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Journal of Alzheimer’s Disease 51 (2016) 837–846 DOI 10.3233/JAD-151026 IOS Press

Apathy and Attentional Biases in Alzheimer’s Disease Sarah A. Chaua,b , Jonathan Chungc,d , Nathan Herrmanna,e , Moshe Eizenmanc,d,f and Krista L. Lanctˆota,b,e,∗ a Neuropsychopharmacology

Research Group, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada b Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada c Institute of Biomaterials and Biomedical Engineering, University of Toronto, ON, Canada d Department of Electrical and Computer Engineering, University of Toronto, ON, Canada e Department of Psychiatry, University of Toronto, Toronto, ON, Canada f Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada

Accepted 27 December 2016

Abstract. Background: Apathy, one of the most prevalent neuropsychiatric symptoms in Alzheimer’s disease (AD), can be difficult to assess as cognition deteriorates. There is a need for more objective assessments that do not rely on patient insight, communicative capacities, or caregiver observation. Objective: We measured visual scanning behavior, using an eye-tracker, to explore attentional bias in the presence of competing stimuli to assess apathy in AD patients. Methods: Mild-to-moderate AD patients (Standardized Mini-Mental Status Examination, sMMSE >10) were assessed for apathy (Neuropsychiatric Inventory [NPI] apathy, Apathy Evaluation Scale [AES]). Participants were presented with 16 slides, each containing 4 images of different emotional themes (2 neutral, 1 social, 1 dysphoric). The duration of time spent, and fixation frequency on images were measured. Results: Of the 36 AD patients (14 females, age = 78.2 ± 7.8, sMMSE = 22.4 ± 3.5) included, 17 had significant apathy (based on NPI apathy ≥4) and 19 did not. These groups had comparable age and sMMSE. Repeated-measures analysis of covariance models, controlling for total NPI, showed group (apathetic versus non-apathetic) by image (social versus dysphoric) interactions for duration (F1,32 = 4.31, p = 0.046) and fixation frequency (F1,32 = 11.34, p = 0.002). Apathetic patients demonstrated reduced duration and fixation frequency on social images compared with non-apathetic patients. Additionally, linear regression models suggest that more severe apathy predicted decreasing fixation frequency on social images (R2 = 0.26, Adjusted R2 = 0.19, F3,32 = 3.65, p = 0.023). Conclusion: These results suggest that diminished attentional bias toward social-themed stimuli is a marker of apathy in AD. Measurements of visual scanning behavior may have the potential to predict and monitor treatment response in apathy. Keywords: Alzheimer’s disease, apathy, attention, cognition, eye movements

INTRODUCTION Alzheimer’s disease (AD), the most common form of dementia, is often accompanied by neuropsy∗ Correspondence to: Krista Lanctˆ ot, Neuropsychopharmacology Research Group, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Suite FG08, Toronto, ON M4 N 3M5, Canada. Fax: +1 416 480 6022; E-mail: [email protected]

chiatric symptoms or behavioral and psychological symptoms. Apathy, characterized by reduced motivation, social disinterest, and emotional blunting in the absence of mood-related changes [1, 2], is the most frequently occurring symptom [3–5]. Epidemiological studies have reported point prevalence ranging from 25% to 93% in community-dwelling outpatients [3–5] and similar rates in nursing home

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S.A. Chau et al. / Apathy and Attentional Biases in Alzheimer’s Disease

patients [6–8]. Furthermore, these prevalence rates increase with more severe cognitive impairment [9, 10]. In addition to being common, apathy has been associated with negative effects such as more rapid cognitive and functional decline [11–14], increased care giver burden [15–17], and higher risk of mortality [18, 19]. The wide range in rates of apathy might be explained by methodological differences between studies, such as the use of different clinical evaluative tools and cut-off values. There is currently no standard approach to assessment though diagnostic criteria for apathy in dementia have been proposed and validated [1]. Efforts have been made to delineate the neurobiologic underpinnings of apathy. Apathy has been associated with themesocorticolimbic dopaminergic (DAergic) pathway [20] and psychostimulants, which work by increasing DA and/or norepinephrine (NE) levels, have demonstrated efficacy in improving symptoms [21–23]. Three domains of apathy are now recognized: Decreased goal-directed overt behavior (including symptoms of decreased effort, initiative, perseverance, and productivity), reduced goal-directed cognition (including reduced interests, lack of planning and concern about one’s health and function), and deficits in emotional concomitants of goal-directed behavior (including flat affect and decreased emotional responsivity to positive or negative events) [24]. Neuroimaging data in AD patients have suggested that the different components of apathy are each associated with unique patterns of brain activation and structural changes [25, 26]. Using single photon emission computed tomography, Benoit et al. [26] found that lack of initiative (behavioral apathy), lack of interest (cognitive apathy), and emotional blunting were correlated with hypoperfusion in the anterior cingulate cortex, orbitofrontal cortex, and dorsolateral prefrontal cortex, respectively. As such, understanding the apathy domains is a current area of research [27]. Recent evidence supports a link between attention and apathy symptoms [21, 28]. Several imaging studies showed that brain regions associated with attention, particularly the anterior cingulate and frontal cortices, have reduced activity and increased atrophy in apathetic compared with non-apathetic AD patients [29, 30]. Clinically, a DAergic agent that improved apathy also improved selective attention in a randomized placebo-controlled trial of dementia patients with apathy [28]. One component of attention that is highly mood and reward dependent is attentional bias or heightened sensitivity to a

particular stimulus resulting in enhanced attention toward that stimulus [31, 32]. Eizenman et al. [33] developed a nonverbal methodology to determine attentional biases through the measurement of visual scanning behavior. They found that, compared with their non depressed counterparts,young depressed patients fixated longer on dysphoric or negatively valenced images, but spent less time fixated on social images. Another research group applied the same methodology and observed that strong biases for dysphoric images were sustained for a 30-s duration [34]. However, the effect of apathy was not considered in those studies. Symptoms of social disinterest and emotional blunting, the defining components of apathy, suggest that apathetic patients may not have the attentional bias for social-themed images seen in non-apathetic patients. In the present study, we compared the visual scanning behavior of apathetic and non-apathetic AD patients in order to characterize the effect of apathy on attentional bias in the presence of emotional stimuli. We hypothesized that attentional biases toward social or positively themed stimuli will be reduced in apathetic compared with non-apathetic AD patients. We also explored the effects of the different apathy subdomains, in addition to overall cognitive and attention abilities, on visual scanning behavior. MATERIALS AND METHODS Subjects Participants were recruited from outpatient clinics at Sunnybrook Health Sciences Centre. Eligibility criteria included: Diagnosis of possible or probable AD based on the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV-TR) [35] and NINCDS-ADRDA criteria [36], mild to moderate disease severity (Standardized Mini-Mental State Exam [37], sMMSE ≥10) and no change in antidementia medications less than 1 month prior to study day. Apathetic AD patients were additionally required to have significant apathy (Neuropsychiatric Inventory [38], NPI apathy subscore ≥4 for at least 4 weeks) and no significant depression (NPI depression subscore

Apathy and Attentional Biases in Alzheimer's Disease.

Apathy, one of the most prevalent neuropsychiatric symptoms in Alzheimer's disease (AD), can be difficult to assess as cognition deteriorates. There i...
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