Evidence for a novel neuronal mechanism driving Alzheimer's disease, upstream of amyloid.

This perspective offers an alternative to the amyloid hypothesis in the etiology of Alzheimer's disease (AD). We review evidence for a novel signaling mechanism based on a little-known peptide, T14. T14 could drive neurodegeneration as an aberrantly activated process of plasticity selective to interconnecting subcortical nuclei, the isodendritic core, where cell loss starts at the pre-symptomatic stages of the disease. Each of these cell groups has the capacity to form T14, which can stimulate production of p-Tau and ß-amyloid, suggestive of an upstream driver of neurodegeneration. Moreover, results in an animal AD model show that antagonism of T14 with a cyclated variant, NBP14, prevents formation of ß-amyloid, and restores cognitive function to that of wild-type counterparts. Any diagnostic and/or therapeutic strategy based on T14-NBP14 awaits validation in clinical trials. However, an understanding of this novel signaling system could bring much-needed fresh insights into the progression of cell loss underlying AD. HIGHLIGHTS: The possible primary mechanism of neurodegeneration upstream of amyloid. Primary involvement of selectively vulnerable subcortical nuclei, isodendritic core. Bioactive peptide T14 trophic in development but toxic in context of mature brain. Potential for early-stage biomarker to detect Alzheimer's disease. Effective therapeutic halting neurodegeneration, validated already in 5XFAD mice.

The Relationships between Caregiver Burden, Physical Frailty, Race, Behavioral and Psychological Symptoms (BPSD), and Other Associated Variables: An Exploratory Study.

Background and Objectives: For persons with dementia, the relationships between caregiver burden, physical frailty, race, behavioral and psychological symptoms (BPSD), and other associated variables are poorly understood. Only one prior study examined the relationships among these variables but did not include race, which is an important social determinant of health outcomes in the United States. To examine these interactions, we conducted a cross-sectional exploratory study based on a model by Sugimoto and colleagues. Materials and Methods: The sample comprised 85 patient-caregiver dyads (58% White) seen in four centers in diverse regions of New York State. All patients met DSM5 criteria for a major neurocognitive disorder, had a Clinical Dementia Rating sum score of ≥3, and Mini-Mental State Examination (MMSE) score of 10 to 26. Other measures included the SHARE-Frailty Instrument(FI), the Neuropsychiatric Inventory (NPI) to assess BPSD, Zarit's Caregiver Burden Interview (CBI), Lawton's Activities of Daily Living (ADL) Scale, the MMSE, the Cumulative Illness Rating Scale for Geriatrics (CIRSG), age, and gender. Results: In our sample, 59% met the criteria for prefrail/subsyndromal or frail/syndromal (SSF) on the SHARE-FI. SSF had significant direct effects on the NPI and significant indirect effects on the CBI mediated through the NPI; the NPI had significant direct effects on the CBI. Race (White) had significant direct effects on the CBI (higher) and SSF (lower) but did not have significant indirect effects on the CBI. MMSE, ADL, and CIRSG were not significantly associated with the NPI or the CBI. Conclusions: Our analysis demonstrated that frailty, race, BPSD, and caregiver burden may directly or indirectly influence one another, and therefore should be considered essential elements of dementia assessment, care, and research. These results must be viewed as provisional and should be replicated longitudinally with larger samples.

Multisectoral Collaborations to Increase Recruitment and Retention of Diverse Older Adults in Biomedical Research.

BACKGROUND: Older adults, especially minoritized racial-ethnic groups, are historically underrepresented in biomedical research. This study summarizes the development and assesses the impact of a review board involving a multisectoral group of stakeholders with the goal of increasing the diversity of older adults in biomedical research. METHODS: A 25-member board of community members, caregivers, researchers, and clinicians from Upstate New York reviewed 3 projects presented by researchers, clinician-scientists, and a pharmaceutical company between January and December 2022. For each biomedical research project, the reviews provided guidance to increase the recruitment and retention of diverse older adults engaged in the study. Review board members and presenters completed surveys to provide feedback on their experience in this collaboration. RESULTS: There was consistent positive feedback from all members and presenters. From member surveys, feedback trended positive in meetings throughout the year. Community members and caregivers initially indicated discomfort in expressing their views; however, these concerns subsided over time. Presenters had a very positive experience in the review board's impact on their recruitment strategy and study design, and therefore very likely to use this service again. Recommendations were made to adjust membership criteria, presentation format, and funding to sustain this effort. CONCLUSIONS: Lack of diversity for older adults represented in biomedical research contributes to ethical and generalizability ramifications. The positive feedback from all stakeholders in our multisectoral board of community members, caregivers, researchers, and clinicians offers a promising structure for developing similar strategies to increase diversity within and beyond biomedical aging research in other communities.

Early Identification of Cognitive Impairment: Utility of the Mini-Cog in Non-Clinical Settings.

While we currently cannot cure Alzheimer's disease or change the course of the disease, there are advantages to early detection. Routine, evidence based, brief cognitive screens offer destigmatized opportunities for diagnosis and improve the possibility of early identification of cognitive impairment. This community-based participatory research project evaluated the use of the Mini-Cog™ instrument to detect cognitive impairment in vulnerable community-dwelling older adults when administered by trained social services providers. Over 9 months, a case manager screened 69 clients ages 65 to 94 (mean 74.67) who met inclusion criteria for the pilot; 84.1% were female, 53.6% were Black, 26% were living with undetected cognitive impairment. Although participants agreed to Mini-Cog™ screening, two-thirds with Mini-Cog™ scores indicating cognitive impairment refused referrals for further evaluation. Future interventions should reduce stigma by educating the public about dementia and engaging members of racial and cultural communities in outreach.

Achieving diversity in study populations: The importance of community engagement.

The majority of clinical trials currently and historically do not include older adults or non-white participants. While more women are being recruited, their numbers are still limited. It is very hard to interpret trial results and apply them to older adults when their participation in clinical trials is limited. The focus of this article is the lack of clinical trial participation by persons of diverse races and ethnicities and the presentation of a model infrastructure grounded in community engagement that is proving to be effective in increasing the interest and participation of older African Americans in research.

Longitudinal Evaluation of a Deprescribing Protocol in Skilled Nursing Facilities.

Objective: To determine whether a deprescribing effort reduced several key classes of medications, and the overall number of medication classes per patient, among long-term residents of skilled nursing facilities (SNFs). Design: Retrospective, longitudinal pre/post evaluation. Data from before and during the implementation of the deprescribing effort (2017 through 2019) were compared with data from the post-intervention year (2020). Setting and Patients: Long-term resident data reported through annual comprehensive reviews conducted at two SNFs located in central New York State between 2017 and 2020 (N = 12,144). Interventions: Multifaceted, interdisciplinary deprescribing effort to reduce medications in SNF residence including clinician education, guideline development, and individual chart reviews began in 2019. Results: The mean number of medications prescribed per resident was lower at both facilities after the intervention (mean = 1.74 at both facilities) versus preintervention (1.90 at Facility 1, 1.86 at Facility 2). Significant decreases were observed in the usage rates for diuretics (-4.2%; P = 0.001), opioids (-3.8%; P = 0.001), and antipsychotics (-2.4%; P = 0.010). The raw antidepressant usage rate increased by 1.5% after the intervention but the change was not significant. Effects were robust to covariate adjustment. Conclusion: A combined, comprehensive approach to deprescribing was associated with a reduction in the overall number of medication classes per resident and in several key classes of medications. Additional research with more data and covariate control is in progress for verification of these findings.

Efficacy and Safety of Megestrol in the Hospitalized Older Person.

Objectives To evaluate the efficacy and safety of megestrol for off-label use in older patients with weight loss. Design Retrospective, nonblinded cohort study. Setting Upstate University Hospital is a 420-bed facility and academic medical center with a level 1 trauma center. Upstate Community Hospital is a 314-bed acute care/hospital/ambulatory care center and long-term care hospital that also provides teaching services. Participants Patients 65 years of age and older without malignancy or acquired immunodeficiency syndrome who were initiated and continued megestrol therapy at the Upstate University hospitals for at least two weeks were included. Of the 1,290 patients initially screened, 16 patients on megestrol were evaluated. An age- and gender-matched control group of 16 patients was utilized for comparison of changes in weight and other variables. Interventions Patients in the megestrol group have received daily doses of megestrol between 160 mg to 800 mg for an average duration of 19 days. Patients in the control group had no history or current use of megestrol utilization. Main Outcome Measurements The primary outcome was an increase in weight. Secondary outcome measures included albumin and thromboembolic events. Changes in weight and albumin were also compared with the control group. Results At a mean duration of 19 days, there was no significant difference in weight gain (0.95 kg, OR = 1.33 [95% CI -1.615-3.527]). Albumin decreased by (0.4 g/dL OR = 0.916 [95% CI 0.12-0.78]) and none of the patients developed a thromboembolic event. Conclusion In older hospitalized patients, megestrol did not increase weight, and did not improve albumin. No thromboembolic events were observed, but this may be because of a limited duration of observation of therapy and the routine use of anticoagulation prophylaxis in the inpatient setting.

Impact of a Clinical Pharmacist Telehealth Service in a Geriatrics Assessment Clinic.

Objective Evaluate the impact of a telepharmacy service at a geriatrics assessment clinic. Design Retrospective, single-center, nonblinded cohort study. Setting Geriatrics assessment clinic. Patients The intervention/pharmacist and the control/no-pharmacist (provider) group included patients new to the clinic 50 years of age or older from over the span of 4 months. Patients who the pharmacist was unable to reach and those who missed appointments with the provider were excluded. Interventions The pharmacist phoned new patients approximately one week prior and one week after their first appointments with a provider. Main Outcome Measure Primary outcome: number of drug-related problems (DRPs) detected by the pharmacist compared with the provider. Secondary outcomes: number of medication history discrepancies, accepted medication-related recommendations, potentially inappropriate medications (PIMs) deprescribed, and adverse drug reactions (ADRs) detected. Results In the intervention/pharmacist (n = 204) vs control/no pharmacist (n = 200) groups, the number of DRPs was significantly greater (338 vs 218; P = 0.031) and driven by unnecessary drug therapies, doses too high, ADRs, and drug-drug interactions (230 vs 147, P = 0.045; 37 vs 7, P = 0.010; 36 vs 17, P = 0.023; 32 vs 1, P = 0.003, respectively). The difference in number of recommendations made by the pharmacist vs medication changes made by the provider was significant: 457 vs 319, P < 0.001, respectively. Conclusions The addition of a clinical pharmacist conducting telepharmacy at a geriatrics assessment clinic had a positive impact on patient care as it relates to DRPs, deprescribing PIMs, and optimizing medication adherence.

Frailty and Biomarkers of Frailty Predict Outcome in Veterans After Open and Endovascular Revascularization.

BACKGROUND: Frailty predicts poor outcome after vascular surgery. We determined the predictive utility of the modified frailty index (mFI) after first-time revascularization and identified biomarkers of frailty predictive of outcome in veterans with peripheral arterial disease. METHODS: A retrospective study was performed of first-time revascularizations (open surgery [OS] and endovascular surgery [ES]) in male veterans (2003-2016). Preoperative mFI scores were calculated, and serum and nonserum biomarkers of frailty were recorded. The primary endpoint was 2-y incidence of reintervention, amputation, and mortality. Secondary endpoints included 30-day morbidity and readmissions. RESULTS: Four hundred and thirty one patients (OS, n = 188; ES, n = 243), mean age of 66 ± 9 y, and 16 mo of median follow-up were studied. Mean mFI was 0.39 ± 0.16 for OS and 0.38 ± 0.15 for ES (P = 0.43). 30-day complications (adjusted odds ratio, 4.89; 95% confidence interval [CI]: 1.67-14.33) and readmissions (adjusted hazard ratio [aHR] 3.32; 95% CI: 1.16-9.55) were increased in the OS versus ES group when stratified by mFI. Survival analysis showed a correlation between risk of amputation, death, and composite outcome with increasing mFI (P < 0.005) in both groups. Frailty independently predicted major amputation (aHR 2.16; 1.06-4.39), mortality (aHR 2.62; 95% CI: 1.17-5.88), and composite outcome (aHR 1.97; 95% CI: 1.06-3.68) when the groups are combined. Except for absolute neutrophil count, all preoperative lab values correlated with mFI (P < 0.5). Higher albumin was independently associated with lower risk of amputation (aHR: 0.58 [0.36-0.94]) and mortality (aHR: 0.45 [0.25-0.83]); higher hemoglobin predicted limb salvage (aHR 0.7 [0.62-0.84]). CONCLUSIONS: Frailty predicts short- and long-term outcomes after first-time revascularization in veterans. Hypoalbuminemia and anemia are associated with higher mFI and independently predict poor outcome, suggesting albumin and hemoglobin are viable biomarkers of frailty in veterans.

Co-creation by the ABIM Geriatric Medicine Board and the AGS - Helping Move Geriatrics Forward.

The American board of internal medicine (ABIM) establishes standards for physicians. The American geriatrics society (AGS) is a not-for-profit membership organization of nearly 6,000 health professionals devoted to improving the health, independence, and quality of life of all older people. Beginning in 2013, ABIM redesigned its governance structure, including the role of the specialty boards. Specialty boards are charged with responsibilities for oversight in four main areas: (1) the assessments used in initial certification and maintenance of certification (MOC); (2) medical knowledge self-assessment and practice assessment in the specialty; (3) building relationships with relevant professional societies and other organizational stakeholders; and (4) issues related to training requirements for initial certification eligibility within the specialty. The aim of this paper is to inform the geriatrics community regarding the function of geriatric medicine board (GMB) of the ABIM, and to invite the geriatrics community to fully engage with and leverage the GMB as a partner to: (1) develop better certification examinations and processes, identifying better knowledge and practice assessments, and in establishing appropriate training and MOC requirements for geriatric medicine; (2) leverage ABIM assets to conduct applied research to guide the field in the areas of training and certification and workforce development in geriatric medicine; (3) make MOC relevant for practicing geriatricians. Active engagement of the geriatrics community with ABIM and the GMB will ensure that certification in geriatric medicine provides the greatest possible value and meaning to physicians, patients, and the public.

Use of Tethered Enzymes as a Platform Technology for Rapid Analyte Detection.

BACKGROUND: Rapid diagnosis for time-sensitive illnesses such as stroke, cardiac arrest, and septic shock is essential for successful treatment. Much attention has therefore focused on new strategies for rapid and objective diagnosis, such as Point-of-Care Tests (PoCT) for blood biomarkers. Here we use a biomimicry-based approach to demonstrate a new diagnostic platform, based on enzymes tethered to nanoparticles (NPs). As proof of principle, we use oriented immobilization of pyruvate kinase (PK) and luciferase (Luc) on silica NPs to achieve rapid and sensitive detection of neuron-specific enolase (NSE), a clinically relevant biomarker for multiple diseases ranging from acute brain injuries to lung cancer. We hypothesize that an approach capitalizing on the speed and catalytic nature of enzymatic reactions would enable fast and sensitive biomarker detection, suitable for PoCT devices. METHODS AND FINDINGS: We performed in-vitro, animal model, and human subject studies. First, the efficiency of coupled enzyme activities when tethered to NPs versus when in solution was tested, demonstrating a highly sensitive and rapid detection of physiological and pathological concentrations of NSE. Next, in rat stroke models the enzyme-based assay was able in minutes to show a statistically significant increase in NSE levels in samples taken 1 hour before and 0, 1, 3 and 6 hours after occlusion of the distal middle cerebral artery. Finally, using the tethered enzyme assay for detection of NSE in samples from 20 geriatric human patients, we show that our data match well (r = 0.815) with the current gold standard for biomarker detection, ELISA-with a major difference being that we achieve detection in 10 minutes as opposed to the several hours required for traditional ELISA. CONCLUSIONS: Oriented enzyme immobilization conferred more efficient coupled activity, and thus higher assay sensitivity, than non-tethered enzymes. Together, our findings provide proof of concept for using oriented immobilization of active enzymes on NPs as the basis for a highly rapid and sensitive biomarker detection platform. This addresses a key challenge in developing a PoCT platform for time sensitive and difficult to diagnose pathologies.

Curricular framework: core competencies in multicultural geriatric care.

Strategies to reduce the documented disparities in health and health care for the rapidly growing numbers of older patients from diverse ethnic populations include increased cultural competence of providers. To assist geriatric faculty in medical and other health professional schools develop cultural competence training for their ethnogeriatric programs, the University of California Academic Geriatric Resource Program partnered with the Ethnogeriatric Committee of the American Geriatrics Society to develop a curricular framework. The framework includes core competencies based on the format of the Core Competencies for the Care of Older Patients developed by the Education Committee of the American Geriatrics Society. Competencies in attitudes, knowledge, and skills for medical providers caring for elders from diverse populations are specified. Also included are recommended teaching strategies and resources for faculty to pursue the development of full curricula.

Long-term cholinesterase inhibitor therapy for Alzheimer's disease: implications for long-term care.

As the population ages and Alzheimer's disease (AD) becomes more prevalent, nursing facilities will be faced with managing more AD patients than in previous decades. Managing this population will pose a significant challenge for the resources of long-term care facilities. In short- and long-term studies, cholinesterase (ChE) inhibitor treatment has been shown to benefit the symptoms of mild to moderate AD. Donepezil trials have extended this finding to patients with moderate to severe AD as well as the more severe symptoms of AD patients residing in nursing home settings. Results from long-term ChE inhibitor trials and the benefits that may be gained by treating AD patients residing in nursing facilities are presented.