Introduction: There is a growing body of evidence that subtle deficits in instrumental activities of daily living (IADL) may be present in mild cognitive impairment (MCI). However, it is not clear if there are IADL domains that are consistently affected across patients with MCI. In this systematic review, therefore, we aimed to summarize research results regarding the performance of MCI patients in specific IADL (sub)domains compared with persons who are cognitively normal and/or patients with dementia. Methods: The databases PsycINFO, PubMed and Web of Science were searched for relevant literature in December 2013. Publications from 1999 onward were considered for inclusion. Altogether, 497 articles were retrieved. Reference lists of selected articles were searched for potentially relevant articles. After screening the abstracts of these 497 articles, 37 articles were included in this review. Results: In 35 studies, IADL deficits (such as problems with medication intake, telephone use, keeping appointments, finding things at home and using everyday technology) were documented in patients with MCI. Financial capacity in patients with MCI was affected in the majority of studies. Effect sizes for group differences between patients with MCI and healthy controls were predominantly moderate to large. Performance-based instruments showed slight advantages (in terms of effect sizes) in detecting group differences in IADL functioning between patients with MCI, patients with Alzheimer’s disease and healthy controls. Conclusion: IADL requiring higher neuropsychological functioning seem to be most severely affected in patients with MCI. A reliable identification of such deficits is necessary, as patients with MCI with IADL deficits seem to have a higher risk of converting to dementia than patients with MCI without IADL deficits. The use of assessment tools specifically designed and validated for patients with MCI is therefore strongly recommended. Furthermore, the development of performance-based assessment instruments should be intensified, as they allow a valid and reliable assessment of subtle IADL deficits in MCI, even if a proxy is not available. Another important point to consider when designing new scales is the inclusion of technology-associated IADL. Novel instruments for clinical practice should be time-efficient and easy to administer.

Having made substantial progress understanding molecules, cells, genes and pathways, aging biology research is now moving toward integration of these parts, attempting to understand how their joint dynamics may contribute to aging. Such a shift of perspective requires the adoption of a formal complex systems framework, a transition being facilitated by large-scale data collection and new analytical tools. Here, we provide a theoretical framework to orient researchers around key concepts for this transition, notably emergence, interaction networks and resilience. Drawing on evolutionary theory, network theory and principles of homeostasis, we propose that organismal function is accomplished by the integration of regulatory mechanisms at multiple hierarchical scales, and that the disruption of this ensemble causes the phenotypic and functional manifestations of aging. We present key examples at scales ranging from sub-organismal biology to clinical geriatrics, outlining how this approach can potentially enrich our understanding of aging.

The traditional evaluation of gait in the laboratory during structured testing has provided important insights, but is limited by its “snapshot” character and observation in an unnatural environment. Wearables enable monitoring of gait in real-world environments over a week. Initial findings show that in-lab and real-world measures differ. As a step towards better understanding these gaps, we directly compared in-lab usual-walking (UW) and dual-task walking (DTW) to daily-living measures of gait. In-lab gait features (e.g., gait speed, step regularity, and stride regularity) derived from UW and DTW were compared to the same gait features during daily-living in 150 elderly fallers (age: 76.5 ± 6.3 years, 37.6% men). In both settings, features were extracted from a lower-back accelerometer. In the real-world setting, subjects were asked to wear the device for 1 week and pre-processing detected 30-s daily-living walking bouts. A histogram of all walking bouts was determined for each walking feature for each subject and then each subject’s typical (percentile 50, median), worst (percentile 10) and the best (percentile 90) values over the week were determined for each feature. Statistics of reliability were assessed using Intra-Class correlations and Bland-Altman plots. As expected, in-lab gait speed, step regularity, and stride regularity were worse during DTW, compared to UW. In-lab gait speed, step regularity, and stride regularity during UW were significantly higher (i.e., better) than the typical daily-living values (p < 0.001) and different (p < 0.001) from the worst and best values. DTW values tended to be similar to typical daily-living values (p = 0.205, p = 0.053, p = 0.013 respectively). ICC assessment and Bland-Altman plots indicated that in-lab values do not reliably reflect the daily-walking values. Gait values measured during relatively long (30-s) daily-living walking bouts are more similar to the corresponding values obtained in the lab during dual-task walking, as compared to usual walking. Still, gait performance during most daily-living walking bouts is worse than that measured during usual and dual-tasking in the lab. The values measured in the lab do not reliably reflect daily-living measures. That is, an older adult’s typical daily-living gait cannot be estimated by simply measuring walking in a structured, laboratory setting.

This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease–specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, −0.07–1.64) at 13 weeks, 6.41 (5.33–7.49) at 52 weeks, and 9.63 (8.33–10.93) at 78 weeks and on nilvadipine was 0.88 (0.02–1.74) at 13 weeks, 5.75 (4.66–6.85) at 52 weeks, and 9.41 (8.09–10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.

Coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), continues to spread globally despite the worldwide implementation of preventive measures to combat the disease. Although most COVID‐19 cases are characterised by a mild, self‐limiting disease course, a considerable subset of patients develop a more severe condition, varying from pneumonia and acute respiratory distress syndrome (ARDS) to multi‐organ failure (MOF). Progression of COVID‐19 is thought to occur as a result of a complex interplay between multiple pathophysiological mechanisms, all of which may orchestrate SARS‐CoV‐2 infection and contribute to organ‐specific tissue damage. In this respect, dissecting currently available knowledge of COVID‐19 immunopathogenesis is crucially important, not only to improve our understanding of its pathophysiology but also to fuel the rationale of both novel and repurposed treatment modalities. Various immune‐mediated pathways during SARS‐CoV‐2 infection are relevant in this context, which relate to innate immunity, adaptive immunity, and autoimmunity. Pathological findings in tissue specimens of patients with COVID‐19 provide valuable information with regard to our understanding of pathophysiology as well as the development of evidence‐based treatment regimens. This review provides an updated overview of the main pathological changes observed in COVID‐19 within the most commonly affected organ systems, with special emphasis on immunopathology. Current management strategies for COVID‐19 include supportive care and the use of repurposed or symptomatic drugs, such as dexamethasone, remdesivir, and anticoagulants. Ultimately, prevention is key to combat COVID‐19, and this requires appropriate measures to attenuate its spread and, above all, the development and implementation of effective vaccines. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.