Findings from biochemical studies in brain and CSF suggest that perturbed sphingolipid metabolism may be an early event involved in the pathogenesis of AD [1
]. In particular, levels of very-long chain ceramides are increased in brain early in the course of AD. A recent epidemiological study also suggests that serum levels of these ceramides are altered in individuals with memory impairment and may predict incident impairment [12
]. In the present study of well-characterized patients, we provide additional evidence that plasma ceramides C22:0 and C24:0 are perturbed in amnestic MCI, considered the earliest stage of AD. While plasma ceramides did not appear to be cross-sectionally associated with cognitive performance or hippocampal volume, plasma ceramide levels in the MCI group were predictive of one-year change in cognitive test performance and hippocampal volume loss, suggesting that these blood-based lipids may predict changes of cognitive status that relate to hippocampal volume loss and be predictors of Alzheimer progression.
Biochemical studies using human autopsy brain tissues and CSF have demonstrated increased levels of very-long chain ceramides in the middle frontal gyrus and white matter of AD patients; some of which were observed in the earliest stage of AD (CDR=0.5) [1
]. Consistent with these findings, gene expression patterns of enzymes participating in the sphingolipid metabolic pathway are also perturbed in mild AD and further suggests that disruptions of ceramide metabolism may be early pathogenic events in AD [11
]. Increased levels of total ceramides measured in CSF of subjects with moderate, compared with mild or severe, AD has also been reported [4
]. Based on these studies, we expected to find elevated plasma ceramides in both MCI and early AD. However, when we compared plasma ceramides across groups, the MCI group had lower mean plasma ceramide levels compared to both normal controls and AD patients. Notably, this finding is consistent with that observed in an epidemiological study in which low serum ceramides levels were cross-sectionally association with memory impairment [12
]. An explanation for these findings was recently provided in a study of how plasma and CSF ceramides in HIV infected subjects was associated with cognitive function. In this study it was found that plasma ceramides showed an inverse relationship to CSF ceramides (Norman Haughey, personal communication). Thus, the lower plasma ceramide levels observed in the MCI group may be indicative of higher brain ceramide levels, which have consistently been found in previous AD studies. Ongoing research will further examine the plasma-CSF ceramide correlation in a group of normal control, MCI and AD patients to further understand the utility of plasma ceramides as a biomarker of AD progression.
One difficulty in developing blood-based biomarkers for AD is in interpreting the relationship between alterations in these biomarkers and neurodegenerative pathology. We therefore examined the cross-sectional and longitudinal predictive association between baseline ceramides and hippocampal atrophy, a well-known, and well-characterized neuropathological marker of AD. While there was not a cross-sectional association between the plasma ceramides and hippocampal volume, high levels of plasma ceramides were associated with greater right hippocampal atrophy among the MCI cases. We do not understand why there was laterality to this association (i.e. it was not also found on the left side). However, consistent longitudinal findings between high levels of plasma ceramides and declines on multiple tests of memory further suggest the involvement of the hippocampus is not simply due to chance.
In the present study, MCI had lower mean levels of all unsaturated ceramides compared to the AD group. However, findings were strongest for the saturated ceramides with 22 and 24-carbon chain lengths, such that mean levels were also lower compared to the NC group. Ceramides C22:0 and C24:0 are the most abundant in plasma () and, as mentioned above, have previously been observed to be altered in brain tissue of AD patients. As the basic biological role of these differing chain lengths, and the importance of saturation is not understood, we currently do not have an explanation for our lack of results with the unsaturated compounds and future studies will need to focus on reasons for the observed specificity to saturated ceramides.
Based on the observed findings presented here, plasma ceramides do not appear to be good diagnostic biomarkers for separating MCI cases from normal controls or patients with AD. This is due to the clear overlap in ceramide levels between groups and because it is not possible to determine where, on the U-shaped curve, an individual is at the time o the blood draw. For example, among the MCI group, we do not know from the baseline plasma levels whether a person is in transition from NC to MCI or MCI to AD. Serial measures of plasma ceramides over time are needed to determine how ceramides change with disease progression and whether change
in these lipids are a better predictor of progression than baseline levels. While the present findings are intriguing, additional research is clearly needed, especially in a study with a larger sample size and longer duration. Nonetheless, the potential identification of a blood-based biomarker that could be used as a routine procedure and be easily incorporated into patient care in either developed or developing counties, where most AD cases will occur in the next half-century, [31
]would be highly advantageous.