Whether CMBs have a role in vascular cognitive impairment or not is still controversial [17]. Different studies with different populations and patient groups have produced less consistent results according to association with cognitive dysfunction and cognitive domains affected [18].
Our study was carried out on 85 Egyptian patients with lacunar stroke. Cerebral microbleeds were frequently observed in 40 patients (47%), which is nearly half of all patients. This is highly consistent with the previous studies of Zhang et al. [19] that studied 85 patients; 35 (41.2%) had cerebral microbleeds. They were more often in mixed and deep brain regions than in the cerebral lobes. There was a significant correlation between cerebral microbleed severity and MoCA score [20]. CMBs were present in 46 (39.7%) patients. CMB number was weakly associated with executive dysfunction. This study did not find association of CMBs with other cognitive domains, including processing speed. On the other hand, in other studies [21], patients with MBs (14.2%) were significantly older, had a higher white matter lesion volume, and more lacunar infarcts. Number of MBs were related to global cognitive function and attention. The relations with cognitive performance were mainly determined by frontal, temporal, and deep located MBs [12]. Nine hundred fifty-nine subjects were studied. MBs were found in 10.4% of the subjects; strictly lobar, but not deep or infratentorial, CMBs are associated with changes in cognitive function, especially in visuospatial/executive functions. Cerebral amyloid angiopathy in this study suggested to be the underlying pathology associated with CMB-related cognitive impairment.
CMBs constituted much less percentage of the population studied. This may be due to the difference in samples’ sizes and nature of these studies being both cohort. It also included variable population groups than small vessel disease [12].
CMBs were detected in older patients, and this was proven as a consistent risk factor across different studies [12, 22]. They attributed the effect of age on accumulation of other vascular risk factors that lead to CMB pathology.
Male gender showed a significant association with microbleed presence. This was consistent with the previous studies [10, 23] that proved being the male gender as one of the risk factors of CMB presence. This association went under research, and was hypothesized as vascular risk factors being more common in males and reference to the role of apolipoprotein APOE4 allele interaction with sex differences and amyloid β-peptide (Aβ) levels [24].
Still, there were some studies [12, 20] that were inconsistent with ours and showed insignificant association between microbleeds and sex, though the high incidence is in males, but were not statistically significant.
Hypertension was considered a statistically significant risk factor for the development of CMBs. Other studies [23, 25] did not only identify hypertension as a risk factor, but also studied the attribution of deep and infratentorial microbleeds to hypertensive microangiopathy mechanism which is consistent with ours.
Chung and colleagues in 2016 did not find any correlation between CMBs and hypertension. This may be explained as studying lobar CMBs, with suggested CAA as an underlying pathology rather than hypertensive arteriopathy mechanism [12]. Correlation between hyperlipidemia and MBs was significant. Such an attribution was consistent with the other studies [23, 26] that studied the effect of accumulated risk factors on CMB incidence. The significant association between hyperlipidemia and patients with deep CMBs was also consistent with other studies [27, 28] that attributed cerebrovascular risk factors to deep located CMBs.
CMBs were more frequent in antiplatelet users than in non-antiplatelet users as found by Pasquini et al. [29]. A meta-analysis on the relationship between antiplatelet therapy and CMBs found that antiplatelet therapy was significantly associated with presence of CMBs in patients with stroke but not in stroke-free individuals [29]. A more recent meta-analysis [30] that included 37 studies did not just clarify the increased risk of CMBs on antiplatelet therapy; moreover, they related their use to the association with strictly lobar microbleeds rather than deep/infratentorial microbleeds.
Fewer studies [31] did not find any correlation between regular antiplatelet use and CMB presence. However, it did not rule out the risk of CMB formation and ICH, but rather, recommended antiplatelet justification and controlled other risk factors in the cases of ischemic cerebrovascular diseases. After all, it described having many potential limitations specially their small study population and a high selection bias, yet, the use of single vs. double antiplatelet did not record statistical significance in CMB-positive group consistently similar to other studies [32].
As regarding MRI parameters, a strong correlation between CMB presence and the presence of other cerebral SVDs was recorded. Subjects with CMBs had significantly higher number of lacunar infarcts and more severe WMLs similar to previous studies [12, 20, 21]. All are markers of small vessel disease pathology that with their progression the incidence of microbleeds increases.
Correlation between CMB presence and cognitive impairment was seen as significant deterioration in both visuospatial/executive function and attention with a decrease in total MoCA score. Association of microbleeds with cognitive decline was consistently reported by previous studies. These results explicitly relate CMB lesions to global and executive dysfunction whether through their direct effect on microstructure brain damage or as a reflection of the underlying vascular pathology in patients with SVD [4].
A controversial study reported that the presence and number of CMBs were not associated with cognitive dysfunction in patients with lacunar stroke and leukoaraiosis [20]. It referred to other SVD markers as having a masking effect on the cognitive deterioration. Also, a cohort study [33] studied the long-term cognitive outcome of CMBs in patients with TIA and minor strokes after 5 years and denied any association with cognitive impairment. Unfortunately, it had a main weak point where 15% of the study sample were examined for the cognitive status through the short version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE, Dutch version) that was obtained from a close relative and not personally performed. This can be opposed by another cohort study [10], which was performed on stroke clinic patients, with much similar population and had results consistent with ours regarding cognitive deterioration, proving CMBs’ relevance to long-term cognitive outcome.
According to CMB location, both frontal and parietal MBs recorded significant associations with visuospatial/executive dysfunction, independent to lacunes and WMCs and other factors. This was consistent with other studies [10, 12] that studied executive function impairment on strictly lobar CMB subjects. These studies explained such association to CAA pathology in these brain regions.
Various brain areas are involved in the visuospatial executive function; visual perception in the parieto-occipital lobe, planning in the frontal lobe, and integration of visual and fine motor sequences in the fronto-parieto-occipital cortices. Visuoperceptual skills requires mental flexibility which mainly rely on frontal lobe function, while self-initiated clock drawing requires intact visuoconstructive skills which are mainly represented in the parietal lobe. This process of contribution of the parieto-frontal cortical networks to integrate visuospatial elements with motor control was detected by functional MRI [34].
Patel and colleagues in 2013 related the association of frontal CMBs to executive dysfunction only under a threshold effect of 9 or more CMBs in small vessel disease patients [20]. Whereas, other study [17] found that individuals with a strictly lobar distribution of CMBs did not have any impaired executive function. However, the executive function decline that was detected between CMB-positive and CMV-negative groups was explained as being driven by deep cerebral SVD (as BG MBs) rather than being due to lobar MBs. However, this study had limitations of the small sub-sample sizes.
Frontal lobe MBs also recorded an association with memory affection. However, it lost its significance with regression analysis to give similar results with previous study. The association between working memory and frontal lobe MBs in a population of symptomatic small vessel disease relationship became non-significant when controlling of other MRI parameters. It may be explained as being highly memory-dependent on WMLs and brain atrophy [20].
Inconsistent with our results, some other studies identified CMBs in patients followed in memory clinics [23, 35]. They showed high prevalence of CMBs in memory clinics and Alzheimer’s disease patients, adding more evidence in vascular cognitive impairment role. Unfortunately, memory affection was studied as a point of significance between both CMB-positive and CMB-negative groups in general without ruling out other MRI parameters as small vessel disease effect.
In the current study, the deep MBs were frequently located in the BG, recording significant association with global cognitive decline and with attention affection in particular. It remained significant after controlling of SVD markers to be consistent with other studies [28, 36]. They offered some explanations about cognitive dysfunction through attribution of the cognitive deficits in CMBs to impairments in attention and calculation in the early stages of Parkinson’s disease, thus reflecting involvement of the BG and frontal-subcortical circuits. CMBs in the BG may cause primary or secondary damage to cholinergic pathways in the cortical-BG circuits [37].
There were still some studies inconsistent with ours according to the involvement of BG CMBs in cognitive dysfunction [10]. Although including a large population, it classified subjects according to CMB location into only two groups which were strictly lobar and deep/infratentorial, with the last accounting only 9% of the sample size [12].
According to the other deep located and infratentorial CMBs, our study did not show any association between their presence and cognition affection at any of MoCA test domains. This was quite consistent with the number of studies [10, 20] that showed no significant associations with their presence and cognitive dysfunction.
However, thalamic CMBs in particular had some debate on its involvement in the development of cognitive dysfunction. Yakushiji and colleagues in 2008 showed an association between the presence of thalamic MBs and reduced both total and orientation scores in the MMSE test. It was explained as being the thalamus part of a neuronal network integrally involved in cognitive function. Other studies were neuroimaging studies on patients with CADASIL, which showed associations between microstructural alterations in the thalamus and low MMSE score [28].
