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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.

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.

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.

Ectopic calcification, or ectopic mineralization, is a pathologic condition in which calcifications develop in soft tissues [...].Ectopic calcification, or ectopic mineralization, is a pathologic condition in which calcifications develop in soft tissues [...].

Purpose Transient improvement of aphasia, motor impairment, and disorders of consciousness after the use of zolpidem, a sedative, has been reported in several movement disorders and hyporesponsive syndromes. Here, we present a patient with Primary Familial Brain Calcification (PFBC), a rare neurodegenerative disease characterized by basal ganglia calcification, who experienced a transient improvement in speech following zolpidem administration. Methods Serendipitously, a 40-year-old female with PFBC and severe dysarthria experienced transient amelioration of dysarthria after treatment with zolpidem, which was prescribed for insomnia. We carried out a comprehensive clinical assessment before and three hours after administration of zolpidem tartrate 10 mg, including standardized evaluations of speech, aphasia, motor function, and patient-perceived difficulties. Results A transient improvement in speech was confirmed after zolpidem intake. However, notable side effects occurred, including worsening of fine motor control, coordination, postural stability, and bradykinesia. Conclusions This case suggests that zolpidem can influence PFBC related neurological symptoms, identifying the facilitation of internal globus pallidus inhibition as a new therapeutic target. Its use in individual patients warrants the weighing of positive and negative clinical effects, patients’ personal preferences, and wearing-off which invariable occurs after repeated use.

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.

ObjectivesRecently, hippocampal calcification as observed on brain CT examinations was identified in over 20% of people over 50 years of age and a relation between hippocampal calcification and cognitive decline was shown. We determined the prevalence and investigated the vascular risk factors of hippocampal calcification in patients with cerebrovascular disease.MethodsHippocampal calcification was scored bilaterally on presence and severity on CT examinations in a cohort of 1130 patients with (suspected) acute ischaemic stroke. Multivariable logistic regression analysis, adjusting for age and gender as well as adjusting for multiple cardiovascular disease risk factors, was used to determine risk factors for hippocampal calcification.ResultsHippocampal calcification was present in 381 (34%) patients. Prevalence increased with age from 8% below 40 to 45% at 80 years and older. In multivariable logistic regression analysis, age per decile (OR 1.41 [95% CI 1.26–1.57], p < 0.01), hypertension (OR 0.74 [95% CI 0.56–0.99], p = 0.049), diabetes mellitus (OR 1.57 [95% CI 1.10–2.25], p = 0.01) and hyperlipidaemia (OR 1.63 [95% CI 1.20–2.22], p < 0.01) were significantly associated with hippocampal calcification.ConclusionsHippocampal calcification was a frequent finding on CT in this cohort of stroke patients and was independently positively associated with hyperlipidaemia and diabetes mellitus, suggesting an atherosclerotic origin.Key Points• Hippocampal calcification is prevalent in over 30% of cerebrovascular disease patients.• Prevalence increases from 8% below 40 to 45% over 80 years.• Hippocampal calcification is associated with cardiovascular risk factors hyperlipidaemia and diabetes mellitus.