Abstract
Objective: To investigate the association between apathy and depression, and specific cognitive deficits in AD.
Background: Apathy and depression are frequent behavioral disorders in patients with AD. However, the neuropsychological correlates of these disorders have rarely been examined.
Methods: A comprehensive neuropsychological and psychiatric evaluation was carried out in 72 patients with AD with apathy and depression, 29 patients with AD with apathy only, 31 patients with AD with depression only, and 52 patients with AD with neither apathy nor depression (control group).
Results: Patients with apathy had significantly lower scores on tests of verbal memory, naming, set shifting, and verbal fluency compared with patients without apathy. The association of depression and apathy produced significantly more severe deficits compared with apathy only on a test of abstract thinking. Finally, depression in the absence of apathy was not associated with more severe cognitive impairments compared with the AD control group.
Conclusions: Apathy, but not depression, is associated with significantly more severe frontal lobe related cognitive deficits in AD.
Apathy and depression are among the most prevalent behavioral disorders in patients with AD.1,2 In a recent study that included 101 consecutive patients with AD, we found that 46% had clinically significant apathy.2 Our study also demonstrated several significant correlates of apathy in AD, such as more severe impairments in activities of daily living, more severe extrapyramidal signs, and a significantly higher frequency of both major depression and dysthymia compared with nonapathetic patients with AD. Although we also demonstrated a significant association between apathy and memory deficits, the study was limited because it included only a small sample of patients with AD with apathy only.
Thus, for the current study we examined a separate consecutive series of 185 patients with probable AD who were assessed with a comprehensive neuropsychological battery that included tests of verbal and visual memory, abstract reasoning, auditory attention, set shifting, verbal fluency, visuospatial reasoning, verbal comprehension, naming, constructional praxis, and manual dexterity. To examine the influence of apathy and depression on cognitive functions, our study had a 2 × 2 design, and included patients with AD with depression but no apathy, apathy but no depression, both apathy and depression, and neither apathy nor depression.
Patients and methods.
Patients.
A consecutive series of 233 patients who attended the dementia clinic of our institute complaining of memory problems were screened for participation in the study. After neurologic and neuropsychological evaluation, 35 patients met the State of California AD Diagnostic and Treatment Centers criteria for vascular dementia,3 and 13 additional people had a normal assessment. Both groups were excluded from further evaluations. Thus, the final sample of our study included 133 patients who met National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria for probable AD,4 and 51 patients with memory deficits on the neuropsychological evaluation but no deficits in other cognitive domains (this group had a Clinical Dementia Rating [CDR] of 0.5,5 which is classified as questionable dementia). We decided to include patients with a CDR of 0.5 because most of these patients were reported to progress into stages of definite dementia.6 Moreover, the inclusion of patients with mild cognitive impairment may protect against a floor effect (i.e., lack of between-group differences due to a poor performance across all cognitive tasks).
Psychiatric examination.
After informed consent, a psychiatrist blinded to the neuropsychological findings carried out a structured psychiatric evaluation using the following instruments.
Structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders–IV (DSM-IV).
The structured clinical interview for DSM-IV is a semistructured diagnostic interview assessing signs and symptoms necessary for the major Axis I DSM-IV diagnoses.7 The interviews were carried out with the patients and at least one first-degree relative who knew them well. Based on the structured clinical interview for DSM-IV responses, DSM-IV diagnoses of major depression or dysthymia were made.
Hamilton Depression Scale.
The Hamilton Depression Scale (HAM-D) is a 17-item interviewer-rated scale for rating the severity of symptoms of depression.8 TheHAM-D was administered to the caregiver.
Overt Aggression Scale.
The Overt Aggression Scale (OAS) measures specific aspects of aggressive behavior based on observable criteria.9 Aggressive behaviors are divided into four categories: verbal aggression, physical aggression against objects, physical aggression against self, and physical aggression against other people.
Dementia Psychosis Scale.
This is an 18-item scale that quantifies the severity and types of delusions in demented patients at the time of the psychiatric evaluation. This scale was rated by a psychiatrist with the patient and at least one close relative or caretaker. We have demonstrated the validity and reliability of this scale in AD.10
Apathy Scale.
This scale includes 14 items that are scored by the patient’s relative or caretaker.11,12 Each question has four possible answers, scored from 0 to 3. Thus, the Apathy Scale scores range from 0 to 42 points, and higher scores indicate more severe apathy. We have demonstrated the reliability and validity of the Apathy Scale in AD.11
All instruments included in the psychiatric assessment (except for the Apathy Scale, which was developed by one of the authors [S.E.S.]) were translated from English into Spanish and back-translated by a certified translator with the help of a bilingual neuropsychiatrist (S.E.S.).
Neuropsychological examination.
Each patient was assessed by a neuropsychologist blinded to psychiatric findings using the following test battery.
Mini-Mental State Examination.
The 11-item Mini-Mental State Examination (MMSE) has been found to be reliable and valid in assessing general cognitive functions and serves as a cognitive screening instrument in patients with dementia.13
Buschke Selective Reminding Test.
This test measures verbal learning and memory during a multiple-trial list-learning task.14 The patient listens to a list of words, and recalls as many words as possible. Each subsequent learning trial involves the presentation only of those words that were not recalled on the immediately preceding trial. The outcome measure was the total number of words recalled.
Benton Visual Retention Test.
This test assesses visual perception and nonverbal memory. Patients are exposed to geometric designs for 10 seconds and are immediately presented with a card containing the correct design among three foils. The patient is asked to select the previously presented design. There are 10 trials, and the number of correct responses is the outcome measure.15
Similarities.
This subtest of the Wechsler Adult Intelligence Scale provides a measure of abstract reasoning.16 Patients were instructed to state the similarity between two words. Responses were scored according to the standardized criteria as indicated in the manual.
Digit Span.
This subtest of the Wechsler Memory Scale examines auditory attention, and includes two parts. Both consist of seven pairs of number sequences that the examiner presents at the rate of one per second. In the first part (Digits Forward), the patient is asked simply to repeat a string of numbers (from two to eight numbers in length) exactly as it is given. In the second part (Digits Backwards), the patient is asked to recite the string of numbers (from two to eight numbers in length) in reversed order.17
Wisconsin Card Sorting Test.
This test measures the ability to develop and apply new concepts and subsequently shift sets, which requires the subjects to suppress a previously correct learned response and learn a new one.18 Assessment of the overall proficiency of the test was judged by the number of categories achieved (maximum of six).
Controlled Oral Word Association Test.
This test examines access to semantic information under a time constraint.19 Patients were instructed to name as many words beginning with the letter “F” as they could in 1 minute. People’s names and proper nouns were not permitted. The letters “A” and “S” were then presented successively, with 1 minute allowed for each letter. The score was the combined number of appropriate words produced in 3 minutes.
Raven’s Progressive Matrices.
This test measures visuospatial reasoning. Patients are presented with a spatial pattern problem with one part removed and four pictured inserts of potential matches, of which only one contains the correct pattern.20 The patient has to select the correct piece to match the original spatial patterns. The patterns become increasingly complex over trials. The performance score is the number correctly identified.
Token Test.
This test measures verbal comprehension of receptive language and response to commands in series of increasing complexity.21
Boston Naming Test.
This test measures the ability to retrieve the name of line drawings of common objects of varying familiarity. The ability to access semantic information is assessed, and the number of correctly named objects is the outcome measure.22
Block Design.
This test, part of the Wechsler Adult Intelligence Scale, examines the presence of constructional, executive, and perceptual abilities. Patients are presented with red and white blocks and are asked to construct replicas of printed designs. Accuracy of production is the outcome measure.17 Time to completion was not considered in the final score.
Purdue Pegboard Test.
This test assesses manipulative dexterity. The apparatus consists of a board containing two parallel rows of 25 holes each and 50 metal pegs. Patients are asked to take the pegs with the dominant (e.g., right) hand and place them as quickly as possible in the right column of holes during a 30-second period. The same procedure is repeated with the nondominant hand, and the score is the number of pins inserted in the time period for each hand.23
Statistical analysis.
Statistical analysis was carried out using means and SDs, analysis of variance (ANOVA), and post-hoc t-tests. Frequency distributions were calculated using chi-square tests and a Yates’ correction for expected cell sizes of less than 5. All p values are two-tailed.
Results.
Demographic and psychiatric findings.
Our sample was divided into groups with apathy or depression based on the following diagnostic scheme: patients meeting the DSM-IV criteria of either major depression or dysthymia were included in the depressed group, whereas patients scoring more than 2 SD of the mean apathy scale score for an age-comparable normal control group (cutoff score = 14 points, as reported in a previous publication2) were considered apathetic. Four groups were thus construed: 1) apathy without depression (apathy-only group; n = 29); 2) depression without apathy (depression-only group; n = 31; 25 with dysthymia and 6 with major depression); 3) both depression and apathy (n = 72; 47 with dysthymia and 25 with major depression); and 4) neither apathy nor depression (control group; n = 52). No significant between-group differences were found for age, sex, years of education, MMSE scores, and scores of agitation and delusions (table 1).
Demographic and psychiatric findings
Neuropsychological findings.
A multivariate analysis of covariance for the neuropsychological variables showed a significant overall effect (Wilks’ lambda = 0.65, p < 0.05). On individual comparisons, patients with apathy only had significantly lower scores than patients without apathy (with or without depression) on the following tests: Buschke-Total Recall (F[3,169] = 3.34, p < 0.05; apathy only versus depression only p < 0.01, apathy only versus control group p < 0.05) and the Boston Naming Test (F[3,166] = 3.54; p < 0.01; apathy only versus depression only p < 0.05; apathy only versus control group p < 0.05); and significantly lower scores than patients with depression only on the Buschke-Delayed Recall (F[3,169] = 3.68; p < 0.01). Patients with apathy (with or without depression) had significantly lower scores than patients without apathy (with or without depression) on the Wisconsin Card Sorting Test (F[3,161] = 3.29; p < 0.05) and verbal fluency (F[3,168] = 4.51; p < 0.005), and significantly lower scores than the control group on the Purdue Pegboard Test (F[3,165] = 5.22; p < 0.001). Finally, patients with apathy and depression had significantly lower scores than the other three groups on the Raven’s Progressive Matrices (F[3,165] = 3.77, p < 0.01). No significant differences on any neuropsychological test were found between patients with depression only and the control group (table 2).
Neuropsychological findings
Discussion.
This study examined neuropsychological correlates of apathy in AD, and there were several important findings. First, patients with AD with apathy had significantly lower scores on tests of verbal memory, naming, set shifting, and verbal fluency than patients with AD without apathy. Second, the copresentation of both depression and apathy did not result in cognitive deficits greater than those for apathy alone, except on a test of abstract thinking, where patients with both apathy and depression had significantly lower scores than patients with apathy only. Finally, depression in the absence of apathy was not associated with more severe cognitive impairments, when depressed patients with AD are compared with patients with AD with neither apathy nor depression.
Before offering further commentary, several limitations of our study should be pointed out. First, we did not divide our sample of depressed patients with AD into those with major and dysthymic depression, and whether a specific type of depression was associated with more severe cognitive impairments could not be examined. However, in a recent study we could not find significant differences in cognitive function between patients with AD with major depression, dysthymia, or no depression.1 Second, our study included patients with questionable dementia (i.e., patients with memory deficits on cognitive testing who did not meet the full criteria for probable AD), and whether all these patients will eventually meet the full criteria for AD is unknown. However, several studies demonstrated that most patients with questionable dementia do progress to the phase of overt dementia. 6 Moreover, in our study the proportion of patients with questionable dementia was similar in all four groups, and the inclusion of patients with mild cognitive impairments may have protected from lack of significant between-group differences due to a “floor effect.” Another limitation is that we do not have neuropathologic confirmation of our clinical diagnoses. Thus, whether our patients with apathy had dementia with Lewy bodies (which was found to be significantly associated with more severe frontal dysfunction than classic AD)24 cannot be ruled out. Finally, we measured the severity of depression with the HAM-D, which may potentially include apathy-related items. However, mean HAM-D scores for AD apathy-only and AD control groups were similar, suggesting that HAM-D scores were not influenced by the severity of apathy.
In a study that examined the neuropsychological correlates of apathy in patients with PD, we found that apathy (with or without depression) was associated with significantly more severe deficits on tasks of verbal fluency and verbal memory.25 Similar to our current findings, patients with both apathy and depression did not show more severe cognitive deficits than patients with apathy only.25 We suggested that apathy in PD may be akin to the concept of bradyphrenia, which was defined by Rogers26 as a slowing of cognitive processing associated with impairment of concentration. In a preliminary study of the cognitive correlates of apathy in a smaller sample of patients with AD, apathy was significantly associated with more severe memory deficits.2 The current study assessed a larger sample of patients with AD, and not only replicated the association between apathy and memory deficits, but showed that patients with AD with apathy (with or without depression) also had significantly more severe deficits on tasks of naming, verbal fluency, and set shifting, thus demonstrating a profile of cognitive deficits similar to those we found previously in patients with PD with apathy. However, apathy in AD may also correlate with overall cognitive disability, and future studies should examine the specificity of the current findings.
Verbal fluency, set shifting, and abstract thinking have all been considered cognitive abilities related to frontal lobe functioning.27 Apathy has been attributed to disruption of corticosubcortical circuits involving the basal ganglia and the frontal lobes.2 Cummings27 suggested that lesions to the dorsolateral frontal cortex, anterior cingulate, or globus pallidus may produce both apathy and deficits on frontal lobe–related tasks, such as verbal fluency and set shifting. Several recent findings validate this hypothesis: first, we demonstrated that patients with stroke with apathetic behavior had a significantly higher frequency of lesions involving the globus pallidus compared with patients with stroke without apathy.11 Second, in both AD and PD, apathy was significantly associated with relatively more severe deficits on frontal lobe–related tasks.25 Third, we found that apathy in AD was significantly associated with more severe extrapyramidal signs compared with patients with AD without apathy, which further suggests disruption of basal ganglia structures in patients with AD with apathy.28
Acknowledgments
Supported in part by grants from the Raúl Carrea Institute of Neurological Research-FLENI and the Fundacion Perez Companc.
Acknowledgment
The authors thank Fred Bylsma, PhD, for his valuable suggestions.
- Received August 21, 1998.
- Accepted in final form January 1, 1999.
References
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