Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation.

Heterozygous GRN (progranulin) mutations cause frontotemporal dementia (FTD) due to haploinsufficiency, and increasing progranulin levels is a major therapeutic goal. Several microRNAs, including miR-29b, negatively regulate progranulin protein levels. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but strategies for increasing target protein levels are limited. Here, we tested the efficacy of ASOs as enhancers of progranulin expression by sterically blocking the miR-29b binding site in the 3' UTR of the human GRN mRNA. We found 16 ASOs that increase progranulin protein in a dose-dependent manner in neuroglioma cells. A subset of these ASOs also increased progranulin protein in iPSC-derived neurons and in a humanized GRN mouse model. In FRET-based assays, the ASOs effectively competed for miR-29b from binding to the GRN 3' UTR RNA. The ASOs increased levels of newly synthesized progranulin protein by increasing its translation, as revealed by polysome profiling. Together, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. This ASO strategy may be therapeutically feasible for progranulin-deficient FTD as well as other conditions of haploinsufficiency.

Blood-brain barrier penetration of non-replicating SARS-CoV-2 and S1 variants of concern induce neuroinflammation which is accentuated in a mouse model of Alzheimer's disease.

COVID-19 and especially Long COVID are associated with severe CNS symptoms and may place persons at risk to develop long-term cognitive impairments. Here, we show that two non-infective models of SARS-CoV-2 can cross the blood-brain barrier (BBB) and induce neuroinflammation, a major mechanism underpinning CNS and cognitive impairments, even in the absence of productive infection. The viral models cross the BBB by the mechanism of adsorptive transcytosis with the sugar N-acetylglucosamine being key. The delta and omicron variants cross the BB B faster than the other variants of concern, with peripheral tissue uptake rates also differing for the variants. Neuroinflammation induced by icv injection of S1 protein was greatly enhanced in young and especially in aged SAMP8 mice, a model of Alzheimer's disease, whereas sex and obesity had little effect.

Healthcare for older adults in North America: challenges, successes and opportunities.

Older adults in North America face similar challenges to successful ageing as other adults around the world, including an increased risk of geriatric syndromes and functional decline, limited access to healthcare professionals specialising in geriatrics and constraints on healthcare spending for Long-Term Services and Supports. Geriatrics as a specialty has long been established, along with the creation of a variety of screening tools for early identification of geriatric syndromes. Despite this, workforce shortages in all older adult care service areas have led to significant gaps in care, particularly in community settings. To address these gaps, innovative programs that expand the reach of geriatric specialists and services have been developed. Opportunities exist for further dissemination of these programs and services, as well as for expansion of an ageing capable workforce.

Frailty in geriatric psychiatry inpatients: a retrospective cohort study.

OBJECTIVE: We aimed to evaluate the prevalence, clinical determinants, and consequences (falls and hospitalization) of frailty in older adults with mental illness. DESIGN: Retrospective clinical cohort study. SETTING: We collected the data in a specialized psychogeriatric ward, in Boston, USA, between July 2018 and June 2019. PARTICIPANTS: Two hundred and fourty-four inpatients aged 65 years old and over. MEASUREMENTS: Psychiatric diagnosis was based on a multi-professional consensus meeting according to DSM-5 criteria. Frailty was assessed according to two common instruments, that is, the FRAIL questionnaire and the deficit accumulation model (aka Frailty Index [FI]). Multiple linear regression analyses were conducted to evaluate the association between frailty and sample demographics (age, female sex, and non-Caucasian ethnicity) and clinical characteristics (dementia, number of clinical diseases, current infection, number of psychotropic, and non-psychotropic medications in use). Multiple regression between frailty assessments and either falls or number of hospital admissions in the last 6 and 12 months, respectively, were analyzed and adjusted for covariates. RESULTS: Prevalence of frailty was high, that is, 83.6% according to the FI and 55.3% according to the FRAIL questionnaire. Age, the number of clinical (somatic) diseases, and the number of non-psychotropic medications were independently associated with frailty identified by the FRAIL. Dementia, current infection, the number of clinical (somatic) diseases, and the number of non-psychotropic medications were independently associated with frailty according to the FI. Falls were significantly associated with both frailty instruments. However, we found only a significant association for the number of hospital admissions with the FI. CONCLUSION: Frailty is highly prevalent among geriatric psychiatry inpatients. The FRAIL questionnaire and the FI may capture different forms of frailty dimensions, being the former probably more associated with the phenotype model and the latter more associated with multimorbidity.

Lowering dementia risk and slowing progression of disease: the role of cognitive reserve and cognitive training.

Almeida-Meza et al found an inverse correlation between cognitive reserve (associated with educational level, complexity of occupations and leisure activities) and dementia incidence. We suggest clarifying studies using their data-set and consider what can be done to modify socioeconomic inequalities that affect cognitive reserve or to slow early dementia.

The effect of a multicomponent exercise protocol (VIVIFRAIL©) on inflammatory profile and physical performance of older adults with different frailty status: study protocol for a randomized controlled trial.

BACKGROUND: To investigate whether an exercise intervention using the VIVIFRAIL© protocol has benefits for inflammatory and functional parameters in different frailty status. METHODS/DESIGN: This is a randomized clinical trial in an outpatient geriatrics clinic including older adults ≥60 years. For each frailty state (frail, pre-frail and robust), forty-four volunteers will be randomly allocated to the control group (n = 22) and the intervention group (n = 22) for 12 weeks. In the control group, participants will have meetings of health education while those in the intervention group will be part of a multicomponent exercise program (VIVIFRAIL©) performed five times a week (two times supervised and 3 times of home-based exercises). The primary outcome is a change in the inflammatory profile (a reduction in inflammatory interleukins [IL-6, TNF- α, IL1beta, IL-17, IL-22, CXCL-8, and IL-27] or an increase in anti-inflammatory mediators [IL-10, IL1RA, IL-4]). Secondary outcomes are change in physical performance using the Short Physical Performance Battery, handgrip strength, fatigue, gait speed, dual-task gait speed, depressive symptoms, FRAIL-BR and SARC-F scores, and quality of life at the 12-week period of intervention and after 3 months of follow-up. DISCUSSION: We expect a reduction in inflammatory interleukins or an increase in anti-inflammatory mediators in those who performed the VIVIFRAIL© protocol. The results of the study will imply in a better knowledge about the effect of a low-cost intervention that could be easily replicated in outpatient care for the prevention and treatment of frailty, especially regarding the inflammatory and anti-inflammatory pathways involved in its pathophysiology. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials (RBR-9n5jbw; 01/24/2020). Registred January 2020. http://www.ensaiosclinicos.gov.br/rg/RBR-9n5jbw/ .

Meaningful Engagement in the Nursing Home.

Throughout her career, Rosalie Kane made a major impact in her efforts to improve quality of life for persons living in nursing homes. Near the end of her career, she suggested that it was time to "re-imagine long term care and to produce livable age-friendly nursing homes." This brief review focuses on the role of meaningful engagement and person-centered care as the next step in enhancing nursing home care. The importance of activities that strengthen cognitive and/or physical function is stressed, as well as improving socialization to reduce loneliness.

Risk of incident dementia following metformin initiation compared with noninitiation or delay of antidiabetic medication therapy.

PURPOSE: Emerging evidence suggests metformin compared with sulfonylurea is associated with an 8% to 10% lower risk for dementia. Guidelines recommend metformin as initial diabetes treatment, but there is still the question of treatment timing. Thus, the risk of dementia associated with initiating metformin compared with not initiating or delaying treatment was examined. METHODS: A retrospective cohort study (1996 to 2015) was conducted with electronic health records from Veteran Health Affairs (VHA; n = 112 845) and Kaiser Permanente Washington (KPW; n = 14 333) healthcare systems. Patients were aged ≥50 years, had a hemoglobin A1c (HbA1c) between 6.5 and <9.5 mg/dL, and did not have dementia or fills for antidiabetic medications before cohort entry. Initiators started metformin monotherapy and noninitiators used no antidiabetic medications in the 6 months after the first qualifying HbA1c. The primary outcome was incident dementia. Propensity scores and inverse probability of treatment weighting (IPTW) controlled for confounding in Cox proportional hazards models. RESULTS: During a median follow-up of 6.2 years in VHA and 6.8 years in KPW, there were 7547 new dementia cases in VHA and 1090 in KPW. After IPTW, there was no association between initiation of metformin (vs no initial treatment) and incident dementia in VHA (HR = 1.04; 95% confidence interval [CI]: 0.95-1.13) or KPW (HR = 0.81; 95% CI: 0.51-1.28). Results did not differ by age, baseline HbA1c, or race. CONCLUSIONS: Results do not support initiating metformin earlier to prevent cognitive decline and, thus, may dampen enthusiasm for metformin as a potential antidementia drug. Randomized clinical trials could help clarify the relationship between metformin and cognitive decline.

Efficacy and safety of linagliptin to improve glucose control in older people with type 2 diabetes on stable insulin therapy: A randomized trial.

AIM: To assess the addition of linagliptin as an alternative to insulin uptitration in older people with type 2 diabetes on stable insulin therapy. MATERIALS AND METHODS: This phase 4, randomized, multicentre, double-blinded, placebo-controlled, 24-week study recruited individuals on stable insulin, with baseline HbA1c 7.0%-10.0%, aged ≥60 years and body mass index ≤45 kg/m2 . HbA1c and fasting plasma glucose were measured at study visits, and participants assessed glycaemic control with a self-monitoring blood glucose device. Adverse events (AEs) were reported during the study. RESULTS: Three hundred and two participants were randomized 1:1 to linagliptin 5 mg qd and placebo, with one third of patients from Japan. Study population age and HbA1c (baseline mean ± SD) were 72.4 ± 5.4 years and 8.2 ± 0.8%, respectively; ~80% of participants were aged ≥70 years; 80% had macrovascular complications, one third had a baseline estimated glomerular filtration rate <60 mL/min/1.73 m2 ; and half had been diagnosed with diabetes for >15 years. Linagliptin significantly improved glucose control at 24 weeks (HbA1c-adjusted mean change vs. placebo: -0.63%; P <0.0001) and the probability of achieving predefined HbA1c targets without hypoglycaemia (HbA1c <8.0%: OR 2.02; P <0.05 and HbA1c <7.0%: OR 2.44; P <0.01). Linagliptin versus placebo was well tolerated, with similar incidences of AEs, including clinically important hypoglycaemia (blood glucose <54 mg/dL) or severe hypoglycaemia. CONCLUSIONS: Addition of linagliptin improves glucose control without an excess of hypoglycaemia in older patients with type 2 diabetes on stable insulin therapy.

Association Between Metformin Initiation and Incident Dementia Among African American and White Veterans Health Administration Patients.

PURPOSE: African American patients are more likely to experience cognitive decline after type 2 diabetes mellitus onset than white patients. Metformin use has been associated with a lower risk of dementia compared with sulfonylureas. Evidence for whether this association differs by race is sparse. METHODS: Veterans Health Administration (VHA) medical record data were obtained for 73,761 African American and white patients aged ≥50 years who used the VHA from fiscal years 2000 to 2015. Patients were free of dementia and diabetes medications during fiscal years 2000 and 2001 and subsequently initiated metformin or sulfonylurea monotherapy. For race and age subgroups, Cox proportional hazards models using propensity scores and inverse probability of treatment weighting to control for confounding were computed to measure the association between metformin vs sulfonylurea initiation and incident dementia. RESULTS: After controlling for confounding, among patients aged ≥50 years, metformin vs sulfonylurea use was associated with a significantly lower risk of dementia in African American patients (hazard ratio [HR] = 0.73; 95% CI, 0.6-0.89) but not white patients (HR = 0.96; 95% CI, 0.9-1.03). The strongest magnitude of association between metformin and dementia was observed among African American patients aged 50 to 64 years (HR = 0.6; 95% CI, 0.45-0.81). Among those aged 65 to 74 years, metformin was significantly associated with lower risk of dementia in both races. Metformin was not associated with dementia in patients aged ≥75 years. CONCLUSIONS: Metformin vs sulfonylurea initiation was associated with a substantially lower risk of dementia among younger African American patients. These results may point to a novel approach for reducing the risk of dementia in African Americans with type 2 diabetes mellitus.

SARCOPENIA: AN ENDOCRINE DISORDER?

Sarcopenia is defined as low muscle function (walking speed or grip strength) in the presence of low muscle mass. A simple screening test-the SARC-F-is available to identify persons with sarcopenia. The major endocrine causes of sarcopenia are diabetes mellitus and male hypogonadism. Other causes are decreased physical activity, loss of motor neuron units, weight loss, inflammatory cytokines, reduced blood flow to muscles, very low 25(OH) vitamin D levels, and decreased growth hormone and insulin-like growth factor 1. Treatment for sarcopenia includes resistance and aerobic exercise, leucine-enriched essential amino acids, and vitamin D. In hypogonadal males, testosterone improves muscle mass, strength, and function. Selective androgen receptor molecules and anti-myostatin activin II receptor molecules are under development as possible treatments for sarcopenia. ABBREVIATIONS: COPD = chronic obstructive pulmonary disease DHEA = dehydroepiandrosterone IGF-1 = insulin-like growth factor 1 GH = growth hormone mTOR = mammalian target of rapamycin SARM = selective androgen receptor molecule.

AGING, DIABETES, AND FALLS.

KEY POINTS Falls are a major health issue for older adults, leading to adverse events and even death. Older persons with type 2 diabetes are at increased risk of falling compared to healthy adults of a similar age. Over 400 factors are associated with falls risk, making identification and targeting of key factors to prevent falls problematic. However, the major risk factors include hypertension, diabetes, pain, and polypharmacy. In addition to age and polypharmacy, diabetes-related loss of strength, sensory perception, and balance secondary to peripheral neuropathy along with decline in cognitive function lead to increased risk of falling. Designing specific interventions to target strength and balance training, reducing polypharmacy to improve cognitive function, relaxation of diabetes management to avoid hypoglycemia and hypotension, and relief of pain will produce the greatest benefit for reducing falls in older persons with diabetes. Abbreviation: DPN = diabetic polyneuropathy.

Testosterone therapy, association with age, initiation and mode of therapy with cardiovascular events: a systematic review.

BACKGROUND: Although male hypogonadism is associated with increased cardiovascular events (CVE), recent concerns are that testosterone supplementation may increase CVE. The purpose was to determine associations with age, initiation or mode of therapy to explain these discrepancies. DATA SYNTHESIS: Meta-analyses were supplemented through Scopus and PubMed with search terms 'testosterone', 'random' and 'trial'. CVE, defined before data extraction, were death, myocardial infarction, acute coronary syndrome, percutaneous coronary intervention, coronary bypass, syncope, arrhythmia, hospital admission for congestive heart failure or cerebrovascular event. RESULTS: There were 45 trials with 5328 subjects evaluated, with a mean age of 63·3 (SD ±7·9) years, followed for mean study duration of 10·6 (± 8·6) months. Overall, testosterone supplementation was not associated with increased CVE risk ratio (rr = 1·10 (95% CI 0·86; 1·41, P = 0·45)). However, there was an increase event rate during the first 12 months (rr = 1·79 (1·13;2·83, P = 0·012)), predominantly in those ≥65 years, (rr = 2·90 (1·35;6·21, P = 0·006)). Within studies with lipid data, CVE were associated with fall in HDL, P = 0·002. Intramuscular testosterone appeared neutral for CVE (rr = 0·96 (0·462;1·98, P = 0·91)) compared with oral testosterone (rr = 2·28 (95% CI 2·28;8·59, P = 0·22)) and transdermal testosterone (rr = 2·80 (1·38;5·68, P = 0·004)). Intramuscular testosterone had the least effect of lowering HDL and non-HDL cholesterol (both P < 0·001). CONCLUSIONS: Testosterone supplementation may be associated with increased CVE in those ≥65 years especially during the first year. Biological actions may differ depending upon mode of testosterone administration with intramuscular testosterone having less cardiovascular risk.

Nutrient interface with biology and aging.

PURPOSE OF REVIEW: To highlight recent conundrums in the interface of nutrition, biology and aging. RECENT FINDINGS: A Mediterranean diet with extra virgin olive oil, or similar plant-based diets, including five helpings of fruit and vegetables, exercise and nonsmoking are the mainstays of aging successfully. Recent studies have questioned the utility of weight loss in older persons, the use of antioxidant vitamin supplements as well as the appropriate level of sodium intake. The understanding of the role of ethnicity in the levels of vitamin D-binding protein has questioned the measurement of 25(OH)vitamin D by itself. Gut microbiota may also appear important for aging. SUMMARY: Continuous scientific advances are leading us to question whether some of our nutrient beliefs need to be altered in older persons.

Pharmacologic Options for the Treatment of Sarcopenia.

Sarcopenia is now clinically defined as a loss of muscle mass coupled with functional deterioration (either walking speed or distance or grip strength). Based on the FRAX studies suggesting that the questions without bone mineral density can be used to screen for osteoporosis, there is now a valid simple questionnaire to screen for sarcopenia, i.e., the SARC-F. Numerous factors have been implicated in the pathophysiology of sarcopenia. These include genetic factors, mitochondrial defects, decreased anabolic hormones (e.g., testosterone, vitamin D, growth hormone and insulin growth hormone-1), inflammatory cytokine excess, insulin resistance, decreased protein intake and activity, poor blood flow to muscle and deficiency of growth derived factor-11. Over the last decade, there has been a remarkable increase in our understanding of the molecular biology of muscle, resulting in a marked increase in potential future targets for the treatment of sarcopenia. At present, resistance exercise, protein supplementation, and vitamin D have been established as the basic treatment of sarcopenia. High-dose testosterone increases muscle power and function, but has a number of potentially limiting side effects. Other drugs in clinical development include selective androgen receptor molecules, ghrelin agonists, myostatin antibodies, activin IIR antagonists, angiotensin converting enzyme inhibitors, beta antagonists, and fast skeletal muscle troponin activators. As sarcopenia is a major predictor of frailty, hip fracture, disability, and mortality in older persons, the development of drugs to treat it is eagerly awaited.

Frailty and Sarcopenia: The New Geriatric Giants.

In the last decade, it has become clear that older persons who are frail or sarcopenic have very high rates of functional deterioration, hospitalization, and death. Recently, it has become recognized that simple screening questionnaires, e.g., the FRAIL and SARC-F, perform as well as more complex testing for the physical phenotype screen and sarcopenia. In this article, we provide a simple algorithm for the management of frailty. The multiple factors responsible for the pathogenesis of sarcopenia are reviewed, focusing on the importance of age-associated loss of motor units innervating muscle. Management of sarcopenia includes resistance exercise, leucine-enriched protein, and vitamin D. A number of newer drugs are under development. General practitioners should be encouraged to screen for frailty and sarcopenia in older persons.

Atrial fibrillation: A major risk factor for cognitive decline.

Atrial fibrillation is a common disease of the elderly, conferring considerable morbidity and mortality related to cardiovascular effects and thromboembolic risks. Anticoagulation, antiarrhythmic medications, and rate control are the cornerstone of contemporary management, whereas ablation and evolving surgical techniques continue to play important secondary roles. Growing evidence shows that atrial fibrillation is also a risk factor for significant cognitive decline through a multitude of pathways, further contributing to morbidity and mortality. At the same time, cognitive decline associated with cryptogenic strokes may be the first clue to previously undiagnosed atrial fibrillation. These overlapping associations support the concept of cognitive screening and rhythm monitoring in these populations. New research suggests modulating effects of currently accepted treatments for atrial fibrillation on cognition; however, there remains the need for large multicenter studies to examine the effects of novel oral anticoagulants, rhythm and rate control, and left atrial appendage occlusion on long-term cognitive function.