[1] 15w Assessing and Predicting Functional Impairment in Alzheimer's Disease: The Emerging Role of Frontal System Dysfunction

[1] 127w Alzheimer's disease (AD) results in neuropsychologic, neuropsychiatric, and functional impairments and is a leading cause of disability among the elderly [1,2]. Impairments in activities of daily living (ADL) contribute significantly to the disability associated with AD. ADL are comprised of instrumental (IADL) and basic (BADL) selfcare abilities (IADL include complex behaviors such as cooking, housekeeping, and medication management, and BADL include basic tasks such as feeding and toileting) [3]. IADL tend to decline earlier in the course of AD than BADL, although each deteriorates as the disease progresses [4][5][6]. ADL impairments result in increased caregiver stress, over-utilization of health care services, and diminished quality of life among individuals with AD [7,8•]. ADL dysfunction also is a leading reason for nursing home placement of patients with dementia [8•,9].

[2] 87w The assessment of ADL represents an important component of the diagnosis and management of AD patients, and an understanding of the determinants of ADL dysfunction may promote the early identification of individuals at risk for functional disability. This chapter reviews ADL assessment methods and summarizes recent studies that have examined the neuropsychologic and neuropsychiatric predictors of functional impairment among patients with AD. The emerging significance of frontal system dysfunction as a determinant of ADL impairment is discussed, and recommendations for clinical practice and future research are provided.

[1] 153w Activities of daily living impairments contribute significantly to the disability associated with AD, and the routine use of formal ADL assessment methods is critical for the diagnosis, staging, and management of patients with AD. Further, an understanding of the predictors of ADL impairment in AD may promote the early identification of individuals in need of assistance and facilitate the implementation of optimal management strategies. The studies reviewed here demonstrate that executive cognitive dysfunction and related neuropsychiatric symptoms (eg, apa-thy) contribute significantly to ADL failures among patients with AD [22-25,26•]. Patients with prominent executive impairment tend to show greater functional deficits (regardless of dementia severity or other cognitive deficits) than those with minimal executive compromise [24], and executive dysfunction and related neuropsychiatric symptoms (eg, apathy) have emerged as important predictors of functional status in AD [26•]. Prominent executive dysfunction or apathy therefore may serve as proxy markers for functional status among patients with AD.

[2] 132w The emerging relationship between executive dysfunction, related neuropsychiatric abnormalities, and functional status and the frequent occurrence of all three in AD [23,26•,29,40] suggests a common neuropathologic substrate. Executive dysfunction is widely recognized as a neuropsychologic consequence of frontal system abnormalities, and many of the neuropsychiatric symptoms that emerge as correlates of functional impairment in AD also are believed to be mediated by frontal systems. For example, apathy, agitation, and anxiety have been linked to frontal system dysfunction among patients with AD in functional imaging studies [30,31]. Functional impairment in AD therefore may reflect the involvement of frontal systems, particularly in the mild-to-moderate stages of dementia. It is well known that the cholinergic deficiency of AD is particularly severe in frontal brain regions [42], and this cholinergic deficiency may have important functional consequences.

[3] 152w Executive cognitive functions are multifaceted and involve planning, organization, mental flexibility, and behavioral inhibition [28]. Impairment in a single or multiple aspects of executive functions may be sufficient to produce ADL impairment, but these studies do not provide information as to the relationship between specific components of executive functions and functional impairment. A recent report by the Committee on Research of the American Neuropsychiatric Association [43••] highlighted the need for further research examining the characteristics and functional consequences of executive dysfunction in numerous populations (including AD); of particular interest is research aimed to determine the extent to which specific components of executive functions are associated with functional declines. Moreover, research aimed at determining the level of executive dysfunction at which patients show clinically meaningful functional deficits will be of particular clinical use. Further research also is needed to clarify the specific neuropsychiatric correlates functional impairment in AD across levels of dementia severity.

[4] 91w Given the frequency of symptoms of frontal system dysfunction among and the increasing evidence of its functional significance in AD, thorough evaluations of executive cognitive abilities and neuropsychiatric symptoms are recommended for patients with AD. Such evaluations may aid in the identification of individuals at highest risk for disability and provide important information regarding treatment planning and long-term care. Health care pro-viders should closely monitor those individuals with marked executive or neuropsychiatric dysfunction early in the course of the illness, because those individuals may be at increased risk for functional disability.

[1] 246w Although debate remains with regard to the preferred instrument for measuring ADL in patients with AD, several valid and reliable instruments are available for this purpose. Examples include the Lawton and Brody ADL Scale (LB ADL) [3], the Progressive Deterioration Scale [13], the Disability Assessment for Dementia [14], and the Alzheimer Disease Cooperative Study ADL Inventory (ADCS-ADL) [15]. All of those scales are recommended for patients in the mild-tomoderate stages of dementia and are completed by an informant (eg, a caregiver or relative who spends a considerable amount of time with the patient in the home and who can report on the patient's functional abilities) rather than the patient. Informant-based measures are strongly preferred for dementia evaluations given the unreliability of dementia patients' self-reports [12,15]; however, potential biases can affect informant ratings. For example, informants may under-or over-exaggerate the patient's level of functional impairment depending on the informant's own mental health status (eg, depression, anxiety) or perceived need for services [16]. One recent study found that family caregivers who were experiencing high levels of burden tended to report higher levels of ADL dysfunction compared with other raters [17]. Further, gender-based or cultural biases may also affect ratings (eg, a man may be rated as "dependent" in housekeeping, because he never participated in that activity). Some of the recently developed scales (eg, the ADCS-ADL scale) make provisions for areas in which an informant cannot provide an accurate rating because of the patient's limited involvement in specific tasks.

[2] 74w Most ADL scales include items designed to assess IADL and BADL, respectively, and provide an estimate of overall ADL performance. Informants are asked to rate the dementia patient's ability to perform specific IADL and BADL skills. Ratings typically indicate independence, partial dependence, or dependence on a given task. Total IADL, BADL, and ADL scores are derived by summing performances across relevant items, and total ADL scores reflect an individual's overall level of functional capability.

[3] 115w The selection of an ADL assessment instrument for use in clinical practice typically depends on the severity of the dementia population being evaluated. IADL tend to decline earlier in the course of dementia than BADL, and scales that emphasize IADL are most useful and appropriate for outpatients with mild-to-moderate dementia. In contrast, scales that emphasize BADL are most useful for inpatients or those with severe dementia. Instruments such as the ADCS-ADL scale [15] and the Disability Assessment for Dementia scale [14] are commonly used in clinical trials involving outpatients, have good reliability and validity, and are sensitive to change over time [14,18]. Those instruments are recommended for use with community-dwelling AD patients with mild-to-moderate dementia.

[1] 124w The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [10] and National Institute of Neurological and Communicative Disorders and Stroke Alzheimer's Disease and Related Disorders Association [11] criteria for AD require the presence of neuropsychologic deficits sufficient to cause significant declines in independent functioning. The routine use of formal ADL assessment instruments is strongly recommended in diagnostic evaluations for dementia [12]. Although ADL can be assessed informally (via unstructured interviews between health care providers and patients' families), unstructured interviews often are difficult to replicate, time consuming, and limited in terms of the number of ADL assessed. Formal ADL assessments typically provide more reliable and comprehensive information, and such evaluations are essential to the diagnosis, tracking, and management of patients with AD.

[2] 157w Specifically, formal ADL assessments yield reliable estimates of functional status that clinicians can use for the Alzheimer's disease (AD) is associated with neuropsychologic and neuropsychiatric dysfunction and is a leading cause of disability among the elderly. Impairments in activities of daily living (ADL) contribute significantly to the disability reported among patients with AD and diminish quality of life for patients and their families. ADL assessment represents an important component of the diagnosis, tracking, and management of AD. Further, an understanding of the determinants of ADL dysfunction is critical for the early identification of individuals at risk for functional disability and for improved patient care. This manuscript reviews methods for assessing ADL in patients with AD and summarizes the available literature on the neuropsychologic and neuropsychiatric correlates of functional impairment in AD. The emerging role of frontal system dysfunction as an important determinant of ADL impairment is discussed, and recommendations for clinical practice and future research are provided.

[3] 87w following important purposes: 1) to identify areas in which assistance is immediately needed, 2) to implement appropriate management or compensatory strategies, and 3) to track a patient's stability or decline over time. Moreover, functional status is increasingly recognized as a primary outcome in pharmacologic and other intervention studies [12], and, if collected systematically and reliably, ADL assessments can serve as an important indicator of treatment effectiveness. The following section reviews some of the commonly used and widely available ADL assessment instruments for use in patients with AD.

[4] 111w Alzheimer's disease is associated with significant neuropsychologic and neuropsychiatric dysfunction [10,11], and numerous studies have demonstrated that dementia severity [5,19,20] and neuropsychiatric symptoms [21,22] contribute to the disability associated with AD. Whereas early investigations of these relationships focused only on global cognitive or neuropsychiatric dysfunction, investigators recently have begun to examine the specific neuropsychologic and neuropsychiatric determinants of ADL dysfunction in an attempt to better understand the symptoms most highly associated with functional disability in AD. Although memory impairment is considered the hallmark feature of AD [10], an emerging body of evidence suggests that symptoms related to frontal system dysfunction may contribute most significantly to functional impairment in this population [22-25,26•].

[5] 151w Frontal system dysfunction is common and perhaps under-recognized among individuals with AD [27,28]. Symptoms of frontal system dysfunction tend to occur early in the course of AD [29] and manifest as executive cognitive deficits (eg, decreased mental flexibility, higher order thinking, and goal-directedness) [27][28][29] and related neuropsychiatric symptoms, including apathy, agitation or irritability, disinhibition, and anxiety [30][31][32]. Executive functions have emerged as a reliable predictor of ADL impairment in healthy elderly individuals [33][34][35][36] and individuals with neurologic disorders other than AD [37,38], and executive functions are receiving considerably more focus in the dementia literature. At present, it appears that the association between executive cognitive dysfunction and functional performance holds, and is stronger than that between dementia severity and ADL even among individuals with a primary memory disorder. Further, frontally mediated neuropsychiatric symptoms commonly associated with executive dysfunction (eg, apathy) also appear to contribute significantly to functional deficits in patients with dementia.

[6] 128w Chen et al. [23] conducted one of the early investigations of the relationship between executive dysfunction, neuropsychiatric symptoms, and functional status in a sample of 31 patients with mild-to-moderate AD. Results indi-cated strong and significant associations between executive dysfunction (as measured by four commonly used neuropsychologic tests), overall neuropsychiatric dysfunction, and ADL, as well as between executive dysfunction and the frontally mediated neuropsychiatric symptoms of agitation and disinhibition, specifically. The associations between executive cognitive dysfunction, frontally mediated neuropsychiatric symptoms, and ADL were stronger than the association between dementia severity and functional status, and most correlations remained significant even after adjusting for dementia severity. Chen et al. [23] therefore concluded that executive dysfunction was independently associated with neuropsychiatric symptoms and functional impairment in their sample of patients with AD.

[7] 148w Subsequent findings support the association between executive dysfunction and functional impairment among patients with AD and continue to suggest that this relationship is independent of other AD-related neuropsychologic deficits. Back-Madruga et al. [24] found that patients with mild AD with prominent executive dysfunction demonstrated significantly more neuropsychiatric and functional impairment compared with patients with AD with similar levels of dementia severity, but without prominent executive deficits. In a related study, Cahn-Weiner et al. [25] examined the use of specific neuropsychologic tests for predicting functional status (as measured by the LB ADL scale [3]) among patients with mild AD. In multiple regression analyses examining the contributions made by executive functions and other cognitive abilities to ADL, executive dysfunction emerged as a significant predictor of ADL, accounting for 40% of the variance in functional status. Memory, language, and other cognitive functions did not emerge as significant predictors of functional impairment.

[8] 211w Building on prior studies demonstrating a link between executive cognitive dysfunction, related neuropsychiatric symptoms, and functional status, Boyle et al. [26•] prospectively examined the extent to which executive dysfunction and frontally mediated neuropsychiatric symptoms predict functional impairment among patients with mildto-moderate AD. Neuropsychologic performance was evaluated using the Mattis Dementia Rating Scale [38], and the initiation-perseveration subscale served as the primary measure of executive cognitive abilities. Frontally mediated neuropsychiatric symptoms were assessed using the informant-rated Frontal Systems Behavioral Inventory [39], which measures apathy, executive behavioral dysfunction, and disinhibition, all of which are common among individuals with mild-to-moderate AD [29]. Finally, ADL (including total ADL, IADL, and BADL) were assessed using the LB ADL scale [3]. As expected, executive cognitive dysfunction and frontally mediated neuropsychiatric symptoms emerged as highly significant predictors of functional status, even after accounting for dementia severity and depressive symptomatology. More specifically, regression analyses revealed that executive cognitive dysfunction and apathy accounted for 44% of the variance in IADL; executive cognitive dysfunction alone explained 17% of the variance in IADL, and apathy scores added an additional 27%. Further, executive dysfunction and overall estimates of frontal-behavioral neuropsychiatric impairment explained 28% of the variance in BADL. Even after accounting for executive dysfunction, apathy remained a strong and significant predictor of BADL.

[9] 146w Although prior findings had indicated an association between apathy and functional status in AD [21,22], the Boyle et al. study [26•] was the first to demonstrate a strong and independent predictive relationship between apathy and IADL and BADL impairment. These associations remained significant even after adjusting for depressive symptomatology. Some previous findings [41] indicated that depression predicts functional status in AD patients (with the strength of the association varying by dementia severity); however, the Boyle et al. [26•] findings call into question the association between depression and functional impairment. At least one additional study reported no association between depression and functional impairment in AD [21], and it is possible that earlier findings were confounded by the presence of apathy in the context of depression. The current findings indicate a more powerful relationship between apathy and functional status than between depression and functional status in mildto-moderate AD.

[10] 116w Taken together, recent findings indicate that frontally mediated neuropsychologic and related neuropsychiatric symptoms (eg, apathy) are important determinants of functional impairment among patients with AD [23-25,26•]. The available data show that executive dysfunction contributes significantly and independently to functional impairments (particularly IADL), over and above dementia severity. Further, the frontally mediated syndrome of apathy appears to have significant functional consequences over and above those associated with executive dysfunction. Additional research is needed to clarify the predictors of functional impairment in AD and to establish the relative importance of specific neuropsychologic versus neuropsychiatric impairments; nevertheless, these findings suggest that symptoms of frontal system dysfunction may play a prominent role in determining functional status among individuals with AD.