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Original Investigation |

Synergistic Effects of Ischemia and β-Amyloid Burden on Cognitive Decline in Patients With Subcortical Vascular Mild Cognitive Impairment

Mi Ji Lee, MD1; Sang Won Seo, MD, PhD1; Duk L. Na, MD1; Changsoo Kim, MD2; Jae Hyun Park, MD1; Geon Ha Kim, MD3; Chi Hun Kim, MD1; Young Noh, MD4; Hanna Cho, MD1,5; Hee Jin Kim, MD1; Cindy W. Yoon, MD6; Byoung Seok Ye, MD1; Juhee Chin, PhD1; Seun Jeon, MS7; Jong-Min Lee, PhD7; Yearn Seong Choe, PhD8; Kyung-Han Lee, MD8; Jae Seung Kim, MD9; Sung Tae Kim, MD, PhD10; Jae-Hong Lee, MD11; Michael Ewers, PhD12; David J. Werring, PhD, FRCP13; Michael W. Weiner, MD14,15
[+] Author Affiliations
1Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea
3Department of Neurology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea
4Department of Neurology, Gachon University Gil Medical Center, Incheon, Korea
5Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
6Department of Neurology, Inha University School of Medicine, Incheon, Korea
7Department of Biomedical Engineering, Hanyang University, Seoul, Korea
8Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
9Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
10Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
11Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
12Institute for Stroke and Dementia Research, Ludwig-Maximilians University, Munich, Germany
13Department of Brain Repair and Rehabilitation, University College London Institute of Neurology, Queen Square, London, England
14Department of Radiology, University of California, San Francisco
15Center for Imaging of Neurodegenerative Diseases, Department of Veterans Affairs Medical Center, San Francisco, California
JAMA Psychiatry. 2014;71(4):412-422. doi:10.1001/jamapsychiatry.2013.4506.
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Importance  Cerebrovascular disease (CVD) and Alzheimer disease are significant causes of cognitive impairment in the elderly. However, few studies have evaluated the relationship between CVD and β-amyloid burden in living humans or their synergistic effects on cognition. Thus, there is a need for better understanding of mild cognitive impairment (MCI) before clinical deterioration begins.

Objective  To determine the synergistic effects of β-amyloid burden and CVD on cognition in patients with subcortical vascular MCI (svMCI).

Design, Setting, and Participants  A cross-sectional study was conducted using a hospital-based sample at a tertiary referral center. We prospectively recruited 95 patients with svMCI; 67 of these individuals participated in the study. Forty-five patients with amnestic MCI (aMCI) were group matched with those with svMCI by the Clinical Dementia Rating Scale Sum of Boxes.

Main Outcomes and Measures  We measured β-amyloid burden using positron emission tomography with carbon 11–labeled Pittsburgh Compound B (PiB). Cerebrovascular disease was quantified as white matter hyperintensity volume detected by magnetic resonance imaging fluid-attenuated inversion recovery. Detailed neuropsychological tests were performed to determine the level of patients’ cognitive impairment.

Results  On evaluation, 22 of the svMCI group (33%) and 28 of the aMCI group (62%) were found to be PiB positive. The mean PiB retention ratio was lower in patients with svMCI than in those with aMCI. In svMCI, the PiB retention ratio was associated with cognitive impairments in multiple domains, including language, visuospatial, memory, and frontal executive functions, but was associated only with memory dysfunction in aMCI. A significant interaction between PiB retention ratio and white matter hyperintensity volume was found to affect visuospatial function in patients with svMCI.

Conclusions and Relevance  Most patients with svMCI do not exhibit substantial amyloid burden, and CVD does not increase β-amyloid burden as measured by amyloid imaging. However, in patients with svMCI, amyloid burden and white matter hyperintensity act synergistically to impair visuospatial function. Therefore, our findings highlight the need for accurate biomarkers, including neuroimaging tools, for early diagnosis and the need to relate these biomarkers to cognitive measurements for effective use in the clinical setting.

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Figure 1.
Statistical Parametric Mapping Analysis of Pittsburgh Compound B (PiB) Retention in the PiB-positive (PiB+) Amnestic Mild Cognitive Impairment (aMCI) and PiB+ Subcortical Vascular Mild Cognitive Impairment (svMCI) Groups

The PiB+ aMCI patients exhibited greater PiB retention in the lateral temporal, posterior cingulate, and medial temporal and frontal cortices than did the PiB+ svMCI patients. The color bar intensity represents the value of the T statistic. The numbers represent the stereotactic z coordinate corresponding to each axial section. Statistical significance was set as a false discovery rate–corrected P < .05 at a cluster extent threshold of 150 voxels.

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Figure 2.
Pittsburgh Compound B (PiB) Retention Ratio in the Amnestic Mild Cognitive Impairment (aMCI) and Subcortical Vascular Mild Cognitive Impairment (svMCI) Groups

The bold horizontal line indicates the cutoff value. PiB retention ratios were compared between aMCI and svMCI by applying analysis of covariance adjusted for age. Significant differences were noted between aMCI and svMCI patients (mean [SD], 1.87 [0.51] vs 1.50 [0.40], P < .001). Circles indicate patients; bars within the boxes, median values; boxes, interquartile range; bars outside the boxes, extreme values; and black square, outlier.

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Figure 3.
Partial Regression Plots of Total Pittsburgh Compound B (PiB) Retention Ratios and Neuropsychological Results in Subcortical Vascular Mild Cognitive Impairment (svMCI) Patients

Significant relationships were shown in language, visuospatial, verbal and visual memory, and frontal executive functions in svMCI patients. The y-axis values are log scores. FDR indicates false discovery rate; BNT, Boston Naming Test; RCFT, Rey-Osterrieth Complex Figure Test; and SVLT, Seoul Verbal Learning Test.

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