Cerebral Microinfarcts Research Articles

Neuropathologic evaluation of cerebrovascular disease in patients with rheumatoid arthritis.

Active RA has been associated with an increased risk of both cardiovascular and peripheral vascular disease. We aimed to compare cerebrovascular changes in patients with and without RA, both with and without a neuropathologic diagnosis of neurodegenerative disease. Patients with RA (n = 32) who died and underwent autopsy between 1994 and 2021 were matched to non-RA controls (n = 32) on age, sex and level of neurodegenerative proteinopathy. Routine neuropathologic examination was performed at the time of autopsy. Cerebrovascular disease severity was evaluated using modified Kalaria and Strozyk scales. Clinical dementia diagnoses were manually collected from patients' medical records. Prior to death, 15 (47%) RA patients and 14 (44%) controls were diagnosed with dementia; 9 patients in each group (60% and 64%, respectively) had Alzheimer's disease. The prevalence of cerebral amyloid angiopathy, microinfarcts, infarcts or strokes was found to be similar between groups. Patients with RA were more likely to have more severe vascular changes in the basal ganglia by Kalaria scale (P = 0.04), but not in other brain areas. There were no significant differences in the presence of large infarcts, lacunar infarcts or leukoencephalopathy by Strozyk scale. Among patients with RA and no clinical diagnosis of dementia, the majority had mild-moderate cerebrovascular abnormalities, and a subset of patients had Alzheimer's disease neuropathologic changes. In this small series of autopsies, patients with and without RA had largely similar cerebrovascular pathology when controlling for neurodegenerative proteinopathies, although patients with RA exhibited more pronounced cerebrovascular disease in the basal ganglia.

The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts.

This study aimed to investigate the effect of aquaporin-4 (AQP4) on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts. A model of diffuse ischemic brain injury was established, and adenovirus was injected stereotactically through the lateral ventricle of mice. The water content of the brain tissue was measured. The co-expression of glial fibrillary acidic protein (GFAP) and AQP4 and the aggregation of p-tau and neuronal marker were detected through immunofluorescence double staining. The expression of phosphorylated microtubule-associated protein tau (p-tau, Ser202/Thr205, Thr205, Ser396, Ser404), interleukin(IL)-6, IL-1β, tumor necrosis factor (TNF)-a, growth associated protein43 (GAP43), GFAP, and ionized calcium-binding adapter molecule 1 (Iba1) was detected through Western blot. It was found that the brain water content in the model group was increased and decreased after the AQP4 interference. Compared with the sham group, the expression of GFAP, p-tau, IL-1β, TNF-a, Iba1, and p-tau was increased in the model group (p < 0.05). Compared with the model group, the expression of p-tau, IL-6, IL-1β, TNF-a, GFAP, and Iba1 was decreased after AQP4 interference (p < 0.05). It is indicated that AQP4 positively regulates neurodegeneration and persistent neuroinflammation caused by tau protein aggregation after cerebral microinfarcts.

Relationships between Late-Life Blood Pressure and Cerebral Microinfarcts in Octogenarians: An Observational Autopsy Study.

Mid-life high blood pressure (BP) is a risk factor for cerebral microinfarcts. Less is known about the relationship between late-life BP and cerebral microinfarcts, the examination of which is the objective of the current study. This case-control study analyzed data from 551 participants (94.6% aged ≥80 years; 58.6% women) in the Adult Changes in Thought (ACT) study who had autopsy data on microinfarcts and four values of systolic and diastolic blood pressure (SBP and DBP) before death. Using the average of four values, SBP was categorized using 10 mmHg intervals; a trend was defined as a ≥10 mmHg rise or fall from the first to fourth values (average gap of 6.5 years). Multivariable-adjusted regression models were used to examine the associations of BP and microinfarcts, adjusting for age, sex, last BP-to-death time, APOE genotype, and antihypertensive medication use. Microinfarcts were present in 274 (49.7%) participants; there were multiple in 51.8% of the participants, and they were located in cortical areas in 40.5%, subcortical areas in 29.6%, and both areas in 29.9% of the participants. All SBP categories (reference of 100-119 mmHg) and both SBP trends were associated with higher odds of both the presence and number of microinfarcts. The magnitude of these associations was numerically greater for subcortical than cortical microinfarcts. Similar associations were observed with DBP. These hypothesis-generating findings provide new information about the overall relationship between BP and cerebral microinfarcts in octogenarians.

Cerebral microinfarcts revisited: Detection, causes, and clinical relevance.

Cerebral microinfarcts (CMIs) are small ischemic lesions invisible to the naked eye at brain autopsy, while the larger ones (0.5-4 mm in diameter) have been visualized in-vivo on magnetic resonance imaging (MRI). CMIs can be detected on diffusion-weighted imaging (DWI) as incidental small DWI-positive lesions (ISDPLs) and on structural MRI for those confined to the cortex and in the chronic phase. ISDPLs may evolve into old cortical-CMIs, white matter hyperintensities or disappear depending on their location and size. Novel techniques in neuropathology and neuroimaging facilitate the detection of CMIs, which promotes understanding of these lesions. CMIs have heterogeneous causes, involving both cerebral small- and large-vessel disease as well as heart diseases such as atrial fibrillation and congestive heart failure. The underlying mechanisms incorporate vascular remodeling, inflammation, blood-brain barrier leakage, penetrating venule congestion, cerebral hypoperfusion, and microembolism. CMIs lead to clinical outcomes, including cognitive decline, a higher risk of stroke and mortality, and accelerated neurobehavioral disturbances. It has been suggested that CMIs can impair brain function and connectivity beyond the microinfarct core and are also associated with perilesional and global cortical atrophy. This review aims to summarize recent progress in studies involving both cortical-CMIs and ISDPLs since 2017, including their detection, etiology, risk factors, MRI correlates, and clinical consequences.

Relationships between Cerebral Vasculopathies and Microinfarcts in a Community-Based Cohort of Older Adults.

Cerebral microinfarcts are associated with cognitive impairment and dementia. Small vessel diseases such as cerebral arteriolosclerosis and cerebral amyloid angiography (CAA) have been found to be associated with microinfarcts. Less is known about the associations of these vasculopathies with the presence, numbers, and location of microinfarcts. These associations were examined in the clinical and autopsy data of 842 participants in the Adult Changes in Thought (ACT) study. Both vasculopathies were categorized by severity (none, mild, moderate, and severe) and region (cortical and subcortical). Odds ratios (OR) and 95% CIs for microinfarcts associated with arteriolosclerosis and CAA adjusted for possible modifying covariates such as age at death, sex, blood pressure, APOE genotype, Braak, and CERAD were estimated. 417 (49.5%) had microinfarcts (cortical, 301; subcortical, 249), 708 (84.1%) had cerebral arteriolosclerosis, 320 (38%) had CAA, and 284 (34%) had both. Ors (95% CI) for any microinfarct were 2.16 (1.46-3.18) and 4.63 (2.90-7.40) for those with moderate (n = 183) and severe (n = 124) arteriolosclerosis, respectively. Respective Ors (95% CI) for the number of microinfarcts were 2.25 (1.54-3.30) and 4.91 (3.18-7.60). Similar associations were observed for cortical and subcortical microinfarcts. Ors (95% Cis) for the number of microinfarcts associated with mild (n = 75), moderate (n = 73), and severe (n = 15) amyloid angiopathy were 0.95 (0.66-1.35), 1.04 (0.71-1.52), and 2.05 (0.94-4.45), respectively. Respective Ors (95% Cis) for cortical microinfarcts were 1.05 (0.71-1.56), 1.50 (0.99-2.27), and 1.69 (0.73-3.91). Respective Ors (95% Cis) for subcortical microinfarcts were 0.84 (0.55-1.28), 0.72 (0.46-1.14), and 0.92 (0.37-2.28). These findings suggest a significant association of cerebral arteriolosclerosis with the presence, number, and location (cortical and subcortical) of microinfarcts, and a weak and non-significant association of CAA with each microinfarct, highlighting the need for future research to better understand the role of small vessel diseases in the pathogenesis of cerebral microinfarcts.

Cerebral Microinfarcts Are Common in Undiagnosed Lung Cancer Patients: A Population-Based Study

Background. Cerebral microinfarcts (CMI) represent covert brain ischemia and were associated with stroke risk and cognitive impairment. Magnetic resonance imaging diffusion-weighted imaging (DWI) hyperintensities have been suggested to represent acute CMI. The relationship between malignancy and CMI is unknown. Aims. We aimed to examine whether CMI is more common in patients with undiagnosed lung cancer, and therefore might serve as a prediction marker for cognitive impairment or cancer-related stroke. Methods. We used the computerized database of Clalit Health Services (the largest healthcare provider in Israel) to identify adults diagnosed with lung cancer who had an MRI brain scan for any indication prior to cancer diagnosis. We analyzed DWI sequences, in order to evaluate CMI incidence in this population, and compared it to control groups of patients with other undiagnosed malignancies and patients without known cancer. Results. Altogether, we reviewed 1822 MRI brain scans, of which 497 scans were taken in patients with undiagnosed lung cancer, 543 scans of noncancer patients, and 793 scans of patients with other undiagnosed malignancies. In the lung cancer group, we found 24 CMI, compared with 4 in the noncancer group ( p = 0.04 ) and 8 in the other cancer group ( p = 0.07 ). Conclusions. CMI is common in undiagnosed lung cancer patients compare to other undiagnosed cancer types or noncancer patients. At the time of lung cancer diagnosis patients may be at risk for future stroke or cognitive decline.

Deep cortical microinfarction induced by femtosecond laser in mice: Long-term secondary pathological changes in corresponding superficial cortex

Background and purposePrevious studies have explored the clinical consequences of cortical microinfarction, mainly age-related cognitive decline. However, functional impairment of deep cortical microinfarction remains poorly understood. Based on anatomical knowledge and previous research, we infer that damage to the deep cortex may lead to cognitive deficits and communication impairment between the superficial cortex and thalamus. This study aimed to develop a new model of deep cortical microinfarction based on femtosecond laser ablation of a perforating artery. MethodsTwenty-eight mice were anesthetized with isoflurane, and a cranial window was thinned using a microdrill. Intensively focused femtosecond laser pulses were used to produce perforating arteriolar occlusions and ischemic brain damage was examined using histological analysis. ResultsOcclusion of different perforating arteries induced different types of cortical microinfarctions. Blocking the perforating artery, which enters the cerebral cortex vertically and has no branches within 300 μm below, can result in deep cortical microinfarction. Moreover, this model showed neuronal loss and microglial activation in the lesions as well as dysplasia of nerve fibers and β-amyloid deposition in the corresponding superficial cortex. ConclusionsWe present here a new model of deep cortical microinfarction in mice, in which specific perforating arteries are selectively occluded by a femtosecond laser, and we preliminarily observe several long-term effects related to cognition. This animal model is helpful in investigating the pathophysiology of deep cerebral microinfarction. However, further clinical and experimental studies are required to explore deep cortical microinfarctions in greater molecular and physiological detail.

BYHW Decoction Improves Cognitive Impairments in Rats with Cerebral Microinfarcts via Activation of the PKA/CREB Pathway.

Cerebral microinfarcts (CMIs) are characterized by sporadic obstruction of small vessels leading to neurons death. They are associated with increased risk of cognitive impairments and may have different risk factors compared with macroinfarcts. CMIs have a high incidence and result in heavy social burden; thus, it is essential to provide reasonable treatment in clinical practice. However, there are relatively few researches on the mechanism and treatment of CMIs, and the literature is composed almost exclusively of community-or hospital based on autopsy or imageological studies focusing on elderly patients. The Bu Yang Huan Wu (BYHW) decoction, a traditional Chinese herbal formula, has long been used to treat stroke and stroke-related diseases, including cognitive impairments. We applied microsphere-induced CMI model in rats to investigate the behavioral and molecular consequences of CMIs and to determine how they were ameliorated by BYHW decoction treatment. We then used the Morris water maze, quantitative proteomics, immunohistochemistry, and other molecular assays and found that activation of the PKA/CREB pathway by BYHW decoction treatment may reverse mitochondrial dysfunction, inhibit apoptosis of hippocampal neurons, and ameliorate CMI-induced cognitive impairments in rats. Collectively, these findings confirmed the therapeutic potential of the BYHW decoction in treating cognitive impairments induced by CMIs and demonstrated a viable mechanism for its action.

PREVALENCE, BURDEN, AND LOCATION OF CEREBRAL MICROINFARCTS AND THEIR ASSOCIATION WITH LATE-LIFE BLOOD PRESSURE

Abstract Little is known about the relationship of late-life blood pressure (BP) profiles (level, trend and variability) with the presence, number and regional distribution (cortical vs subcortical) of cerebral microinfarcts. We examined these associations in older adults (age ≥65) using the Adult Changes in Thought (ACT) data. 551 participants (94.6% ≥80 years, 58.6% women, 94.2% white) had complete data on microinfarcts and 4 BP measures. Late-life BP, defined by the four BP values before death (2 year-time gap between measures), was treated using 3 different approaches: (1) categories (based on mean of 4 values); (2) trend (based on the difference between values 1 and 4); and (3) variability (based on standard deviation of the mean of the changes in 4 BP values from 1 to 4). Multivariable-adjusted logistic regression models were used to examine the associations of the late-life BP with microinfarcts, adjusting for relevant covariates. Each of the 5 systolic BP categories between 120 and 169 mmHg (reference: 110–119 mmHg) had significant twice higher odds (4 times for SBP ≥170) of presence and number of microinfarcts, which was only significant for subcortical region. Similar higher odds were observed for systolic BP trend (increase/decrease/no change), which was significant for both cortical and subcortical microinfarcts. Systolic BP variability had no significant association with microinfarcts. Similar associations were observed with diastolic BP. In conclusion, the presence (especially for subcortical regions) and number of microinfarcts were more likely to be in those with higher mean BP and those whose BP changed over the study.

Effects of New-Generation Antiepileptic Drug Prophylaxis on Delayed Neurovascular Events After Aneurysmal Subarachnoid Hemorrhage.

Neuroelectric disruptions such as seizures and cortical spreading depolarization may contribute to the development of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH). However, effects of antiepileptic drug prophylaxis on outcomes remain controversial in SAH. The authors investigated if prophylactic administration of new-generation antiepileptic drugs levetiracetam and perampanel was beneficial against delayed neurovascular events after SAH. This was a retrospective single-center cohort study of 121 consecutive SAH patients including 56 patients of admission World Federation of Neurological Surgeons grades IV - V who underwent aneurysmal obliteration within 72h post-SAH from 2013 to 2021. Prophylactic antiepileptic drugs differed depending on the study terms: none (2013 - 2015), levetiracetam for patients at high risks of seizures (2016 - 2019), and perampanel for all patients (2020 - 2021). The 3rd term had the lowest occurrence of delayed cerebral microinfarction on diffusion-weighted magnetic resonance imaging, which was related to less development of DCI. Other outcome measures were similar among the 3 terms including incidences of angiographic vasospasm, computed tomography-detectable delayed cerebral infarction, seizures, and 3-month good outcomes (modified Rankin Scale 0 - 2). The present study suggests that prophylactic administration of levetiracetam and perampanel was not associated with worse outcomes and that perampanel may have the potential to reduce DCI by preventing microcirculatory disturbances after SAH. Further studies are warranted to investigate anti-DCI effects of a selective α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonist perampanel in SAH patients in a large-scale prospective study.

Perioperative cerebral microinfarction and quality of life following mitral valve surgery

Abstract Introduction Mitral regurgitation (MR) is the second most common valvular pathology worldwide. When untreated, severe MR is associated with significant morbidity and mortality. Mitral valve surgery is recommended in symptomatic patients and those with evidence of adverse left atrial or left ventricular remodelling. Although uncommon, stroke is a recognised complication of mitral valve surgery and is associated with unfavourable outcomes. While silent cerebral microinfarction has been described following cardiac surgery, its incidence in mitral valve surgery and its impact on quality of life is presently unknown. The main aim of this study was to assess the incidence of perioperative cerebral microinfarction following mitral valve surgery and its impact on medium-term health-related quality of life (HRQoL). Methods Cerebral diffusion-weighted magnetic resonance imaging (DWI-MRI) was conducted pre-operatively and prior to discharge in 31 patients undergoing mitral valve surgery for mitral regurgitation. Blinded analysis was conducted by a neuro-radiologist. HRQoL assessment was undertaken at baseline and at a 6-month follow up with EuroQoL-5 dimensions (EQ-5D-5L) and Hospital Anxiety and Depression Scale (HADS) questionnaires. Results Thirty-one patients underwent paired cerebral DWI-MRI (mitral valve replacement (MVR) n=16 [52%] and mitral valve repair (MVr) n=15 [48%]). Prevalence of atrial fibrillation was similar in both groups (MVR n=9 [56%] vs. MVr n=7 [47%], p=0.59). Peri-operative cerebral microinfarction occurred in 9 patients (29%). Embolic events were numerically higher in the MVR group versus MVr group, but not statistically significant (n=7 [44%] vs. n=2 [13%], p=0.06). Presence of multiple lesions, large lesions &amp;gt;5mm, small lesions &amp;lt;5mm and the total number of lesions did not differ significantly between the two groups. Median volume of lesions was higher in the MVR group versus MVr (0 [0–0.4] vs 0 [0–0], p=0.04) (Table 1). There was no difference in the mean change in HRQoL during 6m follow up between patients with peri-operative cerebral microinfarction and those with no detectable embolic events (Table 2). Within group comparison (MVR group and MVr group) also did not demonstrate any significant difference. Conclusions Peri-operative cerebral microinfarction occurred in almost a third of patients undergoing mitral valve surgery, with higher volume of lesions following MVR. These lesions however, did not exhibit significant impact on medium term health-related quality of life. Funding Acknowledgement Type of funding sources: None.

Clinical features and imaging markers of small vessel disease in symptomatic acute subcortical cerebral microinfarcts

BackgroundAs currently defined, recent small subcortical infarcts (RSSI) do not have a lower size boundary, and the smallest diffusion-weighted imaging (DWI) infarcts, which we term acute subcortical cerebral microinfarcts (As-CMI) with lesion diameter less than 5 mm, might have clinical implications distinct from RSSI. We aimed to investigate the distinct characteristics of As-CMI as compared to the larger size of RSSI regarding vascular risk factors, clinical manifestation, radiological markers of SVD distribution, and outcomes.MethodsIn a consecutive cohort, patients were selected with a magnetic resonance DWI-confirmed RSSI between January 2010 and November 2020. We measured axial infarct diameter and classified patients into two groups: The As-CMI group (diameter < 5 mm) versus the Larger RSSI group (diameter 5-20 mm). Clinical variables, including vascular risk factors, clinical symptoms/signs, lesion locations, and radiological markers of cerebral small vessel disease (SVD) on MRI were analyzed between the two groups. Patients were followed up for 12 months and functional outcomes were measured by the modified ranking scale (mRS).ResultsIn a total of 584 patients with RSSI, 23 (3.9%) were defined as As-CMI. The most common neurological deficits with As-CMI were hemiparalysis (n = 20), followed by central facial/lingual palsy (n = 10) and hemidysesthesia (n = 10). Most As-CMIs were located in the basal ganglia (n = 11), followed by the thalamus (n = 5) and centrum semiovale (n = 4). No different regional distributions and symptoms/signs frequencies were found between the two groups except for a lower percentage of dysarthria in the As-CMI group (p = 0.008). In a multivariate analysis, patients with As-CMI were independently associated with the presence of lacunes (adjusted odds ratio [aOR] 2.88; 95% confidence interval [CI] 1.21–6.84), multiple lacunes (aOR 3.5, CI 1.29–9.48) and higher total SVD burden (aOR 1.68, CI 1.11–2.53). Patients with As-CMI did not show a better functional outcome after 12 months of follow-up.ConclusionsPatients with As-CMI had a non-specific clinical profile but a higher burden of SVD, indicating As-CMI might be s sign of more severe small vascular injury. Whether its vascular features are associated with worse cognitive outcomes requires further investigation.

LDL cholesterol is associated with higher AD neuropathology burden independent of APOE

ObjectiveAPOE is a strong risk factor for Alzheimer’s disease (AD) and associated with higher low-density lipoprotein cholesterol (LDL-C) levels. Moreover, LDL-C is associated with the development of clinically ascertained AD;...

Association of cerebral microvascular dysfunction and white matter injury in Alzheimer's disease.

Patients with Alzheimer's disease (AD) often have cerebral white matter (WM) hyperintensities on MRI and microinfarcts of presumed microvascular origin pathologically. Here, we determined if vasodilator dysfunction of WM-penetrating arterioles is associated with pathologically defined WM injury and disturbances in quantitative MRI-defined WM integrity in patients with mixed microvascular and AD pathology. We analyzed tissues from 28 serially collected human brains from research donors diagnosed with varying degrees of AD neuropathologic change (ADNC) with or without cerebral microinfarcts (mVBI). WM-penetrating and pial surface arteriolar responses to the endothelium-dependent agonist bradykinin were quantified ex vivo with videomicroscopy. Vascular endothelial nitric oxide synthase (eNOS) and NAD(P)H-oxidase (Nox1,2 and 4 isoforms) expression were measured with quantitative PCR. Glial fibrillary acidic protein (GFAP)-labeled astrocytes were quantified by unbiased stereological approaches in regions adjacent to the sites of WM-penetrating vessel collection. Post-mortem diffusion tensor imaging (DTI) was used to measure mean apparent diffusion coefficient (ADC) and fractional anisotropy (FA), quantitative indices of WM integrity. In contrast to pial surface arterioles, white matter-penetrating arterioles from donors diagnosed with high ADNC and mVBI exhibited a significantly reduced dilation in response to bradykinin when compared to the other groups. Expression of eNOS was reduced, whereas Nox1 expression was increased in WM arterioles in AD and mVBI cases. WM astrocyte density was increased in AD and mVBI, which correlated with a reduced vasodilation in WM arterioles. Moreover, in cases with low ADNC, bradykinin-induced WM arteriole dilation correlated with lower ADC and higher FA values. Comorbid ADNC and mVBI appear to synergistically interact to selectively impair bradykinin-induced vasodilation in WM-penetrating arterioles, which may be related to reduced nitric oxide- and excess reactive oxygen species-mediated vascular endothelial dysfunction. WM arteriole vasodilator dysfunction is associated with WM injury, as supported by reactive astrogliosis and MRI-defined disrupted WM microstructural integrity.

Retinal parameters, cortical cerebral microinfarcts, and their interaction with cognitive impairment.

Quantitative changes in retinal vessels and thinning of optic nerves have been associated with subclinical (atherosclerosis, inflammation) and clinical age-related brain pathologies (stroke and neurodegeneration). However, data on the association between both retinal vascular and neuronal parameters with cortical cerebral microinfarcts (CMIs) and how these factors jointly influence cognition are lacking. We investigated the association of retinal vascular and neuronal changes with CMIs on 3 T MRI and explored their interaction with cognitive impairment in a memory-clinic population. A total of 538 participants were included. Retinal vascular parameters (caliber, tortuosity, and fractal dimension) were measured from retinal fundus photographs using a semi-automated computer-assisted program. Retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) thicknesses were obtained from optical coherence tomography. Cortical CMIs were defined as hypointense on T1-weighted MRI, <5 mm in diameter and restricted to the cortex. Cognition was assessed using Clinical Dementia Rating Sum-of-Boxes (CDR-SoB) score and detailed neuropsychological test. Multivariable regression analysis was conducted adjusting for age, sex, hypertension, hyperlipidemia, diabetes mellitus, smoking, diagnosis, white matter hyperintensities volume, lacunes, and cerebral microbleeds. Larger venular caliber (Rate ratios (RR): 1.15, 95% CI: 1.01-1.38, p = 0.014), increased venular fractal dimension (RR: 1.58, 95% CI: 1.31-1.91, p ⩽ 0.001), increased venular tortuosity (RR: 1.54, 95% CI: 1.35-1.75, p ⩽ 0.001), and thinner GC-IPL (RR: 1.24, 95% CI: 1.13-1.36, p ⩽ 0.001) were associated with CMI counts. Among individuals in highest tertile of retinal parameters, a significant interaction was observed between venular tortuosity (RR: 1.12, 95% CI: 1.02-1.22, p-interaction = 0.014) and GC-IPL (RR: 1.05, 95% CI: 1.01-1.11, p-interaction < 0.001) with CMIs on CDR-SoB. Retinal vascular and neuronal parameters are associated with cortical CMIs, and persons with both pathologies are likely to have cognitive impairment. Further studies may be warranted to evaluate the clinical utility of retinal parameters and CMI in risk prediction for cognitive dysfunction.

Acute Cerebral Microinfarcts in Acute Ischemic Stroke: Imaging and Clinical Significance

Background: Limited data exist on the significance of acute cerebral microinfarcts (A-CMIs) in the context of acute ischemic stroke (AIS). We aimed to determine the profile and prognostic significance of A-CMIs on magnetic resonance imaging (MRI) in patients presenting with AIS. Methods: A prospective single-center series of patients with AIS who had 3T MRIs between March 2013 and December 2019. The presence, number, and location of A-CMIs on diffusion-weighted imaging, and markers of cerebral small vessel disease (CSVD), macroinfarcts features, and etiology were classified as cardioembolism (CE) or large artery atherosclerosis (LAA) or none. Results: Among 273 patients, A-CMIs were detected in 130 patients (47.6%), of whom cortical A-CMIs were found in 95 (73.0%) patients. Patients with A-CMIs were significantly older, less likely to have diabetes mellitus, and more likely to have atrial fibrillation and an embolic source (CE or LAA) compared to other patients. Patients with A-CMI had a higher frequency of macroinfarcts (diameter >20 mm), more often multiple and distributed in single or multiple vessel territories than other patients. An embolic source (LAA or CE) was independently associated with cortical A-CMIs (LAA adjusted odds ratio [aOR] 4.0 95% confidence interval [CI] 1.6–9.5; CE aOR 2.5, 95% CI 1.1–5.6), whereas lacunes were independently related to subcortical A-CMIs (aOR 2.6, 95% CI 1.2–5.8). Conclusions: We have shown A-CMIs occur in cortical and subcortical regions in nearly half of AIS patients, where microembolism and CSVD are, respectively, the key presumed etiological mechanism.

Histopathology of Cerebral Microinfarcts and Microbleeds in Spontaneous Intracerebral Hemorrhage

In patients with spontaneous intracerebral hemorrhage caused by different vasculopathies, cerebral microinfarcts have the same aspect on MRI and the same applies to cerebral microbleeds. It is unclear what pathological changes underlie these cerebral microinfarcts and cerebral microbleeds. In the current study, we explored the histopathological substrate of these lesions by investigating the brain tissue of 20 patients (median age at death 77 years) who died from ICH (9 lobar, 11 non-lobar) with a combination of post-mortem 7-T MRI and histopathological analysis. We identified 132 CMIs and 204 CMBs in 15 patients on MRI, with higher numbers of CMIs in lobar ICH patients and similar numbers of CMBs. On histopathology, CMIs and CMBs were in lobar ICH more often located in the superficial than in the deep layers of the cortex, and in non-lobar ICH more often in the deeper layers. We found a tendency towards more severe CAA scores in lobar ICH patients. Other histopathological characteristics were comparable between lobar and non-lobar ICH patients. Although CMIs and CMBs were found in different segments of the cortex in lobar ICH compared to non-lobar ICH patients, otherwise similar histopathological features of cortical CMIs and CMBs distant from the ICH suggest shared pathophysiological mechanisms in lobar and non-lobar ICH caused by different vasculopathies.

Investigation of Experimental Endovascular Air Embolisms Using a New Model for the Generation and Detection of Highly Calibrated Micro Air Bubbles

Background: Air embolism (AE), especially when affecting the brain, is an underrated and potentially life-threatening complication in various endovascular interventions. This study aims to investigate experimental AEs using a new model to generate micro air bubbles (MAB), to assess the impact of a catheter on these MAB, and to demonstrate the applicability of this model in vivo. Materials and Methods: Micro air bubbles were created using a system based on microfluidic channels. The MAB were detected and analyzed automatically. Micro air bubbles, with a target size of 85 µm, were generated and injected through a microcatheter. The MAB diameters proximal and distal to the catheter were assessed and compared. In a subsequent in vivo application, 2000 MAB were injected into the aorta (at the aortic valve) and into the common carotid artery (CCA) of a rat, respectively, using a microcatheter, resembling AE occurring during cardiovascular interventions. Results: Micro air bubbles with a highly calibrated size could be successfully generated (median: 85.5 µm, SD 1.9 µm). After passage of the microcatheter, the MAB were similar in diameter (median: 86.6 µm) but at a lower number (60.1% of the injected MAB) and a substantially higher scattering of diameters (SD 29.6 µm). In vivo injection of MAB into the aorta resulted in cerebral microinfarctions in both hemispheres, whereas injection into the CCA caused exclusively ipsilateral microinfarctions. Conclusion: Using this new AE model, MAB can be generated precisely and reproducibly, resulting in cerebral microinfarctions. This model is feasible for further studies on the pathophysiology and prevention of AE in cardiovascular procedures.

Exploration of the Mechanism Underlying the Association of Incident Microinfarct and Motor Deficit: A Preliminary Functional MRI Study.

Cerebral microinfarcts (CMIs) might cause measurable disruption to brain connections and are associated with cognitive decline, but the association between CMIs and motor impairment is still unclear. To assess the CMIs effect on motor function in vivo and explore the potential neuropathological mechanism based on graph-based network method. We identified 133 non-demented middle-aged and elderly participants who underwent MRI scanning, cognitive, and motor assessment. The short physical performance battery (SPPB) assessed motor function, including balance, walking speed, and chair stand. We grouped participants into 34 incident CMIs carriers and 99 non-CMIs carriers as controls, depending on diffusion-weighted imaging. Then we assessed the independent CMIs effects on motor function and explored neural mechanisms of CMIs on motor impairment via mapping of degree centrality (DC) and eigenvector centrality (EC). CMIs carriers had worse motor function than non-carriers. Linear regression analyses showed that CMIs independently contributed to motor function. CMIs carriers had decreased EC in the precuneus, while increased DC and EC in the middle temporal gyrus and increased DC in the inferior frontal gyrus compared to controls (p < 0.05, corrected). Correlation analyses showed that EC of precuneus was related to SPPB (r = 0.25) and balance (r = 0.27); however, DC (r = -0.25) and EC (r = -0.25) of middle temporal gyrus was related with SPPB in all participants (p < 0.05, corrected). CMIs represent an independent risk factor for motor dysfunction. The relationship between CMIs and motor function may be attributed to suppression of functional hub region and compensatory activation of motor-related regions.

Longitudinal intravital imaging of cerebral microinfarction reveals a dynamic astrocyte reaction leading to glial scar formation.

Cerebral microinfarct increases the risk of dementia. But how microscopic cerebrovascular disruption affects the brain tissue in cellular-level are mostly unknown. Herein, with a longitudinal intravital imaging, we serially visualized in vivo dynamic cellular-level changes in astrocyte, pericyte and neuron as well as microvascular integrity after the induction of cerebral microinfarction for 1month in mice. At day 2-3, it revealed a localized edema with acute astrocyte loss, neuronal death, impaired pericyte-vessel coverage and extravascular leakage of 3kDa dextran (but not 2MDa dextran) indicating microinfarction-related blood-brain barrier (BBB) dysfunction for small molecules. At day 5, the local edema disappeared with the partial restoration of microcirculation and recovery of pericyte-vessel coverage and BBB integrity. But brain tissue continued to shrink with persisted loss of astrocyte and neuron in microinfarct until 30 days, resulting in a collagen-rich fibrous scar surrounding the microinfarct. Notably, reactive astrocytes expressing glial fibrillary acidic protein (GFAP) appeared at the peri-infarct area early at day 2 and thereafter accumulated in the peri-infarct until 30 days, inducing glial scar formation in cerebral cortex. Our longitudinal intravital imaging of serial microscopic neurovascular pathophysiology in cerebral microinfarction newly revealed that astrocytes are critically susceptible to the acute microinfarction and their reactive response leads to the fibrous glial scar formation.