Cerebral Microinfarcts Research Articles

Distinct neuroinflammatory patterns between cerebral microbleeds and microinfarcts in cerebral amyloid angiopathy.

In this neuropathological study, we investigated neuroinflammation surrounding recent and old cerebral microbleeds (CMBs) and cerebral microinfarcts (CMIs) in 18 cases of cerebral amyloid angiopathy (CAA). We used several serial stainings and immunolabellings to identify microvascular lesions, define their recent or old stage, and characterize neuroinflammatory response (scavenging activity and astrogliosis). We found that both CMBs and CMIs induce a neuroinflammatory response, which was more pronounced in old lesion than recent. Astrogliosis and scavenging activity were differentially prominent according to the ischemic/hemorrhagic nature of the lesion. Our findings provide insights into the pathophysiology of microvascular injuries in CAA.

Significance of cerebral microinfarcts in antiphospholipid syndrome: A population-based study.

Acute ischemic stroke (AIS) or transient ischemic attack (TIA) is the most common neurological manifestations of patients with antiphospholipid syndrome (APS). Incidental diffusion-weighted imaging (DWI) positive subcortical and cortical lesions, or acute incidental cerebral microinfarcts (CMI), are microscopic ischemic lesions, detectable on MRI for 10-14 days only. We aimed to look at the prevalence of acute incidental CMI in a cohort of patients with APS and their association with subsequent AIS or TIA. This is a population-based cohort study of adults with APS diagnosis using International Statistical Classification-9 (ICD-9) and supporting laboratory results between January 2014 and April 2020. We included any patient undergoing brain MRI (index event) during the year prior APS diagnosis or at any time point following diagnosis. Age-matched subjects with negative APS laboratory workup were used as a control group. In the first analysis, we compared acute incidental CMI prevalence in both groups. We then performed a second analysis among APS patients only, comparing patients with and without acute incidental CMI for AIS or TIA as the primary outcome. Cox proportional hazards models used to calculate hazards ratio (HR) and 4 years cumulative risk. 292 patients were included, of which, 207 patients with APS. Thirteen patients with APS had acute incidental CMI on MRI (6.3%), compared with none in the control group (p = 0.013). Following multivariable analysis, APS was the sole factor associated with acute incidental CMI (p = 0.026). During a median follow-up of 4 years (IQR 3.5, 4) in patients with APS, following multivariable analysis, acute incidental CMI was associated with subsequent AIS or TIA (HR 6.73 [(95% CI, 1.96-23.11], p < 0.01). Acute incidental CMI are more common among patients with APS than in patients with negative APS tests, and are associated with subsequent AIS or TIA. Detecting acute incidental CMI in patients with APS may guide etiological workup and reevaluation of antithrombotic regimen.

Causal relationship of inflammatory cytokines and serum metabolites in cerebral small vessel disease: a two-step Mendelian randomization study.

The aim was to investigate the causal relationships of inflammatory cytokines and serum metabolites in cerebral small vessel disease (CSVD). Bidirectional Mendelian randomization was first conducted to screen inflammatory cytokines and serum metabolites that were associated with imaging features of CSVD, including white matter hyperintensities, recent small subcortical infarcts, cortical cerebral microinfarcts, cerebral microbleeds, lacunes and enlarged perivascular spaces. Sensitivity analyses were performed to evaluate the robustness and pleiotropy of these results. Subsequently, inflammatory cytokines and serum metabolites that were associated with CSVD were subjected to functional enrichment. Finally, mediation analysis was employed to investigate whether inflammatory cytokines or serum metabolites acted as an intermediary for the other in their causal relationship with CSVD. Of the inflammatory cytokines, five were risk factors (e.g., tumour-necrosis-factor-related apoptosis-inducing ligand) and five (e.g., fibroblast growth factor 19) were protective factors for CSVD. Eleven serum metabolites that increased CSVD risk and 13 metabolites that decreased CSVD risk were also identified. The majority of these markers of CSVD susceptibility were lipid metabolites. Natural killer cell receptor sub-type 2B4 was determined to act as a mediating factor of an unidentified metabolite for the enlargement of perivascular spaces. Several inflammatory cytokines and serum metabolites had causal relationships with imaging features of CSVD. A natural killer cell receptor mediated in part the promotional effect of a metabolite on perivascular space enlargement.

Association of Acute Incidental Cerebral Microinfarcts With Subsequent Ischemic Stroke in Patients With Cancer: A Population-Based Study.

Incidental diffuse-weighted imaging (DWI)-positive subcortical and cortical lesions, or acute incidental cerebral microinfarcts (CMIs), are a common type of brain ischemia, which can be detected on magnetic resonance DWI for approximately 2 weeks after occurrence. Acute incidental CMI was found to be more common in patients with cancer. Whether acute incidental CMI predicts future ischemic stroke is still unknown. We aimed to examine the association between acute incidental CMI in patients with cancer and subsequent ischemic stroke or transient ischemic attack (TIA). This is a retrospective cohort study. We used Clalit Health Services records, representing over half of the Israeli population, to identify adults with lung, breast, pancreatic, or colon cancer who underwent brain MRI between January 2014 and April 2020. We included patients who underwent scan between 1 year before cancer diagnosis and 1 year after diagnosis. Primary outcome was ischemic stroke or TIA using International Classification of Diseases, Ninth Revision codes. Secondary outcomes were intracranial hemorrhage (ICH) and mortality. Records were followed from first MRI until primary outcome, death, or end of follow-up (January 2023). Cox proportional hazards models were used to calculate hazard ratio (HR) for patients with and without acute incidental CMI, as a time-dependent covariate. The study cohort included 1,618 patients with cancer, among whom, 59 (3.6%) had acute incidental CMI on at least 1 brain MRI. The median (interquartile range) time from acute incidental CMI to stroke or TIA was 26 days (14-84). On multivariable analysis, patients with acute incidental CMI had a higher stroke or TIA risk (HR 2.97, 95% CI 1.08-8.18, p = 0.035) compared with their non-CMI counterparts. Acute incidental CMIs were also associated with mortality after multivariable analysis (HR 2.76, 95% CI 2.06-3.71, p < 0.001); no association with ICH was found. Acute incidental CMI on brain MRI in patients with active cancer is associated with an increased risk of near-future ischemic stroke or TIA and mortality. This finding might suggest that randomly detected acute incidental CMI in patients with cancer may guide primary cerebrovascular risk prevention and etiologic workup.

An Alternative Photothrombotic Model of Transient Ischemic Attack.

Animal models mimicking human transient ischemic attack (TIA) and cerebral microinfarcts are essential tools for studying their pathogenetic mechanisms and finding methods of their treatment. Despite its advantages, the model of single arteriole photothrombosis requires complex experimental equipment and highly invasive surgery, which may affect the results of further studies. Hence, to achieve high translational potential, we focused on developing a TIA model based on photothrombosis of arterioles to combine good reproducibility and low invasiveness. For the first time, noninvasive laser speckle contrast imaging (LSCI) was used to monitor blood flow in cerebral arterioles and reperfusion was achieved. We demonstrate that irradiation of mouse cerebral cortical arterioles using a 532-nm laser with a 1-mm-wide beam at 2.4 or 3.7 mW for 55 or 40 s, respectively, after 15 mg/kg intravenous Rose Bengal administration, induces similar ischemia-reperfusion lesions resulting in microinfarct formation. The model can be used to study the pathogenesis of spontaneously developing cerebral microinfarcts in neurodegeneration. Reducing the exposure times by 10 s while maintaining the same other parameters caused photothrombosis of the arteriole with reperfusion in less than 1 h. This mode of photodynamic exposure caused cellular and subcellular level ischemic changes in neurons and promoted the activation of astrocytes and microglia in the first day after irradiation, but not later, without the formation of microinfarcts. This mode of photodynamic exposure most accurately reproduced human TIA, characterized by the absence of microinfarcts.

A rat model of cerebral small vascular disease induced by ultrasound and protoporphyrin

Cerebral small vascular disease (CSVD) has a high incidence worldwide, but its pathological mechanisms remain poorly understood due to the lack of proper animal models. The current animal models of CSVD have several limitations such as high mortality rates and large-sized lesions, and thus it is urgent to develop new animal models of CSVD. Ultrasound can activate protoporphyrin to produce reactive oxygen species in a liquid environment. Here we delivered protoporphyrin into cerebral small vessels of rat brain through polystyrene microspheres with a diameter of 15 μm, and then performed transcranial ultrasound stimulation (TUS) on the model rats. We found that TUS did not affect the large vessels or cause large infarctions in the brain of model rats. The mortality rates were also comparable between the sham and model rats. Strikingly, TUS induced several CSVD-like phenotypes such as cerebral microinfarction, white matter injuries and impaired integrity of endothelial cells in the model rats. Additionally, these effects could be alleviated by antioxidant treatment with N-acetylcysteine (NAC). As control experiments, TUS did not lead to cerebral microinfarction in the rat brain when injected with the polystyrene microspheres not conjugated with protoporphyrin. In sum, we generated a rat model of CSVD that may be useful for the mechanistic study and drug development for CSVD.

Application of artificial intelligence-based magnetic resonance imaging in diagnosis of cerebral small vessel disease.

Cerebral small vessel disease (CSVD) is an important cause of stroke, cognitive impairment, and other diseases, and its early quantitative evaluation can significantly improve patient prognosis. Magnetic resonance imaging (MRI) is an important method to evaluate the occurrence, development, and severity of CSVD. However, the diagnostic process lacks quantitative evaluation criteria and is limited by experience, which may easily lead to missed diagnoses and misdiagnoses. With the development of artificial intelligence technology based on deep learning, the extraction of high-dimensional features in imaging can assist doctors in clinical decision-making, and it has been widely used in brain function and mental disorders, and cardiovascular and cerebrovascular diseases. This paper summarizes the global research results in recent years and briefly describes the application of deep learning in evaluating CSVD signs in MRI imaging, including recent small subcortical infarcts, lacunes of presumed vascular origin, vascular white matter hyperintensity, enlarged perivascular spaces, cerebral microbleeds, brain atrophy, cortical superficial siderosis, and cortical cerebral microinfarct.

Loss of white matter integrity mediates the association between cortical cerebral microinfarcts and cognitive dysfunction: A longitudinal study

Cortical cerebral microinfarcts (CMIs) are associated with loss of white matter (WM) integrity and cognitive impairment in cross-sectional studies, while further investigation using longitudinal datasets is required. This study aims to establish the association between cortical CMIs and WM integrity assessed by diffusion-tensor imaging (DTI) measures and to investigate whether DTI measures mediate the relationship between cortical CMIs and cognitive decline. Cortical CMIs were graded on 3T MRI. DTI measures were derived from histogram analysis of mean diffusivity (MD) and fractional anisotropy (FA). Cognitive function was assessed using a neuropsychological test battery. Linear mixed-effect models were employed to examine associations of cortical CMIs with longitudinal changes in DTI measures and cognitive function. Final analysis included 231 patients (71.14 ± 7.60 years). Presence of cortical CMIs at baseline was associated with longitudinal changes in MD median and peak height and FA median and peak height, as well as global cognition (β = −0.50, 95%CI: −0.91, −0.09) and executive function (β = −0.77, 95%CI: −1.25, −0.28). MD median mediated the cross-sectional association between cortical CMIs and global cognition. Further studies are required to investigate whether cortical CMIs and loss of WM integrity are causally related or if they are parallel mechanisms that contribute to cognitive decline.

Early Impairment of Cerebral Bioenergetics After Cardiopulmonary Bypass in Neonatal Swine.

Objectives: We previously demonstrated cerebral mitochondrial dysfunction in neonatal swine immediately following a period of full-flow cardiopulmonary bypass (CPB). The extent to which this dysfunction persists in the postoperative period and its correlation with other markers of cerebral bioenergetic failure and injury is unknown. We utilized a neonatal swine model to investigate the early evolution of mitochondrial function and cerebral bioenergetic failure after CPB. Methods: Twenty piglets (mean weight 4.4 ± 0.5 kg) underwent 3 h of CPB at 34 °C via cervical cannulation and were followed for 8, 12, 18, or 24 h (n = 5 per group). Markers of brain tissue damage (glycerol) and bioenergetic dysfunction (lactate to pyruvate ratio) were continuously measured in cerebral microdialysate samples. Control animals (n = 3, mean weight 4.1 ± 1.2 kg) did not undergo cannulation or CPB. Brain tissue was extracted immediately after euthanasia to obtain ex-vivo cortical mitochondrial respiration and frequency of cortical microglial nodules (indicative of cerebral microinfarctions) via neuropathology. Results: Both the lactate to pyruvate ratio (P < .0001) and glycerol levels (P = .01) increased in cerebral microdialysate within 8 h after CPB. At 24 h post-CPB, cortical mitochondrial respiration was significantly decreased compared with controls (P = .046). The presence of microglial nodules increased throughout the study period (24 h) (P = .01, R2 = 0.9). Conclusion: CPB results in impaired cerebral bioenergetics that persist for at least 24 h. During this period of bioenergetic impairment, there may be increased susceptibility to secondary injury related to alterations in metabolic delivery or demand, such as hypoglycemia, seizures, and decreased cerebral blood flow.

Superficial small cerebellar infarcts in cerebral amyloid angiopathy on 3 T MRI: A preliminary study

BackgroundStrictly superficial cerebellar microbleeds and cerebellar superficial siderosis have been considered markers of advanced cerebral amyloid angiopathy (CAA), but there are few studies on cerebellar ischemic lesions in CAA. We investigated the presence of superficial small cerebellar infarct (SCI) ≤15 mm and its relation to magnetic resonance imaging (MRI) markers in patients with probable CAA. MethodsEighty patients with probable CAA were retrospectively evaluated. The presence of superficial SCIs was examined, along with cerebellar microbleeds and cerebellar superficial siderosis, using 3-T MRI. Lobar cerebral microbleeds, cortical superficial siderosis (cSS), enlargement of the perivascular space in the centrum semiovale, and white matter hyperintensity were assessed and the total CAA-small vessel disease (SVD) score was calculated. ResultsNine of the 80 patients (11.3%) had a total of 16 superficial SCIs. By tentatively defining SCI <4 mm as cerebellar microinfarcts, 8 out of 16 (50%) superficial SCIs corresponded to cerebellar microinfarcts. The total CAA-SVD score was significantly higher in patients with superficial SCIs (p = 0.01). The prevalence of cSS (p = 0.018), cortical cerebral microinfarct (p = 0.034), and superficial cerebellar microbleeds (p = 0.006) was significantly higher in patients with superficial SCIs. The number of superficial cerebellar microbleeds was also significantly higher in patients with superficial SCIs (p = 0.001). ConclusionsOur results suggest that in patients with CAA, superficial SCIs (including microinfarcts) on MRI may indicate more severe, advanced-stage CAA. These preliminary findings should be verified by larger prospective studies in the future.

Abstract 68: FOXO3 Longevity Genotype Attenuates the Impact of Hypertension on Microinfarct Risks

Background: The G allele of FOXO3 SNP rs2802292, which is associated with human resilience and longevity, has been shown to attenuate the impact of hypertension on the risk of intracerebral hemorrhage. We sought to determine whether the FOXO3 G -allele similarly attenuates the impact of hypertension on the risk of cerebral microinfarcts (CMI). Methods: From a prospective population-based cohort of American men of Japanese ancestry from the Kuakini Honolulu Heart Program (KHHP) and Kuakini Honolulu-Asia Aging Study (KHAAS) that had brain autopsy data, age-adjusted prevalence of any CMI on brain autopsy was assessed. Logistic regression models, adjusted for age at death, cardiovascular risk factors, FOXO3 and APOE- ε 4 genotypes, were utilized to determine the predictors of any CMI. Interaction of FOXO3 genotype and hypertension was analyzed. Results: Among 809 men with complete data, 511 (63.2%) participants had evidence of CMI. A full multivariable model demonstrated that body mass index (OR=1.07, 95% CI=1.01-1.14, P =0.012) was the only predictor of CMI, while hypertension was a borderline predictor (OR=1.44, 95% CI=1.00-2.08, P =0.052). However, a significant interaction between FOXO3 G -allele carriage and hypertension was observed ( P =0.020). In the stratified analyses, among the participants without the longevity-associated FOXO3 G -allele, hypertension was a strong predictor of CMI (OR=2.25, 95% CI=1.34-3.77, P =0.0021), while among those with the longevity-associated FOXO3 G -allele, hypertension was not a predictor of CMI (OR=0.88, 95% CI: 0.51-1.54, P =0.66). Conclusions: The longevity-associated FOXO3 G -allele mitigates the impact of hypertension on the risk of CMI.

Exploring Superselective Intraarterial Thrombolysis for Autologous Fat Injection-Induced Vision Loss.

Intravascular injection represents the most severe complication in fat transplantation procedures. Currently, the prognosis for patients who suffer from blindness due to fat transplantation-induced ocular vascular occlusion is far from optimistic. The aim of this study was to explore and evaluate the efficacy and safety of arterial thrombolysis in the treatment of ocular vascular occlusion caused by fat transplantation. We analyzed the data of 12 patients who underwent intraarterial thrombolysis and conservative treatments for facial autologous fat grafting-associated ocular vascular occlusion. Among the cases, there were 6 instances of ophthalmic artery embolism and 6 cases of central retinal artery occlusion. All patients suffered with sudden blindness, sometimes accompanied by eye pain, ptosis, strabismus, skin necrosis at the injection site, or cerebral microinfarction. They received symptomatic conservative treatments and intraarterial thrombolysis, encompassing mechanical vessel recanalization, vessel dilation, and dissolution of thrombus constituents. Following intraarterial thrombolysis, a noteworthy improvement in the blood flow of both the main trunk and peripheral branches of the ophthalmic artery was observed in the majority of patients when contrasted with their pretreatment status. One patient experienced a headache intraoperatively, while no significant discomfort was reported by the remaining patients. After conservative treatments and intraarterial thrombolysis, all patients experienced improvement in ocular symptoms, skin necrosis, and cerebral infarction. Three patients demonstrated improvement in visual acuity. These patients had surpassed the recommended time window for treatment, yet the occlusion of the ophthalmic artery was not complete. Intraarterial thrombolysis combined with conservative treatments achieves early perfusion and is expected to promote visual recovery. Hospitals that possess the necessary treatment capabilities are encouraged to establish this therapeutic pathway.

Relationship between Cerebral Microinfarcts and Dementia by Sex: Findings from a community-based Autopsy Study.

Cerebral microinfarcts are common in older adults and are associated with cognitive impairment. Less is known about sex-related variation in the relationship between cerebral microinfarcts and dementia in older adults, the examination of which was the objective of this study. This case-control study was based on the 727 participants (419 women) in the Adult Changes in Thought (ACT) autopsy data. Microinfarcts were ascertained by blinded board-certified neuropathologists, and dementia diagnoses were made by the ACT Consensus Diagnosis Conference per DSM-IV. Multivariable logistic regression models were used to estimate adjusted odds ratio (aOR) and 95% confidence interval (CI). Microinfarcts were present in 49% (356/727) of the participants, which was numerically higher in women: 51% (213/419) vs 46% (143/308). aOR (95% CI) for dementia associated with any microinfarct for female and male participants were 1.45 (0.91-2.30) and 1.24 (0.75-2.06), respectively (p for interaction, 0.34). Respective aORs (95%CIs) associated with ≥2 microinfarcts were 1.37 (0.79-2.36) and 1.53 (0.84-2.78), with interaction p, 0.84. Subcortical microinfarcts were present in 36% (138/381) and 23% (78/346) of patients with and without dementia (aOR, 1.65; 95% CI, 1.14-2.38). Respective aOR (95% CI) in female and male participants were 1.70 (1.03-2.82) and 1.59 (0.90-2.80), (p for interaction, 0.55). There was no association with cortical microinfarcts (aOR, 1.19; 95% CI, 0.83-1.69). These findings suggest that association between microinfarcts and dementia is primarily mediated by subcortical microinfarcts, but we found no evidence of sex-related variation. Future studies with greater power are needed to determine if the associations we found are replicable.

The effects of left ventricular geometry on cortical cerebral microinfarcts and cognition

The effects of left ventricular geometry on cortical cerebral microinfarcts and cognition

FOXO3 LONGEVITY GENOTYPE AND CEREBROVASCULAR DISEASE

Abstract The influence of the FOXO3-longevity associated genotype on cerebrovascular disease (CVD) is little studied. There are reports of a protective effect against stroke mortality in some populations. But these findings have not been widely replicated, nor have potential mechanisms been identified. This presentation will present recent, novel insights on the relation of FOXO3 genotype to CVD. We studied a cohort of over 800 American men of Japanese ancestry from the Kuakini Honolulu Heart Program (KHHP) and Kuakini Honolulu-Asia Aging Study (KHAAS). This population-based dataset included brain autopsy data and age-adjusted prevalence of various types of CVD, including intracerebral hemorrhage (ICH) and cerebral microinfarcts (CMI). Logistic regression models, adjusted for age at death, cardiovascular risk factors, FOXO3 and APOE-ε4 genotypes, among other risk factors were utilized to determine the predictors of both outcomes. FOXO3 genotype did not directly modify risk for ICH or CMI. However, the FOXO3 longevity genotype had significant interaction (protective) effects against hypertension-associated ICH and CMI. These data suggest that the longevity-associated FOXO3 G-allele mitigates the impact of hypertension on the risk of ICH and CMI. Further research is needed in other populations.

RELATIONSHIPS BETWEEN CEREBRAL VASCULOPATHIES AND MICROINFARCTS IN COMMUNITY-BASED OLDER ADULTS

Abstract Cerebral microinfarcts are associated with cognitive impairment and dementia. Less is known about the relationships of various vasculopathies (arteriolosclerosis and cerebral amyloid angiopathy (CAA) with microinfarcts. This case-control study examined the associations of the vasculopathies with microinfarcts in 842 older adults in the Adult Changes in Thought (ACT) autopsy data. Arteriolosclerosis was assessed by histological examination using the H&amp;E stain; CAA was assessed using the Congo red histochemical stains; and microinfarcts was ascertained by blinded board-certified neuropathologists. Multivariable-adjusted logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the presence of cerebral microinfarcts associated with the two cerebral vasculopathies. Cerebral microinfarcts were present in 417 (49.5%) participants. Mild, moderate, and severe arteriolosclerosis was present in 13.2%, 43.9%, 29.7% of participants with microinfarcts, and 28.9%, 40.0%, and 12.5% of participants without microinfarcts, respectively. ORs (95% CIs) for microinfarcts associated with moderate and severe arteriolosclerosis were 2.15 (1.45-3.17) and 4.59 (2.88-7.33), respectively. Mild, moderate, and severe CAA was present in 18.0%, 17.5%, and 3.6% of participants with microinfarcts, and 18.1%, 16.5%, and 2.4% of participants without microinfarcts, respectively. ORs (95% CIs) for microinfarcts associated with moderate and severe CAA were 0.97 (0.65-1.44) and 1.37 (0.59-3.21), respectively. Cerebral microinfarcts were common in older adults and were associated with a higher prevalence of arteriolosclerosis, but not with CAA. Our study underscores the need for additional studies to better understand this complex relationship to develop interventions for primary prevention of cognitive impairment.

THE FOXO3 LONGEVITY GENOTYPE ATTENUATES IMPACT OF HYPERTENSION ON CEREBRAL MICROINFARCT RISK

Abstract The G allele of the FOXO3 SNP rs2802292 is associated with human resilience and longevity and has recently been shown to attenuate the impact of hypertension on the risk of intracerebral hemorrhage. We now determined whether FOXO3 G-allele similarly attenuated the impact of hypertension on the risk of cerebral microinfarct (CMI). From a prospective population-based cohort of American men of Japanese ancestry (Kuakini Honolulu Heart Program), age-adjusted prevalence of any (1 or more) CMI on brain autopsies was assessed. Logistic regression models, adjusted for age of death, cardiovascular risk factors, FOXO3 and APOE-ε4 genotypes, were utilized to determine the predictors of any CMI. A potential interaction effect of FOXO3 and hypertension was also analyzed. Among 809 men with complete data, 511 (63.2%) had evidence of any CMI. A full multivariable model demonstrated that body mass index (OR: 1.07, 95% CI: 1.01–1.14; p=0.012) was the only significant predictor of CMI, while hypertension was a borderline predictor (OR: 1.44, 95% CI: 1.00–2.08; p=0.052). A significant interaction between FOXO3 G-allele genotype and hypertension was observed (p=0.02). In the stratified analyses, among the participants without the longevity-associated FOXO3 G-allele, hypertension was a strong predictor of CMI (OR: 2.25, 95% CI: 1.34–3.77;, p=0.0021), while among those with the longevity-associated FOXO3 G-allele, hypertension was not (OR: 0.88, 95% CI: 0.51–1.54; p=0.66). These results suggest that the longevity-associated FOXO3 G-allele attenuated the impact of hypertension on the risk of CMI. More studies of other populations is needed to further validate this interesting relation.

PKCε activator protects hippocampal microvascular disruption and memory defect in 3×Tg-Alzheimer's disease mice with cerebral microinfarcts.

Current evidence suggests that microvessel disease is involved in Alzheimer's disease (AD). Cerebrovascular disease correlates with cardiovascular disease and is complicated in ≈40% of AD patients. The protein kinase C (PKC) ε activator DCPLA can stimulate human antigen (Hu) R that prevents degradation and promotes the translation of mitochondrial Mn-superoxide dismutase (MnSOD) and vascular endothelial growth factor-A (VEGF) mRNAs. To induce brain microinfarcts, we injected triple transgenic (3×Tg) and wild-type (WT) control mice with microbeads (20 μm caliber) into common carotid arteries, with or without the DCPLA-ME (methyl-ester) for 2 weeks. After water maze training, mice at 16 months old were examined for confocal immunohistochemistry at a single cell or microvessel level in the hippocampal CA1 area, important for spatial memory storage, and in the dorsal hippocampus by western blots. In 3×Tg mice without cerebral microinfarcts, an accelerating age-related increase in (mild) oxidative stress and hypoxia inducible factor (HIF)-1α, but a reduction in VEGF, mitochondrial transcription factor A (TFAM), and MnSOD were associated with capillary loss. The change was less pronounced in arterioles. However, in 3×Tg mice with cerebral microinfarcts, increasing arteriolar diameter and their wall cells were related with the strong oxidative DNA damage 8-hydroxy-2'-deoxyguanosine (8-OHdG), apoptosis (cleaved caspase 3), and sustained hypoxia (increased HIF-1α and VEGF/PKCε/extracellular signal regulated kinase or ERK pathway). Microocclusion enhanced the loss of the synaptic marker spinophilin, astrocytic number, and astrocyte-vascular coupling areas and demyelination of axons. DCPLA-ME prevented spatial memory defect; strong oxidative stress-related apoptosis; sustained hypoxia (by reducing HIF-1α and VEGF); and exaggerated cell repair in arteriolar walls, pericapillary space dilation, neuro-glial-vascular disruption, and demyelination. In conclusion, in 3×Tg mice with cerebral microinfarcts, sustained hypoxia (increased HIF-1α and VEGF signals) is dominant with arteriolar wall thickening, and DCPLA has a protective effect on sustained hypoxia.

Lung cancer is associated with acute ongoing cerebral ischemia: A population-based study.

Cerebral microinfarcts (CMIs) are the most common type of brain ischemia; however, they are extremely rare in the general population. CMIs can be detected by magnetic resonance diffusion-weighted imaging (MRI-DWI) only for a very short period of approximately 2 weeks after their formation and are associated with an increased stroke risk and cognitive impairment. We aimed to examine CMI detection rate in patients with lung cancer (LC), which is strongly associated with ischemic stroke risk relative to other cancer types. We used the Clalit Health Services record (representing more than 5 million patients) to identify adults with LC and breast, pancreatic, or colon cancer (non-lung cancer, NLC) who underwent brain magnetic resonance diffusion (MRI) scan within 5 years following cancer diagnosis. All brain MRI scans were reviewed, and CMIs were documented, as well as cardiovascular risk factors. Our cohort contained a total of 2056 MRI scans of LC patients and 1598 of NLC patients. A total of 143 CMI were found in 73/2056 (3.5%) MRI scans of LC group compared to a total of 29 CMI in 22/1598 (1.4%) MRI scans of NLC (p < 0.01). Cancer type (e.g. LC vs NLC) was the only associated factor with CMI incidence on multivariate analysis. After calculating accumulated risk, we found an incidence of 2.5 CMI per year in LC patients and 0.5 in NLC. CMIs are common findings in cancer patients, especially in LC patients and therefore might serve as a marker for occult brain ischemia, cognitive decline, and cancer-related stroke (CRS) risk.

FOXO3 longevity genotype attenuates the impact of hypertension on cerebral microinfarct risk.

The G -allele of FOXO3 SNP rs2802292 , which is associated with human resilience and longevity, has been shown to attenuate the impact of hypertension on the risk of intracerebral hemorrhage (ICH). We sought to determine whether the FOXO3 G -allele similarly attenuates the impact of hypertension on the risk of cerebral microinfarcts (CMI). From a prospective population-based cohort of American men of Japanese ancestry from the Kuakini Honolulu Heart Program (KHHP) and Kuakini Honolulu-Asia Aging Study (KHAAS) that had brain autopsy data, age-adjusted prevalence of any CMI on brain autopsy was assessed. Logistic regression models, adjusted for age at death, cardiovascular risk factors, FOXO3 and APOE-ε4 genotypes, were utilized to determine the predictors of any CMI. Interaction of FOXO3 genotype and hypertension was analyzed. Among 809 men with complete data, 511 (63.2%) participants had evidence of CMI. A full multivariable model demonstrated that BMI [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.01-1.14, P = 0.015) was the only predictor of CMI, while hypertension was a borderline predictor (OR 1.44, 95% CI 1.00-2.08, P = 0.052). However, a significant interaction between FOXO3 G -allele carriage and hypertension was observed ( P = 0.020). In the stratified analyses, among the participants without the longevity-associated FOXO3 G -allele, hypertension was a strong predictor of CMI (OR 2.25, 95% CI 1.34-3.77, P = 0.002), while among those with the longevity-associated FOXO3 G -allele, hypertension was not a predictor of CMI (OR 0.88, 95% CI 0.51-1.54, P = 0.66). The longevity-associated FOXO3 G -allele mitigates the impact of hypertension on the risk of CMI.