Background: There is ambiguity whether frail patients with atrial fibrillation (AF) managed with vitamin K antagonists (VKAs) should be switched to a non-vitamin K oral anticoagulant (NOAC). Methods: We conducted a pragmatic, multicenter, open-label, randomized controlled superiority trial. Older AF patients living with frailty (age ≥75 years plus a Groningen Frailty Indicator (GFI) score ≥3) were randomized to switch from INR-guided VKA treatment to a NOAC or to continued VKA treatment. Patients with a glomerular filtration rate <30 mL/min/1.73 m ² or with valvular AF were excluded. Follow-up was 12 months. The cause-specific hazard ratio (HR) was calculated for occurrence of the primary outcome which was a major or clinically relevant non-major bleeding complication, whichever came first, accounting for death as a competing risk. Analyses followed the intention-to-treat principle. Secondary outcomes included thromboembolic events. Results: Between January 2018 and June 2022, a total of 2,621 patients were screened for eligibility and 1,330 patients were randomized (mean age 83 years, median GFI 4). After randomization 6 patients in the switch to NOAC arm and 1 patient in the continue with VKA arm were excluded due to the presence of exclusion criteria, leaving 662 patients switched from a VKA to a NOAC and 661 patients continued VKAs in the intention-to-treat population. After 163 primary outcome events (101 in the switch arm, 62 in the continue arm), the trial was stopped for futility according to a prespecified futility analysis. The HR for our primary outcome was 1.69 (95% CI 1.23-2.32). The HR for thromboembolic events was 1.26 (95% CI 0.60 to 2.61). Conclusions: Switching INR-guided VKA treatment to a NOAC in frail older patients with AF was associated with more bleeding complications compared to continuing VKA treatment, without an associated reduction in thromboembolic complications.

The Parelsnoer Institute is a collaboration between 8 Dutch University Medical Centers in which clinical data and biomaterials from patients suffering from chronic diseases (so called “Pearls”) are collected according to harmonized protocols. The Pearl Neurodegenerative Diseases focuses on the role of biomarkers in the early diagnosis, differential diagnosis and in monitoring the course of neurodegenerative diseases, in particular Alzheimer’s disease. The objective of this paper is to describe the design and methods of the Pearl Neurodegenerative Diseases, as well as baseline descriptive variables, including their biomarker profile. The Pearl Neurodegenerative Diseases is a 3-year follow-up study of patients referred to a memory clinic with cognitive complaints. At baseline, all patients are subjected to a standardized examination, including clinical data and biobank materials, e.g. blood samples, MRI and cerebrospinal fluid. At present, in total more than 1000 patients have been included, of which cerebrospinal fluid and DNA samples are available of 211 and 661 patients, respectively. First descriptives of a subsample of the data (n = 665) shows that patients are diagnosed with dementia (45%), mild cognitive impairment (31%), and subjective memory complaints (24%). The Pearl Neurodegenerative Diseases is an ongoing large network collecting clinical data and biomaterials of more than 1000 patients with cognitive impairments. The project has started with data analyses of the baseline characteristics and biomarkers, which will be the starting point of future specific research questions that can be answered by this unique dataset.

INTRODUCTION: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid‐β_1‐42 (Aβ42)‐positive status.METHODS: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume.RESULTS: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42‐positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001).DISCUSSION: Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter.Highlights: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aβ42 status in 11 memory clinic cohorts. Aβ42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns.

Vascular Cognitive Impairment (VCI) refers to cognitive dysfunction due to vascular brain injury, as a single cause or in combination with other, often neurodegenerative, etiologies. VCI is a broad construct that captures a heterogeneous patient population both in terms of cognitive and noncognitive symptoms and in terms of etiology and prognosis. This provides a challenge when applying this construct in clinical practice. This paper presents the rationale and design of the TRACE-VCI study, which investigates the clinical features and prognosis of VCI in a memory clinic setting. The TRACE-VCI project is an observational, prospective cohort study of 861 consecutive memory clinic patients with possible VCI. Between 2009 and 2013, patients were recruited through the Amsterdam Dementia Cohort of the VU University Medical Centre (VUMC) (N=665) and the outpatient memory clinic and VCI cohort of the University Medical Centre Utrecht (UMCU) (N=196). We included all patients attending the clinics with magnetic resonance imaging (MRI) evidence of vascular brain injury. Patients with a primary etiology other than vascular brain injury or neurodegeneration were excluded. Patients underwent an extensive 1-day memory clinic evaluation including an interview, physical and neurological examination, assessment of biomarkers (including those for Alzheimer-type pathologies), extensive neuropsychological testing, and an MRI scan of the brain. For prognostic analyses, the composite primary outcome measure was defined as accelerated cognitive decline (change of clinical dementia rating ≥1 or institutionalization) or (recurrent) major vascular events or death over the course of 2 years. The mean age at baseline was 67.7 (SD 8.5) years and 46.3% of patients (399/861) were female. At baseline, the median Clinical Dementia Rating was 0.5 (interquartile range [IQR] 0.5-1.0) and the median Mini-Mental State Examination score was 25 (IQR 22-28). The clinical diagnosis at baseline was dementia in 52.4% of patients (451/861), mild cognitive impairment in 24.6% (212/861), and no objective cognitive impairment in the remaining 23.0% (198/861). The TRACE-VCI study represents a large cohort of well-characterized patients with VCI in a memory clinic setting. Data processing and collection for follow-up are currently being completed. The TRACE-VCI study will provide insight into the clinical features of memory clinic patients that meet VCI criteria and establish key prognostic factors for further cognitive decline and (recurrent) major vascular events.

The oldest-old (subjects aged 90 years and older) population represents the fastest growing segment of society and shows a high dementia prevalence rate of up to 40%. Only a few studies have investigated protective factors for cognitive impairment in the oldest-old. The EMIF-AD 90+ Study aims to identify factors associated with resilience to cognitive impairment in the oldest-old. In this paper we reviewed previous studies on cognitive resilience in the oldest-old and described the design of the EMIF-AD 90+ Study. The EMIF-AD 90+ Study aimed to enroll 80 cognitively normal subjects and 40 subjects with cognitive impairment aged 90 years or older. Cognitive impairment was operationalized as amnestic mild cognitive impairment (aMCI), or possible or probable Alzheimer’s Disease (AD). The study was part of the European Medical Information Framework for AD (EMIF-AD) and was conducted at the Amsterdam University Medical Centers (UMC) and at the University of Manchester. We will test whether cognitive resilience is associated with cognitive reserve, vascular comorbidities, mood, sleep, sensory system capacity, physical performance and capacity, genetic risk factors, hallmarks of ageing, and markers of neurodegeneration. Markers of neurodegeneration included an amyloid positron emission tomography, amyloid β and tau in cerebrospinal fluid/blood and neurophysiological measures. The EMIF-AD 90+ Study will extend our knowledge on resilience to cognitive impairment in the oldest-old by extensive phenotyping of the subjects and the measurement of a wide range of potential protective factors, hallmarks of aging and markers of neurodegeneration. Nederlands Trial Register NTR5867 . Registered 20 May 2016.