Mental calculation impairment in Alzheimer’s disease: a functional magnetic resonance imaging study Florence Re ´my a, * , Fakhereh Mirrashed a , Barry Campbell b , Wolfgang Richter c a MR Technology Department, Institute for Biodiagnostics, National Research Council, 435 Ellice Avenue, Winnipeg, Man. R3B 1Y6, Canada b Department of Geriatric Psychiatry, Saint-Boniface General Hospital, 409 Tache ´ Avenue, Winnipeg, Man. R2H 2A6, Canada c Department of Chemistry and Center for the Study of Brain, Mind and Behavior, Princeton University, Princeton, NJ 08544, USA Received 19 September 2003; received in revised form 16 December 2003; accepted 16 December 2003 Abstract This functional MRI study investigates cerebral activations during mental arithmetic performance, in patients diagnosed with probable Alzheimer’s disease (with mild to moderate severity) and age-matched healthy controls. The arithmetic task consisted in three-digit addition and subtraction problems. The task elicited bilateral parietal and prefrontal activations in the control group, in agreement with previous imaging studies of mental arithmetic. In the Alzheimer group, inferior parietal and lateral prefrontal activations were significantly reduced when compared to controls (corrected P , 0:05). This important reduction of activity was likely responsible for the patients’ poor performance in the task. These results confirm the deficit in calculation abilities, which occurs early in Alzheimer’s disease, and provide additional knowledge of the neural mechanisms underlying this impairment. q 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Alzheimer’s disease; Arithmetic; Functional magnetic resonance imaging; Dyscalculia; Parietal cortex; Prefrontal cortex Alzheimer’s disease (AD) is the most common form of age- related dementia and is characterized by a progressive cognitive decline. Among other cognitive deficits, mental calculation abilities are commonly impaired early in the course of AD [14]. This impairment has been correlated to the degree of dementia [10]. Single-subject analyzes in AD patients have shown a low consistency of specific procedural errors, suggesting that arithmetic impairment arises from deficits in monitoring calculation procedures [9, 12]. Although calculation skills are important in everyday activities, little is known about the neural mechanisms underlying such impairment in AD. The present study was designed to investigate cerebral activations elicited by arithmetic tasks in a group of AD patients with mild to moderate severity and in a group of healthy elderly controls, using functional magnetic resonance imaging (fMRI). In a previous neuroimaging study conducted on a large sample of AD patients, calculation performance has been correlated with resting glucose metabolism in the left inferior parietal cortex [8]. The authors suggested that dysfunction in this region may be responsible for dyscalcu- lia in AD. In healthy subjects, the left inferior parietal cortex has been consistently involved in calculation tasks, along with the lateral prefrontal and premotor cortices [2,6,13,18]. Based on these different findings, we hypothesized that the fMRI activity elicited by arithmetic tasks in the left inferior parietal cortex would be reduced in AD patients when compared to controls. Furthermore, based on the specific calculation deficits in AD previously reported in neuropsy- chological studies [9,12], we hypothesized that lateral prefrontal activations in response to arithmetic tasks would be reduced in AD patients when compared to controls. The study was conducted according to the Declaration of Helsinki and was approved by the National Research Council Human Ethics Committee. Patients diagnosed with probable AD according to the NINCDS/ADRDA criteria [11] (n ¼ 7; one male, six females; age ¼ 70.4 ^ 10.3 years; education ¼ 13.1 ^ 2.8 years) and age- and education-matched cognitively healthy con- trols (n ¼ 11; five males, six females; age ¼ 65.9 ^ 5.7 years; education ¼ 13.3 ^ 2.6 years) volunteered to par- 0304-3940/03/$ - see front matter q 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2003.12.122 Neuroscience Letters 358 (2004) 25–28 www.elsevier.com/locate/neulet * Corresponding author. Tel.: þ 1-204-984-6563; fax: þ1-204-984-7036. E-mail addresses: florence.remy@nrc-cnrc.gc.ca (F. Re ´my), fakhereh. mirrashed@nrc-cnrc.gc.ca (F. Mirrashed), bcampbel@sbgh.mb.ca (B. Campbell), wrichter@princeton.edu (W. Richter).