Plasma ceramides are altered in mild cognitive impairment and predict cognitive decline and hippocampal volume loss

Abstract

Background-A blood-based biomarker of Alzheimer disease (AD) would be superior to CSF and neuroimaging measures in terms of cost, invasiveness and feasibility for repeated measures. We previously reported blood ceramides varied in relation to timing of memory impairment in a population-based study. The present objective was to examine whether plasma ceramides varied by AD severity in a well-characterized clinic sample and were associated with cognitive decline and hippocampal volume loss over one year.Methods-Participants included 25 normal controls (NC), 17 amnestic Mild Cognitive Impairment (MCI), and 21 early probable AD. A thorough neuropsychological battery and neuroimaging with hippocampal volume determination were conducted at baseline and one year later. Plasma ceramides were assayed at baseline using HPLC-coupled electrospray ionization tandem mass spectrometry. : 443-326-5174, Fax: 410-550-1407, mmielke1@jhmi.edu. Disclosure: All authors report no conflicts of interest. The corresponding author had full access to all the data in the study and had final responsibility of the decision to submit for publication.Disclosure Statement: While funding for the neuroimaging and participant follow-up was partially obtained through a grant from GlaxoSmithKline, the authors had access to the data at all times and retain the data. Funding for the plasma lipids were obtained from NIH grants. All authors report no conflicts of interests with regards to GlaxoSmithKline or any other organization. All participants provided informed consent and the study was approved by the Johns Hopkins University Institutional Review Board.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Results-While all saturated ceramides were lower in MCI compared to AD at baseline, Ceramides C22:0 and C24:0 were significantly lower in the MCI group compared to both NC and AD groups (p<0.01). Ceramide levels did not differ (p>0.05) in AD versus NC. There were no cross-sectional associations between ceramides C22:0 and C24:0 and either cognitive performance or hippocampal volume among any group. However, among the MCI group, higher baseline ceramide C22:0 and C24:0 levels were predictive of cognitive decline and hippocampal volume loss one year later. NIH Public AccessAuthor Manuscript Alzheimers Dement. Author manuscript; available in PMC 2011 September 1. Conclusion-Resultssuggest that very long-chain plasma ceramides C22:0 and C24:0 are altered in MCI and predict memory loss and right hippocampal volume loss among subjects with MCI. These plasma ceramides may be early indicators of AD progression.

Serum ceramides increase the risk of Alzheimer disease

“…4 We have previously reported that high blood ceramide levels varied by AD severity and were predictive of cognitive decline and hippocampal volume loss among clinically adjudicated patients with amnestic MCI. 18 The present study supports these findings by showing that high ceramide levels, particularly ceramides d18:1-C16:0, d18:1-C24:0, and lactosylceramide, are most strongly associated with an increased risk of AD dementia. Notably in previous shotgun and targeted studies of blood and brain ceramides, 1,16,18,19 the ceramide d18:1-C24:0 has consistently been altered.…”

“…[1][2][3]16,17 We have shown that blood ceramide levels vary by cognitive status, and that elevations of ceramides in subjects with amnestic mild cognitive impairment (MCI) predict cognitive decline and hippocampal volume loss. 18 In a separate study we also found that high blood ceramides in cognitively normal women predicted memory impairment. 19 However, not all individuals with memory impairment progress to dementia or AD.…”

A Blood-Based, 7-Metabolite Signature for the Early Diagnosis of Alzheimer's Disease

“…In accordance with our findings, decreases in plasma SM levels have been reported in AD patients [21]. Apparently conflicting results have been reported regarding blood ceramide levels, with some authors reporting increases in AD versus NC patients [21,45,46], and others showing no changes in AD patients but decreases in MCI patients with respect to controls [47]. Diverse studies have proposed that SM and ceramide levels are altered to varying degrees depending on the proximity to the onset of memory impairment, suggesting that these lipids may be useful preclinical markers of the memory impairment that frequently precedes AD [44,45].…”

The potential role for sphingolipids in neuropathogenesis of Alzheimer’s disease

“…Тем не менее, в литературе обсуждается возможность использования церамидов в качестве маркеров БА [104][105][106]. Некоторым ограничением может служить неспецифичность этого параметра для БА, поскольку уровень церамидов в СМЖ меняется и при других нейропатологиях.…”

“…В последнее время интенсивно изучается связь между изменениями в спектре сфинголипидов плазмы крови пациентов с БА и развитием когнитивных нарушений для предсказания скорости развития деменции на основании результатов анализа сфинголипидов [104][105][106]. Эта задача может быть решена благодаря развитию метода масс-спектрометрии и его успешного применения в липидологии.…”