Recognition of Apathy as Marker for Dementia Growing

"People are getting excited about apathy nowbecause it may be a behavioral marker for amore rapidly progressing dementia," saidPrasad Padala, MD, assistant professor ofpsychiatry at the University of NebraskaMedical Center in Omaha.

A recent 4-year study linked apathy to a hastened decline in persons with Alzheimer disease (AD).¹ Another recent study found that persons with mild cognitive impairment (MCI) were more likely to convert to AD a year later if they also had apathy.²

Another factor that has increased interest in apathy is the growing understanding of physical changes in the brain. For example, an autopsy study found that among persons with AD, those who had chronic apathy tended to have more neurofibrillary tangles than those without apathy.³ Clinically apathetic persons with dementia may even have a different genetic makeup than persons with dementia who are not apathetic. A recent study showed that persons with AD were more likely to be carriers of the ApoE e4 allele if they also had apathy.⁴

Apathy traditionally has received less attention than other neuropsychiatric states in dementia, such as depression, agitation, aggression, and psychosis. This is slowly changing. Although researchers are becoming more knowledgeable about the condition, treating it remains difficult. "There aren't many medications or other treatments that have shown efficacy in treating apathy," said Tiffany Chow, MD, assistant professor of neurology and geriatric psychiatry at the University of Toronto. But given the new interest in the condition, researchers expect full-scale randomized controlled trials to follow.

COMMON BEHAVIORAL PROBLEM

Apathy, which refers to a loss of motivation, is marked by such characteristics as diminished initiation, poor persistence, lack of interest, indifference, low social engagement, blunted emotional re- sponse, and lack of insight.⁵ It is the most common behavioral disturbance in dementia. Prevalence rates are as high as 80% in clinic samples of patients with primary dementia and range from 27% to 36% in community samples.⁶ An analysis of 3 European studies produced a mean of about 56%.⁷ The incidence of apathy increases with the severity of the dementia.

"In the beginning stages of dementia, people may withdraw from activities because they're aware of what's going on and want to avoid making themselves look bad," said Chow. "Then in the moderate to severe stages, they do shut down and are not able to initiate their own activities."

Apathy has a dramatic effect on persons with dementia and their families. First, the condition leads to decreased function. In one study, persons with apathy were nearly 3 times more likely than those without apathy to be impaired in dressing, bathing, transferring from bed to chair, using the toilet, walking, or eating and more than 3 times more likely to be impaired in all 6 activities.⁸

Second, apathy is linked to executive cognitive dysfunction. For example, a study of 184 patients with probable AD found that apathetic patients had significantly poorer performance in naming, word-list learning, verbal fluency, and set-shifting than those without apathy.⁹ "Without interest or initiative, it's difficult for these patients to use their remaining cognitive function," said Philippe Robert, MD, director of the Memory Center for Care and Research at Nice University Hospital in France.

Third, apathy makes persons less likely to comply with treatment. This can lead to setbacks in treatment not only for dementia but also for concomitant health conditions. Finally, the extreme burden on caregivers created by these deficits tends to increase caregiver distress. "People with apathy tend to depend a lot more on caregivers, even for things they can do on their own," said Padala. Although it has not been proved in studies, patients with apathy may require hired home care and institutional care earlier than other patients with dementia.

Apathy may pack an additional punch for caregivers who are family members because it chips away at the patient's personality. "The caregiver sees the person withdrawing and shutting down, and it seems like they're fading into the distance right before their eyes," said Chow. "A lot of family members say that they prefer someone doing obsessive-compulsive things to just being apathetic," she added.

The situation may be different in a nursing home, where apathetic patients who sit quietly and do not cause disturbances might be viewed as easy to care for. "If I were working in a nursing home, I would probably not be perturbed by apathetic patients as much as by someone who is having active hallucinations," said Padala. This may be one reason why apathy research has traditionally received less funding than research on problems such as agitation and psychosis.

MEASURING APATHY

Conducting research on apathy requires an accurate measurement scale. The most often used scales for measuring apathy in dementia are the Apathy Evaluation Scale (AES), the apathy subscale of the Neuropsychiatric Inventory (NPI), and the Apathy Inventory (IA).

The AES is an 18-item scale that has separate versions for the patient, informant, and clinician. It measures 3 clinical dimensions of apathy: emotional blunting, lack of interest, and lack of initiative. The IA also has 3 versions and measures 3 clinical dimensions but is shorter than the AES. The NPI, which is a long test that is used widely in drug trials, measures 10 common behavioral disturbances in persons with dementia and other neurological disorders. The informant supplies answers to 4 questions related to apathy; a positive response to 1 triggers a subset of 8 more specific questions on apathy.

Other scales include Starkstein's 14-item scale, the Irritability-Apathy Scale, the Cambridge Behavioral Inventory (CBI), and the Lille Apathy Rating Scale (LARS). The Starkstein scale is similar to the AES but shorter. The Irritability-Apathy Scale is a brief, informant-based scale with 5 items related to apathy that is designed for use in persons with AD or Huntington disease. The CBI is an informant-based scale that measures neuropsychiatric symptoms and functional ability in dementia. The LARS is long, with 33 items, but is designed for simplicity because it requests "yes" and "no" answers instead of ratings on a numbered scale.

Diana E. Clarke, PhD, psychiatric epidemiologist in the Department of Mental Health at the Johns Hopkins Bloomberg School of Public Health in Baltimore, said that based on her assessment of the AES, "informant- and clinician-rated scales are better than self-rated scales."¹⁰

"As a screening for whether apathy is present, I think that any of the scales are fine," said Chow. However, comparative studies are needed to see which scales are best at measuring apathy, which is important for treatment studies.

Chow pointed out that it can be difficult to detect apathy in office visits because they are brief, lasting only about 15 or 20 minutes, and many patients are more alert in a medical office. "It drives the families crazy, because they say that the person doesn't respond all day at home and then he's fine in the office." She said this is why it is important for the neurologist or neuropsychiatrist to ask family members whether the person is keeping up with usual activities.

Apathy also correlates with physical changes in the brain. In addition to the recent autopsy study that found a link between chronic apathy and neurofibrillary tangles in persons with AD, another study found that among 31 persons with AD, those with low initiative and interest scores had significantly reduced perfusion in the right anterior cingulate cortex on a single photon emission CT scan compared with those who had normal scores.¹¹

DISTINGUISHING APATHY FROM DEPRESSION

Depression, although not as prevalent, is another condition that is commonly seen in patients with dementia. Apathy and depression have some overlapping characteristics--namely, loss of interest or pleasure in activities. Both are associated with functional and cognitive decline. As a result, the conditions can be confused with each other. To complicate matters, many patients have both apathy and depression.

In the Cache County Study on Memory, Health, and Aging, which looked at more than 5000 persons aged 65 years and older, about 42% of persons with apathy had depression and about 37% of those with depression had apathy.⁶ In the European Alzheimer's Disease Consortium study, which analyzed more than 3000 persons with AD, 22% of the participants had apathy alone, 10% had depression alone, and 15% had apathy and depression.¹²

There are many important differences between apathy and depression, however. "Apathy relates more to indifference, whereas depression is more hopelessness about the future," said Padala. Apathy and depression also look very different in the brain. For example, a recently published study of 84 older persons found that those who were depressed had smaller gray matter volumes in the orbitofrontal areas as measured by MRI, whereas those with apathy had decreased gray matter volume in the right anterior cingulate cortex.¹³ The more severe the apathy, the smaller the gray matter volume.

Differentiating between apathy and depression is important because the treatment approaches are different. For example, Padala pointed out that selective serotonin reuptake inhibitors used for treatment of depression, such as fluoxetine (Prozac) and sertraline (Zoloft), may actually contribute to apathy. "One of my patients explained to me that after he started the medication, he no longer felt depressed, but he also didn't feel anything else," Padala commented.

Conversely, the stimulant methylphenidate (Ritalin), which appears to be helpful in treating apathy, is not effective in depression.

LINK BETWEEN APATHY AND MCI

Investigators are now finding links between apathy and MCI. One study found that among persons with MCI, those in whom AD developed at 1-year follow-up were significantly more likely to have symptoms of apathy at baseline (92%) than those in whom AD did not develop (27%).² Robert told Applied Neurology that his 3-year results, which have been submitted for publication, continue to show that the presence of apathy increases the risk of conversion to AD for persons with MCI.

"The presence of lack of interest--a soft behavioral sign that's easy to detect during a clinical interview--could indicate potential decline in patients with MCI," said Robert. "It's important to carefully check the cognitive status of these patients."

In addition, the Cache County Study of Memory and Aging found that clinical apathy was more common in persons with a mild cognitive syndrome (3.1%) than in those who were cognitively normal (1.4%), although not as common as in persons with dementia (17.3%).

TREATMENT IN ITS INFANCY

The treatment of apathy in dementia is still in its infancy, and it is unclear which treatments are effective. "Our knowledge has been limited by a lack of clinical trials," said Clarke.

Some recent research has focused on cholinesterase inhibitors, but results have been mixed. "Cholinesterase inhibitors help in some cases, but not in the majority," said Chiadi Onyike, MD, assistant professor of psychiatry and behavioral sciences at Johns Hopkins University.

Several studies have analyzed the cholinesterase inhibitor donepezil (Aricept) for treatment of apathy in AD, with varying results. One 6-month, randomized, double-blind, placebo-controlled trial in 290 outpatients with AD found that donepezil significantly reduced apathy, depression, and anxiety.¹⁴ By contrast, a placebo-controlled study in 208 nursing home patients reported that although donepezil significantly reduced agitation, it did not reduce apathy.¹⁵ It is possible that donepezil may be more effective for treating apathy in mild to moderate AD than in late-stage AD, but further studies are needed.

Two 6-month, open-label prospective studies in nursing home patients have looked at the drug rivastigmine (Exelon). The first study, which involved 669 patients with moderate to severe AD, found an improvement in apathy at 3 months but only a trend toward reduced apathy at 6 months. The second study of 173 patients with moderate to severe AD found an improvement in neuropsychiatric symptoms overall but no improvement in apathy.^16,17

Galantamine (Razadyne) improved the condition of patients with apathy and anxiety in a 6-month, placebo-controlled, double-blind study of nearly 600 patients with mild to moderate AD.¹⁸ However, a pooled sample of more than 2000 patients with mild to moderate AD found that galantamine did not improve a combined end point that included effects on hallucinations, anxiety, apathy, and aberrant motor behaviors.¹⁹

A small case series of 3 patients with frontotemporal dementia found that their apathy improved with memantine (Namenda).²⁰

Researchers have also tried stimulants such as methylphenidate, dextroamphetamine (Adderall), and modafinil (Provigil) in persons with apathy and dementia. Padala has reported positive results with the use of methylphenidate in a small case series²¹ and with modafinil in a case study.²²

Onyike said that amantadine (Symmetrel), bromocriptine (Parlodel), and bupropion (Wellbutrin) may be useful in some cases.

The research on nonpharmacological interventions for apathy in dementia is even sparser than that for pharmacological interventions. One study found that persons with dementia and apathy were engaged by live music.²³ An Italian study of elderly persons, most of whom had dementia, suggested that validation therapy improved apathy.²⁴ Other treatments that have been used to treat apathy include Snoezelen (multisensory stimulation) and aromatherapy.²⁵ Onyike said that structured activity programs that socialize the person who is living in a residential community could be useful; another approach is to have the caregiver oversee a regimen of brief focused activities and interpersonal interactions.

FUTURE DIRECTIONS

"Neurologists and neuropsychiatrists are becoming increasingly aware of apathy in dementia and its consequences on the course of the illness and its impact on caregivers," said Clarke. However, she added that "more research is needed . . . to improve our knowledge of the biology and genetics of apathy and dementia and enhance treatment strategies."

Onyike agreed that researchers need to develop a better understanding of apathy. "How does a person develop drive, become aware of it, and initiate actions based on the drive?" he asked. He said that researchers could attempt to answer this question and then work to define the brain circuitry that underlies the process. Robert van Reekum, MD, assistant professor of psychiatry at the University of Toronto, agreed that researchers "need a comprehensive biopsychosocial understanding of motivational behavior." van Reekum said that future research also should involve testing the validity of the upcoming DSM-V diagnosis of apathy, developing and testing measurement tools, conducting randomized controlled trials of promising interventions, and investigating the possibility of various subtypes of apathy.

Chow agreed, saying that a problem with treatment approaches is that "we haven't spent enough time parsing the type of apathy that we're trying to treat." It is possible, for example, that persons with affective apathy might be more likely to respond to antidepressants; those with cognitive apathy might be more responsive to cholinesterase inhibitors. "Until we separate patients out into these different groups, then maybe the drug trials haven't been properly conducted," she said.

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