Though the symptoms of Alzheimer disease go on for years, the phase 3 trials of the cholinesterase inhibitors (ChEIs), the current mainstay of symptomatic pharmacotherapy for this condition, were ...typically of only 3- to 6-months' duration. We have limited data on long-term (that is, a year or more) therapy with these agents. In this review, we explore the available information on the biological and clinical effects of long-term ChEI therapy, what happens when these agents are discontinued, and examine what others have recommended. An individualized approach to deciding on whether to carry on with a ChEI should be taken. If continued, treatment goals should be clarified and patients monitored over time, for both drug-related benefits and adverse effects.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
For community-dwelling older persons with dementia, the presence of multimorbidity can create complex clinical challenges for both individuals and their physicians, and can contribute to poor ...outcomes. We quantified the associations between level of multimorbidity (chronic disease burden) and risk of hospitalization and risk of emergency department (ED) visit in a home care cohort with dementia and explored the role of continuity of physician care (COC) in modifying these relationships.
A retrospective cohort study using linked administrative and clinical data from Ontario, Canada, was conducted among 30,112 long-stay home care clients (mean age 83.0 ± 7.7 y) with dementia in 2012. Multivariable Fine-Gray regression models were used to determine associations between level of multimorbidity and 1-y risk of hospitalization and 1-y risk of ED visit, accounting for multiple competing risks (death and long-term care placement). Interaction terms were used to assess potential effect modification by COC. Multimorbidity was highly prevalent, with 35% (n = 10,568) of the cohort having five or more chronic conditions. In multivariable analyses, risk of hospitalization and risk of ED visit increased monotonically with level of multimorbidity: sub-hazards were 88% greater (sub-hazard ratio sHR = 1.88, 95% CI: 1.72-2.05, p < 0.001) and 63% greater (sHR = 1.63; 95% CI: 1.51-1.77, p < 0.001), respectively, among those with five or more conditions, relative to those with dementia alone or with dementia and one other condition. Low (versus high) COC was associated with an increased risk of both hospitalization and ED visit in age- and sex-adjusted analyses only (sHR = 1.11, 95% CI: 1.07-1.16, p < 0.001, for hospitalization; sHR = 1.07, 95% CI: 1.03-1.11, p = 0.001, for ED visit) but did not modify associations between multimorbidity and outcomes (Wald test for interaction, p = 0.566 for hospitalization and p = 0.637 for ED visit). The main limitations of this study include use of fixed (versus time-varying) covariates and focus on all-cause rather than cause-specific hospitalizations and ED visits, which could potentially inform interventions.
Older adults with dementia and multimorbidity pose a particular challenge for health systems. Findings from this study highlight the need to reshape models of care for this complex population, and to further investigate health system and other factors that may modify patients' risk of health outcomes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nonalcoholic fatty liver disease (NAFLD), a common prelude to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. Defining the molecular mechanisms underlying ...the pathogenesis of NAFLD has been hampered by a lack of animal models that closely recapitulate the severe end of the disease spectrum in humans, including bridging hepatic fibrosis. Here we demonstrate that a novel experimental model employing thermoneutral housing, as opposed to standard housing, resulted in lower stress-driven production of corticosterone, augmented mouse proinflammatory immune responses and markedly exacerbated high-fat diet (HFD)-induced NAFLD pathogenesis. Disease exacerbation at thermoneutrality was conserved across multiple mouse strains and was associated with augmented intestinal permeability, an altered microbiome and activation of inflammatory pathways that are associated with the disease in humans. Depletion of Gram-negative microbiota, hematopoietic cell deletion of Toll-like receptor 4 (TLR4) and inactivation of the IL-17 axis resulted in altered immune responsiveness and protection from thermoneutral-housing-driven NAFLD amplification. Finally, female mice, typically resistant to HFD-induced obesity and NAFLD, develop full disease characteristics at thermoneutrality. Thus, thermoneutral housing provides a sex-independent model of exacerbated NAFLD in mice and represents a novel approach for interrogation of the cellular and molecular mechanisms underlying disease pathogenesis.
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IJS, NUK, SBMB, UL, UM, UPUK
IMPORTANCE: Depression is common in individuals with mild cognitive impairment (MCI) and may confer a higher likelihood of progression to dementia. Prevalence estimates of depression in those with ...MCI are required to guide both clinical decisions and public health policy, but published results are variable and lack precision. OBJECTIVE: To provide a precise estimate of the prevalence of depression in individuals with MCI and identify reasons for heterogeneity in the reported results. DATA SOURCES: A search of literature from database inception to March 2016 was performed using Medline, Embase, and PsycINFO. Hand searching of all included articles was performed, including a Google Scholar search of citations of included articles. STUDY SELECTION: Articles were included if they (1) were published in English, (2) reported patients with MCI as a primary study group, (3) reported depression or depressive symptoms using a validated instrument, and (4) reported the prevalence of depression in patients with MCI. DATA EXTRACTION AND SYNTHESIS: All abstracts, full-text articles, and other sources were reviewed, with data extracted in duplicate. The overall prevalence of depression in patients with MCI was pooled using a random-effects model. Heterogeneity was explored using stratification and random-effects meta-regression. MAIN OUTCOMES AND MEASURES: The prevalence of depression in patients with MCI, reported as a percentage with 95% CIs. Estimates were also stratified by population source (community-based or clinic-based sample), method of depression diagnosis (clinician-administered, informant-based, or self-report), and method of MCI diagnosis (cognitive vs global measure and amnestic vs nonamnestic). RESULTS: Of 5687 unique abstracts, 255 were selected for full-text review, and 57 studies, representing 20 892 patients, met all inclusion criteria. The overall pooled prevalence of depression in patients with MCI was 32% (95% CI, 27-37), with significant heterogeneity between estimates (I2 = 90.7%). When stratified by source, the prevalence of depression in patients with MCI in community-based samples was 25% (95% CI, 19-30) and was 40% (95% CI, 32-48) in clinic-based samples, which was significantly different (P < .001). The method used to diagnose depression did not significantly influence the prevalence estimate, nor did the criteria used for MCI diagnosis or MCI subtype. CONCLUSIONS AND RELEVANCE: The prevalence of depression in patients with MCI is high. A contributor to heterogeneity in the reported literature is the source of the sample, with greater depression burden prevalent in clinic-based samples.
Nuclear factor of activated T cells (NFAT) proteins are Ca²âº-regulated transcription factors that control gene expression in many cell types. NFAT proteins are heavily phosphorylated and reside in ...the cytoplasm of resting cells; when cells are stimulated by a rise in intracellular Ca²âº, NFAT proteins are dephosphorylated by the Ca²âº/calmodulin-dependent phosphatase calcineurin and translocate to the nucleus to activate target gene expression. Here we show that phosphorylated NFAT1 is present in a large cytoplasmic RNA-protein scaffold complex that contains a long intergenic noncoding RNA (lincRNA), NRON noncoding (RNA) repressor of NFAT; a scaffold protein, IQ motif containing GTPase activating protein (IQGAP); and three NFAT kinases, casein kinase 1, glycogen synthase kinase 3, and dual specificity tyrosine phosphorylation regulated kinase. Combined knockdown of NRON and IQGAP1 increased NFAT dephosphorylation and nuclear import exclusively after stimulation, without affecting the rate of NFAT rephosphorylation and nuclear export; and both NRON-depleted T cells and T cells from IQGAP1-deficient mice showed increased production of NFAT-dependent cytokines. Our results provide evidence that a complex of lincRNA and protein forms a scaffold for a latent transcription factor and its regulatory kinases, and support an emerging consensus that lincRNAs that bind transcriptional regulators have a similar scaffold function.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Multimorbidity is increasing among older adults, but the impact of these recent trends on the extent and complexity of polypharmacy and possible variation by sex remains unknown. We examined sex ...differences in multimorbidity, polypharmacy (5+ medications) and hyper-polypharmacy (10+ medications) in 2003 vs 2016, and the interactive associations between age, multimorbidity level, and time on polypharmacy measures.
We employed a repeated cross-sectional study design with linked health administrative databases for all persons aged ≥66 years eligible for health insurance in Ontario, Canada at the two index dates. Descriptive analyses and multivariable logistic regression models were conducted; models included interaction terms between age, multimorbidity level, and time period to estimate polypharmacy and hyper-polypharmacy probabilities, risk differences and risk ratios for 2016 vs 2003. Multimorbidity, polypharmacy and hyper-polypharmacy increased significantly over the 13 years. At both index dates prevalence estimates for all three were higher in women, but a greater absolute increase in polypharmacy over time was observed in men (6.6% from 55.7% to 62.3% vs 0.9% 64.2%-65.1% for women) though absolute increases in multimorbidity were similar for men and women (6.9% 72.5%-79.4% vs 6.2% 75.9%-82.1%, respectively). Model findings showed that polypharmacy decreased over time among women aged < 90 years (especially for younger ages and those with fewer conditions), whereas it increased among men at all ages and multimorbidity levels (with larger absolute increases typically at older ages and among those with 4 or fewer conditions).
There are sex and age differences in the impact of increasing chronic disease burden on changes in measures of multiple medication use among older adults. Though the drivers and health consequences of these trends warrant further investigation, the findings support the heterogeneity and complexity in the evolving association between multimorbidity and polypharmacy measures in older populations.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Clinicians and researchers have shown increasing interest in frailty. Yet, there is still considerable uncertainty regarding the concept and its definition. In this article, we present perspectives ...on key issues and controversies discussed by scientists from 13 different countries, representing a diverse range of disciplines, at the 2006 Second International Working Meeting on Frailty and Aging. The following fundamental questions are discussed: What is the distinction, if any, between frailty and aging? What is its relationship with chronic disease? Is frailty a syndrome or a series of age-related impairments that predict adverse outcomes? What are the critical domains in its operational definition? Is frailty a useful concept? The implications of different models and approaches are examined. Although consensus has yet to be attained, work accomplished to date has opened exciting new horizons. The article concludes with suggested directions for future research.
Prévalence et incidence de la démence fronto-temporale : une revue systématique du sujet.
Contexte :
Les études de population sur la prévalence et l’incidence sont essentielles à la compréhension du ...fardeau associé à la démence fronto-temporale (DFT).
Méthodologie :
Nous avons cherché dans les bases de données MEDLINE et EMBASE les articles publiés entre 2000 et 2012 portant sur l’incidence et/ou la prévalence de la DFT dans la population. Nous avons également examiné les références des articles inclus dans notre étude ainsi que celles des revues systématiques antérieures. Deux évaluateurs ont examiné tous les résumés et le texte intégral des publications et l’extraction des données, et ils en ont évalué la qualité.
Résultats :
Vingt-six études ont été retenues. Des limites méthodologiques expliquent les écarts dans les estimations de prévalence (prévalence ponctuelle de 0,01 à 4,6 par 1 000 ; prévalence d’une période donnée de 0,16 à 31,04 par 1 000) et incidence (0,0 à 0,3 par 1 000 personnes-années). La DFT constituait en moyenne 2,7% (écart de 0 à 9,1%) de tous les cas de démence dans les études de prévalence qui incluaient des sujets de 65 ans et plus par rapport à 10,2% (2,8 à 15,7%) dans les études portant sur des sujets âgés de moins de 65 ans. Les nombres cumulatifs d’hommes (373 52,5%) et de femmes (338 47,5%) tirés des études dans lesquelles cette information était mentionnée étaient pratiquement égaux (p=0,18). La variante comportementale DFT était presque quatre fois plus fréquente que les aphasies progressives primaires.
Conclusions
: Les estimations basées sur la population en ce qui concerne l’épidémiologie de la DFT étaient très variables dans les études que nous avons retenues. Il faudra raffiner le processus diagnostique, possiblement par l’utilisation de biomarqueurs validés ou limitant la constatation des cas à ceux confirmés par des services spécialisés, pour obtenir des estimations plus précises de la prévalence et de l’incidence de la DFT.
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