Low Cholesterol Level Linked to Reduced Semantic Fluency Performance and Reduced Gray Matter Volume in the Medial Temporal Lobe

Abstract

Hyperlipidemia has been proposed as a risk factor of dementia and cognitive decline. However, the findings of the relationship between cholesterol level and cognitive/brain function have been inconsistent. Here, using a well-controlled sample from the Parkinson's Progression Markers Initiative (PPMI), we investigated the probable nonlinear relationship between plasma total cholesterol (TC) level, gray matter volume (GMv), and cognitive performance in 117 non-demented subjects (mean age, 61.5 ± 8.9 years), including 67 Parkinson's disease (PD) patients and 50 demographically matched controls. A quadratic relationship between semantic fluency (SF) performance and TC levels was identified. Within the subjects with a desirable TC level (TC < 200 mg/dl), low TC (lTC) levels were associated with reduced SF performance, as well as reduced GMv in three medial temporal regions [including bilateral anterior hippocampus (HIP)]. In contrast, no significant relationship between TC and cognition performance/GMv was found in individuals with a high cholesterol level (i.e., TC ≥ 200 mg/dl). Further region of interest (ROI)-based analysis showed that individuals with TC levels ranging from 100 to 160 mg/dl had the lowest GMv in the medial temporal regions. These findings suggest that low-normal TC level may be associated with reduced cognitive function and brain atrophy in regions implicated in neurodegenerative diseases, adding to a growing body of literature supporting a probable non-linear relationship between cholesterol level and brain health. However, this finding needs to be verified with other large public cohort data that do not include PD patients.

The Relationship Between Cardiovascular Health and Rate of Cognitive Decline in Young-Old and Old-Old Adults: A Population-Based Study

“…For example, lower cholesterol has been associated with slower cognitive decline in young old individuals, whereas the opposite was found among the old-old [45]. Other studies have also been reporting associations of higher cholesterol level with better cognitive performance [46,47]. Different mechanistic hypotheses can explain this pattern.…”

“…Because cholesterol is an indispensable component of myelin, neuronal membranes, and glial membranes, it is involved in both cerebral structure and function [49]. Low-normal cholesterol levels have been associated with poorer cognitive performance and reduced brain volume in regions implicated in neurodegenerative diseases [47].…”

Elevated lipids are associated with reduced regional brain structure in youth with bipolar disorder

“…Regions of interest (ROIs), selected based on prior literature investigating the neurostructural correlates of either BD [29][30][31] or lipids, [19][20][21][22][23][24][25][26][27][28] included the hippocampus, ACC, and inferior parietal lobe, were defined using annotations from the Desikan-Killiany atlas. Cortical volume and area for each ROI were calculated by summing up the values for each annotation within an ROI.…”

“…Studies in adults show that lipids are associated with brain structure, although the direction of this association is inconsistent. For example, elevated lipids are associated with both increased and decreased cortical volume and/or thickness in the hippocampus, frontal (e.g., cingulate cortex), and parietal regions (e.g., the inferior parietal lobe) 19–28 . Furthermore, defects in brain cholesterol metabolism have been implicated in neurodegenerative diseases such as Alzheimer's disease 18 …”

“…For example, elevated lipids are associated with both increased and decreased cortical volume and/or thickness in the hippocampus, frontal (e.g., cingulate cortex), and parietal regions (e.g., the inferior parietal lobe). [19][20][21][22][23][24][25][26][27][28] Furthermore, defects in brain cholesterol metabolism have been implicated in neurodegenerative diseases such as Alzheimer's disease. 18 Despite the literature on lipid associations with psychiatric symptoms and neurocognition in BD, and with brain structure in adults without BD, no studies to date focus on the association of lipids with brain structure in youth in general or in BD in any age group.…”