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ObjectiveCerebral microbleeds (MBs) are a common finding in patients with cerebral small vessel disease (CSVD) and Alzheimer disease as well as in healthy elderly people, but their pathophysiology remains unclear. To investigate a possible role of veins in the development of MBs, we performed an exploratory study, assessing in vivo presence of MBs with a direct connection to a vein.Methods7-Tesla (7T) MRI was conducted and MBs were counted on quantitative susceptibility mapping (QSM). A submillimeter resolution QSM-based venogram allowed identification of MBs with a direct spatial connection to a vein.ResultsA total of 51 people (mean age [SD] 70.5 [8.6] years, 37% female) participated in the study: 20 had CSVD (cerebral amyloid angiopathy [CAA] with strictly lobar MBs [n = 8], hypertensive arteriopathy [HA] with strictly deep MBs [n = 5], or mixed lobar and deep MBs [n = 7], 72.4 [6.1] years, 30% female) and 31 were healthy controls (69.4 [9.9] years, 42% female). In our cohort, we counted a total of 96 MBs with a venous connection, representing 14% of all detected MBs on 7T QSM. Most venous MBs (86%, n = 83) were observed in lobar locations and all of these were cortical. Patients with CAA showed the highest ratio of venous to total MBs (19%) (HA = 9%, mixed = 18%, controls = 5%).ConclusionOur findings establish a link between cerebral MBs and the venous vasculature, pointing towards a possible contribution of veins to CSVD in general and to CAA in particular. Pathologic studies are needed to confirm our observations.

We thank the authors for the attention dedicated to our study.1 This work reports the presence of microbleeds (MBs) with a spatial connection to veins, as observed on high-resolution Quantitative Susceptibility Mapping. As we openly discuss, we cannot exclude that this observed spatial relationship is not a casual one; only neuropathologic correlation studies can provide certainty. Considering the predominantly arterial pattern of vascular amyloid-β accumulation in cerebral amyloid angiopathy, alternative vessel pathologies—such as venous collagenosis2—are more likely to play a role.

OBJECTIVE: To assess cerebrovascular reactivity in response to a visual task in participants with cerebral amyloid angiopathy (CAA), Alzheimer disease (AD), and mild cognitive impairment (MCI) using fMRI. METHODS: This prospective cohort study included 40 patients with CAA, 22 with AD, 27 with MCI, and 25 healthy controls. Each participant underwent a visual fMRI task using a contrast-reversing checkerboard stimulus. Visual evoked potentials (VEPs) were used to compare visual cortex neuronal activity in 83 participants. General linear models using least-squares means, adjusted for multiple comparisons with the Tukey test, were used to estimate mean blood oxygen level–dependent (BOLD) signal change during the task and VEP differences between groups. RESULTS: After adjustment for age and hypertension, estimated mean BOLD response amplitude was as follows: CAA 1.88% (95% confidence interval [CI] 1.60%–2.15%), AD 2.26% (1.91%–2.61%), MCI 2.15% (1.84%–2.46%), and control 2.65% (2.29%–3.00%). Only patients with CAA differed from controls (p = 0.01). In the subset with VEPs, group was not associated with prolonged latencies or lower amplitudes. Lower BOLD amplitude response was associated with higher white matter hyperintensity (WMH) volumes in CAA (for each 0.1% lower BOLD response amplitude, the WMH volume was 9.2% higher, 95% CI 6.0%–12.4%) but not other groups (p = 0.002 for interaction) when controlling for age and hypertension. CONCLUSIONS: Mean visual BOLD response amplitude was lowest in participants with CAA compared to controls, without differences in VEP latencies and amplitudes. This suggests that the impaired visual BOLD response is due to reduced vascular reactivity in CAA. In contrast to participants with CAA, the visual BOLD response amplitude did not differ between those with AD or MCI and controls.

The study by Gattringer et al.1 of symptomatic patients with a recent small subcortical infarct revealed a dynamic relationship between serum neurofilament light chain (NfL) and microangiopathic MRI changes emphasizing NfL's pivotal role as a new biomarker of active cerebral small vessel disease (CSVD), even if clinically silent. We confirm and extend the authors' findings of CSF NfL by studying an incident chronic CSVD cohort selected through the presence of microhemorrhages (n = 14).2 Compared to controls (n = 33), patients with CSVD displayed significantly higher CSF NfL concentrations (mean [SD] 1.318 [491] vs 11.068 [13.031] pg/mL, F 1 = 8.4, p = 0.006), within the range found in amyotrophic lateral sclerosis (12.016 [9.943] pg/mL, n = 99, F 1 = 0.1, p = 0.7), where increased CSF NfL is already established as a diagnostic biomarker of neuroaxonal injury.3 In chronic CSVD, there was a relationship between CSF NfL, peribasal ganglia white matter hyperintensities ( r = 0.5, p = 0.02),4 and lacunes ( r = 0.5, p = 0.04). Our data support the idea of NfL reflecting CSVD burden. Neurofilaments may also serve as a prognostic/disease activity biomarker in terms of predicting stroke and dementia development.