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Ambulatory actigraphy correlates with apathy in mild Alzheimer's disease
Renaud David, Alice Rivet, Philippe H. Robert, Veronique Mailland, Leah Friedman, Jamie M.
Zeitzer and Jerome Yesavage published online 21 September 2010 The online version of this article can be found at: can be found at:
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Ambulatory actigraphy ! The Author(s) 2010 correlates with apathy in mild Reprints and permissions: Alzheimer's disease Renaud DavidHoˆpital Cimiez, Nice, France Alice RivetHoˆpital Cimiez, Nice, France Philippe H. RobertHoˆpital Cimiez, Nice, France Veronique MaillandHoˆpital Cimiez, Nice, France Leah FriedmanStanford University, Stanford, USA Jamie M. ZeitzerStanford University, Stanford, USA and VA Palo Alto Health Care System, USA Jerome YesavageStanford University, Stanford, USA and VA Palo Alto Health Care System, USA AbstractAim: Apathy is one of the most common behavioral symptoms in Alzheimer's disease (AD). Theaim of our study was to assess the relationship between apathy and locomotor activity in mildAlzheimer's disease (AD).
Methods: Thirty AD subjects and fifteen healthy controls were recruited from the Nice MemoryCenter. Apathy was assessed with the Apathy Inventory (AI). Patients with a score greater thanthree on the AI caregiver version are considered in this report as having apathy. Locomotoractivity was assessed using a wrist-worn actigraph for 75 minutes, during which aneuropsychological and behavioral examination were performed (60 minutes) followed by15 minutes of free activity.
Results: AD patients shown lower motor activity than healthy subjects. AD patients with apathyhad lower motor activity than AD patients without apathy. Apathy total score correlatednegatively with mean motor activity. Most of the total score correlation was accounted for by Corresponding author:R. David, Cimiez Hospital, 4 avenue Reine Victoria, 06003 Nice, FranceEmail: [email protected] correlations between the apathy dimensions lack of initiative and lack of interest, with meanmotor activity.
Conclusion: Ambulatory actigraphy could be a simple technique to assess apathy objectively as partof routine assessment of AD patients.
Keywordsactigraphy, Alzheimer's disease, apathy, locomotor activity There is wide agreement that motivation, interest, action initiation and emotional reactivityare dimensions of apathy, and that lack of motivation is at the core of the syndrome.
The importance of the symptomatology is related to the high frequency of apathy inindividuals with Alzheimer's disease (AD) (Mega, Cummings, & Fiorello, 1996) and otherdementing disorders, and to its negative impact on caregivers. Apathy is, in fact, the mostfrequent neuropsychiatric symptom across all stages of AD (Benoit, et al., 1999; Benoit,et al., 2003). Studies using the Neuropsychiatric Inventory (Cummings, 1997) show thatapathy is present in up to 70% of individuals with Alzheimer's disease (AD).
One of the main difficulties in assessing apathy and other neuropsychiatric symptoms is the absence of a reliable objective measure. Usually, the assessment is subjective structuredinterview-based, using input from either the caregiver and/or the patient.
Ambulatory actigraphy, consisting of a piezoelectric accelerometer designed to record arm movement in three dimensions, has been proposed as objective evaluation method indifferent disorders including sleep/wake disorders (Yesavage, et al., 1998), Attention Deficit/Hyperactivity Disorder (Dane, Schachar, & Tannock, 2000) and Periodic Limb MovementDisorder (Kemlink, Pretl, Sonka, & Nevsimalova, 2007). In neurodegenerative disorders,actigraphy has been used to evaluate agitated behaviors (Mahlberg & Walther, 2007). Thereare significant correlations between Cohen-Mansfield Agitation Inventory total scores andmean wake actigraphic activity (Nagels, et al., 2006). In psychiatric disorders, psychomotorretardation has been studied using actigraphy, showing increased mean motor activityduring wake in depressed patients after four weeks treatment with imipramine (Volkers,et al., 2002).
The aim of the present study was to investigate the relationship between apathy and motor activity in individuals diagnosed with mild Alzheimer's disease. The specifichypotheses were: 1) mean motor activity will be higher in control subjects than in thosewith mild AD; 2) those with mild AD and apathy will have less motor activity than thosewith mild AD and no apathy; and 3) the mean motor activity of the AD subjects will remainsignificantly correlated to apathy even after scores on depression measures are taken intoaccount.
Subjects and clinical assessment Thirty subjects with diagnosis of mild AD and 15 healthy controls were recruited at the NiceMemory Center. Each patient and family gave informed consent to participate in the study.
Diagnosis of AD was established using the Diagnosis and Statistical Manual of Mental David et al.
Disorders (DSM-IV) criteria (American Psychiatric Association, 1994). Patients wereexcluded if they had a history of head trauma with loss of consciousness, psychotic ormajor depressive disorder or aberrant motor activity (tremor, rigidity, Parkinsonism) asdefined by the Unified Parkinson Disease Rating Scale (UPDRS) (Fahn, 1987). All patientswere free of dopaminergic antidepressant and antipsychotic medication. Cholinesteraseinhibitors, if present, were at a stable dose for more than six months prior to study.
General cognitive status was determined in the course of a comprehensive clinical assessment and included the Mini Mental State Examination (MMSE) (Folstein, Folstein,& McHugh, 1975), Trail Making Test (TMT, parts A and B) (Reitan, 1955), digit spans(WAIS III-R), phonological and semantic verbal Fluency (Cardebat, Doyon, Puel, Goulet,& Joanette, 1990), a naming test (DO 80), and according to the MMSE score the free and cuedselective reminding test (FCSRT) (Grober & Buschke, 1987) for the patients with a MMSEscore lower than 17 and the Alzheimer's Disease Assessment Scale for Cognition (Rosen,Mohs, & Davis, 1984) for the subjects with a MMSE score higher than or equal to 17.
Neuropsychiatric symptoms were assessed with the Neuropsychiatric Inventory (NPI), which is based on a structured interview with a caregiver who is familiar with the patient.
Depression was additionally rated with the Montgomery Asberg Depression Rating Scale(MADRS).
Apathy was assessed using the Apathy Inventory (AI), designed to provide a separate assessment of the three dimensions of apathy: emotional blunting, lack of initiative and lackof interest. The patient, caregiver and clinician versions of the AI were each administered asappropriate (P. H. Robert, et al., 2002). The range of scores on the caregiver version is from3 to12, with scores greater than three being considered clinically significant (Brocker, Clairet,Benoit, & Robert, 2003). Thus, individuals with a score greater than three on the caregiverversion are considered in this report as having apathy. The AI clinician version, based on theclinician's (medical doctor, psychologist, member of the care staff) observations during theconsultation, was also administered (Leone et al., 2008).
Actigraphy assessment and procedure Motor activity was assessed over 75 consecutive minutes using a wrist-worn actigraph(Actiwatch-L, MiniMitter) on the non-dominant wrist (see Figure 1). Data were collected Patient in relax room FCSRT delay recall FluencyDenomination Figure 1. Organization of the subject time with the actigraph and stored as integrated activity over 15 seconds using arbitrary units. A neuropsychologicaland behavioral evaluation was performed during the first 60 of the 75 minutes. The last15 minutes were spent ad libitum in the waiting room. Actigraphy data were analyzed todetermine the mean motor activity, the total motor activity, and the number of minuteswithout movement over the entire 75 minutes record (Actiware-Sleep v.3.1, CambridgeNeurotechnology). SPSS 14.0 was used to compute statistics. Group comparisons weremade using the Kruskal-Wallis one-way analysis of variance and specified between groupscomparisons were made with the Mann-Whitney U-Test. Paired group comparisons weremade with the Wilcoxon Signed-Ranks test for matched pairs. Correlations were determinedusing the Spearman rank correlation coefficient.
Descriptive statistics for the three subject groups (controls, AD with apathy, AD withoutapathy) are presented in Table 1. Mean age in the healthy control group was significantlylower than in either AD group (p < 0.05), but age did not significantly differ between the twoAD subgroups (p ¼ 0.63). As planned, mean MMSE score was significantly higher in healthycontrols than AD patients (p < 0.01), but there was no significant difference between the twoAD subgroups (p ¼ 0.058). All groups were equivalent in term of NPI-scored depression andagitation, two parameters that may confound interpretation of actigraphic measurements.
The three subject groups were significantly different on all actigraphic parameters (mean motor activity, p < 0.01; total motor activity, p < 0.01; number of minutes withoutmovements, p < 0.01; number of minutes with movements, p < 0.01).
Table 1. Descriptive statistics for healthy controls and the two groups of AD subjects. Data shown asmean  SD Controls (N ¼ 15) AD with apathy (N ¼ 17) AD without apathy (N ¼ 15) AI total score (caregiver) AI total score (patient) AI total score (clinician) NPI hallucination NPI disinhibition NPI aberrant motor * NPI and the AI caregiver version were not assessed in the control population.
David et al.
Controls had greater mean motor activity and less time spent without movement than both of the groups of AD subjects (Table 2). AD subjects without apathy also exhibitedsignificantly greater mean motor activity and less time spent without movement than ADsubjects with apathy in all comparison time periods. On average, mean motor activity washigher for the three groups during the 15 minutes ad libitum period than during theneuropsychological evaluation, but these differences were not statistically significant(controls, p ¼ 0.075; AD without apathy, p ¼ 0.394; AD with apathy, p ¼ 0.074). Similarlythe percent of time spent without movement was lower during the ad libitum period, exceptfor the AD patients without apathy. However, this difference was only significant for thecontrol group (p < 0.05) (AD without apathy, p ¼ 0.65; AD with apathy, p ¼ 0.43).
Mean motor activity was negatively correlated with age (r ¼ 0.36; p < 0.05), AI patient and caregiver version total scores (r ¼ 0.35; p < 0.05), AI clinician version total score(r ¼ 0.56; p < 0.01) and positively correlated with MMSE score (r ¼ 0.51; p < 0.01). Therewere no significant correlations between mean motor activity and the MADRS (r ¼ 0.03,p ¼ 0.86) or NPI agitation domain (r ¼ 0.33, p ¼ 0.1).
Using partial correlations, relations between mean motor activity and caregiver AI scores remained significant when controlling for age (0.61; p < 0.01), MMSE (0.64; p < 0.01),and MADRS total score (0.6; p < 0.01). This was the same for the AI clinician scores whencontrolling for age (0.43; p < 0.05), MMSE (0.54; p < 0.05), and MADRS total score(0.52; p < 0.05).
In examining the three components of the AI, mean motor activity was significantly correlated with the lack of initiative dimension on all three versions of the AI and withthe lack of interest dimension on the AI clinician and patient versions (Table 3). Emotionalblunting did not correlate with mean motor activity on any of the three AI versions.
Table 2. Actigraphic parameters for the three groups and comparison between AD patients withoutapathy vs AD patients with apathy (Mann-Whitney U-Test: p < 0.05*, p < 0.01**) and AD patients withoutapathy vs. Controls (Mann-Whitney U-Test; p < 0.05y, p < 0.01yy). Data shown as mean  SD AD without apathy Mean motor activity (full 75 min) Mean motor activity (60 min testing) Mean motor activity (15 min ad libitum) Time without movement (full 75 min) Time without movement (60 min testing) Time without movement (15 min ad libitum) Table 3. Correlation between mean motor activity and apathy dimensions for the three versions of theApathy Inventory (Spearman with p < 0.05*, p < 0.01**) Caregiver N ¼ 30 Clinician N ¼ 45 Emotional blunting Lack of initiative Neuropsychiatric symptoms are now proposed as a major component of the dementiasyndrome. There is a growing interest in these symptoms as they can be present from theearliest stages of the disease, constitute a marker of disease progression, are responsible for alarge share of the suffering of patients and caregivers, and strongly determine the patient'slifestyle and management. It is therefore important to have good subjective and objectiveassessment methods of these symptoms.
We found a relationship between motor activity and apathy in individuals with mild AD such that individuals with AD and apathy had less motor activity than individuals with ADbut without apathy. The healthy control subjects had greater motor activity than either ofthe AD groups.
Motor activity was particularly related to the lack of initiative AI dimension within the apathy group either as assessed by caregivers or clinicians. Interestingly lack ofinitiative was found to be the most frequently occurring feature of apathy in a prospectiveEuropean multi-centre study (ICTUS) that evaluated 216 AD patients for apathy, using theAI (Robert, & Benoit, 2005). Lack of initiative was also related to a more general diminishedgoal-directed cognitive activity domain in the ICTUS study The AI is designed to permit a separate assessment of the three apathy dimensions: emotional blunting, lack of initiative, and lack of interest. Actigraphy-derived meanmotor activity was correlated with the apathy dimensions ‘lack of initiative' and ‘lack ofinterest', but not with emotional blunting. This finding is in agreement with Muller's study(Muller, Czymmek, Thone-Otto, & Von Cramon, 2006) that suggests a relationship betweenmotor activity and self-initiated action, which is mainly associated with lack of initiative andinterest rather than with emotional blunting.
Since apathy and the dopamine system are related (David, et al., 2008), as are locomotion and the dopamine system (van den Munckhof, Gilbert, Chamberland, Levesque, & Drouin,2006), it may be that activity levels and apathy are two measurable markers of the dopaminesystem. A better understanding of the relationship between apathy, locomotion, anddopamine may lead to better measurements of apathy.
Among the limitations of the current study is the fact that only a small number of subjects were evaluated. Further, these evaluations occurred across different times of daysand motor activity levels can vary across time of day (Yoon, Kripke, Youngstedt, & Elliott,2003). Since subjects were randomly scheduled, we do not believe that this limitationincreased error to a significant degree, but it will be important to take time of day intoaccount in future studies. A third limitation was that our control group was significantlyyounger than the other groups and age has been related to motor activity (Volkers, et al.,2002).
A fourth consideration is that even though the difference was not statistically significant, AD subjects with apathy were older and had lower MMSE scores than AD patients withoutapathy. However, partial correlations controlling for age and MMSE remained statisticallysignificant between mean motor activity and the AI total score. The AD subjects as a groupalso had moderate agitation and depression, which can respectively enhance (Nagels, et al.,2006) or decrease motor activity (Stanley, Fairweather, & Hindmarch, 1999; Teicher, 1995;Volkers, et al., 2002; Volkers, et al., 2003), but these two parameters did not distinguish theAD subjects with and without apathy.
In summary, the present study showed that AD patients had lower motor activity levels than healthy subjects and AD patients with apathy had lower motor activity levels David et al.
than AD patients without apathy. This suggests that actigraphic locomotor activityassessment may be a useful, objective method to evaluate the severity of apathy in ADpatients.
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Renaud David, MD [corresponding editor] is psychiatrist at the Nice University MemoryCenter. Address: Cimiez Hospital, 4 avenue Reine Victoria, 06003 Nice, France. [email:[email protected]] Alice Rivet is psychologist at the Nice Memory Center. Address: Cimiez Hospital, 4 avenueReine Victoria, 06003 Nice, France. [email: [email protected]] Philippe H. Robert, MD, PhD, is Professor of Psychiatry. He is director of the NiceUniversity Memory Center and co-chair of the Behavioral and Psychological subgroup ofthe European Alzheimer's Disease Consortium (EADC). Address: Cimiez Hospital, 4 avenueReine Victoria, 06003 Nice, France. [email: [email protected]] Veronique Mailland, MD, is geriatrician in the Geriatric Department of the Nice UniversityHospital. Address: Cimiez Hospital, 4 avenue Reine Victoria, 06003 Nice, France. [email:[email protected]] Leah Friedman, PhD, is a Senior Research Associate in the Department of Psychiatry andBehavioral Sciences of Stanford University. Address: Department of Psychiatry, School ofMedicine, David et al.
Jamie M. Zeitzer, PhD, is an Assistant Professor of Psychiatry and Behavioral Sciences atStanford University and a member of MIRECC, Palo Alto VA. His research focuses onhuman sleep and circadian neurobiology. Address: 3801 Miranda Avenue (151Y), Palo AltoCA 94304, USA. [email: [email protected]] Jerome Yesavage, MD, is Professor of Psychiatry and Behavioral Sciences at StanfordUniversity School of Medicine. Address: Stanford, CA 94305-5550, USA. [email:[email protected]]

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