Cognitive Dysfunctions in Middle-Aged Type 2 Diabetic ... - IOS Press

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Type 2 Diabetic Patients and Neuroimaging. Correlations: A Cross-Sectional Study. Natalia Garcıa-Casaresa,b,∗. , Ricardo E. Jorgec, Juan A. Garcıa-Arnésd, ...
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Journal of Alzheimer’s Disease 42 (2014) 1337–1346 DOI 10.3233/JAD-140702 IOS Press

Cognitive Dysfunctions in Middle-Aged Type 2 Diabetic Patients and Neuroimaging Correlations: A Cross-Sectional Study Natalia Garc´ıa-Casaresa,b,∗ , Ricardo E. Jorgec , Juan A. Garc´ıa-Arn´esd , Laura Acione , Marcelo L. Berthiera,b , Pedro Gonzalez-Alegref , Alejandro Nabrozidisb , Antonio Guti´errezb , Mar´ıa Jos´e Arizaa,b , Jose Riojaa,b and Pedro Gonz´alez-Santosa,b a Department b Centro

of Medicine, Faculty of Medicine, University of Malaga, Malaga, Spain de Investigaciones M´edico-Sanitarias (C.I.M.E.S), General Foundation University of Malaga, Malaga,

Spain c Department

of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA of Endocrinology, Carlos Haya Hospital, Malaga, Spain e The Iowa Consortium for Substance Abuse Research and Evaluation, University of Iowa, Iowa City, IA, USA f Department of Neurology, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA d Department

Accepted 12 May 2014

Abstract. Background/Objective: The aim was to assess the neuropsychological performance of a group of middle-aged patients with well-controlled type 2 diabetes mellitus (T2DM) and to examine whether the neuropsychological deficits correlate with structural and functional brain alterations. Methods: We compared 25 subjects with T2DM aged 45–65 years with 25 control participants matched for age, gender, and educational level. The neuropsychological battery was designed to examine executive functions, attention, information processing speed, and verbal memory. Severity of depression was assessed using the Hamilton Depression Rating Scale and cardiovascular risk factors were assessed using the Framingham Cardiovascular Risk Profile Score. The presence of at least one APOE␧4 allele was determined. Reduced gray matter density was analyzed using voxel-based morphometry and brain glucose metabolic changes were assessed by 18 FDG-PET. Results: T2DM subjects had significantly lower scores than subjects without T2DM in the Trail-making Test B (p < 0.004), Color-Word Stroop test (p < 0.005), Semantic Fluency (p < 0.006), Digit-Symbol modalities test (p < 0.02), Text Recall from the Wechsler Memory Scale (p < 0.0001), Rey-Osterrieth Complex Figure-copy (p < 0.004), and delayed reproduction (p < 0.03). Worse executive functions and memory functioning correlated predominantly with less gray matter density and reduced glucose metabolism in the orbital and prefrontal cortex, temporal (middle gyrus, parahippocampus and uncus), and cerebellum regions (p < 0.001). Conclusions: T2DM subjects presented cognitive dysfunctions compared with controls. Clinical-neuroimaging correlations corresponded to brain changes (reduced gray matter density and glucose metabolism) mainly in fronto-temporal areas. Keywords: Cognition, dementia, magnetic resonance imaging, mild cognitive impairment, neuropsychology, positron emission tomography, type 2 diabetes mellitus

INTRODUCTION

∗ Correspondence to: Natalia Garc´ıa Casares, Department of Medicine, Faculty of Medicine, University of Malaga, Boulevard Louis Pasteur 32, 29010 Malaga, Spain. Tel.: +34952137354; Fax: +34952131615; E-mail: [email protected].

Type 2 diabetes (T2DM) is an important risk factor for cognitive impairment and dementia, an association widely study in elderly patients [1–3]. However, less consideration has been given to casecontrol and longitudinal studies in middle-aged T2DM

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N. Garc´ıa-Casares et al. / Cognitive Dysfunctions in Middle-Aged Type 2 Diabetic Patients

patients, though these patients have consistently been reported to experience cognitive deficits in multiple cognitive domains including verbal memory, information-processing speed, and executive functions [1, 4–6]. In addition, neuroimaging studies have examined the structural and functional brain changes in early T2DM stages. These studies include structural magnetic resonance imaging (MRI) studies that have reported global and regional cortical atrophy predominantly in the temporal lobe and hippocampus [7, 8] and deep white matter hyperintense lesions [9–11]; as well as fronto-temporal, Alzheimer-like reduced cerebral metabolism assessed with F-18 fluoro-deoxyglucose positron emission tomography (18 FDG-PET) [12]. It is possible that determining subtle neuropsychological deficits and brain changes in T2DM patients who do not refer a cognitive and functional decline might help to identify the type, etiology and location of functional and structural brain changes that may precede the onset of dementia in these patients. This would then enable preventive treatment strategies to be implemented. We have previously reported data about the brain changes, in a group of middle-aged T2DM patients with no subjective complains of cognitive problems or functional impairment compared with a group of control combining MRI and 18 FDG-PET [13]. In the present study, we also studied the neuropsychological performance between groups in the same sample. In addition we analyzed the association between neuropsychological deficits and structural and functional brain changes assessed by voxel-based morphometry (VBM) with MRI and 18 FDG-PET. We hypothesized that T2DM patients would show poorer scores than controls in measures of executive and memory functioning. In addition, we hypothesized that executive deficits would be associated with atrophic changes and reduced metabolism of the prefrontal cortex involved in executive function. Finally, we also hypothesized that memory deficits would be associated with hippocampal atrophy as well as functional and structural changes in the antero-medial temporal lobe. MATERIALS AND METHODS

T2DM was identified by an endocrinologist from a diabetes outpatient clinic at the hospital affiliated to the University of Malaga. Control subjects were recruited from different sources including non-consanguineous relatives of the T2DM subjects who were enrolled in the study and subjects contacted through advertising in a university newsletter. All subjects were assessed in the Centro de Investigaciones M´edico Sanitarias (CIMES) at the University of Malaga. The inclusion criteria were: (A) a diagnosis of type 2 diabetes according to the American Diabetes Association (ADA) criteria for the diagnosis of diabetes confirmed by an endocrinologist and a fasting glucose measurement below 110 mg/dL and glycated hemoglobin (Hb1Ac)