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Gad A. Marshall, MD; Lorena Monserratt, MA; Dylan Harwood, PhD; Mark Mandelkern, MD, PhD; Jeffrey L. Cummings, MD; David L. Sultzer, MD

Arch Neurol. 2007;64(7):1015-1020.

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 [¹⁸F] 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.

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).

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