Neuropsychological and Neuroimaging Characteristics of Patients with Mild Cognitive Impairment and Negative-Amyloid Deposition

Xiangwei Dai¹Junying Zhang¹Xin Li²Yaojing Chen²Yanan Qiao³Shujuan Zhang³Kewei Chen⁴Lin Ai^5*Dantao Peng^3*Zhanjun Zhang^2*

• ¹Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
• ²Beijing Normal University State Key Laboratory of Cognitive Neuroscience and Learning, Beijing, China
• ³China-Japan Friendship Hospital, Beijing, China
• ⁴Banner Alzheimer's Institute, Phoenix, United States
• ⁵Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing, China

Objectives: Accumulating studies have reported that some mild cognitive impairment (MCI) patients without significant β-amyloid (Aβ) deposition on amyloid PET can later develop Alzheimer's disease (AD). Therefore, this study profiled the cognitive and neural characteristics of MCI patients with negative Aβ deposition to better understand potential features associated with an increased risk of AD progression. Methods: Thirty-seven MCI patients and 32 normal controls (NCs) underwent neuropsychological, structural magnetic resonance imaging, and diffusion tensor imaging scans. MCI patients were stratified into amyloid-positive (Aβpos; n=18) and Aβ-negative (Aβneg; n=19) groups based on 18F-florbetapir positron emission. We compared cognitive performances, white matter (WM) integrity, and gray matter (GM) volume between three groups, and further examined the interplay among brain structural alterations and cognitive changes. Results: Cognitively, relative to NCs, participants in Aβneg MCI group showed significant deficits in multidomain cognitive performances including episodic memory, attention, and executive function, as those in Aβpos MCI group did. Both MCI subgroups exhibited extensive disruptions of WM integrity. Direct comparisons between the Aβneg and Aβpos groups revealed that Aβ-related structural changes were predominantly localized to the left hippocampus and adjacent regions. The increased amyloid deposition was closely associated with elevated mean diffusivity in the cingulum (hippocampus) and reduced hippocampal volume. Moreover, hippocampal volume mediated the relationship between WM disruptions and episodic memory performance. Conclusions: Aβneg MCI display AD-like cognitive and structural abnormalities, particularly involving hippocampus regions may be associated with advanced cognitive decline or dementia progression. These results may help identify high-risk individuals within the heterogeneous Aβneg MCI population.