George A. Kuchel

Geriatric Syndromes: Clinical, Research, and Policy Implications of a Core Geriatric Concept

Geriatricians have embraced the term “geriatric syndrome,” using it extensively to highlight the unique features of common health conditions in older people. Geriatric syndromes, such as delirium, falls, incontinence, and frailty, are highly prevalent, multifactorial, and associated with substantial morbidity and poor outcomes. Nevertheless, this central geriatric concept has remained poorly defined. This article reviews criteria for defining geriatric syndromes and proposes a balanced approach of developing preliminary criteria based on peer‐reviewed evidence. Based on a review of the literature, four shared risk factors—older age, baseline cognitive impairment, baseline functional impairment, and impaired mobility—were identified across five common geriatric syndromes (pressure ulcers, incontinence, falls, functional decline, and delirium). Understanding basic mechanisms involved in geriatric syndromes will be critical to advancing research and developing targeted therapeutic options, although given the complexity of these multifactorial conditions, attempts to define relevant mechanisms will need to incorporate more‐complex models, including a focus on synergistic interactions between different risk factors. Finally, major barriers have been identified in translating research advances, such as preventive strategies of proven effectiveness for delirium and falls, into clinical practice and policy initiatives. National strategic initiatives are required to overcome barriers and to achieve clinical, research, and policy advances that will improve quality of life for older persons.

Synaptic Innervation Density Is Regulated by Neuron-Derived BDNF

In this report, we have examined the role of neuron-derived BDNF at an accessible synapse, that of preganglionic neurons onto their sympathetic neuron targets. Developing and mature sympathetic neurons synthesize BDNF, and preganglionic neurons express the full-length BDNF/TrkB receptor. When sympathetic neuron-derived BDNF is increased 2- to 4-fold in transgenic mice, preganglionic cell bodies and axons hypertrophy, and the synaptic innervation to sympathetic neurons is increased. Conversely, when BDNF synthesis is eliminated in BDNF -/- mice, preganglionic synaptic innervation to sympathetic neurons is decreased. Together these results indicate that variations in neuronal neurotrophin synthesis directly regulate neuronal circuitry by selectively modulating synaptic innervation density.

Detrusor Underactivity: Clinical Features and Pathogenesis of an Underdiagnosed Geriatric Condition

Urinary incontinence and other lower urinary tract symptoms exert a major influence on the health and independence of frail older people. Detrusor underactivity (DU) is defined as a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal time span. DU may influence the clinical presentation and impede the therapy of disorders as common and as disparate as detrusor overactivity, urinary retention, and benign prostatic hyperplasia. Urodynamically, nearly two‐thirds of incontinent nursing home residents exhibit DU. The clinical diagnosis of DU when present alone or in association with other bladder conditions such as detrusor overactivity (detrusor hyperactivity with impaired contractility (DHIC)) is challenging, because symptoms lack adequate precision. A catheterized and increasingly noninvasive ultrasound‐based postvoid residual assessment allows a bedside diagnosis of retention and may suggest the presence of DU in individuals (mostly women) with a low likelihood of bladder outlet obstruction (BOO). Nevertheless, it cannot differentiate primary DU from retention secondary to BOO. The management of individuals with DHIC remains unsatisfactory, because antispasmodic anticholinergic medications may worsen retention, whereas bethanechol does not improve bladder emptying. Human detrusor biopsies reveal axonal degeneration, muscle loss, and fibrosis in DU. Animal studies suggest that multiple risk factors, including retention itself, lack of estrogen, infection, inflammation, and aging, may contribute to DU. Priority areas for future research include efforts to facilitate clinical nonurodynamic diagnosis of probable DU plus translational research designed to address the pathogenesis of this complex multifactorial geriatric syndrome.

Conceptual and methodological issues relevant to cytokine and inflammatory marker measurements in clinical research

Purpose of reviewTo provide clinical investigators with an understanding of factors to consider when wishing to add cytokine and inflammatory marker measurements to their studies. Recent findingsInflammation involves complex and coordinated responses of the immune system to tissue damage. In the absence of tools to routinely assess inflammation within living tissues, measurements of humoral factors such as cytokines and other inflammatory mediators or markers can provide predictive clinical information and insights into disease mechanisms. Historically, enzyme-linked immunosorbent assays (ELISAs) became the gold standard, yet this approach of measuring a single protein in each sample limits the amount of information which can be obtained from limited amounts of human sample. In recent years, commercially available multiplex technologies which detect large numbers of proteins in a limited volume have provided investigators with opportunities to begin addressing the complexity of inflammatory responses. Nevertheless, great attention needs to be paid to many aspects of study design, sample collection, sample measurement and data analysis. These considerations are especially significant when using technologies for which experience remains limited. SummaryWhereas measurements of peripheral levels of inflammatory markers can add important mechanistic elements to human subject research, careful attention to conceptual and methodological considerations is essential, especially when using novel technologies.

Incontinence in the frail elderly: Report from the 4th international consultation on incontinence†

To summarize current knowledge on the etiology, assessment, and management of urinary incontinence (UI) in frail older persons. “Frail” here indicates a person with a clinical phenotype combining impaired physical activity, mobility, muscle strength, cognition, nutrition, and endurance, associated with being homebound or in care institutions and a high risk of intercurrent disease, disability, and death.

White Matter Hyperintensities Predict Functional Decline in Voiding, Mobility, and Cognition in Older Adults

OBJECTIVES: To compare magnetic resonance imaging data with functional assessments of mobility, urinary control, and cognition to determine common or distinctive features in the distribution of brain white matter hyperintensities (WMHs) associated with functional decline and impairment.

Localization of Brain White Matter Hyperintensities and Urinary Incontinence in Community-Dwelling Older Adults

BACKGROUND Because white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) may be linked to geriatric syndromes involving mobility, cognition, and affect, we postulated that involvement of areas critical to bladder control could influence urinary incontinence (UI). METHODS One hundred community-dwelling individuals (75-89 years) were recruited into three groups stratified by age and gender reflecting normal and mildly and moderately impaired mobility. Baseline incontinence status and related symptoms were evaluated in 97 individuals using validated instruments (3IQ, Urinary Incontinence Severity Index, Urogenital Distress Inventory, Incontinence Impact Questionnaire). Regional WMH was measured using an MRI brain imaging segmentation pipeline and WM tract-based parcellation atlas. RESULTS Sixty-two (64%) of the participants were incontinent, mostly with urgency (37; 60%) and moderate-severe symptoms (36; 58%). Incontinent individuals were more likely to be women with worse scores for depression and mobility. WMH located in right inferior frontal regions predicted UI severity, with no significant relationship with incontinence, incontinence type, bother, or functional impact. As regards WM tracts, WMH within regions normally occupied by the anterior corona radiata predicted severity and degree of bother, cingulate gyrus predicted incontinence and severity, whereas cingulate (hippocampal portion) and superior fronto-occipital fasciculus predicted severity. CONCLUSIONS Presence of WMH in right inferior frontal regions and selected WM tracts predicts incontinence, incontinence severity, and degree of bother. Our observations support the findings of recent functional MRI studies indicating a critical role for the cingulum in bladder control, while also suggesting potential involvement of other nearby WM tracts such as anterior corona radiata and superior fronto-occipital fasciculus.

Functional Impact of Relative Versus Absolute Sarcopenia in Healthy Older Women

OBJECTIVES: To determine whether adjustment of muscle mass for height2 or for body mass represents a more‐relevant predictor of physical performance.

Measurement of muscle disease by quantitative second-harmonic generation imaging.

Determining the health of muscle cells by in vivo imaging could impact the diagnosis and monitoring of a large number of congenital and acquired muscular or cardiac disorders. However, currently used technologies are hampered by insufficient resolution, lack of specificity, or invasiveness. We have combined intrinsic optical second-harmonic generation from sarcomeric myosin with a novel mathematical treatment of striation pattern analysis, to obtain measures of muscle contractile integrity that correlate strongly with the neuromuscular health of mice suffering from genetic, acquired, and age-related decline in skeletal muscle function. Analysis of biopsies from a pilot group of human volunteers suggests a similar power in quantifying sarcopenic changes in muscle integrity. These results provide the first strong evidence that quantitative image analysis of sarcomere pattern can be correlated with physiological function, and they invite the application of SHG imaging in clinical practice, either in biopsy samples or via microendoscopy.

Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans.

Significance Suppression of NAD+-dependent sirtuin 1 (SIRT1) is linked to dementia or Alzheimer’s disease (AD) and the metabolic syndrome (MS). Because advanced glycation end products (AGEs) promote MS and neurotoxicity, we conducted studies of C57BL6 mice fed isocaloric diets containing defined AGEs [methyl-glyoxal derivatives (MG)] to determine whether food AGEs promote AD and MS. MG+-fed, but not MG−-fed, mice developed brain SIRT1 deficiency, amyloid-β deposits, cognitive and motor deficits, and MS. These findings were validated in older healthy humans with high baseline circulating MG levels by a time-dependent decline in cognition and insulin sensitivity. The data suggest that food-derived AGEs, an environmental factor, contribute to both AD and MS by causing chronic SIRT1 suppression. Importantly, reduction of food-derived AGEs is feasible and may provide an effective treatment strategy for both these epidemics. Age-associated dementia and Alzheimer’s disease (AD) are currently epidemic. Neither their cause nor connection to the metabolic syndrome (MS) is clear. Suppression of deacetylase survival factor sirtuin 1 (SIRT1), a key host defense, is a central feature of AD. Age-related MS and diabetes are also causally associated with suppressed SIRT1 partly due to oxidant glycotoxins [advanced glycation end products (AGEs)]. Changes in the modern diet include excessive nutrient-bound AGEs, such as neurotoxic methyl-glyoxal derivatives (MG). To determine whether dietary AGEs promote AD, we evaluated WT mice pair-fed three diets throughout life: low-AGE (MG−), MG-supplemented low-AGE (MG+), and regular (Reg) chow. Older MG+-fed mice, similar to old Reg controls, developed MS, increased brain amyloid-β42, deposits of AGEs, gliosis, and cognitive deficits, accompanied by suppressed SIRT1, nicotinamide phosphoribosyltransferase, AGE receptor 1, and PPARγ. These changes were not due to aging or caloric intake, as neither these changes nor the MS were present in age-matched, pair-fed MG− mice. The mouse data were enhanced by significant temporal correlations between high circulating AGEs and impaired cognition, as well as insulin sensitivity in older humans, in whom dietary and serum MG levels strongly and inversely associated with SIRT1 gene expression. The data identify a specific AGE (MG) as a modifiable risk factor for AD and MS, possibly acting via suppressed SIRT1 and other host defenses, to promote chronic oxidant stress and inflammation. Because SIRT1 deficiency in humans is both preventable and reversible by AGE reduction, a therapeutic strategy that includes AGE reduction may offer a new strategy to combat the epidemics of AD and MS.