Association between apathy/depression and executive function in patients with Alzheimer's disease

ABSTRACTBackground: Apathy and depression may be strongly associated with executive dysfunction in Alzheimer's disease (AD). The Frontal Assessment Battery (FAB) is an instrument for assessing executive function. The dual task paradigm is also useful for assessing divided attention. However, the association between apathy/depression and these tasks is unclear.Methods: Both the FAB and the dual task were used to evaluate AD patients. A two-way analysis of variance was then conducted between the FAB and dual task results and the absence versus the presence of depression or the absence versus the presence of apathy.Results: Of 88 patients with AD, 26 had both apathy and depression, 26 had depression only, 18 had apathy only, and 18 had neither. Total FAB scores and dual task scores differed significantly between the AD patients with depression and those without depression; the scores were also different between those with apathy and those without apathy. Also, a significant interaction between depression and apathy was noted for the total FAB and dual task scores.Conclusions: The deficits in the total FAB and dual task scores were larger in AD patients with both apathy and depression compared with patients with either apathy or depression alone. AD patients with both symptoms may have greater deficits in frontal lobe function relative to AD patients with either apathy or depression alone.     

Executive functioning in unipolar depression: a review

While several neuropsychological studies have demonstrated that cognitive deficits are seen across a broad range of cognitive domains, executive deficits associated with frontal lobe dysfunction may be prominent in depression. Executive function refers to cognitive processes that control and integrate other cognitive activities such as episodic memory. These executive functions involve a set of cognitive behaviors which include: dealing with novelty, selecting strategies, inhibiting incorrect responses, monitoring performance and using feedback to adjust future responding. The measurement of executive function relies mainly on the use of neuropsychological tests known to be sensitive to frontal lobe damage such as the Wisconsin and California Card Sorting Tests, verbal fluency tests, Stroop-test, Tower of London Task and Trail Making Test. The present review focuses on studies investigating executive functions in primary unipolar depression with these neuropsychological tasks. Unipolar depressed patients mainly exhibit cognitive inhibition deficits, problem-solving impairments and planning deficits. Cognitive inhibition deficits in depressed patients have been related to a reduction of cognitive resources and psychomotor retardation. Inhibition disturbance could lead depressed patients to process irrelevant information and consequently reduce their capacity to control transient mood changes. Several studies have found evidence of problem solving impairments in depressed patients. Depressed subjects show with card sorting tests difficulties in hypothesis testing with a loss of spontaneous and reactive cognitive flexibility. The cognitive rigidity and hypothesis-testing associated with dorsolateral prefrontal dysfunction in depression may prevent patients to cope with life events and lead to a perpetuation of depressed mood by a continuation of stress exposure. Planning tasks, such as the Tower of London Test, also demonstrate that depressed patients fail to use negative feedback as a motivational boost to improve their performance. Both trait and state factors influence the executive level of depressed patients. Executive deficits have been reported in more severely depressed subjects with melancholic or psychotic features. Executive functioning also might predict a poorer outcome in depression. Thus initiation and perseveration scores - a measure of cognitive flexibility - is associated with relapse and recurrence of depression and residual depressive symptoms. Brain imaging studies show that reduced blood flow, particularly in medial prefrontal cortex and dorsal anterior cingulate cortex subserve executive impairments in depression. However neuroimaging studies underscore the importance of mood-cognitive interactions in depression. A recent working model of depression (Mayberg et al., 1999) implicates failure of the coordinated interactions of distributed cortical-limbic pathways in the neuropsychopathology of depression. According to this model, neocortical (prefrontal and parietal regions) and superior limbic elements (dorsal anterior cingulate) are postulated to mediate impaired attention and executive function, whereas ventral limbic regions (ventral anterior cingulate, subcortical structures) are postulated to mediate circadian and vegetative aspects of depression. Further studies are needed to validate this model at the neuropsychological level as well as the brain level and to elucidate the complex interactions between mood, cognitive resources and executive function in depression.     

Neuropsychological correlates of apathy and depression in patients with dementia

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.     

On the overlap between apathy and depression in dementia

BACKGROUND: Whereas apathy is increasingly recognised as a frequent abnormal behaviour in dementia, its overlap with depression remains poorly understood. AIMS: To assess the psychometric characteristics of a structured interview for apathy, and to examine the overlap between apathy and depression in dementia. METHODS: A total of 150 patients with Alzheimer's disease (AD) underwent a comprehensive psychiatric and cognitive assessment. RESULTS: Twelve per cent of the sample met criteria for both apathy and depression, 7% met criteria for apathy only, and 31% met criteria for depression only. Apathy (but not depression) was significantly associated with more severe cognitive deficits. Apathy and anxiety scores accounted for 65% of the variance of depression scores in dementia, and the diagnosis of apathy had a minor impact on the rating of severity of depression. CONCLUSIONS: The Structured Interview for Apathy demonstrated adequate psychometric characteristics. Using a novel structured interview for apathy in AD we demonstrated that whereas the construct of depression primarily consists of symptom clusters of apathy and anxiety, apathy is a behavioural dimension independent of depression.     

Cognitive impairment related to apathy in early Huntington's disease

OBJECTIVE: To investigate the relationships between cognitive impairment and apathy in patients with early Huntington's disease (HD) and to further explore the influence of depression on the outcome of cognitive changes associated with apathy. METHODS: We included 36 early HD patients, among them 20 were apathetic (HDA) and 16 were not (HDnA). The two groups were matched by age, education and severity of disease. Cognitive functions were evaluated by a comprehensive neuropsychological battery that measures memory, attention, executive function, language and visuospatial abilities. RESULTS: The HDA patients had significantly lower scores on memory, attention and executive function tests when compared with the HDnA patients (p values <0.05). We compared the performance of patients with (50%) and without depression on cognitive tasks and showed that depression per se did not influence performance. Finally, the results demonstrate that interactions between apathy and motor disturbance have a significant effect on cognitive impairment in HD. DISCUSSION: The presence of apathy is associated with more severe deficits of attention, executive function and episodic memory in early HD patients. Furthermore, the findings suggest that depression has little or no effect on cognitive deficits. Finally, apathy increased in parallel with both motor and cognitive dysfunction.     

Depressive symptom quality and neuropsychological performance in dementia

BACKGROUND: It is unknown to what extent depression and cognitive dysfunction are related in subjects with dementia. A limitation of earlier studies is that only general measures of depression have been studied. METHODS: In a sample of 60 subjects with dementia according to DSM-III-R criteria depressive symptoms were divided into factors of mood and motivation disturbance according to a principal components analysis. Correlations were computed between the factor scores and the performance on a number of specific neuropsychological tests. As the symptom content of motivation disturbance suggests subcorticofrontal dysfunction it was hypothesized that this factor is related to impaired executive functions. RESULTS: 77% of the depressive symptoms contributed to the dimension of motivation disturbance and most of these symptoms occurred outside the context of a major depressive episode. Our hypothesis was supported by a significant negative correlation between motivation symptoms and semantic verbal fluency. This relationship seems to have specificity, as both the dimensions of mood symptoms and of general depressive symptoms did not correlate significantly with specific neuropsychological test scores. CONCLUSIONS: The division of depressive symptoms in factors of mood and motivation disturbance contributes to insight into the relationship between depression and cognitive dysfunction in dementia. An advantage of the motivation disturbance factor compared to the regular apathy scales is that it consists of depressive symptoms. Therefore, it becomes evident that apathy or impaired motivation may occur in patients with dementia both in and outside the context of a depressive syndrome.     

Relationship between self-reported apathy and executive dysfunction in nondemented patients with Parkinson disease.

OBJECTIVE: The prevalence of apathy was assessed across select cognitive and psychiatric variables in 32 nondemented patients with Parkinson disease (PD) and 29 demographically matched healthy control participants. BACKGROUND: Apathy is common in PD, although differentiating apathy from motor, cognitive, and/or other neuropsychiatric symptoms can be challenging. Previous studies have reported a positive relationship between apathy and cognitive impairment, particularly executive dysfunction. METHOD: Patients were categorized according to apathy symptom severity. Stringent criteria were used to exclude patients with dementia. RESULTS: Approximately 44% of patients endorsed significant levels of apathy. Those patients performed worse than patients with nonsignificant levels of apathy on select measures of verbal fluency and on a measure of verbal and nonverbal conceptualization. Further, they reported a greater number of symptoms related to depression and behavioral disturbance than did those patients with nonsignificant levels of apathy. Apathy was significantly related to self-report of depression and executive dysfunction. Performance on cognitive tasks assessing verbal fluency, working memory, and verbal abstraction and also on a self-report measure of executive dysfunction was shown to significantly predict increasing levels of apathy. CONCLUSIONS: Our findings suggest that apathy in nondemented patients with PD seems to be strongly associated with executive dysfunction.     

Neuropsychological differences between late-onset and recurrent geriatric major depression

OBJECTIVE: Executive dysfunction, possibly related to vascular pathology, has been well documented in patients with a first episode of major depressive disorder in later life (late-onset geriatric major depression). However, it is unclear whether the neuropsychological presentation differs in patients with a lifetime history of major depressive disorder (recurrent geriatric major depressive disorder). The purpose of this study was to explore differences in neuropsychological function, symptoms, and cardiovascular comorbidity between patients with late-onset and recurrent geriatric major depression. METHOD: The study used a two-by-two factorial design in which one factor was current major depressive disorder (present versus absent) and the second factor was lifetime history of depression (present versus absent). Neuropsychological measures of executive functioning and episodic memory, as well as psychopathological symptoms and comorbid medical illness, were examined in a total of 116 older adults. RESULTS: Patients with late-onset major depressive disorder showed specific deficits in attention and executive function, whereas patients with recurrent major depressive disorder exhibited deficits in episodic memory. The rates of anhedonia and comorbid cardiovascular illness were higher in patients with late-onset geriatric major depressive disorder. CONCLUSIONS: In contrast to recurrent geriatric major depressive disorder, late-onset major depressive disorder is characterized by specific deficits in tasks of attention and executive function, consistent with increased anhedonia and cardiovascular comorbidity. These findings, if confirmed, suggest that recurrent and late-onset geriatric major depressive disorder may represent distinct phenomenological entities. Such phenomenological differences as a function of lifetime history of major depression can guide research in the neurophysiology, prevention, and treatment of geriatric major depressive disorder.     

Effects of recurrent major depressive disorder on behavior and cognitive function in female depressed patients

Little is known about the effects of recurring depressive episodes on cognition and behavior. The objective of the study was to compare cognitive function and depression-related behavior between healthy female subjects and female outpatients with early-onset DSM-IV recurrent major depressive disorder and to investigate the effect of cumulative depressive duration. Neuropsychological tests and scales for apathy, anhedonia and psychomotor retardation were assessed in 23 female patients and 60 healthy age-matched female controls. Significantly higher levels of apathy, anhedonia and psychomotor retardation, and worse performance on tests of executive function were found in the patient group compared with the healthy controls. In the patient group, cumulative depression duration was not significantly correlated with cognitive function, apathy, anhedonia or psychomotor retardation. The deficits in executive function were not related to the actual level of depression. Mild executive dysfunction may be the effect of the illness process underlying recurrent depressive disorder. Repeated or extensive depressive episodes do not seem to additionally affect cognitive deficits or behavior in depressed patients.     

Specificity of symptoms of depression in Alzheimer disease: a longitudinal analysis.

OBJECTIVE: Authors examined the temporal stability of symptoms of major and minor depression and apathy in dementia. METHODS: A consecutive sample of 65 patients with Alzheimer disease (AD) and depression at baseline evaluation received a follow-up psychiatric assessment that included the Structured Clinical Interview for DSM-IV and the Hamilton Rating Scale for Depression an average of 17 months later. RESULTS: Half of the sample had no depression at follow-up, and showed a significant improvement in sadness, guilt, suicidal ideation, disruption in sleep, loss of interest, loss of energy, thoughts of death, social withdrawal, psychomotor changes, changes in appetite/weight, and symptoms of anxiety. No significant changes were found on scores of irritability or apathy. CONCLUSIONS: The study demonstrates the specificity of depressive symptoms in AD and suggests that apathy and depression are different behavioral domains.     

Neuropsychological function in obsessive-compulsive disorder: effects of comorbid conditions on task performance.

BACKGROUND: Neuropsychological testing reveals a pattern of impairment among patients with obsessive-compulsive disorder (OCD) which implicates the orbitofrontal region. Studies of neuropsychological function in OCD differ regarding performance deficits on classical tests of frontal executive function. In some studies, OCD patients did not demonstrate impaired performance on tests of executive function. However, other researchers have documented performance deficits among OCD patients on measures of executive function. Patients with OCD also exhibit performance deficits on tests of visual/spatial memory and verbal memory. Again, in some studies, OCD patients did not demonstrate impaired performance on tests of memory function. How can we account for the conflicting findings? One possibility is that performance deficits on tests of cognitive function are associated with comorbid conditions. In prior work, we observed that OCD patients who did poorly on executive function tasks obtained high scores on a measure of schizotypal personality. A second possibility is that executive function deficits among patients with OCD are associated with comorbid depressive symptoms. METHOD: In the present study, a comprehensive neuropsychological test battery was administered to patients with OCD and matched healthy control subjects. We also administered dimensional measures of schizotypal personality and depression to patients with OCD and controls. We conducted analyses of covariance (ANCOVA), with scores on measures of schizotypal personality and depression used as covariates. RESULTS: OCD patients demonstrated performance deficits on measures of delayed memory, response inhibition, alternation learning, and obtained significantly higher scores on measures of disinhibition, impulsivity, and temporolimbic symptoms; however, OCD patients did not exhibit impaired performance on tests of executive function and verbal fluency, and did not report a significantly greater number of dysexecutive symptoms, when coexistent depressive and schizotypal symptoms were taken into account. CONCLUSION: Findings are consistent with the contention that dysfunction of an orbitofrontal-limbic network underlies OCD.     

Executive dysfunction and the course of geriatric depression.

BACKGROUND: Executive dysfunction is common in geriatric depression and persists after improvement of depressive symptoms. This study examined the relationship of executive impairment to the course of depressive symptoms among elderly patients with major depression. METHODS: A total of 112 nondemented elderly patients with major depression participated in an 8-week citalopram trial at a target daily dose of 40 mg. Executive functions were assessed with the initiation/perseveration subscale of the Dementia Rating Scale and the Stroop Color-Word test. Medical burden was rated with the Cumulative Illness Rating Scale. RESULTS: Both abnormal initiation/perseveration and abnormal Stroop Color-Word scores were associated with an unfavorable response of geriatric depression to citalopram. In particular, initiation/perseveration scores below the median (< or =35) and Stroop scores at the lowest quartile (< or =22) predicted limited change in depressive symptoms. Impairment in other Dementia Rating Scale cognitive domains did not significantly influence the outcome of depression. CONCLUSIONS: Executive dysfunction increases the risk for poor response of geriatric depression to citalopram. Because executive functions require frontostriatal-limbic integrity, this observation provides the rationale for investigation of the role of specific frontostriatal-limbic pathways in perpetuating geriatric depression. Depressed elderly patients with executive dysfunction require vigilant clinical attention because they might be at risk to fail treatment with a selective serotonin reuptake inhibiting antidepressant.     

Neuropsychological performance,disease severity,and depression in progressive supranuclear palsy

To investigate the relationship between disease severity, cognitive impairment and depression in progressive supranuclear palsy (PSP) we studied a group of 25 patients who fulfilled strict research criteria and 25 matched controls. Disease severity was judged from the duration of symptoms, level of physical disability using the Columbia Rating Scale (CRS), and the degree of eye movement abnormality. The neuropsychological battery was designed to assess attention and executive function, visual and auditory perception, semantic memory and language production. Although the PSP group were significantly impaired on almost all of these measures, the most profound deficits were on tests of sustained and divided attention. There was no correlation between cognitive impairment and either disease duration or scores on the CRS, but performance on tests of attention correlated significantly with the degree of ocular motor impairment. Depression was found to be common in PSP but did not correlate with any other parameters. It is concluded that the cognitive deficit in PSP is widespread and independent of depression. The association between the severity of eye movement disorder and deficits in sustained and divided attention leads us to postulate that pathology involving the midbrain periaqueductal region may be critical for breakdown in these fundamental processes.     

Apathy and depression in mild Alzheimer's disease: a cross-sectional study using diagnostic criteria

Apathy and depression are the most frequent neuropsychiatric symptoms in Alzheimer's disease (AD). In a cross-sectional observational study of 734 subjects with probable mild AD, we evaluated the prevalence of apathy and depression. After the use of specific diagnostic criteria, we tested the interaction between the two syndromes and their relation with specific comorbidities, and different functional outcomes. Depression was diagnosed using the diagnostic criteria for depression in AD, and apathy with the diagnostic criteria for apathy in neuropsychiatric disorders. According to the specific diagnostic criteria, depression had a 47.9% prevalence, while apathy prevalence was 41.6%. Apathy and depression were associated in 32.4% of patients (n = 225). 9.4% (n = 65) had only apathy, 15.4% (n = 107) had only depression, and 42.9% had no apathy and no depression (n = 298). The three most frequent depressive symptoms were fatigue or loss of energy (59.4%), decreased positive affect or pleasure in response to social contacts and activities (46.2%), and psychomotor agitation or retardation (36.9%). Concerning apathy, loss of goal-directed cognition was the most frequently altered (63.6%), followed by loss of goal-directed action (60.6%) and loss of goal-directed emotion (43.8%). Patients with both apathy and depression more frequently required a resource allowance for dependency. Neurological comorbidities were more frequent in the "apathy and depression" and "depression alone" groups (p < 0.001). Apathy and depression overlap considerably, and this might be explained by the presence of some non-specific symptoms in both diagnostic criteria. The need for social support is higher when a patient fulfills the two diagnostic criteria.     

IADL functions, cognitive deficits, and severity of depression: a preliminary study.

OBJECTIVE: Despite the documented association of cognitive dysfunction with impairment in instrumental activities of daily living (IADLs) in geriatric depression, the relationship among deficits in distinct IADLs with severity of depression and specific cognitive impairments remains to be clarified. The authors examined the relationship of depression severity and the cognitive domains of attention, initiation/perseveration, construction, conceptualization, and memory to nine distinct IADLs. METHODS: The subjects were 105 nondemented elderly patients but with impairment in at least one IADL and a history or presence of major depression. Impairment in IADLs and severity of depression were assessed with the Philadelphia Multilevel Assessment Instrument (MAI) and the 24-item Hamilton Depression Rating Scale (Ham-D), respectively. Cognitive dysfunction was assessed with the Mini-Mental State Exam (MMSE) and the Mattis Dementia Rating Scale (DRS). RESULTS: Six IADLs were influenced by impairment in at least one of the cognitive domains. Abnormal scores in initiation/perseveration, an aspect of executive dysfunction, was the cognitive impairment affecting most IADLs; it interfered with the ability to shop for groceries, prepare meals, take medicine, and manage money. Impairment in initiation/perseveration had a most prominent effect in the presence of depressive symptoms and affected shopping for groceries and preparing meals. Lack of interest and motivation, part of the depressive syndrome, compounded by behavioral abnormalities resulting from executive dysfunction, may account for this interaction. CONCLUSIONS: These relationships may provide the background for developing interventions targeting functional deficits associated with specific cognitive dysfunctions and depression.     

Motivational symptoms of depression mask preclinical Alzheimer's disease in elderly subjects

BACKGROUND: Althoughthe relationship between depressive disorders and Alzheimer's disease (AD) is debated, there is evidence that depression may be an early symptom of dementia. OBJECTIVE: To evaluate depression features prospectively in elderly subjects with a view to identifying a subgroup affected by preclinical AD. METHODS: We performed a cohort study on cognitive performances with a 12-month follow-up in out-patients referred to the local Neuropsychology Clinic complaining of memory problems. Two hundred and twenty-two consecutive non-demented subjects were studied using a neuropsychological battery and the Beck Depression Inventory (BDI) and assessed again 1 year later for the possible onset of cognitive impairment. Multivariate analysis was performed to detect independent predictors of dementia development among age, education, neuropsychological test scores and BDI scores and subscores. BDI subscores were obtained by dividing items into three domains corresponding to mood-related, somatic and motivation-related symptoms. RESULTS: At the time of the first evaluation, 124 of the 222 subjects were depressed according to DSM-III-R criteria. At 1 year, 31 of the 124 depressed subjects and 2 non-depressed ones had AD according to NINCDS-ADRDA criteria. Stepwise logistic regression analysis indicated that the subjects who went on to develop dementia had significantly higher total BDI scores and motivational BDI subscores. Among depressed subjects, the probability of being diagnosed with dementia during follow-up was significantly associated with a motivational BDI subscore > or = 7 (odds ratio: 3,885, 95% Cl 154-97,902). COMMENT: Close neuropsychological follow-up of depressed elderly subjects complaining of memory failure and showing apathy is recommended to detect the early stage of AD.     

Early detection and differential diagnosis of Alzheimer's disease and depression with neuropsychological tasks

The development of novel treatments for Alzheimer's disease (AD), aimed at ameliorating symptoms and modifying disease processes, increases the need for early diagnosis. Neuropsychological deficits such as poor episodic memory are a consistent feature of early-in-the-course AD, but they overlap with the cognitive impairments in other disorders such as depression, making differential diagnosis difficult. Computerised and traditional tests of memory, attention and executive function were given to four subject groups: mild AD (n = 26); questionable dementia (QD; n = 43); major depression (n = 37) and healthy controls (n = 39). A visuo-spatial associative learning test accurately distinguished AD from depressed/control subjects and revealed an apparent sub-group of QD patients who performed like AD patients. QD patients' performance correlated with the degree of subsequent global cognitive decline. Elements of contextual and cued recall may account for the task's sensitivity and specificity for AD.     

Executive dysfunction and apathy predict functional impairment in Alzheimer disease.

OBJECTIVE: The purpose of this study was to examine the extent to which executive cognitive dysfunction and frontally-mediated behavioral disturbances are associated with functional impairment in patients with mild-to-moderate Alzheimer disease (AD). METHODS: Patients with AD (N=45) completed the Mattis Dementia Rating Scale, and patients' caregivers completed the Frontal Systems Behavioral Inventory and a modified form of the Lawton and Brody Activities of Daily Living (ADLs) Questionnaire. RESULTS: Multiple-regression analyses revealed that executive cognitive dysfunction and apathy scores accounted for 44% of the variance in instrumental activities of daily living; executive cognitive dysfunction alone explained 17% of the variance in instrumental ADLs, and apathy scores explained an additional 27%. Executive dysfunction and frontal-behavioral impairment explained 28% of the variance in basic ADLs (BADLs), and, after accounting for executive dysfunction, apathy was the only symptom found to explain additional unique variance in BADLs. CONCLUSION: These findings suggest that specific cognitive and behavioral symptoms are associated with functional impairment in patients with AD.     

Cognitive and affective empathy in depression linked to executive control

Depression has been linked to executive dysfunction and emotion recognition impairments, associated with abnormalities in fronto-temporal and subcortical brain regions. Little is known about changes of different empathy subcomponents during depression, with potential impairments being related to the interpersonal difficulties of depressed patients. Twenty patients treated for an episode of unipolar depression and 20 matched healthy controls were assessed. Measures of dispositional and behavioural empathy components were administered along with tests of cognitive flexibility, response inhibition and working memory. Relative to controls, depressed patients showed higher self-reported dispositional empathy scores, mainly driven by increased personal distress scores. Patients and controls did not differ significantly in terms of behavioural cognitive empathy, empathic concern and personal affective involvement or in their executive function performance. In the patients, cognitive flexibility and response inhibition accuracy were associated with behavioural empathy. While an increased disposition towards feeling personal distress in response to other people's suffering seems to be in generally related to depressive symptoms, behavioural empathy might depend on the functional integrity of executive control during an episode of clinical depression. Impairments in this regard could contribute to the interpersonal difficulties depressed patients are frequently faced with which might have important implications for treatment.