were associated with higher rate of increase per year. 

All carriers with at least 2 CMHs and with an increased rate of 2 or more CMHs per year were symptomatic and in general, symptomatic carriers had an increased rate in CMHs during the follow-up (1.62 CMH per year; P <.0001; 95% CI, 0.95-2.29).

“In DIAD, having 2-4 CMHs (defined as moderate CMH severity) is a risk factor for developing more and the odds of increase appear higher than what has been reported in sporadic AD. Based on these results, recommendation guidelines for CMHs in such populations may need to be revisited and adapted for familial AD. This study additionally shows that any clinical trial on individuals with DIAD needs careful participant selection and monitoring,” Joseph-Mathurin and colleagues concluded.

Joseph-Mathurin N, Wang G, Kantarci K, et al. Longitudinal accumulation of cerebral microhemorrhages in dominantly inherited Alzheimer disease. Neurology. Published January 25, 2021. doi: 10.1212/WNL.0000000000011542