Apathy and Its Treatment in Alzheimer's Disease and Other Dementias

November 2005, Vol. XXII, Issue 13

Although memory and other cognitive impairments are considered the hallmark features of most dementias, neuropsychiatric abnormalities occur in the majority of such patients (Cohen et al., 1993). Neuropsychiatric symptoms are associated with a rapid course of decline, elevated caregiver distress and overutilization of health care services (Chung and Cummings, 2000; Teri, 1997). Apathy is the most common neuropsychiatric symptom reported among individuals with Alzheimer's disease (AD), affecting approximately 70% of patients in the mild-to-moderate stages (Landes et al., 2001) and increasing in severity as the illness progresses (Mega et al., 1996). Apathy is common in other dementing illnesses as well (e.g., Parkinson's disease [PD], vascular dementia) and may even occur in substantial numbers of patients with mild cognitive impairment (Ready et al., 2003). Apathy is associated with functional impairment and caregiver distress at all levels of disease severity (Boyle et al., 2003; Norton et al., 2001; Rymer et al., 2002).

Apathy is characterized by the loss of initiation and motivation to participate in activities, social withdrawal, and emotional indifference (Marin, 1991). Depression shares some overlapping features (e.g., decreased initiation, social withdrawal), but can be distinguished from apathy primarily on the basis of dysphoria (Marin et al., 1994). Symptoms of dysphoria typically are absent in the apathetic patient, who displays a lack of interest and motivation in the context of emotional indifference. Apathy therefore reflects a syndrome of primary motivational loss, whereas depression reflects a primary mood disturbance.

The Neurobiological Basis

Although the neurobiological basis of apathy remains to be fully elucidated, dysfunction in frontal systems is thought to be important. Three subsystems of the frontal lobes are thought to underlie three distinct neuropsychiatric syndromes: 1) The dorsolateral prefrontal circuit is associated with executive cognitive dysfunction; 2) The lateral orbital prefrontal circuit is associated with disinhibition; and 3) The medial (anterior cingulate) circuit is associated with disorders of motivation, including apathy (Cummings, 1993). In the extreme, large bilateral lesions in the anterior cingulate cortex produce akinetic mutism, a state of profound apathy and amotivational immobility. Neuropathological changes in dementia may result in apathy by affecting this medial frontal circuit, as well as parietotemporal brain regions that subserve motivation and emotion. Cummings and Back (1998) have also proposed that medial frontal and limbic cholinergic deficits may underlie apathy. Dopaminergic pathways that influence frontal-subcortical activation may also play a role in apathy.

Apathy Assessment

A number of instruments have been developed for assessing neuropsychiatric symptoms in individuals with dementia (Table).

The Neuropsychiatric Inventory (NPI) is the most widely used instrument for assessing neuropsychiatric functioning in patients with dementia (Cummings et al., 1994). It is a valid and reliable instrument involving a caregiver interview designed to assess the presence and severity of 10 symptoms: apathy, irritability/lability, dysphoria, delusions, hallucinations, anxiety, agitation/aggression, euphoria, disinhibition and aberrant motor activity. Tekin et al. (2001) reported significant correlations between NPI apathy subscale scores and frontal pathology at autopsy in patients with AD, suggesting that the NPI is useful for this purpose. Moreover, the NPI includes apathy and depression items, which can help clinicians distinguish apathy from depression.

The Frontal Systems Behavior Scale (FrSBe) is a newer instrument that was specifically designed to measure behavioral changes related to frontal system dysfunction (Grace and Malloy, 2001). It is a valid, reliable, 46-item questionnaire that assesses the three frontal behavioral syndromes linked to the frontal circuits described earlier: apathy, disinhibition and executive dysfunction. The FrSBe measure of apathy correlates moderately with the NPI apathy rating (Norton et al., 2001) and other ratings of decreased initiation (Ready et al., 2003), but not with the Geriatric Depression Scale (GDS) (Cahn-Weiner et al., 2002). The FrSBe correlates more highly with activities of daily living impairment than the NPI (Boyle et al., 2003; Norton et al., 2001).

The Apathy Evaluation Scale (AES)-Informant version is an 18-item, informant-rated scale that utilizes a four-point Likert-type scale to assess symptoms of apathy (Marin et al., 1991). Although it is widely used, there are very limited guidelines for interpreting AES scores, and Glenn et al. (2002) reported that the AES had poor sensitivity and specificity with respect to the ability to predict the clinician's designation of a patient as apathetic. The Apathy Inventory (IA) is a new instrument that generates scores for emotional blunting, lack of initiation and lack of interest, in addition to a global apathy score (Robert et al., 2002). Preliminary evidence suggests that the caregiver-rated version of the IA is valid and reliable, and total scores on the IA correlate well with the NPI apathy subscale, suggesting high concurrent validity (Robert et al., 2002). A recent review by Malloy and Grace (2005) provides further information on these and related scales.

Treating Apathy

Cholinesterase inhibitors have some efficacy for reducing the neuropsychiatric symptoms associated with dementia, and apathy is the neuropsychiatric symptom most consistently responsive to treatment (Cummings, 2003; Wynn and Cummings, 2004). Large-scale clinical trials have generally indicated that donepezil (Aricept) improves neuropsychiatric functioning, particularly the symptom of apathy (Birks and Harvey, 2003; Feldman et al., 2001; Gauthier et al., 2002; Trinh et al., 2003). A few studies also indicate that galantamine (Razadyne) and rivastigmine (Exelon) may also have beneficial neuropsychiatric effects (Birks et al., 2000). A placebo-controlled, double-blind study evaluated the effects of galantamine in AD patients with cerebrovascular disease and probable vascular dementia (Erkinjuntti, 2002). Researchers found that galantamine was associated with a significant reduction in apathy and anxiety over six-month follow-up. Dartigues et al. (2002) found that rivastigmine resulted in improvement in apathy, irritability, delusions and anxiety in patients with mild-to-moderate AD over a six-month follow-up.

Preliminary evidence also supports the use of activating pharmacologic agents for treating apathy in patients with dementia (Marin et al., 1995). Psychostimulants such as methylphenidate and dextroamphetamine (Dexedrine, DextroStat) have been shown to reduce symptoms of apathy in case series of patients with AD, PD or cerebrovascular disease (Chatterjee and Fahn, 2002; Galynker et al., 1997; Jansen et al., 2001). Given the phenomenological overlap between apathy and depression, nondepressed dementia patients with apathy may also benefit from the use of antidepressants with stimulant properties. Some evidence suggests that dopaminergic agents may also be useful for reducing apathy, perhaps through enhancement of the functioning of frontostriatal circuits (Corcoran et al., 2004; Muller and von Cramon, 1994; Newburn and Newburn, 2005). Controlled clinical trials are needed to demonstrate convincingly the effectiveness of stimulants, antidepressants and dopaminergic agents in treating apathy in dementia. Additional research is needed to determine the magnitude and duration of positive effect and ensure that reductions in apathy are not accompanied by increases in agitation, psychosis or other side effects. Our research group is currently conducting a double-blind, National Institute on Aging-sponsored study comparing cholinesterase inhibitors alone to cholinesterase inhibitors plus modafinil (Provigil) in the treatment of apathy.

Behavioral Interventions

Combined pharmacological-behavioral approaches have consistently been shown to be more effective than pharmacologic treatments alone in a wide variety of disorders, including depression. In dementia populations, behavior therapy and applied behavioral analysis techniques have been used successfully to improve such diverse problems as incontinence, agitation and aggression (Teri and Gallagher-Thompson, 1991). Although apathy has not been specifically addressed using behavioral interventions to date, evidence suggests that behavioral interventions are effective for treating depression in patients with AD and their caregivers (Teri et al., 1997). Behavioral interventions in dementia have also resulted in improved patient health and lower caregiver burden (Teri et al., 2003). We recently completed a controlled trial of the effectiveness of a novel caregiver-based behavioral training program for reducing apathy in patients with AD and reducing stress among their caregivers. Preliminary findings suggest that behavioral intervention benefited patients with AD and their caregivers (Boyle et al., 2004). Further research examining the benefits of combined, pharmacological-behavioral interventions is needed.

Summary and Conclusions

Apathy is a debilitating and underrecognized syndrome that affects the vast majority of individuals with dementia, results in functional impairment among patients and causes stress among their caregivers. Accurate discrimination of the symptoms of apathy from depression is necessary for optimal treatment. The careful comparison of the symptoms of dysphoria versus symptoms of amotivation is recommended, and a number of instruments have been developed to aid in the discrimination of apathy from depression.

Cholinesterase inhibitors have been shown to reduce the neuropsychiatric symptoms of AD and vascular dementia with apathy showing the most consistent gains. The magnitude and persistence of these changes remains a topic for future research. Traditional antidepressants, activating neurologic agents and combined pharmacological-behavioral treatments also hold promise for the treatment of apathy, but controlled large-scale clinical trials are lacking. For more detailed reviews, the reader is referred to Boyle and Malloy (2004) and Wynn and Cummings (2004).

Dr. Malloy is associate professor at Brown Medical School and co-director of the Butler Hospital Memory Disorders Program.

Dr. Boyle is a neuropsychologist with the Rush Alzheimer's Disease Center and assistant professor in the department of behavioral sciences at Rush University Medical Center.

References

Birks J, Grimley Evans J, Iakovidou V, Tsolaki M (2000), Rivastigmine for Alzheimer's disease. Cochrane Database Syst Rev (4):CD001191 [update].

Birks JS, Harvey R (2003), Donepezil for dementia due to Alzheimer's disease. Cochrane Database Syst Rev (3):CD001190 [update].

Boyle PA, Malloy PF (2004), Treating apathy in Alzheimer's disease. Dement Geriatr Cogn Disord 17(1-2):91-99.

Boyle PA, Malloy PF, Salloway S et al. (2003), Executive dysfunction and apathy predict functional impairment in Alzheimer disease. Am J Geriatr Psychiatry 11(2):214-221.

Boyle PA, O'Connor M, Carruth S et al. (2004), Evaluating the efficacy of a caregiver-based intervention for treating the neuropsychiatric symptoms of Alzheimer's disease. Presented at the 9th International Conference on Alzheimer's Disease and Related Disorders. Philadelphia; July 17-22.

Cahn-Weiner DA, Grace J, Ott BR et al. (2002), Cognitive and behavioral features discriminate between Alzheimer's and Parkinson's disease. Neuropsychiatry Neuropsychol Behav Neurol 15(2):79-87.

Chatterjee A, Fahn S (2002), Methylphenidate treats apathy in Parkinson's disease. J Neuropsychiatry Clin Neurosci 14(4):461-462.

Chung JA, Cummings JL (2000), Neurobehavioral and neuropsychiatric symptoms in Alzheimer's disease: characteristics and treatment. Neurol Clin 18(4):829-846.

Cohen D, Eisdorfer C, Gorelick P et al. (1993), Psychopathology associated with Alzheimer's disease and related disorders. J Gerontol 48(6):M255-M260.

Corcoran C, Wong ML, O'Keane V (2004), Bupropion in the management of apathy. J Psychopharmacol 18(1):133-135.

Cummings JL (1993), Frontal-subcortical circuits and human behavior. Arch Neurol 50(8):873-880.

Cummings JL (2003), Use of cholinesterase inhibitors in clinical practice: evidence-based recommendations. Am J Geriatr Psychiatry 11(2):131-145.

Cummings JL, Back C (1998), The cholinergic hypothesis of neuropsychiatric symptoms in Alzheimer's disease. Am J Geriatr Psychiatry 6(2 suppl 1):S64-S78.

Cummings JL, Mega M, Gray K et al. (1994), The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 44(12):2308-2314.

Dartigues JF, Goulley F, Bourdeix I et al. (2002), [Rivastigmine in current clinical practice in patients with mild to moderate Alzheimer's disease.] Rev Neurol (Paris) 158(8-9):807-812.

Erkinjuntti T (2002), Treatment options: the latest evidence with galantamine (Reminyl). J Neurol Sci 203-204:125-130.

Feldman H, Gauthier S, Hecker J et al. (2001), A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease. [Published erratum Neurology 57(11):2153.] Neurology 57(4):613-620 [see comment].

Galynker I, Ieronimo C, Miner C et al. (1997), Methylphenidate treatment of negative symptoms in patients with dementia. J Neuropsychiatry Clin Neurosci 9(2):231-239.

Gauthier S, Feldman H, Hecker J et al. (2002), Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer's disease. Int Psychogeriatr 14(4):389-404.

Glenn MB, Burke DT, O'Neil-Pirozzi T et al. (2002). Cutoff score on the apathy evaluation scale in subjects with traumatic brain injury. Brain Inj 16(6):509-516.

Grace J, Malloy PF (2001), Frontal Systems Behavior Scale (FrSBe): Professional Manual. Lutz, Fla.: Psychological Assessment Resources, Inc.

Jansen IH, Olde Rikkert MG, Hulsbos HA, Hoefnagels WH (2001), Toward individualized evidence-based medicine: five "N of 1" trials of methylphenidate in geriatric patients. J Am Geriatr Soc 49(4):474-476.

Landes AM, Sperry SD, Strauss ME, Geldmacher DS (2001), Apathy in Alzheimer's disease. J Am Geriatr Soc 49(12):1700-1707.

Malloy P, Grace J (2005), A review of rating scales for measuring behavior change due to frontal systems damage. Cogn Behav Neurol 18(1):18-27.

Marin RS (1991), Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 3(3):243-254.

Marin RS, Biedrzycki RC, Firinciogullari S (1991), Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res 38(2):143-162.

Marin RS, Firinciogullari S, Biedrzycki RC (1994), Group differences in the relationship between apathy and depression. J Nerv Ment Dis 182(4):235-239.

Marin RS, Fogel BS, Hawkins J et al. (1995), Apathy: a treatable syndrome. J Neuropsychiatry Clin Neurosci 7(1):23-30.

Mega MS, Cummings JL, Fiorello T, Gornbein J (1996), The spectrum of behavioral changes in Alzheimer's disease. Neurology 46(1):130-135.

Muller U, von Cramon DY (1994), The therapeutic potential of bromocriptine in neuropsychological rehabilitation of patients with acquired brain damage. Prog Neuropsychopharmacol Biol Psychiatry 18(7):1103-1120.

Newburn G, Newburn D (2005), Selegiline in the management of apathy following traumatic brain injury. Brain Inj 19(2):149-154.

Norton LE, Malloy PF, Salloway S (2001), The impact of behavioral symptoms on activities of daily living in patients with dementia. Am J Geriatr Psychiatry 9(1):41-48.

Ready RE, Ott BR, Grace J, Cahn-Weiner DA (2003), Apathy and executive dysfunction in mild cognitive impairment and Alzheimer disease. Am J Geriatr Psychiatry 11(2):222-228.

Robert PH, Clairet S, Benoit M et al. (2002), The apathy inventory: assessment of apathy and awareness in Alzheimer's disease, Parkinson's disease and mild cognitive impairment. Int J Geriatr Psychiatry 17(12):1099-1105.

Rymer S, Salloway S, Norton L et al. (2002), Impaired awareness, behavior disturbance, and caregiver burden in Alzheimer disease. Alzheimer Dis Assoc Disord 16(4):248-253.

Tekin S, Mega MS, Masterman DM et al. (2001), Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease. Ann Neurol 49(3):355-361.

Teri L (1997), Behavior and caregiver burden: behavioral problems in patients with Alzheimer disease and its association with caregiver distress. Alzheimer Dis Assoc Disord 11(suppl 4):S35-S38.

Teri L, Gallagher-Thompson D (1991), Cognitive-behavioral interventions for treatment of depression in Alzheimer's patients. Gerontologist 31(3):413-416.

Teri L, Gibbons LE, McCurry SM et al. (2003), Exercise plus behavioral management in patients with Alzheimer disease: a randomized controlled trial. JAMA 290(15):2015-2022 [see comments].

Teri L, Logsdon RG, Uomoto J, McCurry SM (1997), Behavioral treatment of depression in dementia patients: a controlled clinical trial. J Gerontol B Psychol Sci Soc Sci 52(4):P159-P166.

Trinh NH, Hoblyn J, Mohanty S, Yaffe K (2003), Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a meta-analysis. JAMA 289(2):210-216 [see comments].

Wynn ZJ, Cummings JL (2004), Cholinesterase inhibitor therapies and neuropsychiatric manifestations of Alzheimer's disease. Dement Geriatr Cogn Disord 17(1-2):100-108.