Positron Emission Tomography Metabolic Correlates of Apathy in Alzheimer Disease

ORIGINAL CONTRIBUTION Positron Emission Tomography Metabolic Correlates of Apathy in Alzheimer Disease Gad A. Marshall, MD; Lorena Monserratt, MA; Dylan Harwood, PhD; Mark Mandelkern, MD, PhD; Jeffrey L. Cummings, MD; David L. Sultzer, MD 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. Arch Neurol. 2007;64(7):1015-1020 Author Affiliations: Departments of Neurology (Drs Marshall and Cummings) and Psychiatry and Biobehavioral Sciences (Drs Harwood, Cummings, and Sultzer), University of California, Los Angeles; Psychiatry Service (Ms Monserratt, and Drs Harwood and Sultzer) and Nuclear Medicine Service (Dr Mandelkern), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles; and Department of Physics, University of California, Irvine, and Department of Neurology, Brigham and Women s Hospital, Boston, Massachusetts (Dr Mandelkern). WHILE COGNITIVE IMpairment is the hallmark of Alzheimer disease (AD), neuropsychiatric symptoms occur frequently and are very distressing to caregivers. Apathy is the most common behavioral manifestation in AD, reported to occur in 29% to 72% of patients, 1,2 and may co-occur with depressed mood or appear independently. 3 Clinical studies, single-photon emission computed tomography studies, magnetic resonance imaging studies, and pathologic correlations of apathy in AD have shown an association with frontal dysfunction without a definitive localization. Neuropsychologic findings in patients with AD support a link between apathy and frontal dysfunction, with greater executive deficits seen in those with apathy. 4,5 Some single-photon emission computed tomography studies of apathy in AD demonstrated hypoperfusion of the anterior cingulate cortex, 6,7 while other studies have shown involvement of the orbitofrontal and right temporoparietal cortices. 6,8,9 One magnetic resonance imaging study showed that AD patients with apathy had greater bilateral anterior cingulate and left supplementary motor cortex atrophy. 10 Two pathologic studies of apathy in AD demonstrated increased neurofibrillary tangle counts in the anterior cingulate cortex. 11,12 We examined the association between apathy and cortical metabolic rate on positron emission tomography (PET) in AD. We postulated that apathy in AD is associated with hypometabolism in the medial frontal regions. METHODS SUBJECTS We enrolled 41 subjects who met criteria from the National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer s Disease and Related Disorders Association Work Group 13 for probable AD. Subjects were recruited from the Veterans Affairs Greater Los Angeles Healthcare System and 1015

Table 1. Demographics and Clinical Scores a Characteristic Subjects With Apathy (n = 14) Subjects Without Apathy (n = 27) t ² P Value Age, y 78.6 (7.1) 73.6 (8.3) 1.94.06 Cognitive symptom duration, y 4.0 (3.0) 2.2 (1.6) 1.99.07 Education, y 12.2 (2.5) 14.4 (4.1) 2.05.048 Male sex, % 92.9 85.2 0.51.65 MMSE 16.8 (5.0) 21.1 (6.2) 2.24.03 NRS depressed mood item 0.7 (0.9) 0.8 (1.0) 0.31.76 SANS-AD global rating for apathy 2.7 (0.9) 0.4 (0.5) 8.79.001 SANS-AD global rating for emotional withdrawal 1.9 (0.9) 0.4 (0.5) 7.12.001 Abbreviations: MMSE, Mini-Mental State Examination; NRS, Neurobehavioral Rating Scale; SANS-AD, Scale for the Assessment of Negative Symptoms in Alzheimer Disease. a All values are mean (SD) unless otherwise indicated. Table 2. Location, Cluster, and Peak Voxel Coordinates of Hypometabolism in Alzheimer Disease Subjects With Apathy Cluster University of California, Los Angeles, outpatient memory disorders clinics. Subjectscompletedacomprehensiveclinicalevaluation, including a detailed history, physical examination, behavioral and cognitive assessments, serum laboratory evaluation, and structural imaging of the brain. Diagnosis of probable AD was made by an experiencedsubspecialtyphysicianandwasconfirmedafterreview of the clinical information by a senior clinical research investigator(d.l.s.). Subjectsdidnotreceiveanypsychotropicmedications, except for 50 mg or less of trazodone daily as needed for sleep for 3 weeks prior to clinical and PET assessments. None of the subjects were taking cholinesterase inhibitors or memantine. The study was approved by the institutional review boards at the Veterans Affairs Greater Los Angeles Healthcare System and the University of California, Los Angeles. Written informed consent was obtained from subjects or legally authorized representatives after study procedures and risks were fully explained in accordance with institutional review board guidelines. CLINICAL DATA Voxel Peak Voxel Talairach Coordinate No. of P t Test P Brain Region Voxels Value Score Value x y z Bilateral anterior 3770.001 4.73.001 10 44 26 cingulate and medial orbitofrontal cortex Bilateral medial thalamus 751.04 3.90.001 4 16 8 The Scale for the Assessment of Negative Symptoms in Alzheimer Disease (SANS-AD) 14 was administered to all subjects. The SANS- AD was developed to assess the following symptoms specifically in AD: affective blunting (6 subscale items and a global rating), avolition/apathy (3 subscale items and a global rating), and social/ emotionalwithdrawal(4subscaleitemsandaglobalrating). Scores rangefrom0to5foreachitem(0=notatall,1=questionable,2=mild, 3=moderate, 4=marked, and 5=severe). To focus on the specific phenomenon of apathy, 2 groups were designated based on absence or presence of clinically meaningful apathy derived from SANS-AD global subscale scores. Subjects with a score of 2 or more in either the avolition/apathy or social/emotional withdrawal global ratings were designated as having apathy, while subjects with a score of less than 2 in both were designated as not having apathy. The affective blunting subscale score was not considered in the assignment, as these symptoms are outside the apathy construct used in this study. The Mini-Mental State Examination (MMSE) 15 was administered to all subjects to measure the severity of global cognitive impairment. The Neurobehavioral Rating Scale (NRS), 16 a 28-item scale covering a wide range of behavioral and cognitive symptoms, was administered to all subjects. The NRS depressed mood item was used in our study; scores range from 0 to 6 (0=not present at all, 6=extremely severe dysphoria). This NRS item assesses the severity of depressed mood, which includes sadness, hopelessness, and dysphoria (as distinct from apathy or disinterest) and has been shown to be reliable in patients with dementia. 16 The NRS delusions item was also used. Subjects underwent clinical assessment, including SANS-AD, MMSE, and NRS, immediately prior to PET imaging. IMAGING DATA The Siemens 953/31 tomographic scanner (Siemens Medical Solutions, HoffmanEstates, Illinois) wasusedtoperformpetimaging of cerebral metabolic activity. The scanner has an inplane spatial resolution (full width at half maximum) of approximately 5 mm and an axial slice thickness of approximately 3 mm. [ 18 F] FluorodeoxyglucosewassynthesizedattheVeteransAffairsGreaterLos AngelesHealthcareSystemPETimagingfacilityinaccordancewith the technique of Hamacher et al. 17 Subjects received 5 to 10 mci (1 Ci equals 3.7 10 10 Bq) of [ 18 F] fluorodeoxyglucose intravenously. During the 40-minute [ 18 F] fluorodeoxyglucose uptake phase, subjects were at rest with eyes open and ears uncovered in a dimly lit room. After the uptake phase, subjects were positioned in the scanner with the imaging plane parallel to the canthomeatal plane. A thin restraining tape was placed across subjects foreheads to maintain head position. Metabolic data were then acquired during a period of approximately 40 minutes. IMAGE AND DATA ANALYSIS Whole-brain voxel-based analyses were performed using statistical parametric mapping software (SPM2; Wellcome Department of Imaging Neuroscience, London, England; http: //www.fil.ion.ucl.ac.uk/spm) in MATLAB 6.5 software (Mathworks, Natick, Massachusetts). For each subject, PET images were transformed to a standard template in Montreal Neurological Institute Talairach and Tournoux atlas space. 18 Activity values were scaled proportionately and images were smoothed with a 6-mm gaussian filter. 1016

A B 4 3 2 1 0 C 4 3 2 1 0 Figure 1. A, Statistical parametric map (glass-brain view) for the 2-sample t test for proportionally scaled [ 18 F] fluorodeoxyglucose positron emission tomographic activity. This contrast compared Alzheimer disease subjects with apathy to Alzheimer disease subjects without apathy. Voxels shown are those for which the apathy group had significantly lower activity than the without-apathy group (P.01, uncorrected). The red v s show crosshair position in B and C. Significant voxels are also displayed on a standard magnetic resonance image with a view of the anterior cingulate gyrus and medial orbitofrontal cortex (B) and the medial thalamus (C). The scales show the value of the t statistic. Twosamplestatisticalparametricmappinganalysesyieldedsignificancemapscomparingrelativeregionalactivityinsubjectswith apathyandsubjectswithoutapathy. Stereotacticcoordinatesofpeak voxel differences within clusters were determined in reference to the Talairach and Tournoux atlas. Clusters with P.05 (uncorrected) were considered statistically significant. Demographic variables, including age, cognitive symptom duration, education, sex, MMSEscore, andnrsdepressedmooditem score, werescreenedfordifferencesbetweensubjectswithandwithout apathy using ttests for continuous variables and 2 test for sex. Demographic variables that were significantly different were individuallyincludedaspredictorvariables(covariates) ina2-sample statistical parametric mapping analysis using a linear regression model to examine the independent effect of apathy on relative regionalactivity. Becauseofpotentialneurobiologicalinteractionbetween apathy and depressed mood, the NRS depressed mood item score and the NRS delusions item score were also included as covariates,despitenotbeingsignificantlydifferentbetweenthe2groups. RESULTS Among enrolled subjects, 27 (66%) did not have apathy, while 14 (34%) had apathy. Table 1 presents the demographics and clinical scores for both groups. Mean MMSE score and years of education were lower in subjects with apathy compared with subjects without apathy (MMSE, t=2.24, P=.03; education, t=2.05, P=.048). Statistical parametric mapping analysis revealed significant reduced activity in the bilateral anterior cingulate region (Brodmann area 24) extending inferiorly to the medial orbitofrontal region (Brodmann area 11/12; cluster level, P.001) as well as in the bilateral medial thalamus (P=.04) in subjects with apathy compared with subjects without (Table 2, Figure 1). With statistical parametric mapping correction for multiple clusters, the 1017

findings in the anterior cingulate and the medial orbitofrontal cluster remained significant (P=.002), but the findings in the medial thalamus cluster were no longer significant (P=.50). While the peak voxel relationship was in the right hemisphere for each of these clusters, the clusters were bilateral and generally symmetric. In the statistical parametric mapping analysis to identify voxels with significant increased activity in subjects with apathy compared with those without apathy, there was increased activity in the left angular gyrus (Brodmann area 39; cluster level, P=.01) in subjects with apathy. The results of the statistical parametric mapping analysis remained the same after covarying for the effect of Table 3. Location, Cluster, and Peak Voxel Coordinates of Hypometabolism in AD Subjects With Apathy, With MMSE as a Covariate Brain Region Cluster No. of Voxels P Value Voxel t Test Score Peak Voxel Talairach Coordinate P Value X Y Z Bilateral anterior cingulate and medial orbitofrontal cortex 6772.001 4.62.001 10 44 26 Bilateral thalamus 922.02 3.78.001 4 16 8 Abbreviations: AD, Alzheimer disease; MMSE, Mini-Mental State Examination. MMSE score on activity (Table 3, Figure 2). The results of the statistical parametric mapping analysis also remained the same after individually covarying for the effects of age, education, cognitive symptom duration, NRS depressed mood item score, and NRS delusions item score on activity, except that the association between apathy and activity in the thalamus was no longer significant (P=.55) after covarying for age. COMMENT Apathy in AD is associated with reduced metabolic activity in the bilateral anterior cingulate gyrus, medial orbitofrontal cortex, and medial thalamus. The relationship with medial thalamus metabolic activity was less robust and no longer significant when corrected for multiple clusters and age. The frontal subcortical circuit implicated in apathy involves the anterior cingulate, nucleus accumbens, globus pallidus, substantia nigra, midline thalamic nuclei, and medial dorsal nucleus of the thalamus 19-21 ; reduced neuronal activity in several of these regions was observed in our study in subjects with AD. The medial orbitofrontal region has reciprocal connections with the anterior cingulate and medial dorsal nucleus of the thalamus, 21 which is reinforced by the results of the current study and may be important in assigning internal relevance to external stimuli that a person encounters. The nucleus basalis of Meynert in the basal forebrain has cho- A B 4 3 2 1 0 Figure 2. A, Statistical parametric map (glass-brain view) for the 2-sample t test for proportionally scaled [ 18 F] fluorodeoxyglucose positron emission tomographic activity comparing Alzheimer disease subjects with apathy to Alzheimer disease subjects without apathy after covarying for Mini-Mental State Examination score. Voxels shown are those for which the apathy group has significantly lower activity than the without-apathy group (P.01, uncorrected). The red v s show crosshair position in B. B, Significant voxels are also displayed on a standard magnetic resonance image with a view of the anterior cingulate gyrus and medial orbitofrontal cortex (the thalamus is not seen on this image). The scale shows the value of the t statistic. 1018

linergic projections to the frontal limbic cortical regions, medial dorsal nucleus of the thalamus, and midline thalamus. Dysfunction of neural systems in these projection fields (perhaps related to reduced cholinergic tone) may be related to the development of apathy in AD. 21 In fact, donepezil, a cholinesterase inhibitor, has been shown to reduce neuropsychiatric symptoms in AD, particularly apathy and hallucinations. 22,23 Positron emission tomographic imaging has not been used previously to address apathy in AD. The results of the current study reinforce the confluence of evidence from other investigational modalities in implicating medial frontal dysfunction in the neurobiology of apathy in AD and other neuropsychiatric diseases 4-7,11,24 and suggest that the specific neurophysiologic contributions to apathy occur across neuropsychiatric disorders. In the current study, medial frontal dysfunction in AD subjects with apathy was independent of severity of global cognitive impairment, age, cognitive symptom duration, and education, underscoring the clinical and physiologic importance of behavioral symptoms in AD. Apathy has also been shown to be phenomenologically distinct from depression. 25 The current study extends this distinction to regional brain function and suggests that neurobiologic correlates of apathy in AD are independent of depressed mood and delusional thoughts. This finding contributes to a better understanding of neuropsychiatric syndromes in AD. The limitations of this study are as follows: first, the construct of apathy is variable and research findings will depend on the specific assessment instrument used. The results of the current study apply to the apathy construct used here. Second, the extent of apathy varies in patients with AD. However, in the current study, a dichotomous analysis was performed (comparing groups with and without apathy) because of the skewed distribution. Finally, many neuropsychiatric symptoms are seen in AD. However, only depressed mood and delusional thoughts were covaried for in the current study to assess the apathy relationship independent of dysphoria, which may co-occur in some patients. In conclusion, apathy in AD independent of severity of global cognitive impairment, age, cognitive symptom duration, education, and depressed mood 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 suggest a specific neurobiologic basis for the expression of apathy in AD. This finding also supports the validity of a medial frontal subcortical circuit related to apathy and helps define the role of distinct neural functional systems associated with particular clinical phenotypes across neuropsychiatric disorders. Accepted for Publication: October 30, 2006. Correspondence: David L. Sultzer, MD, Psychiatry Service, Veterans Affairs Greater Los Angeles Healthcare System, 3-South, 116AE, 11301 Wilshire Blvd, Los Angeles, CA 90073 (dsultzer@ucla.edu). Author Contributions: Dr Sultzer had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Marshall, Harwood, Mandelkern, Cummings, and Sultzer. Acquisition of data: Monserratt, Harwood, Mandelkern, and Sultzer. Analysis and interpretation of data: Marshall, Monserratt, Mandelkern, and Sultzer. Drafting of the manuscript: Marshall, Monserratt, and Mandelkern. Critical revision of the manuscript for important intellectual content: Marshall, Harwood, Mandelkern, Cummings, and Sultzer. Statistical analysis: Marshall, Monserratt, Mandelkern, and Sultzer. Obtained funding: Cummings and Sultzer. Administrative, technical, and material support: Monserratt, Cummings, and Sultzer. Study supervision: Cummings and Sultzer. Financial Disclosure: None reported. Funding/Support: This study was supported by grant MH56031 from the National Institute of Mental Health and by the Department of Veterans Affairs. Additional Contributions: Amy Walston, MD, and Diane Christine, RN, assisted with patient care and clinical assessments. REFERENCES 1. Lyketsos CG, Steinberg M, Tschanz JT, Norton MC, Steffens DC, Breitner JC. Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging. Am J Psychiatry. 2000;157(5):708-714. 2. Mega MS, Cummings JL, Fiorello T, Gornbein J. The spectrum of behavioral changes in Alzheimer s disease. Neurology. 1996;46(1):130-135. 3. Starkstein SE, Petracca G, Chemerinski E, Kremer J. Syndromic validity of apathy in Alzheimer s disease. Am J Psychiatry. 2001;158(6):872-877. 4. Kuzis G, Sabe L, Tiberti C, Dorrego F, Starkstein SE. Neuropsychological correlates of apathy and depression in patients with dementia. Neurology. 1999; 52(7):1403-1407. 5. McPherson S, Fairbanks L, Tiken S, Cummings JL, Back-Madruga C. Apathy and executive function in Alzheimer s disease. J Int Neuropsychol Soc. 2002;8(3): 373-381. 6. Benoit M, Clairet S, Koulibaly PM, Darcourt J, Robert PH. Brain perfusion correlates of the apathy inventory dimensions of Alzheimer s disease. Int J Geriatr Psychiatry. 2004;19(9):864-869. 7. Migneco O, Benoit M, Koulibaly PM, et al. Perfusion brain SPECT and statistical parametric mapping analysis indicate that apathy is a cingulate syndrome: a study in Alzheimer s disease and nondemented patients. Neuroimage. 2001;13(5): 896-902. 8. Craig AH, Cummings JL, Fairbanks L, et al. Cerebral blood flow correlates of apathy in Alzheimer disease. Arch Neurol. 1996;53(11):1116-1120. 9. Ott BR, Noto RB, Fogel BS. Apathy and loss of insight in Alzheimer s disease: a SPECT imaging study. J Neuropsychiatry Clin Neurosci. 1996;8(1): 41-46. 10. Cummings JL, Apostolova LG, Akopyan GG, et al. Structural correlates of apathy in Alzheimer s disease [abstract]. Neurology. 2006;66(5)(suppl 2): A105. 11. Marshall GA, Fairbanks LA, Tekin S, Vinters HV, Cummings JL. Neuropathologic correlates of apathy in Alzheimer s disease. Dement Geriatr Cogn Disord. 2006;21(3):144-147. 12. Tekin S, Mega MS, Masterman DM, et al. Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease. Ann Neurol. 2001;49(3):355-361. 13. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer s Disease. Neurology. 1984;34(7):939-944. 14. Reichman WE, Coyne AC, Amirneni S, Molino B Jr, Egan S. Negative symptoms in Alzheimer s disease. Am J Psychiatry. 1996;153(3):424-426. 15. Folstein MF, Folstein SE, McHugh PR. Mini-mental state : a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975; 12(3):189-198. 1019

16. Sultzer DL, Berisford MA, Gunay I. The Neurobehavioral Rating Scale: reliability in patients with dementia. J Psychiatr Res. 1995;29(3):185-191. 17. Hamacher K, Coenen HH, Stocklin G. Efficient stereospecific synthesis of nocarrier-added 2-[18F]-fluoro-2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution. J Nucl Med. 1986;27(2):235-238. 18. Talairach J, Tournoux P. Co-Planar Stereotactic Atlas of the Human Brain 3-Dimensional Proportional System: An Approach to Cerebral Imaging. New York, NY: Thieme Medical; 1988. 19. Cummings JL. Frontal-subcortical circuits and human behavior. Arch Neurol. 1993; 50(8):873-880. 20. Cummings JL. The Neuropsychiatry of Alzheimer s Disease and Related Dementias. London, England: Martin Dunitz; 2003. 21. Mega MS, Cummings JL, Salloway S, Malloy P. The limbic system: an anatomic, phylogenetic, and clinical perspective. J Neuropsychiatry Clin Neurosci. 1997;9(3):315-330. 22. Feldman H, Gauthier S, Hecker J, et al. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer s disease. Neurology. 2001;57 (4):613-620. 23. Wynn ZJ, Cummings JL. Cholinesterase inhibitor therapies and neuropsychiatric manifestations of Alzheimer s disease. Dement Geriatr Cogn Disord. 2004; 17(1-2):100-108. 24. Rosen HJ, Allison SC, Schauer GF, Gorno-Tempini ML, Weiner MW, Miller BL. Neuroanatomical correlates of behavioural disorders in dementia. Brain. 2005; 128(pt 11):2612-2625. 25. Levy ML, Cummings JL, Fairbanks LA, et al. Apathy is not depression. J Neuropsychiatry Clin Neurosci. 1998;10(3):314-319. New Initiatives: Clinical Trials and Videos We have embarked on 2 new initiatives: Clinical Trials and video presentations. We welcome manuscripts that describe double-blind, randomized, placebo-controlled clinical trials as our primary area of interest. Open-label studies will also receive our special attention. We plan on expediting the review process and time to publication and to include them online ahead of print as these studies are time sensitive and of direct benefit to our patients. We hope you will take advantage of this new initiative. Please refer to the Instructions for Authors when submitting a Clinical Trials paper, including the requirement to register the trial with an accepted clinical trials site. We plan to utilize videos as part of published papers that highlight and provide convincing information about the observational and visual features of a patient s neurologic findings. Please refer to Instructions for Authors for instructions on submitting video presentations. 1020