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Background and objectives:Studies associate chronic kidney disease (CKD) with neurodegeneration. This study investigated the relation between kidney function, blood, cerebrospinal fluid (CSF), and structural brain MRI markers of neurodegeneration, in a sample including individuals with and without CKD.Methods:Participants from the Gothenburg H70 Birth Cohort Study, with data on plasma-neurofilament light (P-NfL), estimated glomerular filtration rate (eGFR) and structural brain MRI were included. Participants were invited to also have CSF collected. The primary endpoint of the present study was to determine any association between CKD and P-NfL. Secondary endpoints included cross-sectional associations between CKD, eGFR and cerebrospinal fluid (CSF)- and MRI-derived markers of neurodegeneration and Alzheimer’s disease (AD) pathology (MRI: cortical thickness, hippocampal volume, lateral ventricle volume, white matter lesion volume; CSF: β-amyloid (Aβ) 42, Aβ42/40, Aβ42/p-tau, t-tau, p-tau, NfL). Participants with P-NfL and eGFR at baseline were re-examined on eGFR, 5.5 (5.3; 6.1) years (median; IQR) after the first visit, and the predictive value of P-NfL levels on incident CKD was estimated longitudinally, using a Cox proportional hazards model.Results:We included 744 participants, 668 without CKD (Age 71 (70; 71) years, 50% males) and 76 with CKD (age 71 (70;71) years, 39% males). Biomarkers from cerebrospinal fluid (CSF) were analysed in 313 participants. 558 individuals returned for a re-examination of eGFR (75% response rate, age 76 (76; 77), 48% males, 76 new cases of CKD). Participants with CKD had higher P-NfL levels than those with normal kidney function (median; 18.8 versus 14.0 pg/mL, pDiscussion:In a community-based cohort of 70-year olds, P-NfL was associated with both prevalent and incident CKD, while CSF and/or imaging measures did not differ by CKD status. Participants with CKD and dementia presented similar levels of P-NfL.

The incidence of Colorectal cancer (CRC) is increasing worldwide. It has variable signs and symptoms starting from change in bowel habit to nausea and vomiting. Chemotherapeutic agents are often prescribed in CRC such as Capecitabine (CCB) and 5-Fluorouracil (FU). CCB is the prodrug of FU in oral dosage form, which makes it preferable by physicians, since no hospitalization is needed for drug administration. CCB is activated to FU in a 3-steps reaction producing 5'-deoxy-5-fluorocytidine (DFCR) (by carboxylesterase (CES) enzyme), then 5'-deoxy-5-fluorouridine (DFUR) (by cytidine deaminase (CDD) enzyme) and finally FU (by thymidine phosphorylase (TYMP) enzyme), the active form, which is later deactivated to give 5,6-dihydro-5-fluorouracil (DHFU). Different patients exhibit variable drug responses and adverse in response to CCB therapy, despite being treated by the same dose, which could be attributed tothe occurrence of different possible enzyme single nucleotide polymorphisms (SNPs) along the activation and deactivation pathways of CCB. The most commonly occurring toxicities in CCB therapy are Hand-Foot syndrome and diarrhea. This study aims at developing and validating a new method for simultaneous determination of CCB and its metabolites by HPLC-UV, followed by a correlation study with the toxicities occurring during therapy, where predictions of toxicity could be based on metabolites level instead ofthe tedious process of genotyping. A new superior analytical method was optimized by a Quality by Design approach using DryLab® software achieving baseline resolution of the 6 analytes within the least possible gradient time of 10 min. The method also showed linearity (in a range from 1 to 500 µg/ml), accuracy, precision and robustness upon validation. LOD was found to be 3 ng/mL for DHFU and CCB, and 0.3 ng/mL for DFUR, DFCR and FU. The LOQ was found to be 10 ng/mL for DHFU and CCB, and 1 ng/mL for DFUR, DFCR and FU. Clinical results showed a positive correlation between the concentration of DFCR and mucositis and between the concentration of DFUR and Hand-Foot Syndrome, confirming that this technique could be used for predicting such toxicities.

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 — Although wearing masks is inevitable these days, the effects of wearing them on physiologic parameters have not been reported. This study aimed to assess the effects of wearing no mask, a three-layer standard surgical mask, and wearing an N95 mask on blood oxygen saturation, aerobic tolerance, and performance during exercise. Methods — Twenty-one participants were enrolled in the study. Each participant was monitored with electrocardiography (ECG) while performing an exercise tolerance test using the Bruce treadmill protocol. Testing was conducted three times on different dates. Participants did not use any mask in the first test but did wear surgical and N95 masks during the second and third tests respectively. Respiratory rate (RR) was assessed for 10 seconds and then multiplied by 6. Heart rate (HR) was monitored by ECG, and oxygen saturation levels were monitored (O2Sat) via digital pulse-oximetry. Assessments were done before warm-up, at the middle and end of each Bruce stage, and as well at 1, 2, and 5 minutes into recovery (masks were worn during recovery). Results — HR, RR, and O2Sat measured data were all significantly different between the three trials at end-stage 3 of Bruce treadmill protocol (p

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.

Neurofilament light protein (NfL) in cerebrospinal fluid (CSF) and plasma (P) are suggested to be interchangeable markers of neurodegeneration. However, evidence is scarce from community-based samples. NfL was examined in a small-scale sample of 287 individuals from the Gothenburg H70 Birth cohort 1944 study, using linear models in relation to CSF and magnetic resonance imaging (MRI) biomarker evidence of neurodegeneration. CSF-NfL and P-NfL present distinct associations with biomarker evidence of Alzheimer's disease (AD) pathology and neurodegeneration. P-NfL was associated with several markers that are characteristic of AD, including smaller hippocampal volumes, amyloid beta (Aβ)

Background Resistance training with blood flow restriction (BFR) results in hypertrophy, and its magnitude depends on various training variables. This study aimed to compare the long-term effect of passive recovery (PR) and active recovery (AR) during low-intensity resistance training with BFR on hormonal levels and performance in young men. Methods In the randomized clinical trial, 20 men were randomly divided into PR and AR groups during resistance training with BFR. The intervention consisted of six upper and lower body movements with 30% of one maximum repetition (1RM), three sessions per week for six weeks. Both groups wore pneumatic cuffs on the proximal part of thighs and arms. The cuff pressure was 60% of the calculated arterial blood occlusion and increased 10% every two weeks. The AR group performed seven repetitions in 30 s break between sets by one second for concentric and eccentric phases and two seconds rest, and the other group had passive rest. The blood samples and a series of performance tests were gathered before and after the intervention. A repeated measure ANOVA was used to analyze data. Results AR and PR interventions significantly improved the C-reactive protein (CRP) (− 38% vs. − 40%), Lactate dehydrogenase (LDH) (− 11% vs. − 3%), Sargent jump (9% vs. 10%), peak power (20% vs.18%), and average power (14% vs. 14%), upper 1RM (8% vs. 8%) and no significant differences were observed between groups. The AR intervention significantly increased growth hormone (GH) (423% vs. 151%, p = 0.03), lower body 1RM (18% vs. 11%) and muscle endurance (34% vs. 22% for the upper body, p = 0.02 and 32% vs. 24% for the lower body, p = 0.04) than the PR group. The PR intervention further increased the minimum power than the AR group (19% vs. 10%). There were no significant changes in testosterone (p = 0.79) and cortisol (p = 0.34) following interventions. Conclusion The findings indicated that by increasing muscle activation and higher metabolic load, AR during resistance training with BFR might cause more remarkable improvements in serum GH, muscle strength, and endurance. Thus, to gain further benefits, AR during training with BFR is recommended. Trial registration: IRCT20191207045644N1. Registration date: 14/03/2020. URL: https://www.irct.ir/search/result?query=IRCT20191207045644N1

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 …

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.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 (HbASigns 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.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: 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.

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.