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OBJECTIVE: To examine the association between antipsychotic use and the risk of acute coronary syndrome (ACS) in elderly de novo users of antipsychotics. DESIGN: A community-based nested case-control study. SETTING: Pharmacy dispensing records from community pharmacies in The Netherlands were linked to hospital discharge records of 950 000 community-dwelling residents from 1998 to 2008. PATIENTS: Cases were 2803 patients aged 60 years or older, with a first hospital admission for ACS identified within a cohort of 26157 elderly persons with at least one antipsychotic prescription (de novo users). For each case, four controls with no hospitalisation for ACS (n=11024) were randomly selected from the same cohort, matched by age, gender and duration of registration in the database. MAIN OUTCOME MEASURES: Relative risks, expressed as ORs, for ACS associated with antipsychotic drug use adjusted for comorbidity. RESULTS: Current exposure to antipsychotics was associated with a decreased risk of hospitalisation for ACS compared with past users (adjusted OR 0.5, 95% CI 0.5 to 0.6). Cumulative use up to 100 Defined Daily Doses was also associated with a decreased risk of hospitalisation (OR 0.7, CI 0.6 to 0.8). No differences in risk were found between typical and atypical antipsychotics, current dosage or different degrees of serotonergic, histaminergic or adrenergic affinity of the antipsychotic. CONCLUSIONS: A decreased risk of hospitalisation for ACS in elderly patients currently using antipsychotics was found. Further research is needed to confirm our results and to determine whether there is a cardioprotective effect or a high non-referral rate in elderly antipsychotic users with ACS. [ABSTRACT FROM AUTHOR]

Background and Purpose: The Total Calcification Score (TCS) is a visual rating scale to measure Primary Familial Brain Calcification (PFBC) related calcification severity on Computed Tomography (CT). We investigated the inter-and intrarater agreement of a modified TCS., Materials and Methods: Patients aged ≥18 years with PFBC or Fahr's syndrome who visited the outpatient clinic of a Dutch academic hospital were included. The TCS was modified, for example by adding hippocampal calcification, and ranged from 0 to 95 points. Fifteen raters evaluated all CTs, of whom three evaluated the CTs twice. Their Entrustable Professional Activity (EPA) level ranged from II (medical student) to V (neuroradiologist). Agreement was assessed using the intraclass correlation coefficient (ICC) for the total score. Kendall's W and weighted Cohen's Kappa were used to determine the inter- and intrarater agreement for individual locations, respectively., Results: Forty patients were included (mean age 60 years, 53% female). The median modified TCS was 34 (range 4-76). For all EPA levels, the interrater agreement of the modified TCS was excellent (ICC=0.97 (95% CI 0.95-0.98)). Kendall's W's were good to excellent for commonly affected locations, but poor to moderate for less commonly affected locations for raters with lower levels of expertise. The intrarater agreement of the modified TCS was excellent. Kappa's of most locations were substantial to almost perfect., Conclusions: The modified TCS can be used with excellent reproducibility of the overall amount of brain calcifications and with limited training, although for some individual calcification locations more expertise is needed., Abbreviations: CI, Confidence Interval; CT, Computed Tomography; EPA, Entrustable Professional Activity; IBGC, Idiopathic Basal Ganglia Calcification; ICC, Intraclass Correlation Coefficient; IQR, Interquartile Range; PFBC, Primary Familial Brain Calcification; SD, Standard Deviation, TCS, Total Calcification Score; UMCU, University Medical Center Utrecht., Competing Interests: The authors declare no conflicts of interest related to the content of this article., (© 2024 by American Journal of Neuroradiology.)

Background: It is unclear whether patients with basal ganglia calcifications (BGC) should undergo infectious disease testing as part of their diagnostic work-up. We investigated the occurrence of possibly associated infections in patients with BGC diagnosed with Fahr's disease or syndrome and consecutively performed a systematic review of published infectious diseases associated with BGC. Methods: In a cross-sectional study, we evaluated infections in non-immunocompromised patients aged ≥ 18 years with BGC in the Netherlands, who were diagnosed with Fahr's disease or syndrome after an extensive multidisciplinary diagnostic work-up. Pathogens that were assessed included the following: Brucella sp., cytomegalovirus, human herpesvirus type 6/8, human immunodeficiency virus (HIV), Mycobacterium tuberculosis , rubella virus, and Toxoplasma gondii . Next, a systematic review was performed using MEDLINE and Embase (2002-2023). Results: The cross-sectional study included 54 patients (median age 65 years). We did not observe any possible related infections to the BGC in this population. Prior infection with Toxoplasma gondii occurred in 28%, and in 94%, IgG rubella antibodies were present. The positive tests were considered to be incidental findings by the multidisciplinary team since these infections are only associated with BGC when congenitally contracted and all patients presented with adult-onset symptoms. The systematic search yielded 47 articles, including 24 narrative reviews/textbooks and 23 original studies (11 case series, 6 cross-sectional and 4 cohort studies, and 2 systematic reviews). Most studies reported congenital infections associated with BGC (cytomegalovirus, HIV, rubella virus, Zika virus). Only two studies reported acquired pathogens (chronic active Epstein-Barr virus and Mycobacterium tuberculosis ). The quality of evidence was low. Conclusions: In our cross-sectional study and systematic review, we found no convincing evidence that acquired infections are causing BGC in adults. Therefore, we argue against routine testing for infections in non-immunocompromised adults with BGC in Western countries.

Background and Purpose: Carotid siphon calcification might contribute to the high prevalence of cerebrovascular disease in pseudoxanthoma elasticum through increased arterial flow pulsatility. This study aimed to compare intracranial artery flow pulsatility, brain volumes, and small-vessel disease markers between patients with pseudoxanthoma elasticum and controls and the association between arterial calcification and pulsatility in pseudoxanthoma elasticum., Materials and Methods: Fifty patients with pseudoxanthoma elasticum and 40 age- and sex-matched controls underwent 3T MR imaging, including 2D phase-contrast acquisitions for flow pulsatility in the assessment of ICA and MCA and FLAIR acquisitions for brain volumes, white matter lesions, and infarctions. All patients with pseudoxanthoma elasticum underwent CT scanning to measure siphon calcification. Flow pulsatility (2D phase-contrast), brain volumes, white matter lesions, and infarctions (3D T1 and 3D T2 FLAIR) were compared between patients and controls. The association between siphon calcification and pulsatility in pseudoxanthoma elasticum was tested with linear regression models., Results: Patients with pseudoxanthoma elasticum (mean age, 57 [SD, 12] years; 24 men) had significantly higher pulsatility indexes (1.05; range, 0.94-1.21 versus 0.94; range, 0.82-1.04; P  = .02), lower mean GM volumes (597 [SD, 53] mL versus 632 [SD, 53] mL; P  < .01), more white matter lesions (2.6; range, 0.5-7.5 versus 1.1; range, 0.5-2.4) mL; P  = .05), and more lacunar infarctions (64 versus 8, P  = .04) than controls (mean age, 58 [SD, 11] years; 20 men). Carotid siphon calcification was associated with higher pulsatility indexes in patients with pseudoxanthoma elasticum (β = 0.10; 95% CI, 0.01-0.18)., Conclusions: Patients with pseudoxanthoma elasticum have increased intracranial artery flow pulsatility and measures of small-vessel disease. Carotid siphon calcification might underlie the high prevalence of cerebrovascular disease in pseudoxanthoma elasticum., (© 2024 by American Journal of Neuroradiology.)

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., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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 ., (© 2024. The Author(s).)

Objective: Cardiovascular disease and frailty are common among the population aged 85+. We hypothesised these patients might benefit from geriatric co-management, as has been shown in other frail patient populations. However, there is limited evidence supporting geriatric co-management in older, hospitalised cardiology patients., Methods: A retrospective cohort study was performed in a large teaching hospital in the Netherlands. We compared patients aged 85 and over admitted to the cardiology ward before (control group) and after the implementation of standard geriatric co-management (intervention group). Data on readmission, mortality, length of stay, number of consultations, delirium, and falls were analysed., Results: The data of 1163 patients were analysed (n = 542 control, n = 621 intervention). In the intervention group, 251 patients did not receive the intervention because of logistic reasons or the treating physician's decision. Baseline characteristics were comparable in the intervention and control groups. Patients in the intervention group had a shorter length of stay (-1 day, p = 0.01) and were more often discharged to a geriatric rehabilitation facility (odds ratio [OR] 1.97, 95% confidence interval [CI] 1.10-3.54, p = 0.02) compared with the control patients. Other outcomes were not significantly different between the groups., Conclusions: After implementation of standard geriatric co-management for hospitalised cardiology patients aged 85 and over, the length of hospital stay shortened and the number of patients discharged to a geriatric rehabilitation facility increased. The adherence to geriatric team recommendations was high. Geriatric co-management would appear to optimise care for older hospitalised patients with cardiac disease., (© 2023. The Author(s).)

(1) Background: Primary Familial Brain Calcification (PFBC) is a neurodegenerative disease characterized by bilateral calcifications of the basal ganglia and other intracranial areas. Many patients experience symptoms of motor dysfunction and cognitive disorders. The aim of this study was to investigate the association between the amount and location of intracranial calcifications with these symptoms. (2) Methods: Patients with suspected PFBC referred to our outpatient clinic underwent a clinical work-up. Intracranial calcifications were visualized on Computed Tomography (CT), and a Total Calcification Score (TCS) was constructed. Logistic and linear regression models were performed. (3) Results: Fifty patients with PFBC were included in this study (median age 64.0 years, 50% women). Of the forty-one symptomatic patients (82.0%), 78.8% showed motor dysfunction, and 70.7% showed cognitive disorders. In multivariate analysis, the TCS was associated with bradykinesia/hypokinesia (OR 1.07, 95%-CI 1.02-1.12, p < 0.01), gait ataxia (OR 1.06, 95%-CI 1.00-1.12, p = 0.04), increased fall risk (OR 1.04, 95%-CI 1.00-1.08, p = 0.03), and attention/processing speed disorders (OR 1.06, 95%-CI 1.01-1.12, p = 0.02). Calcifications of the lentiform nucleus and subcortical white matter were associated with motor and cognitive disorders. (4) Conclusions: cognitive and motor symptoms are common among patients with PFBC, and there is an association between intracranial calcifications and these symptoms.

Background: There is ambiguity whether frail patients with atrial fibrillation 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 patients with atrial fibrillation living with frailty (≥75 years of age plus a Groningen Frailty Indicator score ≥3) were randomly assigned to switch from international normalized ratio-guided VKA treatment to an NOAC or to continued VKA treatment. Patients with a glomerular filtration rate <30 mL·min -1 ·1.73 m -2 or with valvular atrial fibrillation were excluded. Follow-up was 12 months. The cause-specific hazard ratio was calculated for occurrence of the primary outcome that was a major or clinically relevant nonmajor 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 2621 patients were screened for eligibility and 1330 patients were randomly assigned (mean age 83 years, median Groningen Frailty Indicator score 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 an 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 hazard ratio for our primary outcome was 1.69 (95% CI, 1.23-2.32). The hazard ratio for thromboembolic events was 1.26 (95% CI, 0.60-2.61)., Conclusions: Switching international normalized ratio-guided VKA treatment to an NOAC in frail older patients with atrial fibrillation was associated with more bleeding complications compared with continuing VKA treatment, without an associated reduction in thromboembolic complications., Registration: URL: https://eudract.ema.europa.eu; Unique identifier: 2017-000393-11. URL: https://eudract.ema.europa.eu; Unique identifier: 6721 (FRAIL-AF study)., Competing Interests: Disclosures Dr Hemels reports payment for educational lectures from Bayer, BMS/Pfizer, Boehringer Ingelheim, and Daiichi Sankyo. Dr Huisman reports payment to institution from Dutch Healthcare Fund, Dutch Heart Foundation, Bayer Health Care, Pfizer, and Leo Pharma. Dr Kruip reports payment to institution of unrestricted grants from Sobi, payment to institution of research grants from The Netherlands Organisation for Health Research and Development and The Netherlands Thrombosis Foundation, and payment to institution of speaker fees from Sobi, Roche, Dr Geersing reports payment to institution of unrestricted grants from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer, and Daiichi Sankyo. Dr Rutten reports payment to institution of unrestricted grants from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer, and Daiichi Sankyo.

Background: The aim of this study was to assess the prevalence of frailty and other impairments in potential left ventricular assist device (LVAD) and heart transplantation (HTx) candidates by performing a preoperative comprehensive geriatric assessment (CGA) and reviewing the treatment recommendations resulting from the CGA., Methods and Results: This cross-sectional study included 73 patients aged ≥40 years who received a CGA as part of the patient selection procedure for LVAD and HTx. In every patient, a conclusion comprising frailty and other impairments was formulated based on the medical, mental, functional, and social domains and recommendations were made. The mean age was 58 years (range 40-71) and 70 % were male. In 97 % of patients, at least one impairment was identified by the CGA. The most common impairments were polypharmacy, high morbidity burden, reduced renal function, osteopenia, depression, poor quality of life, reduced functionality, (risk of) malnutrition, reduced grip strength and high caregiver burden. A small proportion of the potential LVAD and HTx candidates were frail (7 % according to Fried's frailty criteria, 6 % according to the Edmonton Frail Scale) and 39 % were pre-frail. The domains for which most impairments were found and the domains for which most treatment recommendations were given matched well, with the functional domain as the frontrunner., Conclusion: This study showed that most of the potential candidates for LVAD or HTx have impairments on at least one domain of the CGA. Impairments and associated risks can contribute to the decision making process for candidacy for LVAD and HTx., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Drug-related readmissions (DRAs) are defined as rehospitalizations with an adverse drug event as their main or significant contributory cause. DRAs represent a major adverse health burden for older patients. A prediction model which identified older hospitalized patients at high risk of a DRA <1 year was previously developed using the OPERAM trial cohort, a European cluster randomized controlled trial including older hospitalized patients with multimorbidity and polypharmacy. This study has performed external validation and updated the prediction model consequently., Methods: The MedBridge trial cohort (a multicenter cluster randomized crossover trial performed in Sweden) was used as a validation cohort. It consisted of 2516 hospitalized patients aged ≥65 years. Model performance was assessed by: (1) discriminative power, assessed by the C-statistic with a 95% confidence interval (CI); (2) calibration, assessed by visual examination of the calibration plot and use of the Hosmer-Lemeshow goodness-of-fit test; and (3) overall accuracy, assessed by the scaled Brier score. Several updating methods were carried out to improve model performance., Results: In total, 2516 older patients were included in the validation cohort, of whom 582 (23.1%) experienced a DRA <1 year. In the validation cohort, the original model showed a good overall accuracy (scaled Brier score 0.03), but discrimination was moderate (C-statistic 0.62 [95% CI 0.59-0.64]), and calibration showed underestimation of risks. In the final updated model, the predictor "cirrhosis with portal hypertension" was removed and "polypharmacy" was added. This improved the model's discriminative capability to a C-statistic of 0.64 (95% CI 0.59-0.70) and enhanced calibration plots. Overall accuracy remained good., Conclusions: The updated OPERAM DRA prediction model may be a useful tool in clinical practice to estimate the risk of DRAs in older hospitalized patients subsequent to discharge. Our efforts lay the groundwork for the future development of models with even better performance., (© 2023 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Calcification of the cerebral microvessels in the basal ganglia in the absence of systemic calcium and phosphate imbalance is a hallmark of primary familial brain calcification (PFBC), a rare neurodegenerative disorder. Mutation in genes encoding for sodium-dependent phosphate transporter 2 (SLC20A2), xenotropic and polytropic retrovirus receptor 1 (XPR1), platelet-derived growth factor B (PDGFB), platelet-derived growth factor receptor beta (PDGFRB), myogenesis regulating glycosidase (MYORG), and junctional adhesion molecule 2 (JAM2) are known to cause PFBC. Loss-of-function mutations in XPR1, the only known inorganic phosphate exporter in metazoans, causing dominantly inherited PFBC was first reported in 2015 but until now no studies in the brain have addressed whether loss of one functional allele leads to pathological alterations in mice, a commonly used organism to model human diseases. Here we show that mice heterozygous for Xpr1 (Xpr1 WT/lacZ ) present with reduced inorganic phosphate levels in the cerebrospinal fluid and age- and sex-dependent growth of vascular calcifications in the thalamus. Vascular calcifications are surrounded by vascular basement membrane and are located at arterioles in the smooth muscle layer. Similar to previously characterized PFBC mouse models, vascular calcifications in Xpr1 WT/lacZ mice contain bone matrix proteins and are surrounded by reactive astrocytes and microglia. However, microglial activation is not confined to calcified vessels but shows a widespread presence. In addition to vascular calcifications, we observed vessel tortuosity and transmission electron microscopy analysis revealed microangiopathy-endothelial swelling, phenotypic alterations in vascular smooth muscle cells, and thickening of the basement membrane., (© 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Background: Studies 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., Aim: To 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., Methods: A 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 ., Results: This 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)., Conclusion: Preoperative 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: In clinical practice, it can be difficult to differentiate between intracranial calcifications related to primary familial brain calcification (PFBC) or aging. Also, little is known about the consequences of the amount of intracranial calcifications in patients with PFBC. Therefore, we aimed to compare the amount and distribution of intracranial calcifications in persons with PFBC with controls and between asymptomatic and symptomatic PFBC cases., Methods: This was a case-control study including patients with PFBC and controls. Controls received a CT of the brain because of a trauma and had at least some basal ganglia calcification. The Nicolas score and volume of calcification were used to quantify intracranial calcifications on the CT scans. Receiver operating characteristic curves were obtained to calculate optimal cutoff points to discriminate between cases and controls. Mann-Whitney U tests and logistic regression, adjusted for age and sex, were used to compare the amount of calcification., Results: Twenty-eight cases (median age 65 years, 50.0% male) and 90 controls (median age 74 years, 46.1% male) were included. Calcification scores were higher in cases (median volume: 4.91 cm 3 against 0.03 cm 3 , p < 0.001, median Nicolas score: 26.5 against 2.0, p < 0.001) than controls. Calcifications were also more diffusely distributed in cases. To differentiate between cases and controls, optimal cutoff points were ≥0.2 cm 3 for the calcification volume and ≥6.0 for the Nicolas score. Calcification was higher for symptomatic than asymptomatic cases (calcification volume: 13.62 cm 3 against 1.61 cm 3 , p = 0.01, Nicolas score: 39.0 against 15.5, p = 0.02). After adjustment for age and sex, the Nicolas score remained significantly higher in symptomatic patients, and the calcification volume did not., Discussion: Patients with PFBC had more severe intracranial calcifications, and these calcifications were more diffusely distributed through the brain compared with controls. Symptomatic patients with PFBC might have more intracranial calcifications than asymptomatic persons., Competing Interests: The authors report no relevant disclosures. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.TAKE-HOME POINTS→ Patients with primary familial brain calcification (PFBC) have more severe intracranial calcifications than controls.→ Patients with PFBC have more diffusely distributed intracranial calcifications than controls.→ Symptomatic patients with PFBC might have more intracranial calcifications than asymptomatic patients with PFBC., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Specific subfields within the hippocampus have shown vulnerability to chronic stress, highlighting the importance of looking regionally within the hippocampus to understand the role of psychosocial factors in the development of neurodegenerative diseases. A systematic review on psychosocial factors and hippocampal subfield volumes was performed and showed inconsistent results, highlighting the need for future studies to explore this relationship. The current study aimed to explore the association of psychosocial factors with hippocampal (subfield) volumes, using high-field 7T MRI. Data were from the Memory Depression and Aging (Medea)-7T study, which included 333 participants without dementia. Hippocampal subfields were automatically segmented from T2-weighted images using ASHS software. Generalized linear models accounting for correlated outcomes were used to assess the association between subfields (i.e., entorhinal cortex, subiculum, Cornu Ammonis [CA]1, CA2, CA3, dentate gyrus, and tail) and each psychosocial factor (i.e., depressive symptoms, anxiety symptoms, childhood maltreatment, recent stressful life events, and social support), adjusted for age, sex, and intracranial volume. Neither depression nor anxiety was associated with specific hippocampal (subfield) volumes. A trend for lower total hippocampal volume was found in those reporting childhood maltreatment, and a trend for higher total hippocampal volume was found in those who experienced a recent stressful life event. Among subfields, low social support was associated with lower volume in the CA3 (B = -0.43, 95% CI: -0.72; -0.15). This study suggests possible differential effects among hippocampal (subfield) volumes and psychosocial factors., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Purpose: Basal ganglia calcifications (BGC), a form of vascular calcification, are a common brain computed tomography (CT) finding. We investigated whether BGC are associated with cognitive function and examined the association between vascular risk factors and BGC., Material and Methods: Patients who visited a memory clinic of a Dutch general hospital between April 2009 and April 2015 were included. The patients underwent a standard diagnostic work up including cognitive tests (Cambridge Cognitive Examination, including the Mini Mental State Examination) and brain CT. Vascular risk factors such as hypertension, diabetes mellitus, hyperlipidemia and smoking were assessed. CTs were analyzed for presence and severity (absent, mild, moderate or severe) of BGC. Multivariable logistic regression was used to identify risk factors for BGC and linear regression for the association between BGC and cognitive function., Results: Of the 1992 patients, 40.3% was male. The median age was 80 years and 866 patients (43.5%) had BGC. BGC was associated with female gender (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.06-1.53, p 0.011), and inversely associated with hypertension (OR 0.74, 95% CI 0.60-0.89, p 0.002) and use of antihypertensive drugs (OR 0.79, 95% CI 0.64-0.98, p 0.031). No association was found between presence and severity of BGC and cognitive function or other vascular risk factors., Conclusions: No association with cognitive function was found. Risk factors for BGC were female gender, while hypertension and antihypertensive drug use were associated with a lower risk of BGC., Competing Interests: Declaration of Competing Interest All authors attest that they meet the current International Committee of Medical Journal Editors (ICMJE) criteria for Authorship., (Copyright © 2022 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: The spatial distribution of white matter hyperintensities (WMH) on MRI is often considered in the diagnostic evaluation of patients with cognitive problems. In some patients, clinicians may classify WMH patterns as "unusual", but this is largely based on expert opinion, because detailed quantitative information about WMH distribution frequencies in a memory clinic setting is lacking. Here we report voxel wise 3D WMH distribution frequencies in a large multicenter dataset and also aimed to identify individuals with unusual WMH patterns., Methods: Individual participant data (N = 3525, including 777 participants with subjective cognitive decline, 1389 participants with mild cognitive impairment and 1359 patients with dementia) from eleven memory clinic cohorts, recruited through the Meta VCI Map Consortium, were used. WMH segmentations were provided by participating centers or performed in Utrecht and registered to the Montreal Neurological Institute (MNI)-152 brain template for spatial normalization. To determine WMH distribution frequencies, we calculated WMH probability maps at voxel level. To identify individuals with unusual WMH patterns, region-of-interest (ROI) based WMH probability maps, rule-based scores, and a machine learning method (Local Outlier Factor (LOF)), were implemented., Results: WMH occurred in 82% of voxels from the white matter template with large variation between subjects. Only a small proportion of the white matter (1.7%), mainly in the periventricular areas, was affected by WMH in at least 20% of participants. A large portion of the total white matter was affected infrequently. Nevertheless, 93.8% of individual participants had lesions in voxels that were affected in less than 2% of the population, mainly located in subcortical areas. Only the machine learning method effectively identified individuals with unusual patterns, in particular subjects with asymmetric WMH distribution or with WMH at relatively rarely affected locations despite common locations not being affected., Discussion: Aggregating data from several memory clinic cohorts, we provide a detailed 3D map of WMH lesion distribution frequencies, that informs on common as well as rare localizations. The use of data-driven analysis with LOF can be used to identify unusual patterns, which might serve as an alert that rare causes of WMH should be considered., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: FB is supported by the NIHR biomedical research center at UCLH. MD received honoraria for lectures from Bayer Vital and Sanofi Genzyme, Consultant for Hovid Berhad and Roche Pharma. RWP received honoraria from GE Healthcare and is co-lead of Neurofilament light consortium. CHS is supported by an Alzheimer's Society Fellowship. The remaining authors have nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The prevalence of (hyper)polypharmacy in patients on left ventricular assist device (LVAD) support and its effect on clinical outcomeis unknown. Therefore, we aimed to determine the prevalence of (hyper)polypharmacy in LVAD patients and evaluate its association with mortality and complications., Materials and Methods: 210 patients aged ≥40 years who received a primary LVAD implantation between 2011 and 2019 were included for analysis. Polypharmacy and hyperpolypharmacy were defined as the concomitant use of 5-9 and ≥10 medications at discharge after LVAD implantation, respectively. Cause specific cox regression was used to assess the association of ≥10 medications with mortality, cardiac arrhythmia, driveline infection and major bleeding., Results: The median age of the patients was 57.5 years, and 35.7 % were female. The average number of discharge medications was 8.8 ± 2.3 per patient. The prevalence of patients with 5-9 medications and ≥10 medications was 62.9 % and 34.8 %, respectively. The median follow-up duration was 948 days (interquartile range 874 days). The prescription of ≥10 medications was significantly associated with a higher risk of mortality (HR 2.03; 95 % CI 1.15-3.6, p -value 0.02) adjusted for sex, age, comorbidity and stratified for device type. The prescription of ≥10 medications was not associated with a higher risk of major bleeding, cardiac arrhythmia or driveline infection., Conclusions: (Hyper)polypharmacy is highly prevalent in LVAD patients and is independently associated with a higher risk of mortality. Future research is needed to assess the efficacy of individual risk-benefit profiling of (cardiovascular) medication to ensure appropriate polypharmacy and to decrease negative health outcomes., Competing Interests: LD, LN, WK, MG, ATO, AFW, MHEV and HLK declare that they have no conflict of interest. The UMCU, which employs LWvL and MGvdM, received consultancy fees from Abbott, Medtronic, Vifor, Novarti and Boehringer Ingelheim., (© 2022 The Authors.)

Aim: The aim of this study is to investigate the association between basal ganglia calcification (BGC) and depressive symptoms within older adults with mild cognitive impairment (MCI) or dementia., Methods: For this cross-sectional study, we included patients with MCI or dementia who visited the memory clinic between April 2009 and April 2015. All patients underwent a standard diagnostic workup, including assessment of depressive symptoms with the Geriatric Depression Scale and computed tomography imaging of the brain. Computed tomography scans were assessed for presence and severity of BGC. To analyse the association between BGC and depressive symptoms, binary logistic regression models were performed with adjustment for age, sex, cardiovascular risk factors, and cardiovascular diseases., Results: In total, 1054 patients were included (median age: 81.0 y; 39% male). BGC was present in 44% of the patients, of which 20% was classified as mild, 20% as moderate, and 4% as severe. There were 223 patients (21%) who had a Geriatric Depression Scale score indicative of depressive symptoms. No association was found between the presence or severity of BGC and depressive symptoms., Conclusions: Although both BGC and depressive symptoms were common in patients with MCI or dementia, no association was demonstrated between the presence or severity of BGC and depressive symptoms., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Transcatheter aortic valve replacement (TAVR) is an effective alternative to surgical aortic valve replacement for patients who are at increased surgical risk. Consequently, frailty is common in patients undergoing TAVR., Objectives: This study aims to investigate the impact of frailty on outcomes following TAVR., Methods: A retrospective cohort study was conducted, including all TAVR candidates who visited the geriatric outpatient clinic for preoperative screening. Frailty status was assessed according to the Groningen Frailty Indicator. The primary outcome of the study was defined as the occurrence of postoperative complications, and this was evaluated according to the Clavien-Dindo classification. An additional analysis was performed to assess the impact of frailty on 1-year all-cause mortality and complications within 30 days of TAVR according to the Valve Academic Research Consortium (VARC-2) criteria. The VARC-2 criteria provide harmonized endpoint definitions for TAVR studies., Results: In total, 431 patients with a mean age of 80.8 ± 6.2 years were included, of whom 56% were female. Frailty was present in 36% of the participants. Frailty was associated with a higher risk of the composite outcome of complications [adjusted odds ratio (OR): 1.55 (95% confidence interval, CI: 1.03-2.34)], 30-day mortality [adjusted OR: 4.84 (95% CI: 1.62-14.49)], 3-month mortality [adjusted OR: 2.52 (95% CI: 1.00-6.28)] and 1-year mortality [adjusted OR: 2.96 (95% CI: 1.46-6.00)]., Conclusions: Frailty is common in TAVR patients and is associated with an increased overall risk of postoperative complications, particularly mortality. Increased optimization of screening and treatment of frailty in the guidelines for valvular heart diseases is recommended., (© 2022 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Falls may lead to functional impairment, fear of falling, decreased quality of life, high health care costs and mortality. A case of an older adult presented in this article, illustrates the multifactorial nature of risk of falling and fall prevention strategies. Recently, meta-analyses were performed to determine the effectiveness of interventions to prevent falls and to explore the effect of intervention components in reducing fear of falling. The single interventions whole body vibration, exercise and quality improvement strategies are associated with a reduction in number of fallers. Common components of multiple interventions significantly associated with a reduction in number of fallers are exercise, assistive technology, environmental modifications, quality improvement strategies and basic falls risk assessment. Interventions with meditation, holistic exercises or body awareness are more effective in reducing fear of falling than interventions without these components. The patient's risk evaluation and personal preferences should be taken into account when developing a treatment plan.

Aim: To clarify the role of mediators of ectopic mineralization as biomarkers for arterial calcifications., Methods: MEDLINE and Embase were searched for relevant literature, until January 4th 2022. The investigated biomarkers were: calcium, phosphate, parathyroid hormone, vitamin D, pyrophosphate, osteoprotegerin, receptor activator of nuclear factor-kappa B ligand (RANKL), fibroblast growth factor-23 (FGF-23), Klotho, osteopontin, osteocalcin, Matrix Gla protein (MGP) and its inactive forms and vitamin K. Studies solely performed in patients with kidney insufficiency or diabetes mellitus were excluded., Results: After screening of 8985 articles, a total of 129 articles were included in this systematic review. For all biomarkers included in this review, the results were variable and more than half of the studies for each specific biomarker had a non-significant result. Also, the overall quality of the included studies was low, partly as a result of the mostly cross-sectional study designs. The largest body of evidence is available for phosphate, osteopontin and FGF-23, as a little over half of the studies showed a significant, positive association. Firm statements for these biomarkers cannot be drawn, as the number of studies was limited and hampered by residual confounding or had non-significant results. The associations of the other mediators of ectopic mineralization with arterial calcifications were not clear., Conclusion: Associations between biomarkers of ectopic mineralization and arterial calcification are variable in the published literature. Future longitudinal studies differentiating medial and intimal calcification could add to the knowledge of biomarkers and mechanisms of arterial calcifications., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier Inc.)

Background and Aims: we know little about clinical outcomes of arterial calcifications. This study investigates the risk factors of intracranial artery calcifications and its association with cardiovascular disease and cognitive function., Methods: patients were recruited from a Dutch memory clinic, between April 2009 and April 2015. The intracranial internal carotid artery (iICA) and basilar artery were analysed on the presence of calcifications. Calcifications in the iICA were also assessed on severity and location in the tunica intima or tunica media. Using logistic regression, risk factors of intracranial artery calcifications were analysed, as well as the association of these calcifications with cardiovascular disease, cognitive function and type of cognitive disorder (including subjective cognitive impairment, mild cognitive impairment and dementia). Cognitive function was assessed with the Cambridge Cognitive Examination., Results: 1992 patients were included (median age: 78.2 years, ±40% male). The majority of patients had calcifications in the iICA (±95%). Basilar artery calcifications were less prevalent (±8%). Risk factors for cerebral intracranial calcifications were age (p < 0.001), diabetes mellitus (medial iICA, p = 0.004), hypertension (intimal iICA, p < 0.001) and basilar artery, p = 0.019) and smoking (intimal iICA, p = 0.008). iICA calcifications were associated with stroke and intimal calcifications also with myocardial infarction. Intracranial artery calcifications were not associated with cognitive function or type of cognitive disorder., Conclusion: the majority of memory clinic patients had intracranial artery calcifications. Cardiovascular risk factors are differentially related to medial or intimal iICA calcifications. iICA calcifications were associated with myocardial infarction and stroke, but not with cognitive outcomes., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: To investigate if network thresholding and raw data harmonization improve consistency of diffusion MRI (dMRI)-based brain networks while also increasing precision and sensitivity to detect disease effects in multicentre datasets., Methods: Brain networks were reconstructed from dMRI of five samples with cerebral small vessel disease (SVD; 629 patients, 166 controls), as a clinically relevant exemplar condition for studies on network integrity. We evaluated consistency of network architecture in age-matched controls, by calculating cross-site differences in connection probability and fractional anisotropy (FA). Subsequently we evaluated precision and sensitivity to disease effects by identifying connections with low FA in sporadic SVD patients relative to controls, using more severely affected patients with a pure form of genetically defined SVD as reference., Results: In controls, thresholding and harmonization improved consistency of network architecture, minimizing cross-site differences in connection probability and FA. In patients relative to controls, thresholding improved precision to detect disrupted connections by removing false positive connections (precision, before: 0.09-0.19; after: 0.38-0.70). Before harmonization, sensitivity was low within individual sites, with few connections surviving multiple testing correction (k = 0-25 connections). Harmonization and pooling improved sensitivity (k = 38), while also achieving higher precision when combined with thresholding (0.97)., Conclusion: We demonstrated that network consistency, precision and sensitivity to detect disease effects in SVD are improved by thresholding and harmonization. We recommend introducing these techniques to leverage large existing multicentre datasets to better understand the impact of disease on brain networks., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Alzheimer's disease is characterized by the accumulation of amyloid-β (Aβ) into plaques, aggregation of tau into neurofibrillary tangles, and neurodegenerative processes including atrophy. However, there is a poorly understood spatial discordance between initial Aβ deposition and local neurodegeneration., Objective: Here, we test the hypothesis that the cingulum bundle links Aβ deposition in the cingulate cortex to medial temporal lobe (MTL) atrophy., Methods: 21 participants with mild cognitive impairment (MCI) from the UMC Utrecht memory clinic (UMCU, discovery sample) and 37 participants with MCI from Alzheimer's Disease Neuroimaging Initiative (ADNI, replication sample) with available Aβ-PET scan, T1-weighted and diffusion-weighted MRI were included. Aβ load of the cingulate cortex was measured by the standardized uptake value ratio (SUVR), white matter integrity of the cingulum bundle was assessed by mean diffusivity and atrophy of the MTL by normalized MTL volume. Relationships were tested with linear mixed models, to accommodate multiple measures for each participant., Results: We found at most a weak association between cingulate Aβ and MTL volume (added R2 &lt;0.06), primarily for the posterior hippocampus. In neither sample, white matter integrity of the cingulum bundle was associated with cingulate Aβ or MTL volume (added R2 &lt;0.01). Various sensitivity analyses (Aβ-positive individuals only, posterior cingulate SUVR, MTL sub region volume) provided similar results., Conclusion: These findings, consistent in two independent cohorts, do not support our hypothesis that loss of white matter integrity of the cingulum is a connecting factor between cingulate gyrus Aβ deposition and MTL atrophy.

Neutrophil gelatinase-associated lipocalin (NGAL) is an acute phase protein that has been reported as a potential marker for pre-dementia stages of Alzheimer's disease (AD). Longitudinal studies for its association with the conversion of mild cognitive impairment to AD is still lacking. This study included n = 268 study participants with subjective cognitive decline (SCD) (n=82), mild cognitive impairment (MCI) (n=98) and AD dementia (n=88) at baseline and two-year follow-up clinical assessments. Serum and cerebrospinal fluid (CSF)NGAL, CSF amyloid beta 1-42 , total-Tau, and phospho-Tau levels were measured with ELISA analysis. CSF NGAL levels were significantly lower in MCI participants compared to people with SCD at baseline. Lower baseline CSF NGAL levels predicted MCI converters to AD dementia vs. non-converters after 2-years follow-up. A positive correlation between CSF NGAL and amyloid beta 1-42 was found particularly in MCI participants at baseline. NGAL in CSF holds potential to be used as a predictive marker for the conversion of MCI to AD dementia and may reflect pathophysiological processes of prodromal AD neuropathology., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

We determined the occurrence and association of cortical cerebral microinfarcts (CMIs) at 7 T MRI with risk factors, neuroimaging markers of small and large vessel disease, and cognitive functioning. Within the Medea-7T study, a diverse cohort of older persons with normal cognition, patients with vascular disease, and memory clinic patients, we included 386 participants (68 ± 9 years) with available 7 T and 1.5 T/3T brain MRI, and risk factor and neuropsychological data. CMIs were found in 10% of participants and were associated with older age (RR = 1.79 per +10 years, 95%CI 1.28-2.50), history of stroke or TIA (RR = 4.03, 95%CI 2.18-7.43), cortical infarcts (RR = 5.28, 95%CI 2.91-9.55), lacunes (RR = 5.66, 95%CI 2.85-11.27), cerebellar infarcts (RR = 2.73, 95%CI 1.27-5.84) and decreased cerebral blood flow (RR = 1.35 per -100 ml/min, 95%CI 1.00-1.83), after adjustment for age and sex. Furthermore, participants with >2 CMIs had 0.5 SD (95%CI 0.05-0.91) lower global cognitive performance, compared to participants without CMIs. Our results indicate that CMIs on 7 T MRI are observed in vascular and memory clinic patients with similar frequency, and are associated with older age, history of stroke or TIA, other brain infarcts, and poorer global cognitive functioning.

Objective: To compare the effectiveness of single, multiple, and multifactorial interventions to prevent falls and fall-related fractures in community-dwelling older persons., Methods: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were systematically searched for randomized controlled trials (RCTs) evaluating the effectiveness of fall prevention interventions in community-dwelling adults aged ≥65 years, from inception until February 27, 2019. Two large RCTs (published in 2020 after the search closed) were included in post hoc analyses. Pairwise meta-analysis and network meta-analysis (NMA) were conducted., Results: NMA including 192 studies revealed that the following single interventions, compared with usual care, were associated with reductions in number of fallers: exercise (risk ratio [RR] 0.83; 95% confidence interval [CI] 0.77-0.89) and quality improvement strategies (e.g., patient education) (RR 0.90; 95% CI 0.83-0.98). Exercise as a single intervention was associated with a reduction in falls rate (RR 0.79; 95% CI 0.73-0.86). Common components of multiple interventions significantly associated with a reduction in number of fallers and falls rate were exercise, assistive technology, environmental assessment and modifications, quality improvement strategies, and basic falls risk assessment (e.g., medication review). Multifactorial interventions were associated with a reduction in falls rate (RR 0.87; 95% CI 0.80-0.95), but not with a reduction in number of fallers (RR 0.95; 95% CI 0.89-1.01). The following single interventions, compared with usual care, were associated with reductions in number of fall-related fractures: basic falls risk assessment (RR 0.60; 95% CI 0.39-0.94) and exercise (RR 0.62; 95% CI 0.42-0.90)., Conclusions: In keeping with Tricco et al. (2017), several single and multiple fall prevention interventions are associated with fewer falls. In addition to Tricco, we observe a benefit at the NMA-level of some single interventions on preventing fall-related fractures., (© 2021 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Objective: In 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., Methods: A 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., Results: This 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., Conclusion: Cognitive 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Background and Purpose: Vertebrobasilar artery calcification (VBAC) has been associated with increased stroke occurrence. Little is known on VBAC risk factors, especially for patients with cardiovascular disease. We aimed to assess risk factors associated with VBAC in a cohort of cardiovascular patients referred for a head computed tomography (CT) scan., Materials and Methods: All patients who underwent a clinically indicated, unenhanced, thin slice head CT 6 months before or after inclusion in the SMART study were included. CTs were assessed for presence of VBAC (dichotomously). Relative risks of the associations of age, sex, diabetes mellitus (DM), obesity, body mass index, estimated glomerular filtration rate, hypertension, hyperlipidemia, use of lipid lowering medication, smoking status, high sensitivity C-reactive protein, ankle-brachial index (ABI; ≤0.90, ≥1.30, continuous), internal carotid artery stenosis ≥70%, and carotid intima-media thickness (IMT) with VBAC were estimated using Poisson regression analysis with robust standard errors, adjusted for age and sex., Results: Of the 471 patients included (57% male, median age 58 [interquartile range 47-63]), 117 (24.8%) showed VBAC. Presence of VBAC was associated with older age (RR per 10 years=1.70 [95%CI 1.46-1.99]), DM (RR=1.45 [95%CI 1.03-2.06]), obesity (RR=1.53 [95%CI 1.10-2.12]), ABI ≤0.90 (RR=1.57 [95%CI 1.02-2.41]), and an increased carotid IMT (RR=2.60 per mm [95%CI 1.20-5.62]). Other measurements were not associated with VBAC., Conclusions: We identified several markers associated with VBAC in patients with cardiovascular disease referred for a head CT. Future investigation into the relationship between VBAC and stroke is warranted to determine the potential of VBAC in stroke prevention., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Objective: To assess the efficacy of medication review as an isolated intervention and with several co-interventions for preventing hospital readmissions in older adults., Methods: Ovid MEDLINE, Embase, The Cochrane Central Register of Controlled Trials and CINAHL were searched for randomized controlled trials evaluating the effectiveness of medication review interventions with or without co-interventions to prevent hospital readmissions in hospitalized or recently discharged adults aged ≥65, until September 13, 2019. Included outcomes were "at least one all-cause hospital readmission within 30 days and at any time after discharge from the index admission.", Results: Twenty-five studies met the inclusion criteria. Of these, 11 studies (7,318 participants) contributed to the network meta-analysis (NMA) on all-cause hospital readmission within 30 days. Medication review in combination with (a) medication reconciliation and patient education (risk ratio (RR) 0.45; 95% confidence interval (CI) 0.26-0.80) and (b) medication reconciliation, patient education, professional education and transitional care (RR 0.64; 95% CI 0.49-0.84) were associated with a lower risk of all-cause hospital readmission compared to usual care. Medication review in isolation did not significantly influence hospital readmissions (RR 1.06; 95% CI 0.45-2.51). The NMA on all-cause hospital readmission at any time included 24 studies (11,677 participants). Medication review combined with medication reconciliation, patient education, professional education and transitional care resulted in a reduction of hospital readmissions (RR 0.82; 95% CI 0.74-0.91) compared to usual care. The quality of the studies included in this systematic review raised some concerns, mainly regarding allocation concealment, blinding and contamination., Conclusion: Medication review in combination with medication reconciliation, patient education, professional education and transitional care, was associated with a lower risk of hospital readmissions compared to usual care. An effect of medication review without co-interventions was not demonstrated. Trials of higher quality are needed in this field., (© 2021 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

[Figure: see text].

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., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Acquisition-related differences in diffusion magnetic resonance imaging (dMRI) hamper pooling of multicentre data to achieve large sample sizes. A promising solution is to harmonize the raw diffusion signal using rotation invariant spherical harmonic (RISH) features, but this has not been tested in elderly subjects. Here we aimed to establish if RISH harmonization effectively removes acquisition-related differences in multicentre dMRI of elderly subjects with cerebral small vessel disease (SVD), while preserving sensitivity to disease effects., Methods: Five cohorts of patients with SVD (N = 397) and elderly controls (N = 175) with 3 Tesla MRI on different systems were included. First, to establish effectiveness of harmonization, the RISH method was trained with data of 13 to 15 age and sex-matched controls from each site. Fractional anisotropy (FA) and mean diffusivity (MD) were compared in matched controls between sites using tract-based spatial statistics (TBSS) and voxel-wise analysis, before and after harmonization. Second, to assess sensitivity to disease effects, we examined whether the contrast (effect sizes of FA, MD and peak width of skeletonized MD - PSMD) between patients and controls within each site remained unaffected by harmonization. Finally, we evaluated the association between white matter hyperintensity (WMH) burden, FA, MD and PSMD using linear regression analyses both within individual cohorts as well as with pooled scans from multiple sites, before and after harmonization., Results: Before harmonization, significant differences in FA and MD were observed between matched controls of different sites (p < 0.05). After harmonization these site-differences were removed. Within each site, RISH harmonization did not alter the effect sizes of FA, MD and PSMD between patients and controls (relative change in Cohen's d = 4 %) nor the strength of association with WMH volume (relative change in R 2  = 2.8 %). After harmonization, patient data of all sites could be aggregated in a single analysis to infer the association between WMH volume and FA (R 2  = 0.62), MD (R 2  = 0.64), and PSMD (R 2  = 0.60)., Conclusions: We showed that RISH harmonization effectively removes acquisition-related differences in dMRI of elderly subjects while preserving sensitivity to SVD-related effects. This study provides proof of concept for future multicentre SVD studies with pooled datasets., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Microstructural alterations as assessed by diffusion tensor imaging (DTI) are key findings in both Alzheimer's disease (AD) and small vessel disease (SVD). We determined the contribution of each of these conditions to diffusion alterations., Methods: We studied six samples (N = 365 participants) covering the spectrum of AD and SVD, including genetically defined samples. We calculated diffusion measures from DTI and free water imaging. Simple linear, multivariable random forest, and voxel-based regressions were used to evaluate associations between AD biomarkers (amyloid beta, tau), SVD imaging markers, and diffusion measures., Results: SVD markers were strongly associated with diffusion measures and showed a higher contribution than AD biomarkers in multivariable analysis across all memory clinic samples. Voxel-wise analyses between tau and diffusion measures were not significant., Discussion: In memory clinic patients, the effect of SVD on diffusion alterations largely exceeds the effect of AD, supporting the value of diffusion measures as markers of SVD., (© 2020 the Alzheimer's Association.)

Purpose of Review: There is growing interest in disorders involved in ectopic mineralization. Fahr disease or idiopathic basal ganglia calcification can serve as a model for ectopic mineralization in the basal ganglia, which is fairly common in the general population. In this review, we will focus on causative gene mutations and corresponding pathophysiologic pathways in Fahr disease., Recent Findings: Patients with Fahr disease have a variability of symptoms, such as movement disorders, psychiatric signs, and cognitive impairment, but can also be asymptomatic. Fahr disease is mostly autosomal dominant inherited, and there are mutations found in 4 causative genes. Mutations in SLC20A2 and XPR1 lead to a disrupted phosphate metabolism involving brain-specific inorganic phosphate transporters. Mutations in PDGFB and PDGFRB are associated with disrupted blood-brain barrier integrity and dysfunctional pericyte maintenance. In addition, the MYORG gene has recently been discovered to be involved in the autosomal recessive inheritance of Fahr., Summary: Knowledge about the mutations and corresponding pathways may expose therapeutic opportunities for patients with Fahr disease and vascular calcifications in the brain in general., (© 2019 American Academy of Neurology.)

Intracranial large and small arterial calcifications are a common incidental finding on computed tomography imaging in the general population. Here we provide an overview of the published reports on prevalence of intracranial arterial calcifications on computed tomography imaging and histopathology in relation to risk factors and clinical outcomes. We performed a systematic search in Medline, with a search filter using synonyms for computed tomography scanning, (histo)pathology, different intracranial arterial beds, and calcification. We found that intracranial calcifications are a frequent finding in all arterial beds with the highest prevalence in the intracranial internal carotid artery. In general, prevalence increases with age. Longitudinal studies on calcification progression and intervention studies are warranted to investigate the possible causal role of calcification on clinical outcomes. This might open up new therapeutic directions in stroke and dementia prevention and the maintenance of the healthy brain., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Risk factors for and meaning of basal ganglia calcifications outside Fahr syndrome are poorly understood. We aimed to assess the prevalence of basal ganglia calcifications and the association with vascular risk factors., Materials and Methods: 1133 patients suspected of acute ischemic stroke from the Dutch acute stroke (DUST) study who underwent thin-slice unenhanced brain CT were analyzed. Basal ganglia calcifications were scored bilaterally as absent, mild (dot), moderate (multiple dots or single artery) and severe (confluent). Uni- and multivariable logistic regression analysis was used to determine possible risk factors (age, gender, history of stroke, smoking, hypertension, diabetes mellitus, hyperlipidemia, body mass index (BMI), renal function and family history of cardiovascular disease under 60 years) for presence of basal ganglia calcifications and ordinal regression analysis for severity of basal ganglia calcifications., Results: Mean age was 67.4 years (SD: 13.8), 56.8% were male. 337 (29.7%) patients had basal ganglia calcifications, of which 196 (58%) were mild, 103 (31%) moderate, 38 (11%) severe. In multivariable logistic regression analysis, age (OR: 1.02, 95% CI 1.01-1.03, P < 0.01) and BMI (OR: 0.95, 95% CI 0.91-0.98, p 0.01) were significantly associated with the presence of basal ganglia calcifications. Ordinal regression analysis gave comparable results. Age (OR: 1.02, 95% CI 1.01-1.03, P < 0.01) and BMI (OR: 0.95, 95% CI 0.92-0.99, P 0.01) were significantly associated with severity of basal ganglia calcifications., Conclusions: In this study with patients suspected of acute ischemic stroke, basal ganglia calcifications were common and significantly associated with older age and lower BMI., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Objective: To investigate the relationship between Alzheimer's disease biomarkers and neuropsychiatric symptoms., Methods: Data from two large cohort studies, the Dutch Parelsnoer Institute - Neurodegenerative Diseases and the Alzheimer's Disease Neuroimaging Initiative was used, including subjects with subjective cognitive decline (N = 650), mild cognitive impairment (N = 887), and Alzheimer's disease dementia (N = 626). Cerebrospinal fluid (CSF) levels of Aβ 42 , t-tau, p-tau, and hippocampal volume were associated with neuropsychiatric symptoms (measured with the Neuropsychiatric Inventory) using multiple logistic regression analyses. The effect of the Mini-Mental State Examination (as proxy for cognitive functioning) on these relationships was assessed with mediation analyses., Results: Alzheimer's disease biomarkers were not associated with depression, agitation, irritability, and sleep disturbances. Lower levels of CSF Aβ 42 , higher levels of t- and p-tau were associated with presence of anxiety. Lower levels of CSF Aβ 42 and smaller hippocampal volumes were associated with presence of apathy. All associations were mediated by cognitive functioning., Conclusion: The association between Alzheimer's disease pathology and anxiety and apathy is partly due to impairment in cognitive functioning., (Copyright © 2020 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: to develop a model to predict one- and three-year mortality in patients with dementia attending a hospital, through hospital admission or day/memory clinic., Design: we constructed a cohort of dementia patients through data linkage of three Dutch national registers: the hospital discharge register (HDR), the population register and the national cause of death register., Subjects: patients with dementia in the HDR aged between 60 and 100 years registered between 1 January 2000 and 31 December 2010., Methods: logistic regression analysis techniques were used to predict one- and three-year mortality after a first hospitalisation with dementia. The performance was assessed using the c-statistic and the Hosmer-Lemeshow test. Internal validation was performed using bootstrap resampling., Results: 50,993 patients were included in the cohort. Two models were constructed, which included age, sex, setting of care (hospitalised versus day clinic) and the presence of comorbidity using the Charlson comorbidity index. One model predicted one-year mortality and the other three-year mortality. Model discrimination according to the c-statistic for the models was 0.71 (95% CI 0.71-0.72) and 0.72 (95% CI 0.72-0.73), respectively., Conclusion: both models display acceptable ability to predict mortality. An important advantage is that they are easy to apply in daily practise and thus are helpful for individual decision-making regarding diagnostic/therapeutic interventions and advance care planning., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

MRI-visible perivascular spaces (PVS) in the semioval centre are associated with cerebral amyloid angiopathy (CAA), but it is unknown if PVS co-localize with MRI markers of CAA. To examine this, we assessed the topographical association between cortical cerebral microbleeds (CMBs) - as an indirect marker of CAA - and dilatation of juxtacortical perivascular spaces (jPVS) in 46 patients with amnestic mild cognitive impairment (aMCI) or early Alzheimer's disease (eAD). The degree of dilatation of jPVS <1 cm around each cortical CMBs was compared with a similar reference site (no CMB) in the contralateral hemisphere, using a 4-point scale. Also, jPVS dilatation was compared between patients with and without cortical CMBs. Eleven patients (24%) had cortical CMBs [total=35, median=1, range=1-14] of whom five had >1 cortical CMBs. The degree of jPVS dilatation was higher around CMBs than at the reference sites [Wilcoxon signed rank test, Z = 2.2, p  = 0.03]. Patients with >1 cortical CMBs had a higher degree of jPVS dilation [median=2.2, IQR = 1.8-2.3] than patients without cortical CMBs [median=1.4, IQR = 1.0-1.8], p  = 0.02. We found a topographical association between a high degree of jPVS dilatation and cortical CMBs, supporting a common underlying pathophysiology - most likely CAA.

Objective: To examine the mortality risk, and its risk factors, of older patients with dementia in psychiatric care., Methods: We constructed a cohort of dementia patients through data linkage of four Dutch registers: the Psychiatric Case Register Middle Netherlands (PCR-MN), the hospital discharge register, the population register, and the national cause of death register. All dementia patients in PCR-MN aged between 60 and 100 years between 1 January 2000 and 31 December 2010 were included. Risk factors of mortality were investigated using Cox proportional hazard regression models with adjustment for age, sex, setting of care, nationality, marital status, dementia type, and psychiatric and somatic comorbidities., Results: In total, 4297 patients were included with a median age of 80 years. The 1-year, 3-year, and 5-year mortality were 16.4%, 44.4%, and 63.5%, respectively. Determinants that increased the 1-year mortality were: male sex (adjusted hazard ratio [HR]: 1.49; 95% confidence interval [95% CI], 1.26-1.76), higher age (HR 1.08; 95% CI, 1.07-1.09), inpatient psychiatric care (HR 1.52; 95% CI, 1.19-1.93), more somatic comorbidities (HR 1.67; 95% CI, 1.49-1.87), and cardiovascular disease separately (HR 1.54; 95% CI, 1.30-1.82). Results for 3-year and 5-year mortality were comparable. Living together/married increased the 3- and 5-year mortality, and Dutch nationality increased the 5-year mortality. There were no differences in mortality with different types of psychiatric comorbidity., Conclusion: Mortality of dementia patients in psychiatric care was high, much higher than mortality in the general older population. The results of this study should raise awareness about their unfavourable prognosis, particularly older patients, men, inpatients, and patients with more somatic comorbidity., (© 2019 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Objective: To explore the effect of initiating statins for secondary prevention after a first myocardial infarction (MI) in patients aged 80 years and older., Design: Retrospective cohort study., Setting: Clinical Practice Research Datalink (1999-2016)., Participants: Patients, aged 65 years and older, hospitalized after a first MI without a statin prescription in the year before hospitalization. The age group of 65 to 80 years was included to compare our results to current evidence., Measurements: The primary outcome was a composite of recurrent MI, stroke, and cardiovascular mortality; and the secondary outcome was all-cause mortality. A time-varying Cox model was used to account for statin prescription over time. We compared at least 2 years of statin prescription time with untreated and less than 2 years of prescription time. Analyses were adjusted for potential confounders. The number needed to treat (NNT) was calculated based on the adjusted hazard ratios (HRs) and corrected for deaths during the first 2 years of follow-up., Results: A total of 9020 patients were included. Among the 3900 patients aged 80 years and older, 2 years of statin prescriptions resulted in a lower risk of the composite outcome (adjusted HR = 0.81; 95% confidence interval [CI] = 0.66-0.99) and of all-cause mortality (adjusted HR = 0.84; 95% CI = 0.73-0.97). During 4.5 years of median follow-up, the NNT for prevention of the primary outcome was 59; and for mortality, the NNT was 36. Correcting for 36.2% deaths during the first 2 years increased the NNT on the primary outcome to 93 and to 61 on all-cause mortality., Conclusion: Our data support statin initiation after a first MI in patients aged 80 years and older if continued for at least 2 years. Especially in patients with a low risk of 2-year mortality, statins should be considered. J Am Geriatr Soc 68:329-336, 2020., (© 2019 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals, Inc. on behalf of The American Geriatrics Society.)

Background: Vascular risk factors have been associated with risk of Alzheimer's disease (AD) and volume loss of the hippocampus, but the associations with subfields of the hippocampus are understudied. Knowing if vascular risk factors contribute to hippocampal subfield atrophy may improve our understanding of vascular contributions to neurodegenerative diseases., Objective: To investigate the associations between age, sex, and vascular risk factors with hippocampal subfields volumes on 7T MRI in older persons without dementia., Methods: From the Medea 7T study, 283 participants (67±9 years, 68% men) without dementia had 7T brain MRI and hippocampal subfield segmentation. Subfields were automatically segmented on the 3D T2-weighted 7T images with ASHS software. Using linear mixed models, we estimated adjusted associations of age, sex, and vascular risk factors with z-scores of volumes of the entorhinal cortex (ERC), subiculum (SUB), Cornu Ammonis (CA)1, CA2, CA3, CA4, and dentate gyrus (DG), and tail as multivariate correlated outcomes., Results: Increasing age was associated with smaller volumes in all subfields, except CA4/DG. Current smoking was associated with smaller ERC and SUB volumes; moderate alcohol use with smaller CA1 and CA4/DG, obesity with smaller volumes of ERC, SUB, CA2, CA3, and tail; and diabetes mellitus with smaller SUB volume. Sex, former smoking, and hypertension were not associated with subfield volumes. When formally tested, no risk factor affected the subfield volumes differentially., Conclusion: Several vascular risk factors were associated with smaller volumes of specific hippocampal subfields. However, no statistical evidence was found that subfields were differentially affected by these risk factors.

Introduction: Clinical 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 Analysis: The 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 m 2 ) 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 Dissemination: The 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 Number: EudraCT: 2017-000393-11; The Netherlands Trial Registry: 6721 (FRAIL-AF study)., Competing Interests: Competing interests: G-JG and FHR report unrestricted institutional grants for performing research in the field of atrial fibrillation from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer and Daiichi Sankyo. MEWH reports personal fees from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer and Daiichi Sankyo, and grants from The Netherlands Organisation for Health Research and Development (ZonMw), outside the submitted work. MVH reports grants from The Netherlands Organisation for Health Research and Development (ZonMw), Dutch Healthcare Fund and grants and personal fees from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer, Daiichi Sankyo and Aspen, outside the submitted work. All other authors (LPTJ, SvD, AWH, MCN, NMW, HLK, KCR, RMvdB and WFB) report no competing interests., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)