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Aims To determine if medium- and long-term blood glucose control as well as glycemic variability, which are known to be strong predictors of vascular complications, are associated with underlying cerebral small vessel disease (cSVD) in neurologically asymptomatic individuals with type 1 diabetes. Methods A total of 189 individuals (47.1% men; median age 40.0, IQR 33.0–45.2 years) with type 1 diabetes (median diabetes duration of 21.7, IQR 18.3–30.7 years) were enrolled in a cross-sectional retrospective study, as part of the Finnish Diabetic Nephropathy (FinnDiane) Study. Glycated hemoglobin (HbA1c) values were collected over the course of ten years before the visit including a clinical examination, biochemical sampling, and brain magnetic resonance imaging. Markers of glycemic control, measured during the visit, included HbA1c, fructosamine, and glycated albumin. Results Signs of cSVD were present in 66 (34.9%) individuals. Medium- and long-term glucose control and glycemic variability did not differ in individuals with signs of cSVD compared to those without. Further, no difference in any of the blood glucose variables and cSVD stratified for cerebral microbleeds (CMBs) or white matter hyperintensities were detected. Neither were numbers of CMBs associated with the studied glucose variables. Additionally, after dividing the studied variables into quartiles, no association with cSVD was observed. Conclusions We observed no association between glycemic control and cSVD in neurologically asymptomatic individuals with type 1 diabetes. This finding was unexpected considering the large number of signs of cerebrovascular pathology in these people after two decades of chronic hyperglycemia and warrants further studies searching for underlying factors of cSVD.

Background: Community pharmacy staff in rural and remote areas need to have the skills to recognise mental health signs and symptoms, provide support and appropriate advice. Aims: To evaluate the impact of Mental Health First Aid (MHFA) training through collaborative sessions attended by pharmacy staff and community members. Methods: Pharmacy staff, alongside members of the local farming community, attended collaborative MHFA training in four Queensland towns. This study evaluated the training through pre- and post-training questionnaires and email feedback following practice application of skills. Results: Thirty-two pharmacy staff and 14 community members participated in both pre- and post- questionnaires; 10 males and 36 females varying in age between 18 and 65 with the majority (26, 72.2%) aged 30–49 years. Participants’ understanding of the need to ask a person directly about suicide changed significantly through the training. The pre-and post-course surveys demonstrated a difference in knowledge of both the consumers and pharmacy staff members. Community members’ perception about how pharmacy staff can assist with mental health issues changed significantly and pharmacy staff reported an increase in confidence to approach consumers regarding their mental health. Qualitative feedback from consumers and pharmacy staff 8–12 weeks following the training was positive. Conclusion: Pharmacy staff members are well placed to provide mental health support to farming communities. A collaborative mental health training approach in rural and remote areas that involved pharmacy staff and local community members showed improved knowledge, skills and collaboration between staff and consumers. This approach could easily be adapted to other contexts.

IntroductionCerebral small-vessel disease is common in neurologically asymptomatic individuals with type 1 diabetes. The retinal vasculature is thought to mirror the brain’s vasculature, but data on this association are limited in type 1 diabetes. Our aim was to study associations between diabetic retinopathy severity and cerebral small-vessel disease in type 1 diabetes.Research design and methodsFor this cross-sectional study, we enrolled 189 participants with type 1 diabetes (median age 40 (33–45) years; 53% female; diabetes duration 21.6 (18.2–30.7) years) and 29 healthy age-matched and sex-matched controls as part of the Finnish Diabetic Nephropathy Study. Participants underwent a clinical investigation, brain MRI, and fundus imaging. Signs of cerebral small-vessel disease in brain MRIs were analyzed in relation to diabetic retinopathy severity (Early Treatment Diabetic Retinopathy Study (ETDRS) score).ResultsIn type 1 diabetes, participants with cerebral small-vessel disease had higher ETDRS scores (35 (20–61) vs 20 (20–35), p=0.022) and a higher prevalence of proliferative diabetic retinopathy than those without cerebral small-vessel disease (25% vs 9%, p=0.002). In adjusted analysis, proliferative diabetic retinopathy was associated with cerebral small-vessel disease (OR 2.57 (95% CI 1.04 to 6.35)). Median ETDRS score (35 (20–65) vs 20 (20–35), p=0.024) and proliferative diabetic retinopathy prevalence were higher (29% vs 13%, p=0.002) in participants with versus without cerebral microbleeds. ETDRS scores increased by number of cerebral microbleeds (p=0.001), both ETDRS score (OR 1.05 (95% CI 1.02 to 1.09)) and proliferative diabetic retinopathy (8.52 (95% CI 1.91 to 37.94)) were associated with >2 cerebral microbleeds in separate multivariable analysis. We observed no association with white matter hyperintensities or lacunar infarcts.ConclusionsPresence of cerebral small-vessel disease on brain MRI, particularly cerebral microbleeds, is associated with the severity of diabetic retinopathy.

Although vascular complications are a hallmark of diabetes, cerebral small-vessel disease (cSVD) in type 1 diabetes remains scarcely studied. We recently showed that cSVD is more common in individuals with type 1 diabetes than healthy control subjects and is associated with systolic office blood pressure (BP) (1). Hence, we aimed to further evaluate the impact of BP on cSVD in type 1 diabetes. This substudy of the Finnish Diabetic Nephropathy (FinnDiane) Study aims to assess early markers of cerebrovascular disease in people with type 1 diabetes and has previously been described in detail (1). Of the 191 neurologically asymptomatic study participants, 73 volunteered for a 24-h ambulatory BP monitoring (ABPM). All participants underwent a clinical study visit, and brain MRI assessed for markers of cSVD (white matter hyperintensities, lacunar infarcts, and cerebral microbleeds) (1,2). The 24-h ABPM was conducted in accordance with current standards (3). After ABPM-quality validation, we calculated average BP, mean arterial pressure (two-thirds of diastolic + one-third of systolic BP), pulse pressure (PP) (systolic − diastolic BP), BP variability (average real variability), and nocturnal dipping ([1 − nocturnal systolic / diurnal systolic BP] × 100%). Elevated BP and masked hypertension were defined as described by the European Society of Hypertension (3). We observed cSVD in 20 (27.4%) participants, of whom 14 had cerebral microbleeds, 9 white matter hyperintensities, and 2 lacunes. Table 1 includes clinical characteristics as well as main results for BP measurements based on presence or absence …

Background: Brain metal homeostasis is essential for brain health, and deregulation can result in oxidative stress on the brain parenchyma. Objective: Our objective in this study was to focus on two hemorrhagic MRI manifestations of small vessel disease [cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS)] and associations with cerebrospinal fluid (CSF) iron levels. In addition, we aimed to analyze CSF biomarkers for dementia and associations with CSF metal levels. Methods: This is a cross-sectional study of 196 patients who underwent memory clinic investigation, including brain MRI. CSF was collected and analyzed for metals, amyloid-β (Aβ) 42, total tau (T-tau), and phosphorylated tau (P-tau), and CSF/serum albumin ratios. Statistical analyses were performed using generalized linear models. Results: No significant difference was found between CSF metal levels across diagnostic groups. Higher iron and copper levels were associated with higher CSF levels of Aβ42, T-tau, P-tau, and CSF/serum albumin ratios (p

To investigate the long-term progression of cognitive dysfunction and its neuroanatomical correlates and predictors in multiple sclerosis (MS).A cohort of 37 MS patients reflecting five decades of disease duration and all subtypes was followed over 17.5 years. Matched controls were recruited at the last follow-up. Global cognitive functioning was assessed using a principal component cognitive index based on comprehensive neuropsychological testing. During the last 8.5 years of the study, brain MRI was performed to analyze normalized volumetrics of three global tissue compartments (white and gray matter, lesions) and strategic regions (corpus callosum, thalamus, hippocampus).Cognitive decline progressed continuously throughout the study paralleled by atrophy and lesion accumulation. The cognitive index partly correlated with Expanded Disability Status Scale (ρ = -0.47, p 0.001) and was mainly associated with the lesion fraction (β = -0.48, p 0.001) and callosal fraction (β = 0.39, p = 0.002) in multiple linear regression analysis. The lesion fraction was an independent predictor of the cognitive performance 8.5 years later (β = -0.35, p = 0.008). Symbol Digit Modalities Test was most frequently abnormal (40%), while Rey-Osterrieth Complex Figure Test was more sensitive to detect cognitive decline.Cognitive impairment progresses continuously in MS, associated with atrophy and lesion accumulation, suggesting that interventions targeting these processes could be beneficial at all disease stages. Widespread cognitive functions are more profoundly affected, associated with lesions and corpus callosal atrophy, supporting the idea of an underlying disconnection mechanism for cognitive decline in MS.

BACKGROUND AND PURPOSE: There are, to date, no MR imaging diagnostic markers for Lewy body dementia. Nigrosome 1, containing dopaminergic cells, in the substantia nigra pars compacta is hyperintense on SWI and has been called the swallow tail sign, disappearing with Parkinson disease. We aimed to study the swallow tail sign and its clinical applicability in Lewy body dementia and hypothesized that the sign would be likewise applicable in Lewy body dementia. MATERIALS AND METHODS: This was a retrospective cross-sectional multicenter study including 97 patients (mean age, 65 ± 10 years; 46% women), consisting of the following: controls (n = 21) and those with Lewy body dementia (n = 19), Alzheimer disease (n = 20), frontotemporal lobe dementia (n = 20), and mild cognitive impairment (n = 17). All patients underwent brain MR imaging, with susceptibility-weighted imaging at 1.5T (n = 46) and 3T (n = 51). The swallow tail sign was assessed independently by 2 neuroradiologists. RESULTS: Interrater agreement was moderate (κ = 0.4) between raters. An abnormal swallow tail sign was most common in Lewy body dementia (63%; 95% CI, 41%–85%; P < .001) and had a predictive value only in Lewy body dementia with an odds ratio of 9 (95% CI, 3–28; P < .001). The consensus rating for Lewy body dementia showed a sensitivity of 63%, a specificity of 79%, a negative predictive value of 89%, and an accuracy of 76%; values were higher on 3T compared with 1.5T. The usefulness of the swallow tail sign was rater-dependent with the highest sensitivity equaling 100%. CONCLUSIONS: The swallow tail sign has diagnostic potential in Lewy body dementia and may be a complement in the diagnostic work-up of this condition.

Introduction Whether ischaemic stroke patients with atrial fibrillation (AF) and cerebral microbleeds (CMBs) on MRI can be safely anticoagulated is a hotly debated topic. We performed a systematic review and meta-analysis of published aggregate data, to investigate the risk of subsequent intracerebral haemorrhage (ICH) based on CMBs presence in this stroke population, generally considered for oral anticoagulation. We also suggest a decision-making schema for anticoagulation use in this setting. Methods We searched PubMed for relevant observational studies. Random effects models with DerSimonian-Laird weights were used to investigated the association between CMBs presence at baseline MRI and ICH or ischaemic stroke during follow-up. Results Four studies, with slightly heterogeneous design, including 990 ischaemic stroke patients were pooled in a meta-analysis (crude CMBs prevalence: 25%; 95%CI: 17%–33%). The median follow-up ranged between 17 and 37 months. The future symptomatic ICH rate was 1.6% (16/990), while recurrent ischaemic stroke rate was 5.9% (58/990). Baseline CMB presence was associated with increased risk of symptomatic ICH during follow-up compared to patients without CMBs (OR: 4.16; 95%CI: 1.54–11.25; p = 0.005). There was no association between CMBs presence and recurrent ischaemic stroke risk. Conclusion We have shown that the presence of CMBs in cohorts of ischaemic stroke patients, most with AF on warfarin, is associated with a 4-fold increase in subsequent ICH (but not ischaemic stroke) risk (Class III evidence). These pooled estimates are useful for future trials design. We propose a simple data-driven anticoagulation schema which awaits validation and refinement as new prospective data are accumulated.

BACKGROUND AND PURPOSE: Gadolinium-based contrast agents have been associated with lasting high T1-weighted signal intensity in the dentate nucleus and globus pallidus, with histopathologically confirmed gadolinium retention. We aimed to longitudinally investigate the relationship of multiple gadolinium-based contrast agent administrations to the Signal Intensity Index in the dentate nucleus and globus pallidus and any associations with cognitive function in multiple sclerosis. MATERIALS AND METHODS: The Signal Intensity Index in the dentate nucleus and globus pallidus was retrospectively evaluated on T1-weighted MR imaging in an 18-year longitudinal cohort study of 23 patients with MS receiving multiple gadolinium-based contrast agent administrations and 23 healthy age- and sex-matched controls. Participants also underwent comprehensive neuropsychological testing. RESULTS: Patients with MS had a higher Signal Intensity Index in the dentate nucleus (P < .001), but not in the globus pallidus (P = .19), compared with non-gadolinium-based contrast agent–exposed healthy controls by an unpaired t test. Increasing numbers of gadolinium-based contrast agent administrations were associated with an increased Signal Intensity Index in the dentate nucleus (β = 0.45, P < .001) and globus pallidus (β = 0.60, P < .001). This association remained stable with corrections for the age, disease duration, and physical disability for both the dentate nucleus (β = 0.43, P = .001) and globus pallidus (β = 0.58, P < .001). An increased Signal Intensity Index in the dentate nucleus among patients with MS was associated with lower verbal fluency scores, which remained significant after correction for several aspects of disease severity (β = −0.40 P = .013). CONCLUSIONS: Our data corroborate previous reports of lasting gadolinium retention in brain tissues. An increased Signal Intensity Index in the dentate nucleus and globus pallidus was associated with lower verbal fluency, which does not prove causality but encourages further studies on cognition and gadolinium-based contrast agent administration.

Introduction: Thrombophilias are a known cause of acute ischemic stroke (AIS) in the young. We hypothesized that thrombophilias would be associated with an increased burden of chronic cerebrovascular disease in these patients. Methods: We included patients enrolled in the prospective Cornell AcutE Stroke Academic Registry (CAESAR) who were 18-65 years of age, diagnosed with AIS by brain MRI between 2011-2015, and had thrombophilia testing within 6 months of their stroke. The exposure variable was thrombophilia, defined as at least one positive thrombophilia test according to standard criteria. The primary outcome was the total Age-Related White Matter Changes (ARWMC) score (0-15). Secondary outcomes were the Fazekas score (0-3) and the number of chronic small vessel (subcortical) cerebral infarcts. Outcomes were determined by a single radiologist blinded to thrombophilia status using clinically-performed brain MRIs at the time of index stroke. Doubly robust estimator analyses were used to test the association between an underlying thrombophilia and outcomes. Models were adjusted for age, gender, race, and vascular risk factors. Results: Among 177 patients meeting eligibility criteria, mean age was 47 (SD, 10) years and 50% were women. Thrombophilia was detected in 77 patients (44%). The mean total ARWMC score, Fazekas score, and number of chronic small vessel infarcts were 1.90 (SD, 1.74), 0.91 (SD, 0.69), and 0.16 (SD, 0.63) in patients with thrombophilia and 2.16 (SD, 1.64), 1.07 (SD, 0.69) and 0.35 (SD, 0.81) in patients without thrombophilia. In multivariable analyses, there was no difference in the total ARWMC score (mean difference -0.05, 95% CI -0.43 to 0.33, p=0.80) or Fazekas score (mean difference -0.05, 95% CI -0.21 to 0.11, p=0.52) between patients with thrombophilia and those without. However, in multivariable analyses, the number of chronic infarcts (mean difference -0.22, 95% CI -0.42 to -0.01, p=0.01) was lower in patients with thrombophilia than in those without. Conclusions: In a single-center study of young adults with AIS, underlying thrombophilia was not associated with white matter disease burden. However, contrary to our hypothesis, it was inversely associated with the number of chronic small vessel infarcts.

Background and purpose: Degenerative change of the corpus callosum might serve as a clinically useful surrogate marker for net pathological cerebral impact of diabetes type 1. We compared manual and automatic measurements of the corpus callosum, as well as differences in callosal cross-sectional area between subjects with type 1 diabetes and healthy controls. Materials and methods: This is a cross-sectional study on 188 neurologically asymptomatic participants with type 1 diabetes and 30 healthy age- and sex-matched control subjects, recruited as part of the Finnish Diabetic Nephropathy Study. All participants underwent clinical work-up and brain MRI. Callosal area was manually measured and callosal volume quantified with FreeSurfer. The measures were normalized using manually measured mid-sagittal intracranial area and volumetric intracranial volume, respectively. Results: Manual and automatic measurements correlated well (callosal area vs. volume: rho = 0.83, p

ObjectiveTo assess potential mechanisms of cortical superficial siderosis (cSS), a central MRI biomarker in cerebral amyloid angiopathy (CAA), we performed a collaborative meta-analysis of APOE associations with cSS presence and severity.MethodsWe pooled data from published studies reporting APOE genotype and MRI assessment of cSS in 3 distinct settings: (1) stroke clinic patients with symptomatic CAA (i.e., lobar intracerebral hemorrhage, transient focal neurologic episodes) according to the Boston criteria; (2) memory clinic patients; and (3) population-based studies. We compared cSS presence and severity (focal or disseminated vs no cSS) in participants with ε2+ or ε4+ genotype vs the ε3/ε3 genotype, by calculating study-specific and random effects pooled, unadjusted odds ratios (ORs).ResultsThirteen studies fulfilled inclusion criteria: 7 memory clinic cohorts (n = 2,587), 5 symptomatic CAA cohorts (n = 402), and 1 population-based study (n = 1,379). There was no significant overall association between APOE ε4+ and cSS presence or severity. When stratified by clinical setting, APOE ε4+ was associated with cSS in memory clinic (OR 2.10; 95% confidence interval [CI] 1.11–3.99) but not symptomatic CAA patients. The pooled OR showed significantly increased odds of having cSS for APOE ε2+ genotypes (OR 2.42, 95% CI 1.48–3.95) in both patient populations. This association was stronger for disseminated cSS in symptomatic CAA cohorts. In detailed subgroup analyses, APOE ε2/ε2 and APOE ε2/ε4 genotypes were most consistently and strongly associated with cSS presence and severity.ConclusionCAA-related vasculopathic changes and fragility associated with APOE ε2+ allele might have a biologically meaningful role in the pathophysiology and severity of cSS.

Objective Limited data exist comparing atherectomy (At) with balloon angioplasty for infrapopliteal peripheral arterial disease. The objective of this study was to compare the outcomes of infrapopliteal At with angioplasty vs angioplasty alone in patients with critical limb ischemia. Methods This is a retrospective, single-center, longitudinal study comparing patients undergoing either infrapopliteal At with angioplasty or angioplasty alone for critical limb ischemia, between January 2014 and October 2017. The primary outcome was primary patency rates. Secondary outcomes were reintervention rates, assisted primary patency, secondary patency, major adverse cardiac events, major adverse limb events, amputation-free survival, overall survival, and wound healing rates. Data were analyzed in multivariate generalized linear models with log rank tests to determine survival in Kaplan-Meier curves. Results There were 342 infrapopliteal interventions, 183 percutaneous balloon angioplasty (PTA; 54%), and 159 atherectomies (At) with PTA (46%) performed on 290 patients, with a mean age of 67 ± 12 years; 61% of the patients were male. The PTA and At/PTA groups had similar demographics, tissue loss (79% vs 84%; P = .26), ischemic rest pain (21% vs 16%; P = .51), mean follow-up (19 ± 9 vs 20 ± 9 months; P = .32), mean number of vessels treated (1.7 ± 0.8 vs 1.9 ± 0.8; P = .08) and the mean lesion length treated (6.55 ± 5.00 cm vs 6.02 ± 4.00 cm; P = .08), respectively. Similar 3-month (96 ± 1% vs 94 ± 1%), 6-month (85 ± 2% vs 86 ± 3%), 12-month (68 ± 3% vs 69 ± 4%), and 18-month (57 ± 4% vs 62 ± 4%) primary patency rates were seen in the two groups (P = .87). At/PTA patients had significantly higher reintervention rates as compared with the PTA patients (28% vs 16%; P = .02). Similar assisted primary patency rates (67 ± 4% vs 69 ± 4%; P = .78) and secondary patency rates (61 ± 4% vs 66 ± 4%; P = .98) were seen in the PTA and At/PTA groups at 18 months. The 30-days major adverse cardiac event rates (3% vs 2%; P = .13) and 30-day major adverse limb event rates (5% vs 4%; P = .2) were similar in both groups. Wound healing rates (72 ± 3% vs 75 ± 2%; P = .12), 1-year amputation-free survival (68 ± 4.1% vs 70 ± 2%; P = .5), and 1-year overall survival (76 ± 4% vs 78 ± 4%; P = .39) rates did not differ in the PTA and At/PTA groups. THE At/PTA group had higher local complication rates (7 [4%] vs 1 [0.5%]; P = .03) Conclusions At with angioplasty provides similar patency rates compared with angioplasty alone for infrapopliteal peripheral arterial disease, but associated with higher reintervention and local complication rates. Further appropriately designed studies are required to determine the exact role of At in this subset of patients.

MRI after a CTscan for thoracolumbar spine (TLS) trauma has become commonplace because of the concerns for detection of posterior ligamentous complex injuries in the absence of substantial scientific evidence to support its use. We hypothesized that MRI scans were not necessary in the clinical management of TLS fractures. A prospective study was conducted at our Level I trauma center. A total of 39 neurologically intact patients with TLS fracture on CT were enrolled. The patients’ CT scan and neurological examination were reviewed by a senior neurosurgeon, who determined clinical management based on these data. Assessment was repeated after an MRI of the spine was performed, and a second clinical plan was devised. The two treatment schemes were then compared. MRI resulted in a change in clinical management in 15 per cent of patients. Ten per cent of patients changed from requiring a brace to no brace and merely observation alone. In no patient planned for nonoperative care was surgery deemed necessary after completion of MRI. Among five patients with initial plans for operative intervention, two avoided surgery after the MRI. MRI has little impact on the management of patients with CT-proven thoracic and lumbar spine fractures. Only when surgery is planned based on CT studies does an MRI seem to assist with determining optimal care.

Background and Purpose— We performed a meta-analysis to assess whether leukoaraiosis on brain computed tomographic scans of acute ischemic stroke patients treated with intravenous thrombolysis is associated with an increased risk of symptomatic intracerebral hemorrhage (sICH) or poor functional outcome at 3 to 6 months after stroke, or both. Methods— We searched PubMed and pooled relevant data in meta-analyses using random effects models. Using odds ratios (OR), we quantified the strength of association between the presence and severity of leukoaraiosis and post-thrombolysis sICH or 3- to 6-month modified Rankin Score >2. Results— Eleven eligible studies (n=7194) were pooled in meta-analysis. The risk of sICH was higher in patients with leukoaraiosis (OR, 1.55; 95% confidence interval [CI], 1.17–2.06; P =0.002) and severe leukoaraiosis (OR, 2.53; 95% CI, 1.92–3.34; P P P I 2 , 75.7%; P =0.002). In adjusted analyses, leukoaraiosis was an independent predictor of poor outcome (n=3688; adjusted OR, 1.61; 95% CI, 1.44–1.79; P Conclusions— Leukoaraiosis might increase post-intravenous thrombolysis sICH risk and poor outcome poststroke. Despite increased sICH risk, intravenous tissue-type plasminogen activator treatment has net clinical benefit in patients with leukoaraiosis. Given the risk of bias/confounding, these results should be considered hypothesis-generating and do not justify withholding intravenous thrombolysis.

Alzheimer disease (AD) research has mainly focused on neurodegenerative processes associated with the classic neuropathologic markers of senile plaques and neurofibrillary tangles. Additionally, cerebrovascular contributions to dementia are increasingly recognized, particularly from cerebral small vessel disease (SVD). Remarkably, in AD brains, the apolipoprotein E (ApoE) ɛ4 allele shows male excess for cerebral microbleeds (CMBs), a marker of SVD, which is opposite to the female excess of plaques and tangles. Mouse transgenic models add further complexities to sex-ApoE ɛ4 allele interactions, with female excess of both CMBs and brain amyloid. We conclude that brain aging and AD pathogenesis cannot be understood in humans without addressing major gaps in the extent of sex differences in cerebrovascular pathology.

The effects of angiotensin converting enzyme inhibitors and angiotensin receptor blockers (ACEI/ARBs) on angiogenesis, myocardial remodeling and intermittent claudication have been studied. Clinical studies have shown reduced re-intervention after cardiac stenting with the use of ACEI/ARBs. We hypothesized that the use of ACEI/ARBs decreases re-interventions after endovascular revascularization in tibial artery disease (TAD) patients. This is a retrospective study comparing the effects of ACEI/ARBs on the outcomes after endovascular revascularization for TAD. We divided all patients that underwent endovascular revascularization into Angiotensin converting enzyme inhibitor/Angiotensin receptor blockers (ACEI/ARBs) and No Angiotensin converting enzyme inhibitor/Angiotensin receptor blockers (NoACEI/ARBs) groups. A total of 360 patients underwent endovascular intervention for TAD. One hundred and ninety-six (54%) patients, 124 (57%) males, were on ACEI/ARBs after endovascular intervention for TAD, whereas 164(46%) patients, 87 (53%) males were not. The groups were well matched in the demographic variables except higher incidence of congestive heart failure, coronary artery disease and dialysis in the ACEI/ARBs group (p = .001, 0.02, 0.01 respectively). Reintervention rates were not associated with ACEI/ARBs use (p = .097). Even when corrected for statin use and antiplatelet therapy, no difference was seen in the reintervention rates in the two groups (p = .535, 0.547 respectively). Primary patency, assisted primary patency and secondary patency did not differ with the use of ACEI/ARBs (p = .244 0.096,0.060 respectively). No difference was seen in overall survival between the two groups (p = .690). ACEI/ARBs do not appear to affect the patency and reintervention rates for patients undergoing endovascular revascularization for TAD.

BACKGROUND AND PURPOSE: Cortical lesions are common in multiple sclerosis and are included in the latest diagnostic criteria. The limited sensitivity of cortical MS lesions on conventional MR imaging can be improved by phase-sensitive inversion recovery. Synthetic MR imaging could provide phase-sensitive inversion recovery without additional scanning, but the use of synthetic phase-sensitive inversion recovery remains to be validated. We aimed to compare the ability and clinical value of detecting leukocortical lesions with conventional and synthetic phase-sensitive inversion recovery in MS. MATERIALS AND METHODS: Twenty-one patients with MS prospectively underwent conventional and synthetic phase-sensitive inversion recovery, 3D T1-weighted, and T2 FLAIR imaging. Two neuroradiologists independently performed blinded phase-sensitive inversion recovery lesion assessments; a consensus rating with all sequences was considered the criterion standard. Lesion volumes were segmented. All participants underwent standardized cognitive and physical examinations and Fatigue Severity Scale assessment. Results were analyzed with multiple linear regressions. RESULTS: Interrater and criterion standard agreement for leukocortical lesions was excellent for both conventional and synthetic phase-sensitive inversion recovery (intraclass correlation coefficient = 0.79–0.97). Leukocortical lesion volumes for both sequences were associated with lower information-processing speed (P ≤ .01) and verbal fluency (P ≤ .02). Both phase-sensitive inversion recovery sequences showed a positive effect on the association when combining volumes of leukocortical lesions and white matter lesions with information-processing speed (P ≤ .005) and verbal fluency (P ≤ .03). No associations were found between leukocortical lesion volumes and physical disability or fatigue. CONCLUSIONS: Synthetic and conventional phase-sensitive inversion recovery have a sensitivity similar to that of leukocortical MS lesions. The detected leukocortical lesions are associated with cognitive dysfunction and thus provide clinically relevant information, which encourages assessment of cortical MS involvement at conventional field strengths.

We investigated whether subtypes of Alzheimer's disease (AD), that is, typical, limbic-predominant, hippocampal-sparing, and minimal atrophy AD, had a specific signature of small vessel disease and neurodegeneration. Four hundred twenty-three clinically diagnosed AD patients were included (161 typical, 121 limbic-predominant, 70 hippocampal-sparing, 71 minimal atrophy). One hundred fifty-six fulfilled a biomarkers-based AD diagnosis. White matter hyperintensities and cerebral microbleeds (CMB) had the highest prevalence in limbic-predominant AD, and the lowest prevalence in minimal atrophy AD. CMB existed evenly in lobar and deep brain areas in limbic-predominant, typical, and hippocampal-sparing AD. In minimal atrophy AD, CMB were mainly located in brain lobar areas. Perivascular spaces in the centrum semiovale were more prevalent in typical AD. Small vessel disease contributed to the prediction of Mini-Mental State Examination. Minimal atrophy AD showed highly pathological levels of cerebrospinal fluid As1-42, total tau, and phosphorylated tau, in the absence of overt brain atrophy. Cerebral amyloid angiopathy seems to have a stronger contribution to hippocampal-sparing and minimal atrophy AD, whereas hypertensive arteriopathy may have a stronger contribution to typical and limbic-predominant AD.

The apolipoprotein APOE4 allele confers greater risk of Alzheimer's disease (AD) for women than men, in conjunction with greater clinical deficits per unit of AD neuropathology (plaques, tangles). Cerebral microbleeds, which contribute to cognitive dysfunctions during AD, also show APOE4 excess, but sex-APOE allele interactions are not described. We report that elderly men diagnosed for mild cognitive impairment and AD showed a higher risk of cerebral cortex microbleeds with APOE4 allele dose effect in 2 clinical cohorts (ADNI and KIDS). Sex-APOE interactions were further analyzed in EFAD mice carrying human APOE alleles and familial AD genes (5XFAD (+/-) /human APOE(+/+)). At 7 months, E4FAD mice had cerebral cortex microbleeds with female excess, in contrast to humans. Cerebral amyloid angiopathy, plaques, and soluble Aβ also showed female excess. Both the cerebral microbleeds and cerebral amyloid angiopathy increased in proportion to individual Aβ load. In humans, the opposite sex bias of APOE4 allele for microbleeds versus the plaques and tangles is the first example of organ-specific, sex-linked APOE allele effects, and further shows AD as a uniquely human condition.

Objective To compare corpus callosum area (CCA) and corpus callosum index (CCI) in terms of feasibility and their performance as biomarkers for cognitive and physical disability in multiple sclerosis (MS). A secondary aim was to compare these two methods with volumetric measurements. Methods This study was based on a cohort of 37 MS patients and a group of age- and gender-matched healthy controls. Physical disability was assessed with the expanded disability status scale (EDSS) and cognitive disability with the symbol digit modalities test (SDMT). CCA and CCI were assessed on midsagittal brain MRI by 3 raters with varying radiological experience. Volumes of the brain, gray and white matter, corpus callosum, and MS lesions were acquired with Freesurfer and Lesion Segmentation Toolbox for Statistical Parametric Mapping. Results CCA and CCI were obtained within seconds with excellent intra- and inter-rater agreement, and outperformed volumetric measurements. CCA had the strongest correlations with both SDMT (r = .82, P < .001) and EDSS (r = −.56, P < .001), and the highest accuracy in differentiating patients from controls (95%) and relapse-remitting MS from progressive forms of MS (77%). CCI performed less well (r = .73, P < .001; r = −.45, P < .001; 94%; 71%). CCA also outperformed the volumetric measurements in these regards. Conclusions CCA is a time-effective and robust biomarker that has stronger correlations with both EDSS and information processing speed than CCI and volumetric measurements that are commonly used as outcome measures in MS research and clinical trials.

Background Cerebral microbleeds can confer a high risk of intracerebral hemorrhage, ischemic stroke, death and dementia, but estimated risks remain imprecise and often conflicting. We investigated the association between cerebral microbleeds presence and these outcomes in a large meta-analysis of all published cohorts including: ischemic stroke/TIA, memory clinic, “high risk” elderly populations, and healthy individuals in population-based studies. Methods Cohorts (with > 100 participants) that assessed cerebral microbleeds presence on MRI, with subsequent follow-up (≥3 months) were identified. The association between cerebral microbleeds and each of the outcomes (ischemic stroke, intracerebral hemorrhage, death, and dementia) was quantified using random effects models of (a) unadjusted crude odds ratios and (b) covariate-adjusted hazard rations. Results We identified 31 cohorts ( n = 20,368): 19 ischemic stroke/TIA ( n = 7672), 4 memory clinic ( n = 1957), 3 high risk elderly ( n = 1458) and 5 population-based cohorts ( n = 11,722). Cerebral microbleeds were associated with an increased risk of ischemic stroke (OR: 2.14; 95% CI: 1.58–2.89 and adj-HR: 2.09; 95% CI: 1.71–2.57), but the relative increase in future intracerebral hemorrhage risk was greater (OR: 4.65; 95% CI: 2.68–8.08 and adj-HR: 3.93; 95% CI: 2.71–5.69). Cerebral microbleeds were an independent predictor of all-cause mortality (adj-HR: 1.36; 95% CI: 1.24–1.48). In three population-based studies, cerebral microbleeds were independently associated with incident dementia (adj-HR: 1.35; 95% CI: 1.00–1.82). Results were overall consistent in analyses stratified by different populations, but with different degrees of heterogeneity. Conclusions Our meta-analysis shows that cerebral microbleeds predict an increased risk of stroke, death, and dementia and provides up-to-date effect sizes across different clinical settings. These pooled estimates can inform clinical decisions and trials, further supporting cerebral microbleeds role as biomarkers of underlying subclinical brain pathology in research and clinical settings.

BACKGROUND AND PURPOSE: Cerebral microbleeds are thought to represent cerebral amyloid angiopathy when in lobar regions of the brain and hypertensive arteriopathy when in deep and infratentorial locations. By studying cerebral microbleeds, their topography, and risk factors, we aimed to gain an insight into the vascular and amyloid pathology of dementia diagnoses and increase the understanding of cerebral microbleeds in dementia. MATERIALS AND METHODS: We analyzed 1504 patients (53% women; mean age, 63 ± 10 years; 10 different dementia diagnoses) in this study. All patients underwent MR imaging as part of the dementia investigation, and all their clinical parameters were recorded. RESULTS: Among the 1504 patients with dementia, 22% had cerebral microbleeds. Cerebral microbleed topography was predominantly lobar (P = .01) and occipital (P = .007) in Alzheimer disease. Patients with cerebral microbleeds were significantly older (P < .001), were more frequently male (P < .001), had lower cognitive scores (P = .006), and more often had hypertension (P < .001). Risk factors for cerebral microbleeds varied depending on the dementia diagnosis. Odds ratios for having cerebral microbleeds increased with the number of risk factors (hypertension, hyperlipidemia, diabetes, male sex, and age 65 and older) in the whole patient group and increased differently in the separate dementia diagnoses. CONCLUSIONS: Prevalence, topography, and risk factors of cerebral microbleeds vary depending on the dementia diagnosis and reflect the inherent pathology of different dementia diagnoses. Because cerebral microbleeds are seen as possible predictors of intracerebral hemorrhage, their increasing prevalence with an increasing number of risk factors, as shown in our study, may require taking the number of risk factors into account when deciding on anticoagulant therapy in dementia.

Background: Cognitive impairment is common in multiple sclerosis (MS) and may be subtle. The corpus callosum is essential for connectivity-demanding cognitive tasks and is significantly affected in MS, therefore it may serve as a marker for cognitive function. Objective: The objective of this paper is to longitudinally study the normalized corpus callosum area (nCCA) as a marker of cognitive function and disability in MS. Methods: Thirty-seven MS patients were followed from 1996 with follow-ups in 2004 and 2013. A healthy matched control group was recruited. The Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT) were assessed. The nCCA was measured on T2-weighted images. Volumetry was performed with FreeSurfer. Results: Disease duration spanned five decades (1.6–46 years). Annual corpus callosal atrophy rate decreased with disease duration. nCCA was strongly correlated with SDMT ( r = 0.793, p < 0.001) and moderately correlated with EDSS ( r = −0.545, p < 0.001) after adjusting for disease duration, age and sex. The correlations of brain parenchymal fraction, white matter fraction, gray matter fraction and normalized lesion volume were less strong. Conclusions: The nCCA correlates well with physical and cognitive disability in time perspectives close to two decades, outperforming volumetric measurements. The nCCA is fast and could be feasible for clinical implementation where it may help identify patients in need of neuropsychological evaluation.

Objective:To gain further insight into cortical superficial siderosis (cSS), a new hemorrhagic neuroimaging marker of cerebral amyloid angiopathy (CAA), and to investigate the clinical, neuroimaging, genetic, and CSF biomarker profile of cSS in a large, consecutive memory clinic series.Methods:We included 1,504 memory clinic patients undergoing dementia investigation including a brain MRI in our center. Routine CSF biomarker analysis was performed in 1,039 patients and APOE genotyping in 520 patients. MRIs were systematically evaluated for presumed marker of small vessel disease: cSS, cerebral microbleeds, enlarged perivascular spaces, white matter hyperintensities, and lacunes.Results:cSS was detected in 40 patients (2.7%; 95% confidence interval [CI] 1.9–3.6); cSS was focal in 33 cases (2.2%; 95% CI 1.5–3.1) and disseminated in 7 (0.5%; 95% CI 0.2–1). Vascular dementia had the highest cSS prevalence (13%; 95% CI 5.4–24.9), followed by Alzheimer disease (5%; 95% CI 3.1–7.5). The most commonly affected area was the occipital lobe (70%; 95% CI 53.5–83.4). cSS was associated with lobar cerebral microbleeds (odds ratio [OR] 7.9; 95% CI 3.4–18.1; p < 0.001), high-degree centrum semiovale perivascular spaces (OR 1.7; 95% CI 1.2–2.6; p = 0.008), and white matter hyperintensities (OR 1.5; 95% CI 1.0–2.2; p = 0.062). APOE ε4/4 genotype was more common in cSS cases compared to those without. CSF β-amyloid 42 was lower in patients with cSS (coefficient −0.09; 95% CI −0.15 to −0.03; p = 0.004).Conclusions:Our large series of memory clinic patients provides evidence that cSS is related to cerebrovascular disease and may be a manifestation of severe CAA, even in patients without intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Incidental MR imaging findings resembling MS in asymptomatic individuals, fulfilling the Okuda criteria, are termed “radiologically isolated syndrome.” Those with radiologically isolated syndrome are at high risk of their condition converting to MS. The epidemiology of radiologically isolated syndrome remains largely unknown, and there are no population-based studies, to our knowledge. Our aim was to study the population-based incidence of radiologically isolated syndrome in a high-incidence region for MS and to evaluate the effect on radiologically isolated syndrome incidence when revising the original radiologically isolated syndrome criteria by using the latest radiologic classification for dissemination in space. MATERIALS AND METHODS: All 2272 brain MR imaging scans in 1907 persons obtained during 2013 in the Swedish county of Vastmanland, with a population of 259,000 inhabitants, were blindly evaluated by a senior radiologist and a senior neuroradiologist. The Okuda criteria for radiologically isolated syndrome were applied by using both the Barkhof and Swanton classifications for dissemination in space. Assessments of clinical data were performed by a radiology resident and a senior neurologist. RESULTS: The cumulative incidence of radiologically isolated syndrome was 2 patients (0.1%), equaling an incidence rate of 0.8 cases per 100,000 person-years, in a region with an incidence rate of MS of 10.2 cases per 100,000 person-years. There was no difference in the radiologically isolated syndrome incidence rate when applying a modified version of the Okuda criteria by using the newer Swanton classification for dissemination in space. CONCLUSIONS: Radiologically isolated syndrome is uncommon in a high-incidence region for MS. Adapting the Okuda criteria to use the dissemination in space–Swanton classification may be feasible. Future studies on radiologically isolated syndrome may benefit from a collaborative approach to ensure adequate numbers of participants.

BACKGROUND AND PURPOSE: Quantitative MR imaging techniques are gaining interest as methods of reducing acquisition times while additionally providing robust measurements. This study aimed to implement a synthetic MR imaging method on a new scanner type and to compare its diagnostic accuracy and volumetry with conventional MR imaging in patients with MS and controls. MATERIALS AND METHODS: Twenty patients with MS and 20 healthy controls were enrolled after ethics approval and written informed consent. Synthetic MR imaging was implemented on a Siemens 3T scanner. Comparable conventional and synthetic proton-density–, T1-, and T2-weighted, and FLAIR images were acquired. Diagnostic accuracy, lesion detection, and artifacts were assessed by blinded neuroradiologic evaluation, and contrast-to-noise ratios, by manual tracing. Volumetry was performed with synthetic MR imaging, FreeSurfer, FMRIB Software Library, and Statistical Parametric Mapping. Repeatability was quantified by using the coefficient of variance. RESULTS: Synthetic proton-density–, T1-, and T2-weighted images were of sufficient or good quality and were acquired in 7% less time than with conventional MR imaging. Synthetic FLAIR images were degraded by artifacts. Lesion counts and volumes were higher in synthetic MR imaging due to differences in the contrast of dirty-appearing WM but did not affect the radiologic diagnostic classification or lesion topography (P = .50–.77). Synthetic MR imaging provided segmentations with the shortest processing time (16 seconds) and the lowest repeatability error for brain volume (0.14%), intracranial volume (0.12%), brain parenchymal fraction (0.14%), and GM fraction (0.56%). CONCLUSIONS: Synthetic MR imaging can be an alternative to conventional MR imaging for generating diagnostic proton-density–, T1-, and T2-weighted images in patients with MS and controls while additionally delivering fast and robust volumetric measurements suitable for MS studies.

Cerebral microbleeds, a marker of small vessel disease, are thought to be of importance in cognitive impairment. We aimed to study topographical distribution of cerebral microbleeds, and their involvement in disease pathophysiology, reflected by cerebrospinal fluid biomarkers; 1039 patients undergoing memory investigation underwent lumbar puncture and a brain magnetic resonance imaging scan. Cerebrospinal fluid samples were analyzed for amyloid β(Aβ)42, total tau(T-tau), tau phosphorylated at threonine 18(P-tau) and cerebrospinal fluid/serum albumin ratios. Magnetic resonance imaging sequences were evaluated for small vessel disease markers, including cerebral microbleeds, white matter hyperintensities and lacunes. Low Aβ42 levels were associated with lobar cerebral microbleeds in the whole cohort and Alzheimer’s disease ( P

Background and purpose Cerebral microbleeds are thought to have potentially important clinical implications in dementia and stroke. However, the use of both T2* and SWI MR imaging sequences for microbleed detection has complicated the cross-comparison of study results. We aimed to determine the impact of microbleed sequences on microbleed detection and associated clinical parameters. Materials and methods Patients from our memory clinic (n = 246; 53% female; mean age, 62) prospectively underwent 3T MR imaging, with conventional thick-section T2*, thick-section SWI, and conventional thin-section SWI. Microbleeds were assessed separately on thick-section SWI, thin-section SWI, and T2* by 3 raters, with varying neuroradiologic experience. Clinical and radiologic parameters from the dementia investigation were analyzed in association with the number of microbleeds in negative binomial regression analyses. Results Prevalence and number of microbleeds were higher on thick-/thin-section SWI (20/21%) compared with T2*(17%). There was no difference in microbleed prevalence/number between thick- and thin-section SWI. Interrater agreement was excellent for all raters and sequences. Univariate comparisons of clinical parameters between patients with and without microbleeds yielded no difference across sequences. In the regression analysis, only minor differences in clinical associations with the number of microbleeds were noted across sequences. Conclusions Due to the increased detection of microbleeds, we recommend SWI as the sequence of choice in microbleed detection. Microbleeds and their association with clinical parameters are robust to the effects of varying MR imaging sequences, suggesting that comparison of results across studies is possible, despite differing microbleed sequences.

Cerebral microbleeds (CMBs) are hypothesised to have an important yet unknown role in the dementia disease pathology. In this study we analysed increasing number of CMBs and their independent associations with routine cerebrospinal fluid (CSF) biomarkers in a continuum of cognitive impairment. A total of 1039 patients undergoing dementia investigation were analysed and underwent lumbar puncture, and an MRI scan. CSF samples were analysed for amyloid β (Aβ) 42, total tau (T-tau), tau phosphorylated at threonine 18 (P-tau) and CSF/serum albumin ratios. Increasing number of CMBs were independently associated with low Aβ42 levels, in the whole cohort, Alzheimer’s disease and mild cognitive impairment ( p

Dear editor, Cerebral microbleeds—an important marker of small vessel disease in the brain—have been fascinating clinicians and researchers for almost two decades, since they started to be increasingly detected due to the clinical use of heamosiderin-sensitive MRI sequences. This enduring interest in the topic is driven by the high prevalence of these lesions in cerebrovascular disorders, dementia and in the elderly, in combination with the many unsettled clinical dilemmas created by their presence. The literature on cerebral microbleeds has seen a geometric increase, with new important studies published on the topic almost on a weekly basis, several including global collaborations. Scientists have started exploring the power of social media to fundamentally speed up the pace at which knowledge on a topic is developed, shared and discussed, both within scientific communities and with the general public. We have recently launched a Twitter space where those with a clinical research interest in cerebral microbleeds could connect. The idea for this dedicated space evolved from several discussions with friends and colleagues working in this area, and the @microbleeds platform was born (Figure 1). Our Twitter space is initially intended to provide an international microblogging and social media platform to allow for the large-scale and rapid communication of ideas, news, updates, and studies on cerebral microbleeds, further encouraging a collaborative approach. By sharing comments, links, information, and notes about new developments with trusted sources, the platform will enable real-time highlighting and tracking of what’s going on in the world of microbleeds. This allows for a continuous ongoing discussion on microbleeds, and their unraveling clinical associations and implications, and emphasizes areas in need for more research. Our vision is for this space to form the foundation for bringing together a community of microbleeds enthusiasts and interested parties—a process heavily dependent on peer support. The @microbleeds space will gradually start to provide regular updates, present important findings in weekly chats and promote news on small vessel disease research opportunities and relevant conferences/events from around the world with live tweets from our members. It can involve both professional collaboration and communication with the public. Stay tuned @microbleeds.