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Intracranial internal carotid artery (iICA) calcification is associated with stroke and is often seen as a proxy of atherosclerosis of the intima. However, it was recently shown that these calcifications are predominantly located in the tunica media and internal elastic lamina (medial calcification). Intimal and medial calcifications are thought to have a different pathogenesis and clinical consequences and can only be distinguished through ex vivo histological analysis. Therefore, our aim was to develop CT scoring method to distinguish intimal and medial iICA calcification in vivo. First, in both iICAs of 16 cerebral autopsy patients the intimal and/or medial calcification area was histologically assessed (142 slides). Brain CT images of these patients were matched to the corresponding histological slides to develop a CT score that determines intimal or medial calcification dominance. Second, performance of the CT score was assessed in these 16 patients. Third, reproducibility was tested in a separate cohort. First, CT features of the score were circularity (absent, dot(s), <90°, 90-270° or 270-360°), thickness (absent, ≥1.5mm, or <1.5mm), and morphology (indistinguishable, irregular/patchy or continuous). A high sum of features represented medial and a lower sum intimal calcifications. Second, in the 16 patients the concordance between the CT score and the dominant calcification type was reasonable. Third, the score showed good reproducibility (kappa: 0.72 proportion of agreement: 0.82) between the categories intimal, medial or absent/indistinguishable. The developed CT score shows good reproducibility and can differentiate reasonably well between intimal and medial calcification dominance in the iICA, allowing for further (epidemiological) studies on iICA calcification.

Many healthcare interventions are complex, consisting of multiple, possibly interacting, components. Several methodological articles addressing complex interventions in the meta-analytical context have been published. We hereby provide an overview of methods used to evaluate the effects of complex interventions with meta-analytical models. We summarized the methodology, highlighted new developments, and described the benefits, drawbacks, and potential challenges of each identified method. We expect meta-analytical methods focusing on components of several multicomponent interventions to become increasingly popular due to recently developed, easy-to-use, software tools that can be used to conduct the relevant analyses. The different meta-analytical methods are illustrated through two examples comparing psychotherapies for panic disorder.

Diffusion tensor imaging (DTI) based fiber tractography (FT) is the most popular approach for investigating white matter tracts in vivo, despite its inability to reconstruct fiber pathways in regions with \"crossing fibers.\" Recently, constrained spherical deconvolution (CSD) has been developed to mitigate the adverse effects of \"crossing fibers\" on DTI based FT. Notwithstanding the methodological benefit, the clinical relevance of CSD based FT for the assessment of white matter abnormalities remains unclear. In this work, we evaluated the applicability of a hybrid framework, in which CSD based FT is combined with conventional DTI metrics to assess white matter abnormalities in 25 patients with early Alzheimer's disease. Both CSD and DTI based FT were used to reconstruct two white matter tracts: one with regions of \"crossing fibers,\" i.e., the superior longitudinal fasciculus (SLF) and one which contains only one fiber orientation, i.e. the midsagittal section of the corpus callosum (CC). The DTI metrics, fractional anisotropy (FA) and mean diffusivity (MD), obtained from these tracts were related to memory function. Our results show that in the tract with \"crossing fibers\" the relation between FA/MD and memory was stronger with CSD than with DTI based FT. By contrast, in the fiber bundle where one fiber population predominates, the relation between FA/MD and memory was comparable between both tractography methods. Importantly, these associations were most pronounced after adjustment for the planar diffusion coefficient, a measure reflecting the degree of fiber organization complexity. These findings indicate that compared to conventionally applied DTI based FT, CSD based FT combined with DTI metrics can increase the sensitivity to detect functionally significant white matter abnormalities in tracts with complex white matter architecture.

Background Fahr’s disease and syndrome are rare disorders leading to calcification of the small arteries in the basal ganglia of the brain, resulting in a wide range of symptoms comprising cognitive decline, movement disorders and neuropsychiatric symptoms. No disease-modifying therapies are available. Studies have shown the potential of treatment of ectopic vascular calcifications with bisphosphonates. This paper describes the rationale and design of the CALCIFADE trial which evaluates the effects of etidronate in patients with Fahr’s disease or syndrome. Methods The CALCIFADE trial is a randomised, placebo-controlled, double-blind trial which evaluates the effects of etidronate 20 mg/kg during 12 months follow-up in patients aged ≥ 18 years with Fahr’s disease or syndrome. Etidronate and placebo will be administered in capsules daily for two weeks on followed by ten weeks off. The study will be conducted at the outpatient clinic of the University Medical Center Utrecht, the Netherlands. The primary endpoint is the change in cognitive functioning after 12 months of treatment. Secondary endpoints are the change in mobility, neuropsychiatric symptoms, volume of brain calcifications, dependence in activities of daily living, and quality of life. Results Patient recruitment started in April 2023. Results are expected in 2026 and will be disseminated through peer-reviewed journals as well as presentations at national and international conferences. Conclusions Fahr’s disease and syndrome are slowly progressive disorders with a negative impact on a variety of health outcomes. Etidronate might be a new promising treatment for patients with Fahr’s disease or syndrome. Trial registration ClinicalTrials.gov, NCT05662111. Registered 22 December 2022, https://clinicaltrials.gov/ct2/show/NCT01585402 .

Calcifications within the hippocampus were recently described for the first time on computed tomography (CT). These calcifications appeared in patients older than 50 years, the prevalence increases with age and they may be associated with cognitive decline. The aim of this study was to determine the histological basis (the presence, severity and location) of these CT-detected hippocampal calcifications of post-mortem brains. CT scans of seven post-mortem brains were scored for the presence and severity (mild, moderate, severe) of hippocampal calcification. After this, samples from nine hippocampi (bilateral in two brains, unilateral in five brains) were stained with hematoxylin and eosin (HE) to indicate the cytoarchitecture, with Elastica van Gieson to analyse the elastic connective tissue of the vessel walls and with von Kossa for detection of calcium. In four brains (six hippocampi), calcifications were both found on CT and in corresponding histology. In three brains (three hippocampi), calcifications were absent on CT and corresponding histology. In histology, mild calcifications were located in the tail and severe calcifications involved the tail, body and sometimes the head of the hippocampus. The calcifications co-localised with precapillaries, capillaries and arteries of the molecular and granular layers of the dentate gyrus and the Cornu Ammonis 1. In this study, calcifications of the hippocampus as seen on CT scans were histologically located in vascular structures of the tail, body and head of the hippocampus.

Incidental basal ganglia calcifications are a common finding on computed tomography (CT). We investigated the histological characteristics of these calcifications and their association with CT findings, using post-mortem basal ganglia tissue from 22 patients. Eight patients had basal ganglia calcifications on histology, and six patients had calcifications on CT, varying from mild to severe. Four patients had calcifications identified by both histology and CT, and two patients had calcifications detected by CT but not by histology, possibly because of insufficient tissue available. Calcifications were found mainly in the tunica media of arterioles located in the globus pallidus, which suggests that incidental CT calcifications are vascular in nature. However, tunica media calcifications, and thereby incidental basal ganglia calcifications, are probably not related to atherosclerosis.

It was recently shown that calcification of the hippocampus can be detected on computed tomography (CT) images and these calcifications occur in up to 20% of people over 50 years of age. However, little is known about hippocampal calcification and its relation to cognition and cognitive decline. Therefore, the aim of this study was to (1) determine the prevalence of hippocampal calcification on CT in memory clinic patients controls, and (2) to assess its relation with cognitive decline. 67 patients from a memory clinic (cases) were matched by age and gender to a control group. In both groups, hippocampal calcification was assessed by two raters on thin slice, non-contrast enhanced brain CT images. Calcifications were scored bilaterally on presence and severity (absent, mild, moderate, severe). Mini Mental State Exam (MMSE) score was determined in cases. Hippocampal calcification presence was significantly higher in cases (N = 26, 38.8%) compared to controls (N = 9, 13.4%) (P < .01) with an odds ratio of 4.40 (95%CI: 1.63-14.87). In cases, MMSE score was significantly lower in those with hippocampal calcification compared to those without (21.6 vs 24.5, p = .02). In this case-control study we found significantly more hippocampal calcification in patients with cognitive decline as compared to controls. Furthermore, within the cases, MMSE score was significantly lower in those with hippocampal calcification.

BackgroundStudies have found statin treatment to be associated with improved 1-year survival after transcatheter aortic valve implantation (TAVI), suggesting pleiotropic effects of statins on preventing perioperative complications. Statin treatment is not associated with postoperative cardiovascular complications or mortality; however, other postoperative complications have not been investigated.AimTo explore whether preoperative statin treatment is associated with a lower short-term risk of mortality, readmission and major postoperative complications in older patients undergoing TAVI.MethodsA retrospective cohort study including patients aged 65 years and older who had undergone a comprehensive geriatric assessment prior to TAVI between January 2014 and January 2021. The primary outcomes were 90-day mortality, 90-day readmissions and major postoperative complications according to the Clavien-Dindo classification. Multivariable logistic regression was performed with adjustment for potential confounders, namely age, gender, comorbidity, body mass index, smoking, diminished renal function, alcohol use and falls .ResultsThis study included 584 patients, of whom 324 (55.5%) were treated with a statin. In the statin treated group, 15 (4.6%) patients died within 90 days of TAVI compared with 10 (3.8%) patients in the non statin group (adjusted OR 1.17; 95% CI 0.51 to 2.70). The number of 90-day readmissions was 39 (12.0%) and 34 (13.1%) (adjusted OR 0.91; 95% CI 0.54 to 1.52), respectively. In the statin treated group, 115 (35.5%) patients experienced a major complication compared with 98 (37.7%) in the non-statin group (adjusted OR 0.95; 95% CI 0.67 to 1.37).ConclusionPreoperative statin treatment is not associated with improved short-term outcomes after TAVI. A randomised controlled trial with different statin doses may be warranted to investigate whether initiating statin treatment before TAVI improves both postoperative outcomes and long-term survival.

IntroductionClinical guidelines recommend non-vitamin K antagonist oral anticoagulants (NOACs) over vitamin K antagonists (VKAs) for stroke prevention in most patients with atrial fibrillation (AF). Frail elderly were under-represented in the landmark NOAC-trials, leaving a knowledge gap on the optimal anticoagulant management (VKA or NOAC) in this increasing population. The aim of the Frail-AF (FRAIL-AF) study is to assess whether switching from international normalised ratio (INR)-guided VKA-management to a NOAC-based treatment strategy compared with continuing VKA-management is safe in frail elderly patients with AF.Methods and analysisThe FRAIL-AF study is a pragmatic, multicentre, open-label, randomised controlled clinical trial. Frail elderly (age ≥75 years plus a Groningen Frailty Indicator score ≥3) who receive VKA-treatment for AF in the absence of a mechanical heart valve or severe mitral valve stenosis will be randomised to switch to a NOAC-based treatment strategy or to continue INR-guided VKA-management. Patients with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2) will be excluded from randomisation. Based on existing trial evidence in non-frail patients, we will aim to explore whether NOAC-treatment is superior to VKA-therapy in reducing major or clinically relevant non-major bleeding events. Secondary outcomes include minor bleeding, the composite of ischaemic and haemorrhagic stroke, health-related quality of life and cost-effectiveness. The follow-up period for all subjects is 12 months.Ethics and disseminationThe protocol was approved by the Medical Research Ethics Committee of the University Medical Center Utrecht, the Netherlands and by the Central Committee on Research Involving Human Subjects, the Netherlands. All patients are asked written informed consent. Results are expected in 2022 and will be disseminated through peer-reviewed journals as well as presentations at national and international conferences.Trial registration numberEudraCT: 2017-000393-11; The Netherlands Trial Registry: 6721 (FRAIL-AF study).

ObjectiveIn recent years, transcatheter aortic valve implantation (TAVI) has become the treatment of choice for patients with symptomatic aortic valve stenosis considered to be at increased or high surgical risk. The aim of this study was to identify predictors of postoperative adverse events in older adults undergoing TAVI.MethodsA prospective observational cohort study of patients who were referred to a geriatric outpatient clinic for a geriatric assessment prior to TAVI was conducted. The outcomes were mortality and hospital readmission within 3 months of TAVI and the occurrence of major postoperative complications during hospitalisation according to the Clavien-Dindo classification. These three outcomes were also combined to a composite outcome. Univariate and multivariate logistic regression analyses were performed to identify predictors of the outcomes and composite outcome of adverse events.ResultsThis cohort included 490 patients who underwent TAVI (mean age 80.7±6.2 years, 47.3% male). Within 3 months of TAVI, 19 (3.9%) patients died and 46 (9.4%) patients experienced a hospital readmission. A total of 177 (36.1%) patients experienced one or more major complications according to the Clavien-Dindo classification during hospitalisation and 193 patients (39.4%) experienced the composite outcome of adverse events. In multivariate analyses, cognitive impairment was identified as an independent predictor of major postoperative complications (OR 2.16; 95% CI 1.14 to 4.19) and the composite outcome of adverse events (OR 2.40; 95% CI 1.21 to 4.79). No association was found between the other variables and the separate outcomes and composite outcome.ConclusionCognitive impairment is associated with postoperative adverse events in older patients undergoing TAVI. Therefore, it is important to screen for cognitive impairment prior to TAVI and it is recommended to include this in current TAVI guidelines.