Temporal Dynamics of Cortical Microinfarcts in Cerebral Small Vessel Disease

Question: What are the cumulative incidence and temporal dynamics of acute cortical microinfarcts? Findings In this cohort study of 54 participants with cerebral small vessel disease who were recruited to undergo 10 monthly 3-T magnetic resonance imaging (MRI) scans, including high-resolution diffusion-weighted imaging, 21 acute cortical microinfarcts were observed in 7 of 54 participants (13%). All acute cortical microinfarcts disappeared on follow-up MRI. Meaning We show that incident acute cortical microinfarcts never evolved into chronically MRI-detectable lesions and suggest that these acute microinfarcts underlie part of the submillimeter cortical microinfarcts visible only on neuropathology, thereby providing a source for the high microinfarct burden encountered on neuropathology. Importance Neuropathology studies show a high prevalence of cortical microinfarcts (CMIs) in aging individuals, especially in patients with cerebrovascular disease and dementia. However, most, are invisible on T1- and T2-weighted magnetic resonance imaging (MRI), raising the question of how to explain this mismatch. Studies on small acute infarcts, detected on diffusion-weighted imaging (DWI), suggest that infarcts are largest in their acute phase and reduce in size thereafter. Therefore, we hypothesized that a subset of the CMI that are invisible on MRI can be detected on MRI in their acute phase. However, to our knowledge, a serial imaging study investigating the temporal dynamics of acute CMI (A-CMI) is lacking. Objective: To determine the prevalence of chronic CMI (C-CMI) and the cumulative incidence and temporal dynamics of A-CMI in individuals with cerebral small vessel disease (SVD). Design, Setting, Participants and Exposures The RUN DMC-Intense study is a single-center hospital-based prospective cohort study on SVD performed between March 2016 and November 2017 and comprising 10 monthly 3-T MRI scans, including high-resolution DWI, 3-dimensional T1, 3-dimensional fluid-attenuated inversion recovery, and T2. One hundred six individuals from the previous longitudinal RUN DMC study were recruited based on the presence of progression of white matter hyperintensities on MRI between 2006 and 2015 and exclusion of causes of cerebral ischemia other than SVD. Fifty-four individuals (50.9%) participated. The median total follow-up duration was 39.5 weeks (interquartile range, 37.8-40.3). Statistical data analysis was performed between May and October 2019. Main Outcomes and Measures: We determined the prevalence of C-CMI using the baseline T1, fluid-attenuated inversion recovery, and T2 scans. Monthly high-resolution DWI scans (n = 472) were screened to determine the cumulative incidence of A-CMI. The temporal dynamics of A-CMI were determined based on the MRI scans collected during the first follow-up visit after A-CMI onset and the last available follow-up visit. Results The median age of the cohort at baseline MRI was 69 years (interquartile range, 66-74 years) and 34 participants (63%) were men. The prevalence of C-CMI was 35% (95% CI, 0.24-0.49). Monthly DWI detected 21 A-CMI in 7 of 54 participants, resulting in a cumulative incidence of 13% (95% CI, 0.06-0.24). All A-CMI disappeared on follow-up MRI. Conclusions and Relevance: Acute CMI never evolved into chronically MRI-detectable lesions. We suggest that these A-CMI underlie part of the submillimeter C-CMI encountered on neuropathological examination and thereby provide a source for the high CMI burden on neuropathology. This cohort study examines the prevalence of chronic cortical microinfarcts and the cumulative incidence and temporal dynamics of acute cortical microinfarcts in Finnish individuals with cerebral small vessel disease

Pro-inflammatory Monocyte Phenotype During Acute Progression of Cerebral Small Vessel Disease

Background: The etiology of cerebral small vessel disease (SVD) remains elusive, though evidence is accumulating that inflammation contributes to its pathophysiology. We recently showed retrospectively that pro-inflammatory monocytes are associated with the long-term progression of white matter hyperintensities (WMHs). In this prospective high-frequency imaging study, we hypothesize that the incidence of SVD progression coincides with a pro-inflammatory monocyte phenotype. Methods: Individuals with SVD underwent monthly magnetic resonance imaging (MRI) for 10 consecutive months to detect SVD progression, defined as acute diffusion-weighted imaging-positive (DWI+) lesions, incident microbleeds, incident lacunes, and WMH progression. Circulating inflammatory markers were measured, cytokine production capacity of monocytes was assessed after ex vivo stimulation, and RNA sequencing was performed on isolated monocytes in a subset of participants. Results: 13 out of 35 individuals developed SVD progression (70 ± 6 years, 54% men) based on incident lesions (n = 7) and/or upper quartile WMH progression (n = 9). Circulating E-selectin concentration (p < 0.05) and the cytokine production capacity of interleukin (IL)-1β and IL-6 (p < 0.01) were higher in individuals with SVD progression. Moreover, RNA sequencing revealed a pro-inflammatory monocyte signature including genes involved in myelination, blood–brain barrier, and endothelial–leukocyte interaction. Conclusions: Circulating monocytes of individuals with progressive SVD have an inflammatory phenotype, characterized by an increased cytokine production capacity and a pro-inflammatory transcriptional signature

Alterations and test-retest reliability of functional connectivity network measures in cerebral small vessel disease

While structural network analysis consolidated the hypothesis of cerebral small vessel disease (SVD) being a disconnection syndrome, little is known about functional changes on the level of brain networks. In patients with genetically defined SVD (CADASIL,n= 41) and sporadic SVD (n= 46), we independently tested the hypothesis that functional networks change with SVD burden and mediate the effect of disease burden on cognitive performance, in particular slowing of processing speed. We further determined test-retest reliability of functional network measures in sporadic SVD patients participating in a high-frequency (monthly) serial imaging study (RUN DMC-InTENse, median: 8 MRIs per participant). Functional networks for the whole brain and major subsystems (i.e., default mode network, DMN;fronto-parietal task control network, FPCN;visual network, VN;hand somatosensory-motor network, HSMN) were constructed based on resting-state multi-band functional MRI. In CADASIL, global efficiency (a graph metric capturing network integration) of the DMN was lower in patients with high disease burden (standardized beta = -.44;p[corrected] = .035) and mediated the negative effect of disease burden on processing speed (indirect path: std. beta = -.20,p= .047;direct path: std. beta = -.19,p= .25;total effect: std. beta = -.39,p= .02). The corresponding analyses in sporadic SVD showed no effect. Intraclass correlations in the high-frequency serial MRI dataset of the sporadic SVD patients revealed poor test-retest reliability and analysis of individual variability suggested an influence of age, but not disease burden, on global efficiency. In conclusion, our results suggest that changes in functional connectivity networks mediate the effect of SVD-related brain damage on cognitive deficits. However, limited reliability of functional network measures, possibly due to age-related comorbidities, impedes the analysis in elderly SVD patients

Investigating the origin and evolution of cerebral small vessel disease: The RUN DMC - InTENse study

Background Neuroimaging in older adults commonly reveals signs of cerebral small vessel disease (SVD). SVD is believed to be caused by chronic hypoperfusion based on animal models and longitudinal studies with inter-scan intervals of years. Recent imaging evidence, however, suggests a role for acute ischaemia, as indicated by incidental diffusion-weighted imaging lesions (DWI+ lesions), in the origin of SVD. Furthermore, it becomes increasingly recognised that focal SVD lesions likely affect the structure and function of brain areas remote from the original SVD lesion. However, the temporal dynamics of these events are largely unknown. Aims (1) To investigate the monthly incidence of DWI+ lesions in subjects with SVD;(2) to assess to which extent these lesions explain progression of SVD imaging markers;(3) to investigate their effects on cortical thickness, structural and functional connectivity and cognitive and motor performance;and (4) to investigate the potential role of the innate immune system in the pathophysiology of SVD. Design/methods The RUN DMC - InTENse study is a longitudinal observational study among 54 non-demented RUN DMC survivors with mild to severe SVD and no other presumed cause of ischaemia. We performed MRI assessments monthly during 10 consecutive months (totalling up to 10 scans per subject), complemented with clinical, motor and cognitive examinations. Discussion Our study will provide a better understanding of the role of DWI+ lesions in the pathophysiology of SVD and will further unravel the structural and functional consequences and clinical importance of these lesions, with an unprecedented temporal resolution. Understanding the role of acute, potentially ischaemic, processes in SVD may provide new strategies for therapies

Different microvascular alterations underlie microbleeds and microinfarcts

OBJECTIVE: Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid β (Aβ) in the walls of cortical vessels and the accrual of microbleeds and microinfarcts over time. The relationship between CAA severity and microbleeds and microinfarcts as well as the sequence of events that lead to lesion formation remain poorly understood. METHODS: We scanned intact formalin-fixed hemispheres of 12 CAA cases with MRI, followed by histopathological examination in pre-defined areas and serial sectioning in targeted areas with multiple lesions. RESULTS: In total 1,168 cortical microbleeds and 472 cortical microinfarcts were observed on ex vivo MRI. Increasing CAA severity at the whole-brain or regional level was not associated with the number of microbleeds or microinfarcts. However, locally, the density of Aβ positive cortical vessels was lower surrounding a microbleed compared to a simulated control lesion, and higher surrounding microinfarcts. Serial sectioning revealed that for (n=28) microbleeds both Aβ (4%) and smooth muscle cells (4%) were almost never present in the vessel wall at the site of bleeding, but Aβ was frequently observed upstream or downstream (71%), as was extensive fibrin(ogen) build-up (87%). In contrast, for (n=22) microinfarcts vascular Aβ was almost always observed at the core of the lesion (91%, p<0.001) as well as upstream or downstream (82%), but few vessels associated with microinfarcts had intact smooth muscle cells (9%). INTERPRETATION: These observations provide a model for how a single neuropathologic process such as CAA may result in hemorrhagic or ischemic brain lesions potentially through two different mechanistic pathways

Assessing cortical cerebral microinfarcts on iron-sensitive MRI in cerebral small vessel disease

Recent studies suggest that a subset of cortical microinfarcts may be identifiable on T2* but invisible on T1 and T2 follow-up images. We aimed to investigate whether cortical microinfarcts are associated with iron accumulation after the acute stage. The RUN DMC – InTENse study is a serial MRI study including individuals with cerebral small vessel disease (SVD). 54 Participants underwent 10 monthly 3 T MRIs, including diffusion-weighted imaging, quantitative R1 (=1/T1), R2 (=1/T2), and R2* (=1/T2*) mapping, from which MRI parameters within areas corresponding to microinfarcts and control region of interests (ROIs) were retrieved within 16 participants. Finally, we compared pre- and post-lesional values with repeated measures ANOVA and post-hoc paired t-tests using the mean difference between lesion and control ROI values. We observed 21 acute cortical microinfarcts in 7 of the 54 participants (median age 69 years [IQR 66–74], 63% male). R2* maps demonstrated an increase in R2* values at the moment of the last available follow-up MRI (median [IQR], 5 [5–14] weeks after infarction) relative to prelesional values (p =.08), indicative of iron accumulation. Our data suggest that cortical microinfarcts are associated with increased R2* values, indicative of iron accumulation, possibly due to microhemorrhages, neuroinflammation or neurodegeneration, awaiting histopathological verification

Temporal Dynamics of Cortical Microinfarcts in Cerebral Small Vessel Disease

Importance: Neuropathology studies show a high prevalence of cortical microinfarcts (CMIs) in aging individuals, especially in patients with cerebrovascular disease and dementia. However, most, are invisible on T1- and T2-weighted magnetic resonance imaging (MRI), raising the question of how to explain this mismatch. Studies on small acute infarcts, detected on diffusion-weighted imaging (DWI), suggest that infarcts are largest in their acute phase and reduce in size thereafter. Therefore, we hypothesized that a subset of the CMI that are invisible on MRI can be detected on MRI in their acute phase. However, to our knowledge, a serial imaging study investigating the temporal dynamics of acute CMI (A-CMI) is lacking. Objective: To determine the prevalence of chronic CMI (C-CMI) and the cumulative incidence and temporal dynamics of A-CMI in individuals with cerebral small vessel disease (SVD). Design, Setting, Participants and Exposures: The RUN DMC-Intense study is a single-center hospital-based prospective cohort study on SVD performed between March 2016 and November 2017 and comprising 10 monthly 3-T MRI scans, including high-resolution DWI, 3-dimensional T1, 3-dimensional fluid-attenuated inversion recovery, and T2. One hundred six individuals from the previous longitudinal RUN DMC study were recruited based on the presence of progression of white matter hyperintensities on MRI between 2006 and 2015 and exclusion of causes of cerebral ischemia other than SVD. Fifty-four individuals (50.9%) participated. The median total follow-up duration was 39.5 weeks (interquartile range, 37.8-40.3). Statistical data analysis was performed between May and October 2019. Main Outcomes and Measures: We determined the prevalence of C-CMI using the baseline T1, fluid-attenuated inversion recovery, and T2 scans. Monthly high-resolution DWI scans (n = 472) were screened to determine the cumulative incidence of A-CMI. The temporal dynamics of A-CMI were determined based on the MRI scans collected during the first follow-up visit after A-CMI onset and the last available follow-up visit. Results: The median age of the cohort at baseline MRI was 69 years (interquartile range, 66-74 years) and 34 participants (63%) were men. The prevalence of C-CMI was 35% (95% CI, 0.24-0.49). Monthly DWI detected 21 A-CMI in 7 of 54 participants, resulting in a cumulative incidence of 13% (95% CI, 0.06-0.24). All A-CMI disappeared on follow-up MRI. Conclusions and Relevance: Acute CMI never evolved into chronically MRI-detectable lesions. We suggest that these A-CMI underlie part of the submillimeter C-CMI encountered on neuropathological examination and thereby provide a source for the high CMI burden on neuropathology

The contribution of acute infarcts to cerebral small vessel disease progression

Objective To determine the contribution of acute infarcts, evidenced by diffusion‐weighted imaging positive (DWI+) lesions, to progression of white matter hyperintensities (WMH) and other cerebral small vessel disease (SVD) markers. Methods We performed monthly 3T magnetic resonance imaging (MRI) for 10 consecutive months in 54 elderly individuals with SVD. MRI included high‐resolution multishell DWI, and 3‐dimensional fluid‐attenuated inversion recovery, T1, and susceptibility‐weighted imaging. We determined DWI+ lesion evolution, WMH progression rate (ml/mo), and number of incident lacunes and microbleeds, and calculated for each marker the proportion of progression explained by DWI+ lesions. Results We identified 39 DWI+ lesions on 21 of 472 DWI scans in 9 of 54 subjects. Of the 36 DWI+ lesions with follow‐up MRI, 2 evolved into WMH, 4 evolved into a lacune (3 with cavity <3mm), 3 evolved into a microbleed, and 27 were not detectable on follow‐up. WMH volume increased at a median rate of 0.027 ml/mo (interquartile range = 0.005–0.073), but was not significantly higher in subjects with DWI+ lesions compared to those without (p = 0.195). Of the 2 DWI+ lesions evolving into WMH on follow‐up, one explained 23% of the total WMH volume increase in one subject, whereas the WMH regressed in the other subject. DWI+ lesions preceded 4 of 5 incident lacunes and 3 of 10 incident microbleeds. Interpretation DWI+ lesions explain only a small proportion of the total WMH progression. Hence, WMH progression seems to be mostly driven by factors other than acute infarcts. DWI+ lesions explain the majority of incident lacunes and small cavities, and almost one‐third of incident microbleeds, confirming that WMH, lacunes, and microbleeds, although heterogeneous on MRI, can have a common initial appearance on MRI. ANN NEUROL 2019;86:582–59

Hippocampal Disconnection in Early Alzheimer's Disease : A 7 Tesla MRI Study

Background: In patients with Alzheimer's disease (AD), atrophy of the entorhinal cortex (ERC) and hippocampal formation may induce degeneration of connecting white matter tracts. Objective: We examined the association of hippocampal subfield and ERC atrophy at 7 tesla MRI with fornix and parahippocampal cingulum (PHC) microstructure in patients with early AD. Methods: Twenty-five patients with amnestic mild cognitive impairment (aMCI) (n = 15) or early AD (n = 10) and 17 controls underwent 3 tesla diffusion MRI to obtain fractional anisotropy (FA) of the fornix and PHC and 7 tesla MRI to obtain ERC and hippocampal subfield volumes. Linear regression analyses were performed, adjusted for age, gender, and intracranial volume. Results: Fornix FA was significantly lower and subiculum, cornu ammonis (CA) 1, and dentate gyrus & CA4 volume were significantly smaller in patients with MCI or AD as compared to controls. In patients with MCI or AD, fornix FA was positively associated with subiculum volume (beta = 0.53, 95% CI 0.10; 0.96), but not with ERC/other subfield volumes. PHC FA was not associated with ERC/subfield volumes. Conclusion: These findings indicate that in early AD subiculum atrophy is associated with lower FA of the fornix, which primarily consists of axons originating in the subiculum. This suggests that degeneration of subicular cell bodies and their axons are related processes in early AD

Histopathology of diffusion-weighted imaging-positive lesions in cerebral amyloid angiopathy

Small subclinical hyperintense lesions are frequently encountered on brain diffusion-weighted imaging (DWI) scans of patients with cerebral amyloid angiopathy (CAA). Interpretation of these DWI+ lesions, however, has been limited by absence of histopathological examination. We aimed to determine whether DWI+ lesions represent acute microinfarcts on histopathology in brains with advanced CAA, using a combined in vivo MRI-ex vivo MRI-histopathology approach. We first investigated the histopathology of a punctate cortical DWI+ lesion observed on clinical in vivo MRI 7 days prior to death in a CAA case. Subsequently, we assessed the use of ex vivo DWI to identify similar punctate cortical lesions post-mortem. Intact formalin-fixed hemispheres of 12 consecutive cases with CAA and three non-CAA controls were subjected to high-resolution 3 T ex vivo DWI and T2 imaging. Small cortical lesions were classified as either DWI+/T2+ or DWI-/T2+. A representative subset of lesions from three CAA cases was selected for detailed histopathological examination. The DWI+ lesion observed on in vivo MRI could be matched to an area with evidence of recent ischemia on histopathology. Ex vivo MRI of the intact hemispheres revealed a total of 130 DWI+/T2+ lesions in 10/12 CAA cases, but none in controls (p = 0.022). DWI+/T2+ lesions examined histopathologically proved to be acute microinfarcts (classification accuracy 100%), characterized by presence of eosinophilic neurons on hematoxylin and eosin and absence of reactive astrocytes on glial fibrillary acidic protein-stained sections. In conclusion, we suggest that small DWI+ lesions in CAA represent acute microinfarcts. Furthermore, our findings support the use of ex vivo DWI as a method to detect acute microinfarcts post-mortem, which may benefit future histopathological investigations on the etiology of microinfarcts