Impact of leptin on memory function and hippocampal structure in mild cognitive impairment

Abstract

Metabolic changes have been suggested to contribute to dementia and its precursor mild cognitive impairment (MCI), yet previous results particularly for the "satiety hormone" leptin are mixed. Therefore, we aimed to determine if MCI patients show systematic differences in leptin, independent of sex, adipose mass, age, and glucose and lipid metabolism, and whether leptin levels correlated with memory performance and hippocampal integrity. Forty MCI patients (20 females, aged 67 years ± 7 SD) were compared to 40 healthy controls (HC) that were pair-wise matched for sex, age, and body fat. Memory performance was assessed using the auditory verbal learning test. Volume and microstructure of the hippocampus were determined using 3T-neuroimaging. Fasting serum markers of leptin, glucose and lipid metabolism, and other confounding factors were assayed. MCI patients, compared with HC, showed lower serum leptin, independent of sex, age, and body fat (P < 0.001). Glucose and lipid markers did not attenuate these results. Moreover, MCI patients exhibited poorer memory and lower volume and microstructural integrity within hippocampal subfields. While leptin and memory were not significantly correlated, mediation analyses indicated that lower leptin contributed to poorer memory through its negative effect on right hippocampus volume and left hippocampus microstructure. We demonstrated that MCI is associated with lower serum leptin independent of sex, age, body fat, glucose, and lipid metabolism. Our data further suggest that inefficient leptin signaling could partly contribute to decreases in memory performance through changes in hippocampus structure, a hypothesis that should now be verified in longitudinal studies. Hum Brain Mapp 37:4539-4549, 2016. © 2016 Wiley Periodicals, Inc.

Obesity and Brain Function: The Brain–Body Crosstalk

“…An abnormally high level of leptin (hyperleptinemia) plays a role in polygenic obesity, while low leptin (hypoleptinemia) is associated with weight loss from an obese state [ 48 ]. Further, cross-sectional data suggest that inefficient leptin signalling is partly associated with changes in hippocampus structure and decreases in memory performance [ 49 ]. Lower leptin was found to contribute to poorer memory through its negative effect on hippocampus volume and microstructure [ 49 ].…”

“…Further, cross-sectional data suggest that inefficient leptin signalling is partly associated with changes in hippocampus structure and decreases in memory performance [ 49 ]. Lower leptin was found to contribute to poorer memory through its negative effect on hippocampus volume and microstructure [ 49 ]. In rodents, leptin deficits are associated with impairments in synaptic signalling [ 50 ].…”

Interactions between metabolic, reward and cognitive processes in appetite control: Implications for novel weight management therapies

“…Leptin administration has been reported to improve memory function in rodents ( Farr et al, 2006 ; Oomura et al, 2006 ), whereas cognitive performance is impaired in genetic models of leptin deficiency ( Li et al, 2002 ; Paz-Filho et al, 2008 ). As with insulin, leptin resistance is also associated with impaired cognition, especially during aging, and impaired leptin function may contribute to cognitive impairment in MCI in humans ( Holden et al, 2009 ; Witte et al, 2016 ).…”

Microglia, neurodegeneration and loss of neuroendocrine control

“…Changes in the hypothalamic signaling of neuroprotective hormones, which also regulate the inflammatory responses of microglia and astrocytes, will further accelerate hypothalamic dysfunction in neurodegenerative diseases. For instance, plasma leptin levels, adjusted for body weight, are reduced in Alzheimer's disease patients and in patients with age-associated dementia (Johnston et al, 2014;Witte et al, 2016). In addition, leptin transport through the blood brain barrier is impaired in animal models of Alzheimer's disease (Dietrich et al, 2008).…”