Angiotensin receptor blocker use is associated with upregulation of the memory-protective angiotensin type 4 receptor (AT4R) in the postmortem brains of individuals without cognitive impairment.

The reported primary dementia-protective benefits of angiotensin II type 1 receptor (AT1R) blockers (ARB) are believed, at least in part, to arise from systemic effects on blood pressure. However, there is a specific and independently regulated brain renin-angiotensin system (RAS). Brain RAS acts mainly through three receptor subtypes; AT1R, AT2R, and AT4R. The AT1R promotes inflammation and mitochondrial reactive oxygen species generation. AT2R increases nitric oxide. AT4R is essential for dopamine and acetylcholine release. It is unknown whether ARB use is associated with changes in the brain RAS. Here, we compared the impact of treatment with ARB on not cognitively impaired individuals and individuals with Alzheimer's dementia using postmortem frontal-cortex samples of age- and sex-matched participants (70-90 years old, n = 30 in each group). We show that ARB use is associated with higher brain AT4R, lower oxidative stress, and amyloid-ß burden in NCI participants. In AD, ARB use was associated with lower brain AT1R but had no impact on inflammation, oxidative stress, or amyloid-ß burden. Our results may suggest a potential role for AT4R in the salutary effects for ARB on the brains of not cognitively impaired older adults.

Metformin use and mortality and length of stay among hospitalized patients with type 2 diabetes and COVID-19: A multiracial, multiethnic, urban observational study.

Introduction: Diabetes mellitus is a common comorbidity among patients with coronavirus disease 2019 (COVID-19). Diabetic patients with COVID-19 have a two-fold increased risk of death and tend to have more severe infection compared to the general population. Metformin, a first-line medication for diabetes management, has anti-inflammatory and immunomodulatory effects. Previous studies focusing on metformin and COVID-19 clinical outcomes have had mixed results, with some showing a mortality benefit or decreased complications with metformin use. To date, few studies have analyzed such outcomes among a diverse, multiracial community. Methods: This was a retrospective review of patients with Type 2 diabetes and a confirmed COVID-19 infection admitted to an urban academic medical center from January 1, 2020 to May 7, 2020. Baseline characteristics were collected. The primary outcomes of the study were in-hospital mortality and length of stay (LOS). Results: A total of 4462 patients with Type 2 diabetes and confirmed COVID-19 were identified. 41.3% were Black, and 41.5% were Hispanic. There were 1021 patients in the metformin group and 3441 in the non-metformin group. Of note, more participants in the metformin group had comorbid disease and/or advanced diabetes. We found no statistically significant differences between the metformin and non-metformin group in in-hospital mortality (28.1% vs 25.3%, P=0.08) or length of hospital stay in days (7.3 vs. 7.5, P=0.59), even after matching patients on various factors (29.3% vs. 29.6%, P=0.87; 7.7 vs. 8.1, P=0.23). Conclusion: While patients had more comorbid disease and advanced diabetes in the metformin group, there were no significant differences with regard to in-hospital mortality or length of stay due to COVID-19 compared to the non-metformin group. Prospective studies are needed to determine if there is clinical benefit for initiating, continuing, or re-initiating metformin in patients hospitalized with COVID-19.

Introducing CatchU™: A Novel Multisensory Tool for Assessing Patients' Risk of Falling.

To date, only a few studies have investigated the clinical translational value of multisensory integration. Our previous research has linked the magnitude of visual-somatosensory integration (measured behaviorally using simple reaction time tasks) to important cognitive (attention) and motor (balance, gait, and falls) outcomes in healthy older adults. While multisensory integration effects have been measured across a wide array of populations using various sensory combinations and different neuroscience research approaches, multisensory integration tests have not been systematically implemented in clinical settings. We recently developed a step-by-step protocol for administering and calculating multisensory integration effects to facilitate innovative and novel translational research across diverse clinical populations and age-ranges. In recognizing that patients with severe medical conditions and/or mobility limitations often experience difficulty traveling to research facilities or joining time-demanding research protocols, we deemed it necessary for patients to be able to benefit from multisensory testing. Using an established protocol and methodology, we developed a multisensory falls-screening tool called CatchU ™ (an iPhone app) to quantify multisensory integration performance in clinical practice that is currently undergoing validation studies. Our goal is to facilitate the identification of patients who are at increased risk of falls and promote physician-initiated falls counseling during clinical visits (e.g., annual wellness, sick, or follow-up visits). This will thereby raise falls-awareness and foster physician efforts to alleviate disability, promote independence, and increase quality of life for our older adults. This conceptual overview highlights the potential of multisensory integration in predicting clinical outcomes from a research perspective, while also showcasing the practical application of a multisensory screening tool in routine clinical practice.

Higher Angiotensin II Type 1 Receptor Levels and Activity in the Postmortem Brains of Older Persons with Alzheimer's Dementia.

Aging is a key risk factor in Alzheimer's dementia (AD) development and progression. The primary dementia-protective benefits of angiotensin II subtype 1 receptor (AT1R) blockers are believed to arise from systemic effects on blood pressure. However, a brain-specific renin-angiotensin system (b-RAS) exists, which can be altered by AT1R blockers. Brain RAS acts mainly through 3 angiotensin receptors: AT1R, AT2R, and AT4R. Changes in these brain angiotensin receptors may accelerate the progression of AD. Using postmortem frontal cortex brain samples of age- and sex-matched cognitively normal individuals (n = 30) and AD patients (n = 30), we sought to dissect the b-RAS changes associated with AD and assess how these changes correlate with brain markers of oxidative stress, inflammation, and mitochondrial dysfunction as well as amyloid-ß and paired helical filament tau pathologies. Our results show higher protein levels of the pro-inflammatory AT1R and phospho-ERK (pERK) in the brains of AD participants. Brain AT1R levels and pERK correlated with higher oxidative stress, lower cognitive performance, and higher tangle and amyloid-ß scores. This study identifies molecular changes in b-RAS and offers insight into the role of b-RAS in AD-related brain pathology.

Coronavirus Related Mortality in the Geriatrics Ambulatory Practice.

BACKGROUND: Older adults often have atypical presentations of common diseases and COVID-19 is no exception. Presentations range from asymptomatic to overwhelming symptoms that result in hospitalization, intubation, or death. The number of COVID-19 related deaths among older adults in the outpatient practice during the peak of the pandemic is unclear. METHODS: The objective is to describe the COVID-19 status and clinical characteristics of patients in a Geriatrics Ambulatory Practice who died during the peak of the COVID-19 pandemic. Design: Retrospective chart review Participants: 54 adults age 65 years and older. Methods: COVID-19 status defined by positive test result and presumed COVID-19 status based upon clinical presentation. RESULTS: Out of 1200 active patients in the Geriatrics Ambulatory Practice, 54 (4.5%) died between January 1st, 2020 and June 30th, 2020. The study sample was 63% female, 33% Hispanic/Latino, 27% Black/African American, and 22% white. The mean (SD) age was 86(8.6) years, range (72-107 years). The most prevalent medical comorbidities in decreasing order of frequency were hypertension (88.9%), diabetes (51.9%), and cognitive impairment (51.9%). Nineteen (35%) were COVID-19 positive and 8 had presumed COVID-19. There were no statistically significant differences in age, gender, race/ethnicity, and medical comorbidities between the COVID-19 or presumed COVID-19 group compared to those with No COVID-19. CONCLUSION: Approximately 35% of Geriatric patients who died during the first 6 months of 2020 had confirmed COVID-19 and an additional 15% had presumed COVID-19. The actual number of COVID-19 related deaths among older adults in the ambulatory practice during the peak of the pandemic is difficult to estimate and likely underestimated.

Brain Renin-Angiotensin System at the Intersect of Physical and Cognitive Frailty.

The renin-angiotensin system (RAS) was initially considered to be part of the endocrine system regulating water and electrolyte balance, systemic vascular resistance, blood pressure, and cardiovascular homeostasis. It was later discovered that intracrine and local forms of RAS exist in the brain apart from the endocrine RAS. This brain-specific RAS plays essential roles in brain homeostasis by acting mainly through four angiotensin receptor subtypes; AT1R, AT2R, MasR, and AT4R. These receptors have opposing effects; AT1R promotes vasoconstriction, proliferation, inflammation, and oxidative stress while AT2R and MasR counteract the effects of AT1R. AT4R is critical for dopamine and acetylcholine release and mediates learning and memory consolidation. Consequently, aging-associated dysregulation of the angiotensin receptor subtypes may lead to adverse clinical outcomes such as Alzheimer's disease and frailty via excessive oxidative stress, neuroinflammation, endothelial dysfunction, microglial polarization, and alterations in neurotransmitter secretion. In this article, we review the brain RAS from this standpoint. After discussing the functions of individual brain RAS components and their intracellular and intracranial locations, we focus on the relationships among brain RAS, aging, frailty, and specific neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and vascular cognitive impairment, through oxidative stress, neuroinflammation, and vascular dysfunction. Finally, we discuss the effects of RAS-modulating drugs on the brain RAS and their use in novel treatment approaches.

Motoric Cognitive Risk Syndrome in Polypharmacy.

OBJECTIVES: Risk factors for motoric cognitive risk syndrome (MCR), a predementia syndrome characterized by slow gait and cognitive complaints, have been identified, but few are reversible. Polypharmacy is a potentially reversible risk factor for cognitive decline, but the relationship between MCR and polypharmacy has not been examined. Our aim was to compare the epidemiology of MCR and polypharmacy. DESIGN: Cross-sectional. SETTING: Community-based Health and Retirement Study cohort. PARTICIPANTS: A total of 1119 adults 65 years and older (mean age = 74.7 ± 7.0 y; 59% female). MEASUREMENTS: Polypharmacy is defined as the use of five or more regularly scheduled medications. MCR is defined as cognitive complaints and slow gait in an individual without dementia. RESULTS: The prevalence of MCR among 417 participants with polypharmacy was 10%; it was 6% among 702 participants without polypharmacy. The odds of meeting MCR criteria in those with polypharmacy was 1.8 (confidence interval = 1.0-3.0; P = .035) compared with those without polypharmacy, even after adjusting for high-risk medication use. CONCLUSION: Our results show the coexistence of MCR and polypharmacy in older adults, suggesting a potentially modifiable risk factor for dementia. J Am Geriatr Soc 68:1072-1077, 2020.

The effect of polypharmacy on prefrontal cortex activation during single and dual task walking in community dwelling older adults.

INTRODUCTION: Polypharmacy, defined as the use of 5 or more medications is associated with multiple adverse outcomes in older adults, including falls and slow gait velocity. However, the relationship between polypharmacy and cortical control of locomotion has not been reported. The purpose of this study was to examine the relationship between polypharmacy and activation patterns in the prefrontal cortex (PFC), a brain region involved in higher order control of locomotion during attention-demanding conditions. METHODS: Using Functional Near Infrared Spectroscopy (fNIRS) to quantify PFC oxygenated hemoglobin (HbO2) levels, we performed a cross sectional analysis of 325 community dwelling adults age ≥65 years, and examined HbO2 levels during single tasks (Single-Task-Walk (STW), (talking, cognitive interference (Alpha)) and Dual-Task Walk (DTW)). RESULTS: The prevalence of polypharmacy was 33% (n = 104) amongst the 325 participants (mean age 76.4 ± 6.7 years, 56% women). Among the 221 participants with no polypharmacy there was an increase in HbO2 levels from STW to DTW (estimate = -0.625; p = <0.001) and from Alpha to DTW (estimate=-0.079; p = 0.031). Polypharmacy status, however, moderated the change in HbO2 levels comparing the two single tasks to the dual-task walking condition. Specifically, the presence of polypharmacy was associated with an attenuated increase in HbO2 levels from STW to DTW (estimate = 0.149; p = 0.027) and with a decline in HbO2 levels from Alpha to DTW (estimate = 0.169; p = 0.009) after adjustments for potential confounders including medical comorbidities and the use of high-risk medications. CONCLUSION: The results of this study further support the need for clinicians to reduce polypharmacy in older adults, given its significant association with the PFC hemodynamic response during attention-demanding locomotion.

The effect of diabetes on prefrontal cortex activation patterns during active walking in older adults.

BACKGROUND: Gait alterations were documented in diabetic patients. However, the effect of diabetes on cortical control of gait has not been reported. We evaluated the effect of diabetes on prefrontal cortex (PFC) Oxygenated Hemoglobin (HbO2) levels during active walking in older adults. METHODS: Of the total sample (n = 315; mean age = 76.84 ±â€¯6.71ys; % female = 56.5) 43 participants (13.7%) had diabetes. The experimental paradigm consisted of two single tasks: Normal-Walk (NW); and Cognitive Interference (Alpha); and one dual-task condition consisting of the two single tasks, Walk-While-Talk (WWT). Functional Near-Infrared-Spectroscopy (fNIRS) was used to quantify PFC HbO2 levels. RESULTS: Older adults without diabetes showed higher PFC HbO2 levels in WWT compared to both NW and Alpha. HbO2 levels during NW were not different between the two groups. Consistent with Neural Inefficiency, older adults with diabetes exhibited higher HbO2 levels during Alpha while performing significantly worse than those without diabetes. Moreover, the presence of diabetes was associated with attenuated HbO2 levels during WWT. This pattern is consistent with Capacity Limitations suggesting a failure to recruit brain resources vis-à-vis the more cognitively challenging WWT condition. CONCLUSIONS: A distinct functional neural signature of diabetes was established during active and attention demanding walking among older adults without overt neurological disease.

Gait Performance in Hypertensive Patients on Angiotensin-Converting Enzyme Inhibitors.

OBJECTIVE: To examine the relationship between angiotensin-converting enzyme inhibitor (ACEI) use and gait performance in older adults. DESIGN: Cross-sectional survey. SETTING: Community. PARTICIPANTS: A total of 281 community-dwelling older adults with hypertension enrolled in an aging study. MEASUREMENTS: Quantitative variables used to define gait performance included velocity (cm/s), stride length (cm), swing time (s), stride length variability (SD), and swing time variability (SD). RESULTS: There were 72 hypertensive participants on ACEIs and 209 were on other antihypertensive medications. Linear regression analysis adjusted for age, sex, and potential confounders revealed that hypertensive participants on an ACEI walked 7.29 cm/s slower (P = .016) and stride length was 6.86 cm shorter (P = .006) compared with those not on ACEIs. There were no significant differences on the other gait variables examined. CONCLUSION: ACEI use was associated with worse gait performance in elderly hypertensives. Biological mechanisms need to be explored, and clinicians should consider monitoring gait speed in hypertensive patients on ACEIs.

Geriatrics medication management rounds: a novel approach to teaching rational prescribing with the use of the medication screening questionnaire.

Prescribing for older adults has become increasingly complex as treatment regimens have intensified, and the use of herbal and over-the-counter medications has increased. This article describes an educational intervention called Geriatrics Medication Management Rounds, which uses a new and comprehensive assessment tool called the Medication Screening Questionnaire (MSQ). This case-based interactive session is aimed at teaching trainees and postgraduate physicians and pharmacists to examine the pharmacology, potential drug and disease interactions, efficacy, adherence issues, and goals of care for a geriatric patient's medication regimen. Twenty-three sessions were held from January 2008 to January 2009, with 241 participants overall and an average of 10.4 participants per session. Of the 163 participants who completed an evaluation, all agreed or strongly agreed that the learning goals were clearly established, and 99% agreed or strongly agreed that the overall quality of the session was excellent. Participants described the sessions as excellent, interactive, informative, and educational. Teaching medication management through a case-based format with the MSQ is an effective format that is interactive and informative, as demonstrated by positive quantitative and qualitative evaluations. These sessions may be replicated in other settings and with other disciplines.

Appropriate proton pump inhibitor use among older adults: a retrospective chart review.

BACKGROUND: Proton pump inhibitors (PPIs) are widely used, but not always with a clear indication. Nonindicated use is of particular concern among older adults, who may have multiple comorbidities and take more medications, increasing their risk for adverse drug reactions. OBJECTIVE: This study examined the appropriateness of PPI use at an outpatient geriatric practice and the association between particular patient characteristics and appropriate use of these medications. METHODS: This was a retrospective chart review of a group of randomly identified community-dwelling adults aged >or=65 years with a current prescription for a PPI (as of August 2006) from a geriatric ambulatory care practice within an urban academic medical center. The main outcome was appropriateness of PPI use, categorized as indicated, possibly indicated, or not indicated, based on US Food and Drug Administration-approved indications and national gastroenterology guidelines. RESULTS: Out of approximately 2500 patients in the geriatric practice, 702 (approximately 28%) were identified as having a current prescription for a PPI. From these, 110 charts were randomly selected for review, of which 10 were excluded based on predefined criteria. The sample was 79% female and 46% white, with a mean age of 82.8 years (range, 66-99 years). PPI use was indicated in 64% of these patients, possibly indicated in 7%, and not indicated in 29%. Compared with indicated PPI use, nonindicated use was significantly associated with use for <1 year (relative risk = 2.20; 95% CI, 1.00-4.86; P = 0.05). Nonindicated PPI use was not significantly associated with age, female sex, nonwhite race, or PPI initiation in the inpatient setting. CONCLUSION: Almost 30% of patients receiving a PPI in this academic geriatric practice had no documented indication for PPI use.