ABSTRACT
Cerebral small vessel disease (SVD) is common during ageing and can present as stroke, cognitive decline, neurobehavioural symptoms, or functional impairment. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive and other symptoms and affect activities of daily living. Standards for Reporting Vascular Changes on Neuroimaging 1 (STRIVE-1) categorised and standardised the diverse features of SVD that are visible on structural MRI. Since then, new information on these established SVD markers and novel MRI sequences and imaging features have emerged. As the effect of combined SVD imaging features becomes clearer, a key role for quantitative imaging biomarkers to determine sub-visible tissue damage, subtle abnormalities visible at high-field strength MRI, and lesion-symptom patterns, is also apparent. Together with rapidly emerging machine learning methods, these metrics can more comprehensively capture the effect of SVD on the brain than the structural MRI features alone and serve as intermediary outcomes in clinical trials and future routine practice. Using a similar approach to that adopted in STRIVE-1, we updated the guidance on neuroimaging of vascular changes in studies of ageing and neurodegeneration to create STRIVE-2.
Subject(s)
Cerebral Small Vessel Diseases , Cognitive Dysfunction , Neurodegenerative Diseases , Humans , Activities of Daily Living , Neuroimaging , Magnetic Resonance Imaging/methods , Brain/diagnostic imaging , Cerebral Small Vessel Diseases/diagnostic imagingABSTRACT
The aim of our study was to assess whether a well-established federal state-wide Stroke Care Pathway delivering high quality stroke care can cope with the COVID-19 pandemic and associated measures to contain the virus spread. The retrospective analysis is based on a prospective, quality-controlled, population-based registry of all stroke patients in the Tyrol, a federal state of Austria and one of the early hot-spots of COVID-19 in Europe. Patient characteristics, pre-hospital management, intra-hospital management and post-hospital were analysed. All residents of the Tyrol suffering ischemic stroke in 2020 (n = 1160) and four pre-COVID-19 years (n = 4321) were evaluated. In 2020, the annual number of stroke patients was the highest in this population-based registry. When local hospitals were overwhelmed with SARS-CoV-2-patients, stroke subjects were temporarily allocated to the comprehensive stroke centre. Stroke severity, quality metrics of stroke management, serious complications, and post-stroke mortality did not differ between 2020 and the four comparator years. Notably, iv. thrombolysis-rate was similar (19.9% versus 17.4%, P = 0.25) and endovascular stroke treatment even better (5.9% versus 3.9%, P = 0.003) but resources for in-patient rehabilitation were limited (25.8% versus 29.8%, P = 0.009). Concluding, a well-established Stroke Care Pathway was able to maintain high-quality acute stroke care even when challenged by a global pandemic.
Subject(s)
COVID-19 , Stroke , Humans , Pandemics , SARS-CoV-2 , Retrospective Studies , Prospective Studies , Critical Pathways , Stroke/epidemiologyABSTRACT
BACKGROUND: Small hyperintense lesions are found on diffusion-weighted imaging (DWI) in patients with sporadic small vessel disease (SVD). Their exact role in SVD progression remains unclear due to their asymptomatic and transient nature. The main objective is to investigate the role of DWI+lesions in the radiological progression of SVD and their relationship with clinical outcomes. METHODS: Participants with SVD were included from the Radboud University Nijmegen Diffusion tensor MRI Cohort. DWI+lesions were assessed on four time points over 14 years. Outcome measures included neuroimaging markers of SVD, cognitive performance and clinical outcomes, including stroke, all-cause dementia and all-cause mortality. Linear mixed-effect models and Cox regression models were used to examine the outcome measures in participants with a DWI+lesion (DWI+) and those without a DWI+lesion (DWI-). RESULTS: DWI+lesions were present in 45 out of 503 (8.9%) participants (mean age: 66.7 years (SD=8.3)). Participants with DWI+lesions and at least one follow-up (n=33) had higher white matter hyperintensity progression rates (ß=0.36, 95% CI=0.05 to 0.68, p=0.023), more incident lacunes (incidence rate ratio=2.88, 95% CI=1.80 to 4.67, p<0.001) and greater cognitive decline (ß=-0.03, 95% CI=-0.05 to -0.01, p=0.006) during a median follow-up of 13.2 (IQR: 8.8-13.8) years compared with DWI- participants. No differences were found in risk of all-cause mortality, stroke or dementia. CONCLUSION: Presence of a DWI+lesion in patients with SVD is associated with greater radiological progression of SVD and cognitive decline compared with patients without DWI+lesions.
Subject(s)
Cerebral Small Vessel Diseases , Dementia , Stroke , Humans , Aged , Follow-Up Studies , Cerebral Small Vessel Diseases/complications , Diffusion Magnetic Resonance Imaging/methods , Stroke/complications , Dementia/diagnostic imaging , Dementia/complications , Magnetic Resonance ImagingABSTRACT
Background: Neuroimaging markers of cerebral small vessel disease (SVD) are common in older individuals, but the pathophysiological mechanisms causing these lesions remain poorly understood. Although hypertension is a major risk factor for SVD, the direct causal effects of increased blood pressure are unknown. The Hyperintense study is designed to examine cerebrovascular and structural abnormalities, possibly preceding SVD, in young adults with hypertension. These patients undergo a diagnostic work-up that requires patients to temporarily discontinue their antihypertensive agents, often leading to an increase in blood pressure followed by a decrease once effective medication is restarted. This allows examination of the effects of blood pressure increase and decrease on the cerebral small vessels. Methods: Hyperintense is a prospective observational cohort study in 50 hypertensive adults (18-55 years) who will temporarily discontinue antihypertensive medication for diagnostic purposes. MRI and clinical data is collected at four timepoints: before medication withdrawal (baseline), once antihypertensives are largely or completely withdrawn (T = 1), when patients have restarted medication (T = 2) and reached target blood pressure and 1 year later (T = 3). The 3T MRI protocol includes conventional structural sequences and advanced techniques to assess various aspects of microvascular integrity, including blood-brain barrier function using Dynamic Contrast Enhanced MRI, white matter integrity, and microperfusion. Clinical assessments include motor and cognitive examinations and blood sampling. Discussion: The Hyperintense study will improve the understanding of the pathophysiological mechanisms following hypertension that may cause SVD. This knowledge can ultimately help to identify new targets for treatment of SVD, aimed at prevention or limiting disease progression.
ABSTRACT
Cerebral small vessel disease (SVD) is considered a disconnection syndrome, which can be quantified using structural brain network analysis obtained from diffusion MRI. Network analysis is a demanding analysis approach and the added benefit over simpler diffusion MRI analysis is largely unexplored in SVD. In this pre-registered study, we assessed the clinical and technical validity of network analysis in two non-overlapping samples of SVD patients from the RUN DMC study (n = 52 for exploration and longitudinal analysis and n = 105 for validation). We compared two connectome pipelines utilizing single-shell or multi-shell diffusion MRI, while also systematically comparing different node and edge definitions. For clinical validation, we assessed the added benefit of network analysis in explaining processing speed and in detecting short-term disease progression. For technical validation, we determined test-retest repeatability.Our findings in clinical validation show that structural brain networks provide only a small added benefit over simpler global white matter diffusion metrics and do not capture short-term disease progression. Test-retest reliability was excellent for most brain networks. Our findings question the added value of brain network analysis in clinical applications in SVD and highlight the utility of simpler diffusion MRI based markers.
Subject(s)
Cerebral Small Vessel Diseases , Diffusion Tensor Imaging , Brain/diagnostic imaging , Cerebral Small Vessel Diseases/diagnostic imaging , Disease Progression , Humans , Magnetic Resonance Imaging , Reproducibility of ResultsABSTRACT
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)-1ß 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.
ABSTRACT
OBJECTIVE: To test the hypothesis that multi-shell diffusion models improve the characterization of microstructural alterations in cerebral small vessel disease (SVD), we assessed associations with processing speed performance, longitudinal change, and reproducibility of diffusion metrics. METHODS: We included 50 patients with sporadic and 59 patients with genetically defined SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) with cognitive testing and standardized 3T MRI, including multi-shell diffusion imaging. We applied the simple diffusion tensor imaging (DTI) model and 2 advanced models: diffusion kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI). Linear regression and multivariable random forest regression (including conventional SVD markers) were used to determine associations between diffusion metrics and processing speed performance. The detection of short-term disease progression was assessed by linear mixed models in 49 patients with sporadic SVD with longitudinal high-frequency imaging (in total 459 MRIs). Intersite reproducibility was determined in 10 patients with CADASIL scanned back-to-back on 2 different 3T MRI scanners. RESULTS: Metrics from DKI showed the strongest associations with processing speed performance (R 2 up to 21%) and the largest added benefit on top of conventional SVD imaging markers in patients with sporadic SVD and patients with CADASIL with lower SVD burden. Several metrics from DTI and DKI performed similarly in detecting disease progression. Reproducibility was excellent (intraclass correlation coefficient >0.93) for DTI and DKI metrics. NODDI metrics were less reproducible. CONCLUSION: Multi-shell diffusion imaging and DKI improve the detection and characterization of cognitively relevant microstructural white matter alterations in SVD. Excellent reproducibility of diffusion metrics endorses their use as SVD markers in research and clinical care. Our publicly available intersite dataset facilitates future studies. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with SVD, diffusion MRI metrics are associated with processing speed performance.
Subject(s)
CADASIL/diagnostic imaging , Cerebral Small Vessel Diseases/diagnostic imaging , Diffusion Magnetic Resonance Imaging/methods , White Matter/diagnostic imaging , Adult , Aged , CADASIL/physiopathology , CADASIL/psychology , Cerebral Hemorrhage/diagnostic imaging , Cerebral Small Vessel Diseases/physiopathology , Cerebral Small Vessel Diseases/psychology , Diffusion Tensor Imaging , Disease Progression , Female , Humans , Image Processing, Computer-Assisted , Leukoaraiosis/diagnostic imaging , Male , Middle Aged , Stroke, Lacunar/diagnostic imagingABSTRACT
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.
Subject(s)
Brain/pathology , Cerebral Amyloid Angiopathy/pathology , Cerebral Hemorrhage/pathology , Diffusion Magnetic Resonance Imaging , Aged, 80 and over , Autopsy/methods , Cerebral Amyloid Angiopathy/diagnosis , Diffusion Magnetic Resonance Imaging/methods , Female , Humans , Magnetic Resonance Imaging/methods , Neuroimaging/methodsABSTRACT
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.
Subject(s)
Cerebral Small Vessel Diseases , Cognitive Dysfunction , Connectome/standards , Default Mode Network , Diffusion Tensor Imaging/standards , Nerve Net , Adult , Aged , Aged, 80 and over , CADASIL/diagnostic imaging , CADASIL/pathology , CADASIL/physiopathology , Cerebral Small Vessel Diseases/diagnostic imaging , Cerebral Small Vessel Diseases/pathology , Cerebral Small Vessel Diseases/physiopathology , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/pathology , Cognitive Dysfunction/physiopathology , Connectome/methods , Cross-Sectional Studies , Default Mode Network/diagnostic imaging , Default Mode Network/pathology , Default Mode Network/physiopathology , Diffusion Tensor Imaging/methods , Female , Humans , Longitudinal Studies , Male , Middle Aged , Nerve Net/diagnostic imaging , Nerve Net/pathology , Nerve Net/physiopathology , Reproducibility of ResultsABSTRACT
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.
Subject(s)
Cerebral Infarction/diagnostic imaging , Cerebral Infarction/epidemiology , Cerebral Infarction/etiology , Cerebral Small Vessel Diseases/complications , Cerebral Small Vessel Diseases/pathology , Aged , Cohort Studies , Diffusion Magnetic Resonance Imaging/methods , Female , Humans , Incidence , Male , Time FactorsABSTRACT
OBJECTIVE: To investigate the prevalence of asymptomatic diffusion-weighted imaging-positive (DWI+) lesions in individuals with cerebral small vessel disease (SVD) and identify their role in the origin of SVD markers on MRI. METHODS: We included 503 individuals with SVD from the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN DMC) study (mean age 65.6 years [SD 8.8], 56.5% male) with 1.5T MRI in 2006 and, if available, follow-up MRI in 2011 and 2015. We screened DWI scans (n = 1,152) for DWI+ lesions, assessed lesion evolution on follow-up fluid-attenuated inversion recovery, T1 and T2* images, and examined the association between DWI+ lesions and annual SVD progression (white matter hyperintensities [WMH], lacunes, microbleeds). RESULTS: We found 50 DWI+ lesions in 39 individuals on 1,152 DWI (3.4%). Individuals with DWI+ lesions were older (p = 0.025), more frequently had a history of hypertension (p = 0.021), and had a larger burden of preexisting SVD MRI markers (WMH, lacunes, microbleeds: all p < 0.001) compared to individuals without DWI+ lesions. Of the 23 DWI+ lesions with available follow-up MRI, 14 (61%) evolved into a WMH, 8 (35%) resulted in a cavity, and 1 (4%) was no longer visible. Presence of DWI+ lesions was significantly associated with annual WMH volume increase and yearly incidence of lacunes and microbleeds (all p < 0.001). CONCLUSION: Over 3% of individuals with SVD have DWI+ lesions. Although DWI+ lesions play a role in the progression of SVD, they may not fully explain progression of SVD markers on MRI, suggesting that other factors than acute ischemia are at play.
Subject(s)
Cerebral Small Vessel Diseases/diagnostic imaging , Diffusion Magnetic Resonance Imaging , Aged , Aged, 80 and over , Brain/diagnostic imaging , Disease Progression , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prospective StudiesABSTRACT
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;86:582-592.
Subject(s)
Brain Infarction/pathology , Cerebral Small Vessel Diseases/pathology , Aged , Aged, 80 and over , Brain Infarction/complications , Cerebral Small Vessel Diseases/complications , Diffusion Magnetic Resonance Imaging , Disease Progression , Female , Humans , Incidence , Intracranial Hemorrhages/complications , Intracranial Hemorrhages/pathology , Male , Neuroimaging , Stroke, Lacunar/complications , Stroke, Lacunar/pathology , White Matter/blood supply , White Matter/pathologyABSTRACT
OBJECTIVE: Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid ß (Aß) 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 magnetic resonance imaging (MRI), followed by histopathological examination in predefined 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 Aß-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 Aß (4%) and smooth muscle cells (4%) were almost never present in the vessel wall at the site of bleeding, but Aß was frequently observed upstream or downstream (71%), as was extensive fibrin(ogen) buildup (87%). In contrast, for (n = 22) microinfarcts, vascular Aß 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 2 different mechanistic pathways. ANN NEUROL 2019;86:279-292.
Subject(s)
Cerebral Amyloid Angiopathy/diagnostic imaging , Cerebral Hemorrhage/diagnostic imaging , Cerebral Infarction/diagnostic imaging , Microvessels/diagnostic imaging , Aged , Aged, 80 and over , Cerebral Amyloid Angiopathy/pathology , Cerebral Hemorrhage/pathology , Cerebral Infarction/pathology , Female , Humans , Magnetic Resonance Imaging/methods , Male , Microvessels/pathology , Middle AgedABSTRACT
Background and Purpose- Cerebral small vessel disease (cSVD) is the major vascular cause of cognitive decline and dementia. The pathogenesis of cSVD remains largely unknown, although several studies suggest a role for systemic inflammation. In certain pathophysiological situations, monocytes can reprogram toward a long-term proinflammatory phenotype, which has been termed trained immunity. We hypothesize that trained immunity contributes to the progression of cSVD. Methods- Individuals with mild-to-severe cSVD participated in the study. Severity of cSVD was determined by the white matter hyperintensities (WMH) volume (mL) on magnetic resonance imaging in 2006, 2015, and the progression between 2006 and 2015 (ΔWMH). Cytokine production was assessed after ex vivo stimulation of peripheral blood mononuclear cells and monocytes. Additionally, monocyte subsets were identified by flow cytometry. Results- Fifty-one subjects (70±6 years, 60% men, 5.1±6.4 mL ΔWMH) were included. Circulating hsIL (high-sensitivity interleukin)-6 correlated with cSVD ( P=0.005, rs=0.40). Cytokine production capacity by monocytes was associated with cSVD progression. Basal IL-8 and IL-17 production ( P=0.08, rs=0.25; P=0.03, rs=0.30) and IL-6 production after Pam3Cys stimulation in monocytes was associated with cSVD (n=35: P=0.008, rs=0.44). Conversely, interferon (IFN)-γ production in Candida albicans stimulated peripheral blood mononuclear cells was negatively correlated with cSVD ( P=0.009, rs=-0.36). Flow cytometry revealed a correlation of the intermediate monocyte subset with cSVD ( P=0.01, rs=0.36). Conclusions- Severity and progression of cSVD are not only correlated with systemic inflammation (hsIL-6) but also with trained immunity characteristics of circulating monocytes, in terms of an altered cytokine production capacity and a shift toward the proinflammatory intermediate monocyte subset.
Subject(s)
Cerebral Small Vessel Diseases/immunology , Immunity, Innate/immunology , Immunologic Memory/immunology , Interferon-gamma/immunology , Interleukin-17/immunology , Interleukin-6/immunology , Interleukin-8/immunology , Aged , Candida albicans , Disease Progression , Female , Humans , Interferon-gamma/drug effects , Interleukin-8/drug effects , Lipoproteins/pharmacology , Male , Middle Aged , Monocytes/drug effects , Monocytes/immunology , Severity of Illness IndexABSTRACT
Cerebral small vessel disease (SVD) is commonly observed on neuroimaging among elderly individuals and is recognized as a major vascular contributor to dementia, cognitive decline, gait impairment, mood disturbance and stroke. However, clinical symptoms are often highly inconsistent in nature and severity among patients with similar degrees of SVD on brain imaging. Here, we provide a new framework based on new advances in structural and functional neuroimaging that aims to explain the remarkable clinical variation in SVD. First, we discuss the heterogeneous pathology present in SVD lesions despite an identical appearance on imaging and the perilesional and remote effects of these lesions. We review effects of SVD on structural and functional connectivity in the brain, and we discuss how network disruption by SVD can lead to clinical deficits. We address reserve and compensatory mechanisms in SVD and discuss the part played by other age-related pathologies. Finally, we conclude that SVD should be considered a global rather than a focal disease, as the classically recognized focal lesions affect remote brain structures and structural and functional network connections. The large variability in clinical symptoms among patients with SVD can probably be understood by taking into account the heterogeneity of SVD lesions, the effects of SVD beyond the focal lesions, the contribution of neurodegenerative pathologies other than SVD, and the interaction with reserve mechanisms and compensatory mechanisms.
Subject(s)
Cerebral Small Vessel Diseases , Nerve Net , Cerebral Small Vessel Diseases/diagnostic imaging , Cerebral Small Vessel Diseases/pathology , Cerebral Small Vessel Diseases/physiopathology , Humans , Nerve Net/diagnostic imaging , Nerve Net/pathology , Nerve Net/physiopathologyABSTRACT
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.
ABSTRACT
PURPOSE: As a single-shot sequence with a long train of refocusing pulses, Half-Fourier Acquisition Single-Shot Turbo-Spin-Echo (HASTE) suffers from high power deposition limiting use at high resolutions and high field strengths, particularly if combined with acceleration techniques such as simultaneous multi-slice (SMS) imaging. Using a combination of multiband (MB)-excitation and PINS-refocusing pulses will effectively accelerate the acquisition time while staying within the SAR limitations. In particular, uncooperative and young patients will profit from the speed of the MB-PINS HASTE sequence, as clinical diagnosis can be possible without sedation. Materials and MethodsMB-excitation and PINS-refocusing pulses were incorporated into a HASTE-sequence with blipped CAIPIRINHA and TRAPS including an internal FLASH reference scan for online reconstruction. Whole brain MB-PINS HASTE data were acquired on a Siemens 3T-Prisma system from 10 individuals and compared to a clinical HASTE protocol. ResultsThe proposed MB-PINS HASTE protocol accelerates the acquisition by about a factor 2 compared to the clinical HASTE. The diagnostic image quality proved to be comparable for both sequences for the evaluation of the overall aspect of the brain, the detection of white matter changes and areas of tissue loss, and for the evaluation of the CSF spaces although artifacts were more frequently encountered with MB-PINS HASTE. ConclusionsMB-PINS HASTE enables acquisition of slice accelerated highly T2-weighted images and provides good diagnostic image quality while reducing acquisition time.
Subject(s)
Brain/diagnostic imaging , Cerebral Small Vessel Diseases/diagnostic imaging , Image Processing, Computer-Assisted/methods , Magnetic Resonance Imaging/methods , Aged , Artifacts , Brain/blood supply , Female , Fourier Analysis , Humans , Male , Middle AgedABSTRACT
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 (ß = 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.