Behavioural and emotional symptoms of apathy are associated with distinct patterns of brain atrophy in neurodegenerative disorders

Apathy is a neurocognitive syndrome of reduced goal-directed behaviour and is an important cause of disability in neurodegenerative disorders. Frontal–subcortical dysfunction is thought to be important in apathy, but the contribution of individual brain regions to different aspects of the apathy syndrome is poorly understood. We aimed to test the hypotheses that apathy in two distinct neurodegenerative disorders would be associated with frontal lobe atrophy and that reduced initiative and emotional blunting would be associated with distinct patterns of atrophy in functionally relevant brain areas. Seventeen patients with progressive supranuclear palsy (PSP) and 17 patients with Alzheimer’s disease (AD) underwent structural MRI scanning at 3 T to provide data for voxel based morphometric analysis. Apathy was defined using Robert’s 2009 diagnostic criteria and specific symptoms were assessed with the Apathy Inventory. Patients with and without apathy were matched for important demographic and clinical characteristics. Apathy was associated with atrophy of the ventromedial orbitofrontal cortex and left insula in both AD and PSP. Reduced initiative was specifically associated with atrophy of the anterior cingulate and ventrolateral orbitofrontal cortex whilst emotional blunting was specifically associated with atrophy of the left insula. These findings provide further support for the role of medial frontal regions and insular cortex in apathy and suggest that behavioural and emotional aspects of the apathy syndrome may have distinct neuroanatomical bases.     

Positron emission tomography metabolic correlates of apathy in Alzheimer disease

BACKGROUND: Apathy is the most common neuropsychiatric manifestation in Alzheimer disease (AD). Clinical, single-photon emission computed tomography, magnetic resonance imaging, and pathologic studies of apathy in AD have suggested an association with frontal dysfunction, most supportive of anterior cingulate abnormalities, but without a definitive localization. OBJECTIVE: To examine the association between apathy and cortical metabolic rate on positron emission tomography in AD. DESIGN: Forty-one subjects with probable AD underwent [(18)F] fluorodeoxyglucose positron emission tomography imaging and neuropsychiatric and cognitive assessments. Global subscale scores from the Scale for the Assessment of Negative Symptoms in Alzheimer Disease were used to designate the absence or presence of clinically meaningful apathy. Whole-brain voxel-based analyses were performed using statistical parametric mapping (SPM2; Wellcome Department of Imaging Neuroscience, London, England), which yielded significance maps comparing the 2 groups. RESULTS: Twenty-seven (66%) subjects did not have apathy, whereas 14 (34%) had apathy. Statistical parametric mapping analysis revealed significant reduced activity in the bilateral anterior cingulate region extending inferiorly to the medial orbitofrontal region (P < .001) and the bilateral medial thalamus (P = .04) in subjects with apathy. The results of the statistical parametric mapping analysis remained the same after individually covarying for the effects of global cognitive impairment, depressed mood, and education. CONCLUSIONS: Apathy in AD is associated with reduced metabolic activity in the bilateral anterior cingulate gyrus and medial orbitofrontal cortex and may be associated with reduced activity in the medial thalamus. These results reinforce the confluence of evidence from other investigational modalities in implicating medial frontal dysfunction and related neuronal circuits in the neurobiology of apathy in AD and other neuropsychiatric diseases.     

Apathy and executive function in Alzheimer's disease.

Apathy is a common behavioral disturbance in patients with Alzheimer's disease (AD). Recent studies have linked the presence of apathy to alterations in frontal lobe functions, but few studies have explored the relationship using standard neuropsychological measures in patients with AD. We administered a comprehensive battery of neuropsychological tests and a behavior rating scale to 80 patients with AD. We explored the relationship of apathy to executive dysfunction. AD patients with apathy performed significantly worse on tests of executive function (WAIS-R Digit Symbol, Trail-Making, Stroop Color Interference Test) than AD patients without apathy. The presence of dysphoria did not modify these results and no significant relationships were found between tests of executive functions and dysphoria. Performance on executive measures as a group were effective in correctly classifying patients as apathetic or nonapathetic with 75% accuracy. Neuropsychological measures not dependent on executive functions were unrelated to apathy. Apathy is associated with executive dysfunction and not with other neuropsychological deficits. Apathy is distinct from dysphoria.     

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.     

Apathy is associated with white matter abnormalities in anterior,medial brain regions in persons with HIV infection

Apathy is a relatively common psychiatric syndrome in HIV infection, but little is known about its neural correlates. In the present study, we examined the associations between apathy and diffusion tensor imaging (DTI) indices in key frontal white matter regions in the thalamocorticostriatal circuit, which has been implicated in the expression of apathy. Nineteen participants with HIV infection and 19 demographically comparable seronegative comparison subjects completed the Apathy subscale of the Frontal Systems Behavioral Scale as a part of a comprehensive neuropsychiatric research evaluation. When compared to the seronegative participants, the HIV+ group had significantly more frontal white matter abnormalities. Within HIV+ persons, and as predicted, higher ratings of apathy were associated with greater white matter alterations in the anterior corona radiata, genu, and orbital medial prefrontal cortex. The associations between white matter alterations and apathy were independent of depression and were stronger among participants with lower current cluster of differentiation 4 (CD4) counts. All told, these findings indicate that apathy is independently associated with white matter abnormalities in anterior, medial brain regions in persons infected with HIV, particularly in the setting of lower current immune functioning, which may have implications for antiretroviral therapy.     

Neuroanatomical correlates of apathy in Parkinson's disease: A magnetic resonance imaging study using voxel‐based morphometry

Apathy is generally defined as a disorder of motivation and is considered one of the most common neuropsychiatric disturbances in Parkinson's disease (PD). Only few studies addressed the neuroanatomical correlates of apathy in PD. The aim of this article was to determine the structural correlates of apathy in PD patients. Fifty‐five PD patients underwent a neuropsychiatric and neuropsychological examination, and a 3 T magnetic resonance imaging scan was acquired. A voxel‐based multiple regression analysis was used to calculate correlation between gray matter density and severity measures of apathy. Apathy correlates with decreased cognitive functioning and more depressive symptoms but not with more severe motor symptoms. High apathy scores were correlated with low gray matter density values in a number of cortical brain areas: the bilateral precentral gyrus (BA 4, 6), the bilateral inferior parietal gyrus (BA 40), the bilateral inferior frontal gyrus (BA 44, 47), the bilateral insula (BA 13), the right (posterior) cingulate gyrus (BA 24, 30, 31), and the right precuneus (BA 31). Apathy in PD correlates with reduced gray matter density in a number of brain regions. The involvement of the cingulate gyrus and inferior frontal gyrus is in line with the results of earlier studies addressing apathy in patients with Alzheimer's disease or depressive disorder. Further studies addressing the pathogenesis of apathy are needed. © 2010 Movement Disorder Society.     

Relationship of cognitive impairment to psychiatric symptoms in multiple sclerosis

Psychiatric and cognitive changes are common in patients with multiple sclerosis (MS), but their relationship has not received much attention. We studied the relationship between psychiatric symptoms and verbal memory, working memory, and mental speed in 78 patients with MS and 40 healthy control subjects using linear regression analyses. The MS group exhibited impaired performance on all cognitive tests. Apathy was associated with intrusions and depression with impaired memory and mental speed. The association between apathy and intrusions supports the hypothesis that lesions in frontal areas or frontal connections contribute to a specific neuropsychiatric syndrome in patients with MS.     

Brain perfusion correlates of the apathy inventory dimensions of Alzheimer's disease

BACKGROUND: Apathy is defined as a lack of motivation in behavior, cognition and affect. This syndrome is frequent in various neuropsychiatric diseases but little is known about its pathophysiology. OBJECTIVES: The aim of this study was to investigate the metabolic correlates of the behavioral, cognitive and emotional, aspects of apathy in Alzheimer's disease (AD). METHOD: Thirty AD patients were included. Lack of initiative, lack of interest and of emotional blunting were assessed with the Apathy Inventory (IA), a tool designed to provide a separate assessment of the behavioral, cognitive and emotional, aspects of apathy. Brain perfusion was measured by (99m)Tc-labeled bicisate (ECD) single photon emission tomography. RESULTS: The Statistical Parametric Mapping software provides negative correlation between IA total score and brain perfusion in left and right superior orbito-frontal gyrus, and to a lesser extent in left middle frontal gyrus (BA10). Lack of initiative score was negatively correlated with perfusion in right anterior cingulate cortex. Lack of interest score was negatively correlated with perfusion in right middle orbitofrontal gyrus). Emotional blunting score correlated negatively with in left superior dorsolateral prefrontal cortex activity. CONCLUSION: These results underline that the cognitive, behavioral and affective components of motivation are mediated by different fronto-sub-cortical circuits and are differently lateralized. In particular, left prefrontal hypoperfusion is involved in emotional blunting, as it was often demonstrated in depressive disorders. These distinct components of apathy may be targeted by different therapeutic means, in which dopaminergic enhancement might play a major role.     

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.     

Apathy correlates with cognitive function but not CD4 status in patients with human immunodeficiency virus

Apathy is a prominent neuropsychiatric symptom associated with human immunodeficiency virus (HIV). The increased frequency of apathy in this population may reflect the direct involvement of the virus on the central nervous system (CNS), but the severity of apathy has not been shown to consistently relate to markers of disease activity or other neuropsychiatric complications of the virus. We examined the relationship between ratings of apathy and performance on measures of cognitive function and immune system status in a sample of HIV-infected patients. Apathy was significantly elevated among HIV-infected individuals compared to healthy comparison subjects. Apathy was significantly related to performance on measures of learning efficiency and a measure of cognitive flexibility. Ratings of apathy did not relate to CD4 cell count, but they were associated with disease duration. In addition, ratings of depression were independent of ratings of apathy. These findings suggest that apathy does not co-vary with a proxy measure of active disease status, but apathy does relate to several measures of cognitive dysfunction in patients with HIV. As such, the increased prevalence of apathy among HIV-infected adults may reflect HIV-associated neurologic dysfunction.     

Structural correlates of apathy in Alzheimer's disease

BACKGROUND: Apathy is the most common noncognitive symptom in Alzheimer's disease (AD). The structural correlates of apathy in AD have not yet been described. METHODS: We analyzed magnetic resonance imaging data of 35 AD patients with and without apathy. RESULTS: There was a significant linear association between apathy severity and cortical gray matter atrophy in the bilateral anterior cingulate [Brodmann area (BA) 24; r = 0.39-0.42, p = 0.01] and left medial frontal cortex (BA 8 and 9; r = 0.4, p < 0.02). Left mean cingulate cortical thinning predicted the presence/absence of apathy at the trend level of significance. CONCLUSION: Our study demonstrates a strong association between apathy and the integrity of medial frontal regions in AD.     

Different apathy clinical profile and neural correlates in behavioral variant frontotemporal dementia and Alzheimer's disease

Objectives

Apathy is one of the most common and disabling syndromes of dementia. Clinical apathy expression and neuroanatomical basis of apathy seem to differ between behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD), although evidence is scarce and poorly understood. Our main purposes were to compare the clinical apathy profile from patients with bvFTD and AD and analyze the relationship between apathy and brain metabolism measured using positron emission tomography imaging with ¹⁸F fluorodeoxyglucose (FDG‐PET).

Methods

Forty‐two bvFTD, 42 AD, and 30 healthy volunteers without cognitive or behavioral complaints were included. Apathy was defined using Robert's 2009 diagnostic criteria, and specific apathy characteristics were assessed with the Lille Apathy Rating Scale. All participants underwent FDG‐PET brain scan to provide data for voxel‐based morphometric analysis.

Results

Multivariate analysis showed that subjects affected by bvFTD displayed greater impairment of emotional apathy and self‐awareness in comparison with AD sample. Additionally, FDG‐PET imaging analyses revealed that apathy was associated with different neuroanatomical substrates in each dementia group: left lateral prefrontal, medial frontal/anterior cingulate, lateral orbitofrontal and anterior insular cortices in bvFTD, and right anterior cingulate in AD.

Conclusions

These results support that apathy is a complex syndrome, with different clinical expressions across different pathological conditions. Those differences in qualitative aspects of apathy seem to be associated with differences in the damage sites, as shown by our FDG‐PET imaging analysis. Our findings provide a better knowledge about pathophysiology of apathy in dementia, which could have practical implications for therapeutic management. Copyright © 2017 John Wiley & Sons, Ltd.     

Lack of initiative and interest in Alzheimer's disease: a single photon emission computed tomography study

Apathy is defined as a lack of motivation. The aim of this study was to investigate the relation between two major dimensions of apathy (lack of initiative and lack of interest) and brain perfusion. in patients with Alzheimer's disease (AD). Brain perfusion was measured by single photon emission tomography (SPECT). Thirty-one AD patients were included. Lack of initiative and interest were assessed with the Apathy Inventory. Nineteen AD subjects presented a lack of initiative and interest pathological score whereas 12 AD subjects did not. The lack of initiative and interest score correlated significantly with the right frontal and the right inferior temporal lobes. The AD patients with lack of initiative and interest showed a significantly lower perfusion in the right anterior cingulate than the AD patients without lack of initiative and interest. These results derive from rather small subgroups of patients but have the interest to dismantle the complementary aspects of emotion and motivation in apathy and suggest that the latter one is more related to cingulate area.     

Olfaction and apathy in Alzheimer's disease,mild cognitive impairment,and healthy older adults

Objectives: Apathy is a prevalent neuropsychiatric manifestation in individuals with Alzheimer's disease (AD) that is associated with decreased social functioning and increased caregiver burden. Olfactory deficits are also commonly observed in AD, and prior work has indicated a link between increased apathy and olfactory dysfunction in individuals with Parkinson's disease. Here, we examined odor identification performance in patients with probable AD (n = 172), individuals with mild cognitive impairment (MCI; n = 112), and neurologically and psychiatrically healthy older adults (n = 132) and its relation to apathy, depression, and overall psychopathology. Method: Participants were administered the Sniffin’ Sticks odor identification test and measures assessing severity of apathy, depression, and overall neuropsychiatric symptomatology. Results: Consistent with previous research, AD and MCI patients were significantly worse at identifying odors than healthy older adults. Additionally, a sex by diagnosis interaction was observed. AD patients had significantly higher levels of apathy relative to MCI and control participants. Of note, across the entire sample odor identification deficits were correlated with level of apathy at the level of p < 0.01, but not with depression or neuropsychiatric symptom severity, when controlling for Mini-Mental State Examination (MMSE) score. Conclusion: Collectively, these data suggest that olfactory disturbance and apathy in AD may result from the progression of disease pathology in shared neural substrates.     

Relationship between apathy and sleep disturbance in mild and moderate Alzheimer's disease: an actigraphic study

Apathy is the most frequently reported neuropsychiatric symptom across all stages of Alzheimer's disease (AD). Both apathy and sleep disorders are known to have independent negative effects on the quality of life in individuals with AD. The aim of this study was to assess the relationship between apathy and sleep/wake patterns in individuals with AD using ambulatory actigraphy. One hundred and three non-institutionalized individuals with AD wore a wrist actigraph continuously over seven consecutive 24-h periods. Apathy was assessed using the Neuropsychiatric Inventory. Daytime mean motor activity (dMMA) was calculated from daytime wrist actigraphy data. Actigraphic parameters of sleep included total sleep time (TST), wake after sleep onset (WASO), time in bed (TIB), WASO normalized by TIB, sleep latency, and nighttime mean motor activity (nMMA). Among the 103 individuals with AD (aged 76.9 ± 7.2 years; MMSE = 21.4 ± 4.3), those with apathy had significantly lower dMMA, higher WASO (both raw and normalized), and spent more time in bed during the night than those without apathy. Sleep latency, nMMA and TST did not differ significantly between the two subgroups. To our knowledge, this study is the first to identify a relationship between apathy and sleep disturbance in those with mild or moderate AD: apathy was associated with increased TIB during the night and more WASO. These results suggest that AD patients with apathy have less consolidated nocturnal sleep than those without apathy.     

The nosological position of apathy in clinical practice

Apathy is increasingly recognised as a common behavioural syndrome in psychiatric disorders, but it is conceptually ill defined. The aim of this study was to examine the concept of apathy as it is currently used in neurology and psychiatry, by review of the literature and conceptual analysis. There is no consensus on diagnostic criteria for apathy as a syndrome. Apathy is mostly defined as a disorder of motivation, and operationalised as diminished goal oriented behaviour and cognition. There is discussion about whether an emotional dimension should form part of the definition of apathy. Abulia is considered a more severe type of apathy, but its nosological position is still unclear. A structured clinical interview and a proposal for diagnostic criteria for apathy in dementia have been recently validated. There are several valid and reliable scales to measure the severity of apathy in patients with psychiatric and neurological disorders. In summary, apathy is increasingly recognised as a common behavioural syndrome associated with neuropsychiatric disorders. There is a need for consensus on diagnostic criteria to facilitate future research. From a nosological perspective, future studies should examine the overlap with other psychiatric and neurodegenerative conditions and further validate specific diagnostic and assessment tools.     

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.     

Longitudinal evaluation of neuropsychiatric symptoms in Huntington's disease

A group of 111 patients with Huntington's disease (HD) underwent a minimum of three annual neuropsychiatric assessments, using the Problem Behaviors Assessment for Huntington's Disease (PBA-HD). Longitudinal prevalence of neuropsychiatric symptoms was notably higher than baseline prevalence, suggesting that previous studies may have underestimated the extent of this clinical problem. Moreover, apathy, irritability, and depression were each associated with distinct longitudinal profiles. Apathy progressed over time and across disease stages. Irritability also increased significantly, but only in early stages of HD. Depression did not increase significantly at any stage of disease. The neuropsychiatric syndrome of apathy appears to be intrinsic to the evolution and progression of HD.     

Striatal dopamine transporter levels correlate with apathy in neurodegenerative diseases A SPECT study with partial volume effect correction

OBJECTIVES: The aim of the present study was to stress the relationship between neuropsychiatric symptoms and most particularly apathy and striatal dopamine uptake in patients with Alzheimer's disease (AD) or dementia with Lewy body (DLB). PATIENTS AND METHODS: Twenty-two patients (AD n=14; DLB n=8) were included. All patients had neuropsychological and behavioral examination including Mini Mental Test Examination (MMSE), Neuropsychiatric Inventory (NPI), and UPDRS for the motor activity assessment. Apathy dimensions, emotional blunting, lack of initiative and lack of interest were assessed using the Apathy Inventory (AI). Dopamine transporter (DAT) striatal uptake was assessed using (123)I-FP-CIT (DaTSCAN) SPECT. Quantitative measurements were obtained in 3D using a method which compensates for physical detection biases including partial volume effect. RESULTS: We observed a correlation between DAT uptake and NPI's domains only for apathy. More specifically using the AI, lack of initiative significantly correlated with bilateral putamen DAT uptake. Using partial correlation coefficients controlling for the UPDRS score, the correlation remained significant between lack of initiative and right and left putamen DAT uptake. CONCLUSION: These results demonstrate a relationship between apathy and DAT levels independent from motor activity. They suggest that the patients with neurodegenerative diseases presenting with apathy are characterized by some degree of dopaminergic neuronal loss.