The term “geriatric syndrome” is used to capture those clinical conditions in older persons that do not fit into discrete disease categories. Many of the most common conditions cared for by geriatricians, including delirium, falls, frailty, dizziness, syncope and urinary incontinence, are classified as geriatric syndromes. Nevertheless, the concept of the geriatric syndrome remains poorly defined.

While heterogeneous, geriatric syndromes share many common features. They are highly prevalent in older adults, especially the frail elderly. Their impact on quality of life and disability is substantial. Multiple underlying factors, involving multiple organ systems, tend to contribute to, and define, geriatric syndromes. As noted by Fried et al.(1), frequently the chief complaint does not represent the specific pathologic condition underlying the change in health status. In some cases, the two processes may involve distinct and distant organs with a disconnect between the site of the underlying physiologic insult and the resulting clinical symptom. For example, when an infection involving the urinary tract precipitates delirium, it is the altered neural function in the form of cognitive and behavioral changes which permits the diagnosis of delirium and determines many functional outcomes. The fact that these syndromes cross organ systems and discipline-based boundaries, along with their multifactorial nature, challenges traditional ways of viewing clinical care and research.

The concept of a geriatric syndrome has already facilitated the development of multicomponent intervention strategies and the establishment of ‘V’codes through the Centers for Medicare and Medicaid Services (CMS) for falls history. Nevertheless, the lack of a working definition has limited the usefulness of this term in clinical, research and policy arenas. Such a definition should seek to encompass the overarching clinical features which have led clinicians to apply this term to seemingly diverse conditions. Moreover, little progress has been made in developing a mechanistic understanding of common geriatric syndromes, with no agreement for how such research should be conducted.

The goals of this special article are to describe the advantages and limitations of establishing formal criteria for geriatric syndromes, to evaluate shared risk factors across five distinct geriatric syndromes, to propose potential mechanistic approaches for conducting basic to clinical translational research into geriatric syndromes, and to discuss local and national efforts to translate geriatric syndrome research to practice and policy. It is hoped that this article will help to catalyze further development in the field of geriatric syndromes—in clinical, research, and policy domains.

The conceptualization of geriatric syndromes has been evolving over time(2). In general terms, a “syndrome” has been defined as “a group of signs and symptoms that occur together and characterize a particular abnormality”(3) or “the aggregate of symptoms and signs associated with any morbid process, and constituting together the picture of the disease”(2;4). Thus, in current medical usage, a syndrome refers to a pattern of symptoms and signs with a single underlying cause that may not yet be known(5) (Figure 1).

Figure 1 Schematic conceptual representation of clinical conditions defined by the terms “disease”, “syndrome” and “geriatric syndrome”, illustrating differences in numbers and complexity of relevant factors, including (more ...)

Geriatric syndromes, by contrast, refer to “multifactorial health conditions that occur when the accumulated effects of impairments in multiple systems render [an older] person vulnerable to situational challenges”(6). Thus, the geriatric usage of the term “syndrome” emphasizes multiple causation of a unified manifestation(2;5). With this usage, the conceptualization of geriatric syndromes aligns itself well with the concept of “phenotype”, defined as “the observable characteristics, at the physical, morphologic, or biochemical level, of an individual, as determined by the genotype and environment”(4). This concept emphasizes the multiple contributors to observable characteristics, such as the frailty phenotype(7).

Geriatric syndromes pose some special clinical considerations. First, for a given geriatric syndrome, multiple risk factors and multiple organ systems are often involved. Second, diagnostic strategies to identify the underlying causes can sometimes be ineffective, burdensome, dangerous, and costly. Finally, therapeutic management of the clinical manifestations can be helpful even in the absence of a firm diagnosis or clarification of the underlying causes.

Are there alternative options for terminology? Rather than “geriatric syndrome”, alternative terms might be “final common pathway” or “end product”. In this conceptualization, the geriatric syndrome represents the result of a series of processes or changes, suggesting multiple contributors. This conceptualization parallels other medical conditions like renal failure and hypertension, where multiple causes may contribute, where it may not always be appropriate to search for underlying cause(s), and where management does not always depend on the underlying cause(s).

Within medical research and practice, establishing formal criteria to define syndromes has a long tradition. Examples include criteria within rheumatology to define rheumatoid arthritis(8) and systemic lupus erythematosus(9); the National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) clinical criteria for Alzheimer’s Disease(10); and psychiatric diagnoses in the Diagnostic and Statistical Manuals(11). The advantages of such criteria include improved communication in both clinical and research settings, enhanced ability to directly compare syndromes between studies and to pool study findings, and the ability to create International Classification of Diseases (ICD-9) codes and billable diagnoses. The development of formalized criteria will also assist with creating unified concepts, to facilitate pathophysiologic studies and enhance the search for common mediators. For areas such as delirium and chronic fatigue syndrome, operational definitions have been developed that have facilitated research in these areas. Despite these advantages, premature establishment of formal criteria—without an adequate evidence base--can create rigid conceptualizations, stymie development and progress within the field, and lead to inappropriate application of concepts by clinicians and researchers with the potential for inaccurate diagnosis and therapeutic mismanagement. Examples of this phenomenon include the premature classification of diabetes as Type I and Type II, or the hyperlipidemias as Types I–V, which held back inquiry and progress for many years.

A balanced approach would be to develop preliminary criteria for select geriatric syndromes with an adequate evidence base by working committees assembled by professional organizations, such as the American Geriatrics Society (AGS). These preliminary criteria can be sent out for comment by other organizations and by the AGS membership. Once published, these criteria could be regularly updated and allowed to evolve over time. For research studies, these criteria would be helpful to compare research samples and results, to pool study findings, to modify, expand, or focus study samples, and to appropriately target interventions.

A defining feature of geriatric syndromes is that multiple risk factors contribute to their etiology(3). Previous work has suggested that some geriatric syndromes might share underlying risk factors(6). We propose a unifying conceptual model for geriatric syndromes (Figure 2), demonstrating that shared risk factors may lead to these syndromes and to the overarching geriatric syndrome of frailty. While there is not yet a consensus definition, frailty is defined here as impairment in mobility, balance, muscle strength, cognition, nutrition, endurance, and physical activity(12). Frailty and the other geriatric syndromes may also feed-back to result in the development of more risk factors and more geriatric syndromes. These pathways in turn lead to the final outcomes of disability, dependence, and death. This conceptual model provides a unifying framework and holds important implications for elucidating both pathophysiologic mechanisms and management strategies.

Figure 2 A unifying conceptual model demonstrates that shared risk factors may lead to geriatric syndromes, which may in turn lead to frailty, with feedback mechanisms enhancing the presence of shared risk factors and geriatric syndromes. Such self-sustaining (more ...)

While each geriatric syndrome is distinct, we hypothesized that they would have shared risk factors. Thus, we carried out a systematic review of the medical literature designed to examine previously identified risk factors for some common geriatric syndromes, and to identify common risk factors across all of these syndromes. We selected five geriatric syndromes for this investigation, based on the following criteria: they are common, associated with a high degree of morbidity, demonstrated to be preventable in some cases, and investigated with multiple previous risk factor studies. The five geriatric syndromes investigated were pressure ulcers, incontinence, falls, functional decline, and delirium.

Table 1 Risk Factors for Pressure Ulcers Based on a Systematic Literature Review*

Shared risk factors identified consistently across all geriatric syndromes in this study included older age, functional impairment, cognitive impairment, and impaired mobility. While some risk factors (e.g., falls, diabetes) occurred across multiple geriatric syndromes, only the 4 identified risk factors occurred across all of the geriatric syndromes we examined.

The research community can point to many accomplishments achieved by a bench-to-bedside translational approach(90;91), which has been most impressive when addressing inborn errors of metabolism(92). At the same time, there has been a growing awareness that optimum clinical care cannot be based entirely on a biological framework(1;93-95). This observation is particularly pertinent to the management of geriatric syndromes where it is imperative to also consider relevant social, spiritual and economic domains. While it is extremely difficult to study the pathophysiology of complex multifactorial geriatric syndromes, such studies must be undertaken if we are to have any chance at altering the natural history of these core contributors to late-life disability.

The pathophysiology of many non-geriatric conditions can be viewed along a traditional linear model (A in Figure 3). For example, a genetic alteration can lead to a disease process involving one organ system. In other cases, a clinical cluster of diseases involving multiple organ systems may develop(96). Although the term “syndrome” has been applied to genetic conditions with a multi-organ phenotype, the linear model is still applicable, since a direct relationship exists between altered genetics and the clinical phenotype(96). However, this linear model does not lend itself well to the study of common diseases such as diabetes, hypertension, atherosclerosis or cancer, which can only rarely be attributed to a single gene alteration. Moreover, this model also fails to incorporate the types of non-biological considerations discussed above. The concentric model (B in Figure 3) has been proposed as a means of highlighting the complexity of oncogenesis, together with the belief that the targeting of multiple pathways contributing to tumor survival and growth will improve treatment outcomes(97). We propose that this model can be adapted to study the pathophysiology of geriatric syndromes since it permits one to incorporate the multifactorial complexity inherent in these conditions.

Figure 3 Mechanistic research addressing the pathophysiology of complex multifactorial geriatric syndromes will require the development of new conceptual models. The traditional linear model (A) has proven highly effective for the discovery of pathophysiologically (more ...)

The above model is also attractive in that it permits us to address the pathophysiology of geriatric syndromes in a manner which reflects the complex interactions between an individual’s vulnerabilities and exposure to specific challenges. Even young and robust older individuals will fall, will develop cognitive deficits, or will become incontinent if challenged with a sufficiently great force, anticholinergic dose or physical restraint. The nature of such enhanced vulnerability is starting to be captured in frailty, falls, delirium and incontinence research. For example, multiple risk factors including sedative use, cognitive impairment, lower extremity disability, palmomental reflex, abnormalities of balance and gait, as well as foot problems all enhance the risk of falls(98). The risk increases linearly with the number of risk factors in the model, ranging from 8% for none to 78% in the presence of 4 or more risk factors(98). While this has led to innovative efforts incorporating multicomponent elements into strategies for the prevention of key geriatric syndromes (99;100), it has been difficult to conceptualize pathophysiologic studies to investigate such complex multifactorial conditions or to envision biologically-based treatments which could alter their natural history.

Traditional translational research is poorly-suited to address the pathophysiology of geriatric syndromes. First of all, it is possible to undertake careful research without establishing cause and effect since simple correlations between molecular changes and clinical outcomes may not establish causality even when demonstrated prospectively(101). In many ways, the use of genetically-modified animals (largely mice) has revolutionized the conduct of research designed to address the pathophysiology of complex conditions, such as osteoporosis(102;103) and Alzheimer’s disease(104) by linking the presence or absence of a gene to a specific phenotype. These technological advances have led to a great increase in the use of mice in such research. For example, PubMed citations using mice to study osteoporosis increased 25-fold from 1975-85 to 1995-2005, while mouse studies relevant to Alzheimer’s disease increased 50-fold. Such approaches will continue to grow, since approximately 10,000 of the nearly 25,000 genes in the mouse genome have already been deleted with knockout mouse mutations, and many other mutations are expected to become available in the near future(105).

Nonetheless, attempts to define the pathophysiology of complex multifactorial geriatric syndromes using current approaches can be problematic. For example, a decision to focus all efforts on a single risk factor may lack geriatric relevance since it addresses only a small portion of the overall risk and fails to consider other risk factors. By contrast, any research attempt to address all relevant risk factors runs the risk of being unfocussed. Moreover, unlike the use of multicomponent behavioral strategies for prevention, multicomponent strategies involving many biological interventions targeting different pathways could lead to unacceptable adverse effects in the frail elderly, given the well-established risk of polypharmacy in this population(106). If we are to develop strategies for altering the natural history of common geriatric syndromes, it will be essential to reconcile the need for defining relevant mechanisms with the underlying multifactorial complexity.

In spite of the enormity of the task, several promising directions need to be explored. One strategy involves capitalizing on the fact that some interventions exert highly specific effects on restricted populations of cells, while the effects of other strategies are more “pleiotropic” involving sometimes varying effects across many different cells and tissues. Examples of such potentially beneficial pleiotropic interventions include hormones, statins, antioxidants, as well as behavioral modifications such as exercise, improved nutrition and weight loss. Not only is it essential to test such interventions, it is also imperative to explore the basic mechanisms by which each exerts effects which are both pleiotropic and beneficial in the context of specific geriatric syndromes. While few investigators have pursued the development of animal models of individual geriatric syndromes, such a possibility should not be summarily dismissed. For example, the vulnerability of commonly used inbred mouse strains such as C57BL6J to develop a specific phenotype has been used in osteoporosis, diabetes, and atherosclerosis research(107;108). More recently, it has become apparent that the pattern of aging may vary greatly between different strains and that individual strains may exhibit a vulnerability to develop phenotypic features typical of geriatric syndromes, such as sarcopenic obesity(109).

Another approach involves an evaluation of the interactions between different risk factors in what could be termed the interactive concentric model of geriatric syndrome pathophysiology (C in Figure 3). Investigators are beginning to identify interactive synergisms between different risk factors for individual geriatric syndromes. For example, Cappola et al. have shown that the combination of low IGF-1 and high IL-6 levels in the same individual confers a higher risk for progressive disability and mortality in older women in a manner which suggests the presence of interactive synergisms between these two risk factors(110). It remains to be seen whether IGF-1 and IL-6 are actual mediators of relevant biological effects or markers of some other process. Nevertheless, these findings may have important clinical implications. The presence of such synergy implies that the pathways by which each of these risk factors contributes to progressive disability may biologically interact. The presence of such biological overlap between distinct risk factors (large arrow in Figure 3), may offer unique opportunities for making sense of this complexity and for identifying priority targets for developing clinically useful interventions.

Detrusor underactivity, a multifactorial geriatric condition which contributes to urinary retention in the frail elderly(111), is defined by detrusor muscle loss, fibrosis and axonal degeneration in human bladder biopsies(111;112). In animal studies using genetically modified mice, MIF (macrophage migration inhibitory factor), an atypical and abundant uroepithelial cytokine, has been implicated in the pathways by which two different risk factors--urinary retention/outlet obstruction(113) and lack of estrogen(114)--mediate bladder muscle loss and fibrosis. Moreover, aging, as well as comorbidities such as urinary tract infections(115), may also mediate their effects on detrusor underactivity via this pathway. Thus, it may be possible to use preclinical animal, as well as theoretical, models in an effort to define the efficacy of interventions designed to target such shared pathways in geriatric syndromes, analogous to the methods used by oncologists to anticipate the effects of drug combinations(116).

While research on geriatric syndromes has helped to clarify risk factors and to establish effective intervention strategies, by and large the results based on this evidence have failed to translate into clinical practice. The translation of geriatric syndrome research into practice faces unique challenges, which may heighten the barriers to evidence-based implementation(117). Beyond the complex nature of geriatric syndromes, numerous factors pose barriers to dissemination, including: 1) the lack of commonly accepted definitions for the recognition, diagnosis and coding of geriatric syndromes; 2) the lack of simple, measurable interventions; 3) the need for substantial provider time and longitudinal follow-up to intervene and assess effectiveness—i.e. intervention for geriatric syndromes requires human capital, rather than simply a new drug or technology; 4) the interventions often require new behaviors or attitude shifts on the part of the patient and/or the provider(s) (such as working with interdisciplinary teams, or focusing on identifying contributors like urinary tract infection or drugs rather than ordering a brain scan for a delirious patient), and often require system-wide changes across extended systems of care with coordination across multiple disciplines; 5) there are not enough champions for these interventions, particularly in the face of many other competing clinical demands and mandates; and 6) the multifactorial nature of the geriatric syndromes—requiring a coordinated, multifaceted approach—does not adhere with the traditional disease model which drives most medical practice (94).

In this section, the evidence-practice gap will be examined for two common geriatric syndromes, delirium and falls. Two examples of local efforts to translate research into practice for these conditions will be highlighted, along with the barriers to dissemination. Finally, a description of national efforts to link research to practice through policy initiatives will be provided.

Overview Delirium, defined as an acute decline in attention and global cognitive functioning, is a common and life-threatening problem for hospitalized older patients. Occurring in 14–56% of patients, delirium is associated with hospital mortality rates of 22–76%(118). Despite its clinical importance, delirium is unrecognized in 66–70% of patients(119) and is documented in the medical record of only 3% of patients when present(120). This lack of recognition has precluded effective intervention for delirium. Several recent intervention trials(99;121–124) have documented that 30–40% of delirium may be preventable, and intervention may also reduce delirium duration.

Intervention Strategy and Dissemination Process The Hospital Elder Life Program (HELP) has been demonstrated to be effective for prevention of delirium and functional decline(99;125), and to be cost-effective for both acute hospital costs(126) and long-term nursing home placement(127). Moreover, a HELP dissemination site demonstrated reduction in delirium rates and hospital costs in a quality improvement study(128). Since 1999, the HELP Dissemination Program has been established to facilitate the translation of research into practice by providing assistance with the implementation of HELP at other hospitals. Interested sites purchase the HELP dissemination package, which includes program manuals, business tools, training videotapes or compact discs, and tracking software. Sites receive ongoing support from the HELP Dissemination Team, the HELP website (http://www.hospitalelderlifeprogram.org) with its program resources and on-line discussion forum, semiannual special interest group meetings, and annual HELP conference.

Barriers to Dissemination In two qualitative studies(129;130), Bradley et al identified common challenges to translating the HELP model into practice. The initial study(129) examined challenges in initial implementation of the intervention, and identified six common challenges: gaining internal support despite differing goals of administration and clinical staff; ensuring effective clinician leadership; integrating with existing geriatric programs (coordination vs. competition); balancing program fidelity with local resources (reduce duplication; adaptation); documenting positive outcomes despite limited resources for research, and maintaining momentum despite unrealistic timeframes, limited resources, and staff turnover. In a subsequent study, Bradley et al.(130) identified 3 common challenges to sustaining the intervention: presence of clinical leadership, adaptation to local circumstances, and obtaining long-term funding. Obtaining long-term funding represented the ultimate challenge across all sites, and most successful sites demonstrated local benefits and elicited funding through the hospital’s operating budget.

Overview Falls pose a serious health problem for older persons, occurring in 30% of adults over age 65 and 40% over age 80(98;131). Falls are the leading cause of unintentional injury, which ranks as the sixth leading cause of death among the elderly(131). In addition, falls lead to functional decline, hospitalization, institutionalization, and increased healthcare costs(98;131). To date, over 60 intervention trials have been conducted including multifactorial targeted risk factor intervention studies(132), which have resulted in an approximately 30% relative risk reduction in fall rate. Moreover, fall prevention has been demonstrated to be cost-effective, and perhaps cost-saving(132). Despite this evidence, fall prevention has been largely neglected in clinical practice. A recent survey of primary care providers documented that only 37% ask patients about falls(133).

Dissemination Process In a local effort to catalyze translation of research into practice, the Connecticut Collaboration for Fall Prevention (CCFP) was implemented to disseminate current evidence throughout the health care system in the greater Hartford, Connecticut area and to embed fall risk evaluation and management into practice by changing knowledge, attitudes, and behavior of health care providers (134). Health care providers targeted for these efforts included emergency departments in 7 local hospitals, 212 primary care offices (>500 physicians), 26 home care agencies (>200 staff), and 130 rehabilitation centers (>300 physical therapists). Practice materials on fall risk evaluation and management were developed and circulated, including checklists, manuals, passbooks, and website (http://www.fallprevention.org/). A variety of professional behavior change strategies(134;135) were implemented, including general methods to heighten fall awareness and targeted methods to increase fall-related practices. The methods to heighten fall awareness included media presentations (e.g., television, radio, newspaper), monthly newsletters, posters and brochures at clinical and community sites, lectures and in-services, and efforts to publicize the website. The methods to increase fall-related practices included working groups to facilitate buy-in from local leaders, repeated contacts with providers (i.e., academic detailing(136)), and patient-mediated strategies (i.e., encouraging direct patient requests for fall management).

Barriers to Dissemination Through interviews with CCFP working groups(134), barriers to the translation of evidence-based strategies were identified, including knowledge, attitudinal, and organizational barriers. Knowledge barriers included that both providers and seniors were not aware of the preventable nature of falls; providers were not familiar with geriatrics or lacked expertise in fall prevention; providers were not aware of the expertise of other providers who would represent appropriate referral resources; and the false perception that fall risk evaluation and management were not allowed by Medicare. Attitudinal barriers included the lack of importance assigned to falls by providers; providers believing they were already addressing the problem; and patients not requesting attention to their falls. Finally, organizational barriers included the fragmented, uncoordinated nature of our healthcare system; rapid turnover of providers; arcane Medicare reimbursement system for fall-related services; healthcare focusing on diseases rather than multifactorial geriatric syndromes; competing demands on providers who are bombarded with guidelines; and the lack of a mandate to address falls in clinical practice. Clearly, local efforts can go only so far without a national push.

Table 2 provides examples of national efforts to translate research into practice and policy for geriatric syndromes (117). Examples provided span the areas of educational and clinical efforts, quality improvement approaches, accreditation standards, reimbursement and payment policies, and legislative policies. While many other initiatives exist, Table 2 provides a few representative examples of areas that are initiated or in process. These examples provide a valuable framework to further address the full scope of common geriatric syndromes.

Table 2 Examples of National Efforts to Translate Research into Practice and Policy*

Medicare reimbursement for common geriatric syndromes remains a critical issue which will need to be addressed to provide appropriate healthcare for these conditions. Considerable work will be needed to accomplish this goal. Payers are concerned about the potential cost of services, the potential for fraud and abuse, the fact that coordination of services are typically not covered by Medicare, and the statutory limitations on coverage (i.e., Medicare usually covers only acute episodes of care). Providers report challenges in providing care to older patients because Medicare is not accustomed to handling the multi-provider, multi-setting model needed to address geriatric syndromes; component services may be processed by different types of Medicare contractors; and variable interpretation of Medicare policies occurs among carriers and intermediaries. Clearly, these are areas that must be better addressed to provide optimal care for patients with geriatric syndromes.

Geriatric syndromes represent common, serious conditions for older persons, holding substantial implications for functioning and quality of life. In large part, these conditions are most prevalent in the older population, and thus, pose distinctive challenges for clinicians caring for this population. The lack of formal criteria to define geriatric syndromes has limited progress in the field. We propose that a more formal recognition of the concepts underlying geriatric syndromes, supported by an improved dialogue between different disciplines, is needed to ensure future progress.

Geriatric syndromes are multifactorial, and shared risk factors—including older age, cognitive impairment, functional impairment, and impaired mobility—were demonstrated across the common geriatric syndromes of pressure ulcers, incontinence, falls, functional decline, and delirium. These findings support the likelihood of shared pathophysiologic mechanisms, and raise the possibility of a unified approach to prevention of these syndromes.

Studies designed to elucidate the pathophysiology of geriatric syndromes are essential, but must embrace the complex and multifactorial nature of these conditions. Identifying shared common ground or mechanisms will represent a major advance. Simple linear models linking one cause to one effect are not likely to suitably address these conditions. More complex models, such as concentric models proposed in oncology, should incorporate both multiple potential pathways to the outcome, as well as the potential for interaction or synergisms between pathways or causes.

Even with substantial progress in clarifying risk factors and intervention strategies for some common geriatric syndromes, such as delirium and falls, these advances have failed to translate widely into clinical practice or policy initiatives. Dissemination programs have been established for delirium and fall prevention, and success and barriers to dissemination have been systematically evaluated. Barriers still exist at patient, provider, and organizational levels.

Table 3 presents a call to action to enhance progress in geriatric syndromes. The challenge of caring for our older population, as exemplified by these common geriatric syndromes, will require paradigm shifts and new approaches to optimize care. These challenges will stretch all of us, as consumers, providers, payers, and policy-makers, to improve our health care system to better address the needs of our rapidly aging population.

Table 3 A Call to Action to Enhance Progress in Geriatric Syndromes

This work was presented in part as a Symposium at the American Geriatrics Society 2006 Annual Scientific Meeting. The authors would like to thank the AGS Research Committee for sponsorship of this symposium. Dr. Inouye is supported in part by Grants K24AG00949 and R21AG025193 from the National Institute on Aging, and by the Milton and Shirley F. Levy Family Chair. Dr. Studenski is supported in part by Grant K07AG023641 and by the Pittsburgh OAIC (P30AG024827). Dr. Tinetti is supported in part by a grant from the Patrick and Catherine Weldon Donaghue Medical Research Foundation, by the Yale OAIC (P30AG021342) and by the Gladys Phillips Crofoot Chair. Dr. Kuchel is supported in part by a grant from the Patrick & Catherine Weldon Donaghue Medical Research Foundation and by the Travelers in Geriatrics and Gerontology.