Loss of spontaneous vasomotion precedes impaired cerebrovascular reactivity and microbleeds in a mouse model of cerebral amyloid angiopathy.

Background: Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease in which amyloid-ß accumulates in vessel walls. CAA is a leading cause of symptomatic lobar intracerebral hemorrhage and an important contributor to age-related cognitive decline. Recent work has suggested that vascular dysfunction may precede symptomatic stages of CAA, and that spontaneous slow oscillations in arteriolar diameter (termed vasomotion), important for amyloid-ß clearance, may be impaired in CAA. Methods: To systematically study the progression of vascular dysfunction in CAA, we used the APP23 mouse model of amyloidosis, which is known to develop spontaneous cerebral microbleeds mimicking human CAA. Using in vivo 2-photon microscopy, we longitudinally imaged unanesthetized APP23 transgenic mice and wildtype littermates from 7 to 14 months of age, tracking amyloid-ß accumulation and vasomotion in individual pial arterioles over time. MRI was used in separate groups of 12-, 18-, and 24-month-old APP23 transgenic mice and wildtype littermates to detect microbleeds and to assess cerebral blood flow and cerebrovascular reactivity with pseudo-continuous arterial spin labeling. Results: We observed a significant decline in vasomotion with age in APP23 mice, while vasomotion remained unchanged in wildtype mice with age. This decline corresponded in timing to initial vascular amyloid-ß deposition (∼8-10 months of age), although was more strongly correlated with age than with vascular amyloid-ß burden in individual arterioles. Declines in vasomotion preceded the development of MRI-visible microbleeds and the loss of smooth muscle actin in arterioles, both of which were observed in APP23 mice by 18 months of age. Additionally, evoked cerebrovascular reactivity was intact in APP23 mice at 12 months of age, but significantly lower in APP23 mice by 24 months of age. Conclusions: Our findings suggest that a decline in spontaneous vasomotion is an early, potentially pre-symptomatic, manifestation of CAA and vascular dysfunction, and a possible future treatment target.

Temporal Ordering of Biomarkers in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.

BACKGROUND: The temporal ordering of biomarkers for cerebral amyloid angiopathy (CAA) is important for their use in trials and for the understanding of the pathological cascade of CAA. We investigated the presence and abnormality of the most common biomarkers in the largest (pre)symptomatic Dutch-type hereditary CAA (D-CAA) cohort to date. METHODS: We included cross-sectional data from participants with (pre)symptomatic D-CAA and controls without CAA. We investigated CAA-related cerebral small vessel disease markers on 3T-MRI, cerebrovascular reactivity with functional 7T-MRI (fMRI) and amyloid-ß40 and amyloid-ß42 levels in cerebrospinal fluid. We calculated frequencies and plotted biomarker abnormality according to age to form scatterplots. RESULTS: We included 68 participants with D-CAA (59% presymptomatic, mean age, 50 [range, 26-75] years; 53% women), 53 controls (mean age, 51 years; 42% women) for cerebrospinal fluid analysis and 36 controls (mean age, 53 years; 100% women) for fMRI analysis. Decreased cerebrospinal fluid amyloid-ß40 and amyloid-ß42 levels were the earliest biomarkers present: all D-CAA participants had lower levels of amyloid-ß40 and amyloid-ß42 compared with controls (youngest participant 30 years). Markers of nonhemorrhagic injury (>20 enlarged perivascular spaces in the centrum semiovale and white matter hyperintensities Fazekas score, ≥2, present in 83% [n=54]) and markers of impaired cerebrovascular reactivity (abnormal BOLD amplitude, time to peak and time to baseline, present in 56% [n=38]) were present from the age of 30 years. Finally, markers of hemorrhagic injury were present in 64% (n=41) and only appeared after the age of 41 years (first microbleeds and macrobleeds followed by cortical superficial siderosis). CONCLUSIONS: Our results suggest that amyloid biomarkers in cerebrospinal fluid are the first to become abnormal in CAA, followed by MRI biomarkers for cerebrovascular reactivity and nonhemorrhagic injury and lastly hemorrhagic injury. This temporal ordering probably reflects the pathological stages of CAA and should be taken into account when future therapeutic trials targeting specific stages are designed.

KLRG1 Cell Depletion as a Novel Therapeutic Strategy in Patients with Mature T-Cell Lymphoma Subtypes.

PURPOSE: Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms. EXPERIMENTAL DESIGN: Primary specimens, cell lines, patient-derived xenograft models, commercially available, and proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation. RESULTS: Here we demonstrate that surface KLRG1 is highly expressed on tumor cells in subsets of patients with extranodal NK/T-cell lymphoma (ENKTCL), T-prolymphocytic leukemia (T-PLL), and gamma/delta T-cell lymphoma (G/D TCL). The majority of the CD8+/CD57+ or CD3-/CD56+ leukemic cells derived from patients with T- and NK-large granular lymphocytic leukemia (T-LGLL and NK-LGLL), respectively, expressed surface KLRG1. The humanized afucosylated anti-KLRG1 monoclonal antibody (mAb208) optimized for mouse in vivo use depleted KLRG1+ TCL cells by mechanisms of ADCC, ADCP, and CDC rather than apoptosis. mAb208 induced ADCC and ADCP of T-LGLL patient-derived CD8+/CD57+ cells ex vivo. mAb208 effected ADCC of subsets of healthy donor-derived KLRG1+ NK, CD4+, CD8+ Tem, and TemRA cells while sparing KLRG1- naïve and CD8+ Tcm cells. Treatment of cell line and TCL patient-derived xenografts with mAb208 or anti-CD47 mAb alone and in combination with the PI3K-δ/γ inhibitor duvelisib extended survival. The depletion of macrophages in vivo antagonized mAb208 efficacy. CONCLUSIONS: Our findings suggest the potential benefit of a broader treatment strategy combining therapeutic antibodies with PI3Ki for the treatment of patients with mature T-cell and NK-cell neoplasms. See related commentary by Varma and Diefenbach, p. 2300.

Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease.

Importance: Increased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors. Objective: To estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes. Design, Setting, and Participants: This cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers-the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer's Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019). Main Outcome and Measures: The main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH. Results: Data from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = -3.1 [P = .002]; ADNI: t = -5.6 [P < .001]; HABS: t = -2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001). Conclusions and Relevance: The findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Left ventricular hypertrophy and left atrial size are associated with ischemic strokes among non-vitamin K antagonist oral anticoagulant users.

BACKGROUND: Ischemic strokes (IS) occurring in patients taking non-vitamin K antagonist oral anticoagulants (NOACs) are becoming increasingly more frequent. We aimed to determine the clinical, echocardiographic, and neuroimaging markers associated with developing IS in patients taking NOACs for atrial fibrillation. METHODS: From a quaternary care center, clinical/radiologic data were collected from consecutive NOAC users with IS and age-matched controls without IS. Brain MRIs were reviewed for markers of cerebral small vessel disease. Variables with significant differences between groups were entered into a multivariable regression model to determine predictors of IS. Among IS patients, a Cox regression analysis was constructed to determine predictors of IS recurrence during follow-up. RESULTS: 112 patients with IS and 94 controls were included in the study. Variables significantly different between groups included apixaban use, dabigatran use, prior cerebrovascular events, hemoglobin A1c (HbA1c), left ventricular hypertrophy, left atrial volume index, and severe white matter hyperintensities. After multivariable adjustment, prior cerebrovascular events (aOR 23.86, 95% CI [6.02-94.48]), HbA1c levels (aOR 2.36, 95% CI [1.39-3.99]), left ventricular hypertrophy (aOR 2.73, 95% CI [1.11-6.71]) and left atrial volume index (aOR 1.05, 95% CI [1.01-1.08]) increased the risk of stroke, whereas apixaban use appeared to decrease the risk (aOR 0.38, 95% CI [0.16-0.92]). Malignancy was associated with IS recurrence (aHR 4.90, 95% CI [1.35-18.42]) after adjustment for age and chronic renal failure. CONCLUSIONS: Prior cerebrovascular events, diabetes, left ventricular hypertrophy, and increased left atrial size are risk factors for developing an IS among NOAC users.

Imaging With PET/CT of Diffuse CD8 T-Cell Infiltration of Skeletal Muscle in Patients With Inclusion Body Myositis.

BACKGROUND AND OBJECTIVES: Inclusion body myositis (IBM) is a progressive autoimmune skeletal muscle disease in which cytotoxic CD8+ T cells infiltrate muscle and destroy myofibers. IBM has required a muscle biopsy for diagnosis. Here, we administered to patients with IBM a novel investigational PET tracer 89Zr-Df-crefmirlimab for in vivo imaging of whole body skeletal muscle CD8 T cells. This technology has not previously been applied to patients with autoimmune disease. METHODS: Four patients with IBM received 89Zr-Df-crefmirlimab followed by PET/CT imaging 24 hours later, and the results were compared with similar imaging of age-matched patients with cancer. Mean standardized uptake value (SUVmean) was measured for reference tissues using spherical regions of interest (ROIs). RESULTS: 89Zr-Df-crefmirlimab was safe and well-tolerated. PET imaging demonstrated diffusely increased uptake qualitatively and quantitatively in IBM limb musculature. Quantitation of 89Zr-Df-crefmirlimab intensity in ROIs demonstrated particularly increased CD8 T-cell infiltration in patients with IBM compared with patients with cancer in quadriceps (SUVmean 0.55 vs 0.20, p < 0.0001), biceps brachii (0.62 vs 0.26, p < 0.0001), triceps (0.61 vs 0.25, p = 0.0005), and forearm finger flexors (0.71 vs 0.23, p = 0.008). DISCUSSION: 89Zr-Df-crefmirlimab uptake in muscles of patients with IBM was present at an intensity greater than the comparator population. The ability to visualize whole body in vivo cytotoxic T-cell tissue infiltration in the autoimmune disease IBM may hold utility as a biomarker for diagnosis, disease activity, and therapeutic development and potentially be applicable to other diseases with cytotoxic T-cell autoimmunity.

A Retrospective Pilot Comparison Trial Investigating Clinical Outcomes in Cardiac Surgical Patients Who Received Sugammadex Reversal During 2018 to 2021.

OBJECTIVES: To compare the number of eligible urgent and elective cardiac surgical patients who could be extubated successfully within 6 hours of surgery and who received sugammadex versus those who did not. DESIGN: This retrospective pilot study compared outcomes in cardiac surgical patients undergoing cardiopulmonary bypass between 2018 to 2021 who received sugammadex versus those who did not. SETTING: At a tertiary-care hospital in the Northshore of Chicago. PARTICIPANTS: A total of 358 elective or urgent cardiac surgical patients who underwent cardiopulmonary bypass (by 1 cardiac surgeon) and were extubated within 24 hours of the end of surgery at Evanston Hospital in Evanston, IL, were included. INTERVENTIONS: Data were examined in the following 2 groups of patients: those who were administered sugammadex and those who were not. MEASUREMENTS AND MAIN RESULTS: After performing propensity matching for age, sex, body mass index, kidney or liver disease, the number of preoperative conditions (defined as the sum of the presence of the following medical conditions: diabetes, immunosuppressive disease, on home oxygen, on inhaled bronchodilator, or sleep apnea), number of patients who underwent elective or urgent surgery in each group, surgery time, cardiopulmonary bypass duration, number of intraoperative blood products, use of intraoperative midazolam and propofol, a statistically significant increase in the percentage of patients in the sugammadex group were extubated within 6 hours of the end of surgery versus those who did not receive sugammadex (96.67% v 81.33%, p = 0.0428). In addition, there was a statistically significant reduction in time to extubation (hours) (4.72 ± 2.92) v (3.57± 1.96 p = 0.0098) in the sugammadex group. All other outcomes did not meet statistical significance. CONCLUSION: This retrospective study suggested that using sugammadex reversal in cardiac surgical patients undergoing cardiopulmonary bypass may result in more patients meeting the Society of Thoracic Surgery benchmark extubation criteria within 6 hours of the end of surgery.

Decreased ratios of matrix metalloproteinases to tissue-type inhibitors in cerebrospinal fluid in sporadic and hereditary cerebral amyloid angiopathy.

BACKGROUND: To evaluate the potential of cerebrospinal fluid (CSF) levels of matrix metalloproteinases and tissue-type inhibitors (MMP; TIMP), and ratios of MMPs to TIMPs, to function as biomarkers for sporadic or hereditary cerebral amyloid angiopathy (CAA). METHODS: CSF concentrations of the matrix metalloproteinases MMP-2, MMP-9 and MMP-14, as well as the tissue inhibitors of metalloproteinases TIMP-1, TIMP-2 and TIMP-3, were determined using immunoassays. These assays were applied to two, independent study groups of sporadic CAA (sCAA) (n = 28/43) and control subjects (n = 40/40), as well as to groups of pre-symptomatic (n = 11) and symptomatic hereditary Dutch-CAA (D-CAA) patients (n = 12), and age-matched controls (n = 22/28, respectively). RESULTS: In the sCAA/control cohorts, inconsistent differences were found for individual MMPs and TIMPs, but MMP-2/TIMP-2 (discovery/validation: p = 0.004; p = 0.02) and MMP-14/TIMP-2 ratios (discovery/validation: p < 0.001; p = 0.04) were consistently decreased in sCAA, compared to controls. Moreover, MMP-14 was decreased in symptomatic D-CAA (p = 0.03), compared to controls. The MMP-14/TIMP-1 (p = 0.03) and MMP-14/TIMP-2 (p = 0.04) ratios were decreased in symptomatic D-CAA compared to controls and also compared to pre-symptomatic D-CAA (p = 0.004; p = 0.005, respectively). CONCLUSION: CSF MMP-2/TIMP-2 and MMP-14/TIMP-2 were consistently decreased in sCAA, compared to controls. Additionally, MMP-14/TIMP-2 levels were also decreased in symptomatic D-CAA, compared to both pre-symptomatic D-CAA and controls, and can therefore be considered a biomarker for sporadic and late-stage hereditary forms of CAA.

Decreased Cerebrospinal Fluid Amyloid ß 38, 40, 42, and 43 Levels in Sporadic and Hereditary Cerebral Amyloid Angiopathy.

OBJECTIVE: Vascular amyloid ß (Aß) accumulation is the hallmark of cerebral amyloid angiopathy (CAA). The composition of cerebrospinal fluid (CSF) of CAA patients may serve as a diagnostic biomarker of CAA. We studied the diagnostic potential of the peptides Aß38, Aß40, Aß42, and Aß43 in patients with sporadic CAA (sCAA), hereditary Dutch-type CAA (D-CAA), and Alzheimer disease (AD). METHODS: Aß peptides were quantified by immunoassays in a discovery group (26 patients with sCAA and 40 controls), a validation group (40 patients with sCAA, 40 patients with AD, and 37 controls), and a group of 22 patients with D-CAA and 54 controls. To determine the diagnostic accuracy, the area under the curve (AUC) was calculated using a receiver operating characteristic curve with 95% confidence interval (CI). RESULTS: We found decreased levels of all Aß peptides in sCAA patients and D-CAA patients compared to controls. The difference was most prominent for Aß42 (AUC of sCAA vs controls for discovery: 0.90, 95% CI = 0.82-0.99; for validation: 0.94, 95% CI = 0.89-0.99) and Aß43 (AUC of sCAA vs controls for discovery: 0.95, 95% CI = 0.88-1.00; for validation: 0.91, 95% CI = 0.83-1.0). All Aß peptides except Aß43 were also decreased in sCAA compared to AD (CSF Aß38: AUC = 0.82, 95% CI = 0.71-0.93; CSF Aß40: AUC = 0.88, 95% CI = 0.80-0.96; CSF Aß42: AUC = 0.79, 95% CI = 0.66-0.92). INTERPRETATION: A combined biomarker panel of CSF Aß38, Aß40, Aß42, and Aß43 has potential to differentiate sCAA from AD and controls, and D-CAA from controls. ANN NEUROL 2023;93:1173-1186.

Sex Differences in Onset and Progression of Cerebral Amyloid Angiopathy.

BACKGROUND: Cerebral Amyloid Angiopathy (CAA) disease course is highly variable even in hereditary forms. Sex may be a possible modifying factor. We investigated biological sex differences in clinical disease course and magnetic resonance imaging-markers in sporadic (sCAA) and Dutch-type hereditary CAA (D-CAA). METHODS: Patients with D-CAA and sCAA were included from hospital and research databases of the Leiden University Medical Center (2012-2020) and Massachusetts General Hospital (1994-2012). Key outcomes were: sex differences in symptomatic intracerebral hemorrhage (sICH) onset, recurrence and survival (analyzed using Kaplan Meier survival and regression analyses), and sex differences in magnetic resonance imaging-markers in D-CAA (explored using scatterplots), and in sCAA (investigated using regression analysis). RESULTS: We included 136 patients with D-CAA (mean age 57 years, 56% women, 64% with previous sICH) and 370 patients with sCAA (mean age 76 years, 51% women, all with previous sICH). Men and women with D-CAA did not differ for sICH onset (median age 54 in men and 56 in women [P=0.13]). Men with D-CAA had a slightly higher number of sICH compared with women (median 2 versus 1; adjusted RR, 1.5 [95% CI, 1.1-1.9]) and a shorter interval between the first and second sICH (median 1.8 years for men and 3.1 years for women, P=0.02). Men with sCAA had their first sICH at an earlier age (median 75 versus 78 years, respectively, P=0.003) and more lobar microbleeds (median 1 versus 0, P=0.022) compared with women with sCAA. No substantial differences were found in the other magnetic resonance imaging markers. Survival after first sICH was comparable between sexes for D-CAA (P=0.12) and sCAA (P=0.23). CONCLUSIONS: Men with CAA seem to have an earlier onset (sCAA) and more hemorrhagic disease course (sCAA and D-CAA) compared with women. Future studies are necessary to confirm these findings and determine the underlying role of sex-related factors.

A Causal Classification System for Intracerebral Hemorrhage Subtypes.

OBJECTIVE: Determining the underlying causes of intracerebral hemorrhage (ICH) is of major importance, because risk factors, prognosis, and management differ by ICH subtype. We developed a new causal CLASsification system for ICH Subtypes, termed CLAS-ICH, based on recent advances in neuroimaging. METHODS: CLAS-ICH defines 5 ICH subtypes: arteriolosclerosis, cerebral amyloid angiopathy, mixed small vessel disease (SVD), other rare forms of SVD (genetic SVD and others), and secondary causes (macrovascular causes, tumor, and other rare causes). Every patient is scored in each category according to the level of diagnostic evidence: (1) well-defined ICH subtype; (2) possible underlying disease; and (0) no evidence of the disease. We evaluated CLAS-ICH in a derivation cohort of 113 patients with ICH from Massachusetts General Hospital, Boston, USA, and in a derivation cohort of 203 patients from Inselspital, Bern, Switzerland. RESULTS: In the derivation cohort, a well-defined ICH subtype could be identified in 74 (65.5%) patients, including 24 (21.2%) with arteriolosclerosis, 23 (20.4%) with cerebral amyloid angiopathy, 18 (15.9%) with mixed SVD, and 9 (8.0%) with a secondary cause. One or more possible causes were identified in 42 (37.2%) patients. Interobserver agreement was excellent for each category (kappa value ranging from 0.86 to 1.00). Despite substantial differences in imaging modalities, we obtained similar results in the validation cohort. INTERPRETATION: CLAS-ICH is a simple and reliable classification system for ICH subtyping, that captures overlap between causes and the level of diagnostic evidence. CLAS-ICH may guide clinicians to identify ICH causes, and improve ICH classification in multicenter studies. ANN NEUROL 2023;93:16-28.

External ventricular drain placement is associated with lower mortality after intracerebral hemorrhage with intraventricular hemorrhage.

BACKGROUND AND AIMS: Many patients with intracerebral hemorrhage (ICH) develop intraventricular hemorrhage (IVH), which is associated with higher mortality and worse clinical outcome. External ventricular drains (EVDs) are often placed, but there is little data on how much patients benefit from this intervention. We explored the use, timing, and location of EVD in ICH patients and any association with clinical outcome. RESULTS: During the study period, 2870 patients presented with primary ICH, and 2486 were included in analyses. Overall, patients were 73 (± 13) years old; 54% were male, and 46% had associated IVH. An EVD was placed in 29% of patients with IVH and 4% of those without. IVH patients with EVD were younger (67 ± 13 vs 74 ± 13, p < 0.001), had larger IVH volumes (17 mL vs 8 mL, p < 0.001), and lower GCS scores (7 vs 10, p < 0.001), compared to those without EVD. Ninety-day mortality was available in 2486 (100%) patients, while 90-day mRS was available in 1673 (67.3%). In univariate analysis, EVD placement was associated with lower likelihood of 90-day mortality (53% vs 59%, p = 0.048) but higher likelihood of poor outcome (88% vs 85%, p < 0.001) in those for whom this was available. Those with poor outcomes underwent faster EVD placement (0.46 days vs. 0.96 days, p = 0.01). In multivariate analysis, EVD placement was associated with lower 90-day mortality (OR 0.19, 95% CI 0.053-0.657, p = 0.009), but not with lower odds of poor outcome (OR 1.64, 95% CI 0.508-5.309, p = 0.4). In multivariate analysis, days to EVD placement was associated with lower 90-day mortality (OR 0.69, 95% CI 0.49-0.96, p = 0.027). CONCLUSION: IVH is relatively common after ICH. After controlling for potential confounds, EVD placement is associated with lower mortality, but not clearly with better neurologic outcome. In addition, more rapid EVD placement is associated with higher mortality, potentially reflecting early development of herniation or obstructive hydrocephalus.

Brain Deep Medullary Veins on 7T MRI in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.

BACKGROUND: Deep medullary vein (DMV) changes occur in cerebral small vessel diseases (SVD) and in Alzheimer's disease. Cerebral amyloid angiopathy (CAA) is a common SVD that has a high co-morbidity with Alzheimer's disease. So far, DMVs have not been evaluated in CAA. OBJECTIVE: To evaluate DMVs in Dutch-type hereditary CAA (D-CAA) mutation carriers and controls, in relation to MRI markers associated with D-CAA. METHODS: Quantitative DMV parameters length, tortuosity, inhomogeneity, and density were quantified on 7 Tesla 3D susceptibility weighted MRI in pre-symptomatic D-CAA mutation carriers (n = 8), symptomatic D-CAA mutation carriers (n = 8), and controls (n = 25). Hemorrhagic MRI markers (cerebral microbleeds, intracerebral hemorrhages, cortical superficial siderosis, convexity subarachnoid hemorrhage), non-hemorrhagic MRI markers (white matter hyperintensities, enlarged perivascular spaces, lacunar infarcts, cortical microinfarcts), cortical grey matter perfusion, and diffusion tensor imaging parameters were assessed in D-CAA mutation carriers. Univariate general linear analysis was used to determine associations between DMV parameters and MRI markers. RESULTS: Quantitative DMV parameters length, tortuosity, inhomogeneity, and density did not differ between pre-symptomatic D-CAA mutation carriers, symptomatic D-CAA mutation carriers, and controls. No associations were found between DMV parameters and MRI markers associated with D-CAA. CONCLUSION: This study indicates that vascular amyloid-ß deposition does not affect DMV parameters. In patients with CAA, DMVs do not seem to play a role in the pathogenesis of MRI markers associated with CAA.

Clinical and neuroimaging risk factors associated with the development of intracerebral hemorrhage while taking direct oral anticoagulants.

BACKGROUND AND AIMS: Intracerebral hemorrhage (ICH) associated with direct oral anticoagulant (DOAC) usage confers significant mortality/disability. We aimed to understand the clinical and neuroimaging features associated with developing ICH among DOAC users. METHODS: Clinical and radiological data were collected from consecutive DOAC users with ICH (DOAC-ICH) and age-matched controls without ICH from a single referral center. The frequency/distribution of MRI markers of hemorrhage risk were assessed. Baseline demographics and neuroimaging markers were compared in univariate tests. Significant associations (p < 0.1) were entered into a multivariable regression model to determine predictors of ICH. RESULTS: 86 DOAC-ICH and 94 ICH-free patients were included. Diabetes, coronary artery disease, prior ischemic stroke, smoking history, and antiplatelet usage were more common in ICH patients than ICH-free DOAC users. In the neuroimaging analyses, severe white matter hyperintensities (WMHs), lacunes, cortical superficial siderosis (cSS), and cerebral microbleeds (CMBs) were more common in the ICH cohort than the ICH-free cohort. In the multivariable regression, diabetes [OR 3.53 95% CI (1.05-11.87)], prior ischemic stroke [OR 14.80 95% CI (3.33-65.77)], smoking history [OR 3.08 95% CI (1.05-9.01)], CMBs [OR 4.07 95% CI (1.45-11.39)], and cSS [OR 39.73 95% CI (3.43-460.24)] were independently associated with ICH. CONCLUSIONS: Risk factors including diabetes, prior stroke, and smoking history as well as MRI biomarkers including CMBs and cSS are associated with ICH in DOAC users. Although screening MRIs are not typically performed prior to initiating DOAC therapy, these data suggest that patients of high-hemorrhagic risk may be identified.

Forkhead box O3 longevity genotype may attenuate the impact of hypertension on risk of intracerebral haemorrhage.

OBJECTIVE: Since the G allele of forkhead box O3 ( FOXO3 ) single nucleotide polymorphism (SNP) rs2802292 is associated with resilience and longevity, ostensibly by mitigating the adverse effects of chronic cardiometabolic stress on mortality, our aim was to determine the association between the FOXO3 SNP rs2802292 genotype and risk of hypertension-mediated intracerebral haemorrhage (ICH). METHODS: From a prospective population-based cohort of Japanese American men from the Kuakini Honolulu Heart Program (KHHP), age-adjusted prevalence of ICH by hypertension was assessed for the whole cohort after stratifying by FOXO3 genotype. Cox regression models, adjusted for age, cardiovascular risk factors and, FOXO3 and APOE genotypes, were utilized to determine relative risk of hypertension's effect on ICH. All models were created for the whole cohort and stratified by FOXO3 G -allele carriage vs. TT genotype. RESULTS: Among 6469 men free of baseline stroke, FOXO3 G -allele carriage was seen in 3009 (46.5%) participants. Overall, 183 participants developed ICH over the 34-year follow-up period. Age-adjusted ICH incidence was 0.90 vs. 1.32 per 1000 person-years follow-up in those without and with hypertension, respectively ( P  = 0.002). After stratifying by FOXO3 genotype, this association was no longer significant in G allele carriers. In the whole cohort, hypertension was an independent predictor of ICH (relative risk [RR] = 1.70, 95% confidence interval [CI] 1.25, 2.32; P  = 0.0007). In stratified analyses, hypertension remained an independent predictor of ICH among the FOXO3 TT -genotype group (RR = 2.02, 95% CI 1.33, 3.07; P  = 0.001), but not in FOXO3 G -allele carriers (RR = 1.39, 95% CI 0.88, 2.19; P  = 0.15). CONCLUSIONS: The longevity-associated FOXO3   G allele may attenuate the impact of hypertension on ICH risk.

Infiltration of Mature KLRG1 Expressing Cytotoxic T Cells in Oral Lichen Planus.

BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disease affecting oral mucosa. Its pathogenesis includes T cell infiltration. T cells may be naïve or in response to antigen stimulation, progress through differentiation stages. The differentiated states of T cells in OLP mucosa have not previously been reported. METHODS: Available OLP microarray gene expression data from Gene Expression Omnibus were analyzed for markers of T cell cytotoxicity. Immunohistochemical studies of T cell subset markers CD4 and CD8 and the T cell differentiation marker killer cell lectin-like receptor G1 (KLRG1) were performed on paraffin embedded formalin fixed oral mucosa biopsy samples from 10 patients with OLP. RESULTS: Gene expression analysis of OLP oral mucosa samples disclosed increased transcript expression of KLRG1, CD8A, and granzyme K (GZMK). By immunohistochemistry, prominent CD4 + and CD8 + T cell infiltration was seen in all patient samples. KLRG1 + T cells were abundant, constituting a mean of 51% (range 40-65%) of the number of CD8 + T cells. KLRG1 + T cells localized at the epithelium and lamina propria junction, infiltrating both basal and intraepithelial regions and adjacent to both basal and intraepithelial keratinocytes. CONCLUSIONS: OLP oral mucosa T cell infiltration includes KLRG1 + highly differentiated cytotoxic T cells, suggesting continued antigen exposure driving T cells to a highly differentiated phenotype. The known phenotype of these cells, together with microarray detected increases in cytotoxic molecules, suggests that highly differentiated cytotoxic T cells contribute to oral mucosa injury in OLP.

Longitudinal Progression of Magnetic Resonance Imaging Markers and Cognition in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.

BACKGROUND: Hemorrhagic and ischemic magnetic resonance imaging lesions as well as the more recently described decrease in vasomotor reactivity have been suggested as possible biomarkers for cerebral amyloid angiopathy (CAA). Analyses of these markers have been primarily cross-sectional during the symptomatic phase of the disease, with little data on their longitudinal progression, particularly in the presymptomatic phase of the disease when it may be most responsive to treatment. We used the unique opportunity provided by studying Dutch-type hereditary cerebral amyloid angiopathy (D-CAA) to determine longitudinal progression of CAA biomarkers during the presymptomatic as well as the symptomatic phase of the disease. METHODS: In this longitudinal case-control study, magnetic resonance imaging markers and cognitive performance were assessed at baseline and after ≈4 years in 10 presymptomatic and 6 symptomatic D-CAA mutation carriers and 20 control subjects. These magnetic resonance imaging markers included hemorrhagic and ischemic manifestations, measurements of cerebral blood flow, and vasomotor reactivity to visual stimulation. RESULTS: In presymptomatic D-CAA mutations carriers, vasomotor reactivity showed a decline over time for blood-oxygen-level-dependent amplitude (P=0.011) and prolongation of time to peak (P<0.001). In contrast, no significant changes in hemorrhagic markers, ischemic markers, cerebral blood flow, and cognition were found. In symptomatic D-CAA mutation carriers, the number of intracerebral hemorrhages increased over the 4-year period (P=0.007). CONCLUSIONS: Our findings indicate that in the presymptomatic phase of D-CAA, cerebrovascular reactivity measured by the blood-oxygen-level-dependent amplitude and time to peak to visual stimulation progressively worsens and can thus be regarded as a disease progression marker. In the symptomatic phase, the most salient marker of progression appears to be recurrent intracerebral hemorrhage.

Vascular Contributions to Brain Health: Cross-Cutting Themes.

As life expectancy grows, brain health is increasingly seen as central to what we mean by successful aging-and vascular brain health as central to overall brain health. Cerebrovascular pathologies are highly prevalent independent contributors to age-related cognitive impairment and at least partly modifiable with available treatments. The current Focused Update addresses vascular brain health from multiple angles, ranging from pathophysiologic mechanisms and neuroimaging features to epidemiologic risk factors, social determinants, and candidate treatments. Here we highlight some of the shared themes that cut across these distinct perspectives: (1) the lifetime course of vascular brain injury pathogenesis and progression; (2) the scientific and ethical imperative to extend vascular brain health research in non-White and non-affluent populations; (3) the need for improved tools to study the cerebral small vessels themselves; (4) the potential role for brain recovery mechanisms in determining vascular brain health and resilience; and (5) the cross-pathway mechanisms by which vascular and neurodegenerative processes may interact. The diverse perspectives featured in this Focused Update offer a sense of the multidisciplinary approaches and collaborations that will be required to launch our populations towards improved brain health and successful aging.

Effect of vascular amyloid on white matter disease is mediated by vascular dysfunction in cerebral amyloid angiopathy.

We postulated that vascular dysfunction mediates the relationship between amyloid load and white matter hyperintensities (WMH) in cerebral amyloid angiopathy (CAA). Thirty-eight cognitively healthy patients with CAA (mean age 70 ± 7.1) were evaluated. WMH was quantified and expressed as percent of total intracranial volume (pWMH) using structural MRI. Mean global cortical Distribution Volume Ratio representing Pittsburgh Compound B (PiB) uptake (PiB-DVR) was calculated from PET scans. Time-to-peak [TTP] of blood oxygen level-dependent response to visual stimulation was used as an fMRI measure of vascular dysfunction. Higher PiB-DVR correlated with prolonged TTP (r = 0.373, p = 0.021) and higher pWMH (r = 0.337, p = 0.039). Prolonged TTP also correlated with higher pWMH (r = 0.485, p = 0.002). In a multivariate linear regression model, TTP remained independently associated with pWMH (p = 0.006) while PiB-DVR did not (p = 0.225). In a bootstrapping model, TTP had a significant indirect effect (ab = 0.97, 95% CI: 0.137-2.461), supporting that the association between PiB-DVR and pWMH is mediated by TTP response. There was no longer a direct effect independent of the hypothesized pathway. Our study suggests that the effect of vascular amyloid load on white matter disease is mediated by vascular dysfunction in CAA. Amyloid lowering strategies might prevent pathophysiological processes leading to vascular dysfunction, therefore limiting ischemic brain injury.