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.     

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.     

Caregiver perception of apathy in persons with mild cognitive impairment or Alzheimer's disease: a longitudinal study

Objective: Discrepancy between self- and caregiver apathy ratings was examined longitudinally for persons with mild cognitive impairment or Alzheimer's disease. Particular focus was on the distinction between the positive and negative caregiver bias and its predictive value for a clinical diagnosis of apathy.

Method: Apathy rating discrepancy was based on the apathy evaluation scale. Dyads were categorized depending on whether the caregiver reported fewer deficits (positive caregiver bias) or more deficits (negative caregiver bias) than the cognitively impaired person did.

Results: Caregiver ratings and rating discrepancy showed a significant increase from baseline to follow-up. By contrast, self- and clinician ratings showed no change across the two time points. Ratings with a negative caregiver bias remained stable, while those with a positive caregiver bias showed a significant increase in the caregiver ratings but also a significant decrease in the self-ratings. A negative caregiver bias at baseline was significantly related to greater likelihood of having clinical apathy at follow-up, adjusted for an array of control variables.

Conclusion: Positive and negative caregiver bias should be distinguished, as they seem to reflect distinct dyadic processes and are relevant for clinical outcome. Furthermore, negative rating discrepancies can be considered a risk factor for developing apathy.     

Prevalence and clinical correlates of psychotic symptoms in Alzheimer's disease

Psychotic symptoms occur commonly in Alzheimer's disease (AD), predict a more rapid rate of cognitive decline and increase the risk of aggressive behaviour. Seventy patients with probable AD, recruited from an old age psychiatry service, were assessed to determine the prevalence and clinical correlates of delusions and hallucinations. Psychiatric symptoms were measured using the Behavioural Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD), Hamilton Rating Scale for Depression (HRSD) and the Depressive Signs Scale (DSS). Thirty-four per cent of the sample experienced delusions and 11% hallucinations in the previous month. Men were more likely than women to have experienced psychotic symptoms. Psychotic and non-psychotic groups did not differ in age, age at illness onset, dementia severity, HRSD or DSS scores. This study confirms the high prevalence of psychotic symptoms in AD patients encountered in clinical practice, and suggests that psychosis and depression represent independent behavioural disturbances in AD. © 1998 John Wiley & Sons, Ltd.     

The apathy inventory: assessment of apathy and awareness in Alzheimer's disease,Parkinson's disease and mild cognitive impairment

OBJECTIVE: This study was designed to establish the validity and reliability of the apathy inventory (IA), a rating scale for global assessment of apathy and separate assessment of emotional blunting, lack of initiative, and lack of interest. METHOD: Information for the IA can be obtained from the patient or from a caregiver. We evaluated 115 subjects using the IA, consisting of 19 healthy elderly subjects, 24 patients with Mild Cognitive Impairment (MCI), 12 subjects with Parkinson's disease (PD) and 60 subjects with Alzheimer's disease (AD). RESULTS: Internal consistency, item reliability, and between-rater reliability were high. A test-retest reliability study demonstrated that caregiver responses to IA questions were stable over short intervals. A concurrent validity study showed that the IA assesses apathy as effectively as the Neuro Psychiatric Inventory apathy domain. In the caregiver-based evaluation, AD subjects had significantly higher scores than controls, both for global apathy score and for the lack of interest dimension. When the AD patients were subdivided according to diagnostic criteria for apathy, apathetic patients had significantly higher scores than non apathetic patients. With the patient-based evaluations, no differences were found among the AD, MCI and control groups. The scores in the patient-based evaluations were only higher for the PD group versus the control subjects. The results also indicated that AD patients had poor awareness of their emotional blunting and lack of initiative. CONCLUSIONS: The IA is a reliable method for assessing in demented and non-demented elderly subjects several dimensions of the apathetic syndrome, and also the subject's awareness of these symptoms.     

Reduction of white matter integrity correlates with apathy in Parkinson's disease

Background: Apathy is a common non-motor symptom in Parkinson's disease (PD), but little is known about apathy and white matter (WM) change. In this study, we investigated whether fractional anisotropy (FA) of the WM can distinguish apathetic patients from non-apathetic PD patients, and whether the FA value correlates with the severity of apathy in PD.

Methods: Thirty-nine PD patients participated in our study, of which 18 participants were with apathy symptom, and 21 without apathy symptom. Diffusion tensor imaging was performed on all the subjects.

Results: Compared to non-apathetic PD patients, the apathetic group had reduced FA values in the genu and body of corpus callosum, bilateral anterior corona radiata, left superior corona radiata and left cingulum. Furthermore, in these WM regions, the FA values were negatively correlated with the Lille Apathy Rating Scale scores in apathetic subjects.

Conclusion: The WM change is associated with apathy in PD patients. In addition, the FA values of specific regions of WM could be a promising marker to predict the severity of apathy.     

A prospective longitudinal study of apathy in Alzheimer's disease

BACKGROUND: Apathy and depression are the most frequent behavioural and psychiatric disorders in Alzheimer's disease, and may both have a negative impact on the progression of the illness. OBJECTIVES: To examine the clinical correlates of apathy in Alzheimer's disease (AD), and to determine whether apathy is a significant predictor of more rapid cognitive, functional and emotional decline. METHODS: Using a structured psychiatric evaluation, we examined a consecutive series of 354 subjects meeting clinical criteria for AD. Apathy was assessed by the Apathy Scale, and diagnosed using standardised criteria. Additional measurements included scales for depression, functional impairment, and global cognitive functions. A follow up evaluation was carried out in 247 patients (70% of the total sample) between 1 and 4 years after the baseline evaluation. RESULTS: Apathy was significantly associated with older age (p = 0.009), and a higher frequency of minor and major depression (p < 0.0001). Apathy at baseline was a significant predictor of depression at follow up (p = 0.01), and was associated with a faster cognitive (p = 0.0007) and functional decline (p = 0.006). CONCLUSIONS: Apathy in AD is a behavioural marker of a more aggressive dementia, characterised by a faster progression of cognitive, functional, and emotional impairment.     

Prevalence and correlates of anxiety in Alzheimer's disease

We assessed a consecutive series of 398 patients with probable Alzheimer's disease (AD) for the presence of Generalized Anxiety Disorder (GAD) using a standardized neuropsychiatric evaluation. Five percent of patients showed GAD during the 4 weeks preceding the psychiatric evaluation. AD patients with GAD showed significantly higher scores of depression, irritability, overt aggression, mania, and pathological crying than AD patients without GAD. The most severe symptoms of anxiety were those of tension, fears, insomnia, and physical complaints. Depression and Anxiety 7:166–170, 1998. © 1998 Wiley-Liss, Inc.     

The relation of testosterone levels with fatigue and apathy in Parkinson's disease

Objective

Fatigue and apathy are frequent in patients with Parkinson's disease (PD). Testosterone deficiency in male patients may contribute in development of fatigue and apathy as well. We investigated whether a possible relation exists between serum testosterone levels, fatigue and apathy in male PD patients.

Materials and methods

We included 29 non-demented and non-depressed PD patients and 30 age- and sex-matched healthy subjects. Fatigue Severity Scale (FSS) and Apathy Evaluation Scale (AES-C) were used for the evaluations. In PD patients and healthy subjects, a relationship between FSS, AES-C scores and plasma testosterone levels were assessed. In addition, a correlation between FSS, AES-C and Unified Parkinson's Disease Rating Scale was investigated in PD group.

Results

The mean scores of FSS and AES-C were significantly higher in PD patients than those of the control group. The Unified Parkinson's Disease Rating Scale (UPDRS) scores were significantly correlated with FSS and AES-C scores. Mean free testosterone level was significantly lower in PD patients than controls (p = 0.008). f-Testosterone levels of PD patients were not correlated with FSS or AES-C scores.

Conclusion

Apathy and fatigue are frequent in PD and show significant correlation with the severity of the disease. f-Testosterone levels are not related with apathy or fatigue in male PD patients and the role of testosterone in the pathophysiology of these non-motor symptoms is still controversial.     

The Role of Dopamine in Symptoms and Treatment of Apathy in Alzheimer's Disease

Background: Alzheimer's disease (AD) is characterized by a number of serious and debilitating behavioral and psychological symptoms of dementia (BPSD). The most common of these BPSD is apathy, which represents a major source of morbidity and premature institutionalization in the AD population. Many studies have identified discrete changes to the dopaminergic (DAergic) system in patients with AD. The DAergic system is closely related to the brain reward system (BRS) and some studies have suggested that dysfunction in the DAergic system may account for symptoms of apathy in the AD population. Method: Changes to the dopamine (DA) system in AD will be reviewed, and evidence supporting the involvement of the DAergic system in the development of apathy will be examined. Additionally, some pharmacological interventions with DA activity have been identified. The utility of these treatments in the AD population will be reviewed, with a focus on apathy as an outcome. Results: Evidence presented in this review suggests that DA dysfunction in discrete brain areas is an important correlate of apathy in AD and that the DAergic system may be a rational target for pharmacological treatment of apathy.     

Awareness dimensions and associated factors in Alzheimer's disease

ObjectivesWe recently reported the major role depression and apathy in awareness among Alzheimer patients, using the stage of the disease as an exposure factor and exploring different assessment methods. Using the same patient data, we aimed here to explore the different dimensions of awareness assessed by different sub-scales in awareness scales.MethodSixty-one Alzheimer patients were examined using four awareness scales relating to three assessment methods: (a) patient-caregiver discrepancy; (b) clinical rating; and (c) prediction of performance discrepancy. Global cognition, executive functioning, autonomy, depression and apathy were also assessed. Multivariate logistic models were performed using disease stage as an exposure factor for awareness scales and sub-scales. Correlations across the different factors and patient and caregiver awareness ratings were computed.ResultsThe patient-caregiver discrepancy and clinical rating methods (a, b) both identified the factors associated with awareness in the overall scales and the sub-scales as being depression and/or apathy. Depression correlated with patient self-ratings while apathy correlated with caregiver ratings. The prediction of performance discrepancy method (c) identified different factors in the overall scale, executive factors in three sub-scales involving executive domains and the memory factor in a sub-scale involving the mnesic domain.DiscussionThe awareness scales using a referential based on a human rating (a, b) suggest that awareness is unidimensional, with depression impacting self-reports and apathy influencing caregiver/clinical reports. Scales based on a test rating (c) appear to be more closely associated with the dimensions assessed. This highlights the role of the reference system for awareness assessment in Alzheimer's disease.     

Verbal aggression in Alzheimer's disease. Clinical, functional and neuropsychological correlates

OBJECTIVES: To determine the clinical, functional and neuropsychological correlates of verbal aggression in Alzheimer's disease in a group of consecutive first attendees to a memory clinic. METHODS: 150 people were evaluated and diagnosed as suffering with probable Alzheimer's disease. These people were tested using the Behave-AD for the presence of verbal aggression, delusions, depression and agitation. They were also assessed with cognitive, functional and neuropsychological scales. RESULTS: Twenty-eight per cent of this group of Alzheimer patients had exhibited some verbal aggression in the preceding month. Male gender (p = 0.022), the presence of paranoid and delusional ideation (p = 0.003) and agitation (p = 0.042) were significantly associated with verbal aggression in a stepwise backward logistic regression analysis. CONCLUSION: The presence of verbal aggression should prompt the clinician to search for delusional ideation, which may respond to pharmacotherapy.     

阿尔茨海默病患者淡漠综合征的临床评价研究

目的 评价阿尔茨海默病(Alzheimer's disease,AD)患者应用淡漠评估量表临床医师评定版(apathy evaluation scale-clinician administered,AES-C)评估的价值,探讨阿尔茨海默病患者淡漠症状的影响因素.方法 选取26例阿尔茨海默病患者为研究组(n=26),同时选择26例正常对照组(n=26).对2组分别进行以淡漠评估量表(AES-C)为主的多个量表评定.收集患者年龄、性别、文化程度等一般资料,评估AES-C量表的内部一致性.通过单因素分析相关影响因素,探讨AES-C得分和认知功能损害的联系.结果 年龄、文化程度相关系数分别为0.169和-0.162(P<0.05),表明AES-C与年龄呈弱正相关,与文化程度呈弱负相关;研究组患者中淡漠症状的存在与认知功能的定向力、记忆力、执行能力及总体水平呈负相关(P<0.05);研究组和对照组AES-C与GDS得分之间的相关系数为0.423,二者存在弱相关,差异具有统计学意义(r=0.423,P<0.05).结论 淡漠评估量表可靠性较好,可用于评估阿尔茨海默病淡漠症状.淡漠在阿尔茨海默病患者中普遍存在,淡漠症状的严重程度与认知功能损害呈显著相关,这些患者的认知功能损害程度也越严重.阿尔茨海默病患者的淡漠发生可能与认知功能减退、年龄和抑郁症状等多种因素相关.     

Association between apolipoprotein E epsilon4 allele and apathy in probable Alzheimer's disease

OBJECTIVE: There have been inconclusive results to date on the association between the Apolipoprotein E (ApoE) genotype and neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD). We investigated whether ApoE epsilon4 allele is associated with NPS in probable AD. METHOD: Data for 197 subjects with probable AD were analysed. The Neuropsychiatric Inventory was used to evaluate the frequency and severity of NPS. Multiple logistic regression models were used to test the association between ApoE genotype and NPS in AD. RESULTS: The ApoE epsilon3/3 genotype was present in 52.3%, epsilon3/4 in 44.1%, and epsilon4/4 in 3.6% of patients. ApoE epsilon4 carriers showed a higher frequency of apathy than non-carriers. After multiple adjustments, the ApoE epsilon4 allele was significantly associated with apathy. CONCLUSION: Our results suggest a relationship between the ApoE epsilon4 allele and apathy in patients with AD.     

Glycation in Parkinson's disease and Alzheimer's disease

Glycation is a spontaneous age‐dependent posttranslational modification that can impact the structure and function of several proteins. Interestingly, glycation can be detected at the periphery of Lewy bodies in the brain in Parkinson's disease. Moreover, α‐synuclein can be glycated, at least under experimental conditions. In Alzheimer's disease, glycation of amyloid β peptide exacerbates its toxicity and contributes to neurodegeneration. Recent studies establish diabetes mellitus as a risk factor for several neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. However, the mechanisms underlying this connection remain unclear. We hypothesize that hyperglycemia might play an important role in the development of these disorders, possibly by also inducing protein glycation and thereby dysfunction, aggregation, and deposition. Here, we explore protein glycation as a common player in Parkinson's and Alzheimer's diseases and propose it may constitute a novel target for the development of strategies for neuroprotective therapeutic interventions. © 2016 International Parkinson and Movement Disorder Society