Sphingomyelin in Brain and Cognitive Development: Preliminary Data

Schneider, Nora; Hauser, Jonas; Oliveira, Armando M.; Cazaubon, Elise; Mottaz, Sara Colombo; O’Neill, Barry V.; Steiner, Pascal; Deoni, Sean

doi:10.1523/eneuro.0421-18.2019

Cited by 95 publications

(71 citation statements)

References 48 publications

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“…Previous research has implicated disturbances in sphingolipid balance in cognitive development (54,55), function (55), ageing (55,56) and AD (57) However, due to a lack of longitudinal metabolite data, we cannot rule out the possibility that later life sphingolipid levels may be a proxy for those of earlier life. In this regard, childhood cognition and education could be mediators of early life sphingolipid levels and later life cognitive function; or perhaps they may be linked by common genetic or environmental causes.…”

Section: Discussionmentioning

confidence: 90%

“…Previous research has implicated disturbances in sphingolipid balance in cognitive development (54,55), function (55), ageing (55,56) and AD (57). Sphingolipids are a lipid family comprised of sphingomyelins, ceramides and glycosphingolipids, and are present in large quantities in the CNS (57).…”

Section: Discussionmentioning

confidence: 99%

“…Forming important components of cell membranes, they are highly dynamic and display crucial roles in cognitive development and function (55). In this regard, all yellow module hubs were sphingomyelin species the most abundant sphingolipid with pivotal roles in myelin integrity and function (54). However, despite findings highlighting altered sphingolipid balance in cognitive decline and AD, replication of specific sphingolipids has proved challenging.…”

Section: Discussionmentioning

confidence: 99%

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Metabolic correlates of late midlife cognitive function: findings from the 1946 British Birth Cohort

Green

Lord

et al. 2020

Preprint

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BackgroundInvestigating associations between metabolites and late midlife cognitive function could reveal potential markers and mechanistic insights relevant to early dementia. Here, we aimed to identify the metabolic underpinnings of cognitive outcomes in late midlife by exploring and integrating associations of single metabolites, metabolic pathways and networks. We further aimed to untangle the influence of life course factors on these relationships; a previously unexplored avenue using a systems biology approach.Methods and FindingsLevels of 1019 metabolites were detected by liquid chromatography-mass spectrometry (Metabolon Inc) and quantified at age 60-64 among participants of the British 1946 Birth Cohort (N=1740). Cognitive outcomes were assessed at the same age and 5-9 years later, and included short-term memory (age 60-64, 69 and change), delayed memory (age 60-64), processing speed (age 60-64, 69 and change) and Addenbrooke’s Cognitive Examination III (age 69). Using a combination of linear regression analysis, quantitative pathway analysis and weighted gene correlation network analysis, we evaluated relationships between metabolite measures (single-metabolites, pathways and network modules) and cognitive outcomes. Single-metabolite and network analyses were sequentially adjusted for life course factors across four models, including: sex and blood clinic information (model 1); model 1 + BMI and lipid medication (model 2); model 2 + childhood cognition, education and socioeconomic position (model 3); model 3 + smoking, exercise, alcohol intake, blood pressure and diet (model 4).After correcting for multiple tests, we identified 155 metabolites, 10 pathways and 5 modules to show relationships with cognitive outcomes. Thirty-five metabolites were influential in their module and identified in single-metabolite analyses. Notably, we report independent relationships between a module comprised of acylcarnitines and processing speed, revealing palmitoylcarnitine (C16) as a key driver of associations (model 4: ß = −0.10, 95%CI = −0.15 to −0.052). Two modules demonstrated associations with several cognitive outcomes that were partly explained by life course factors: one enriched in modified nucleosides and amino acids (ß range (model 1) = −0.12 to −0.09, attenuation (model 4)= 39.2 to 55.5%), and another in vitamin A and C metabolites (ß range (model 1) = 0.11 to 0.23, attenuation (model 4) = 68.6 to 92.6%). Our other findings, including a module enriched in sphingolipid pathways (ß range (model 1) = 0.085 to 0.10, attenuation (model 4) = 87.0 to 116%), were entirely explained by life course factors particularly childhood cognition and education. The limitations of this study include those commonly seen with population-based cohorts, such as possible residual confounding and generalisability to other populations, as well as a lack of longitudinal metabolite data.ConclusionsUsing a large birth cohort study with information across the life course, we highlighted potential metabolic mechanisms underlying cognitive function in late midlife, suggesting marker candidates and life course relationships for further study.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Metabolic correlates of late midlife cognitive function: findings from the 1946 British Birth Cohort

Green

Lord

et al. 2020

Preprint

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“…Many previous reports have suggested that dietary PLs such as PC, PS, and SM are critical to maintain brain development and cognitive performance 12,41,42 . These lipids contain two fatty acids that are ester-linked to glycerol at sn-1 and sn-2, and a polar head group that is held at sn-3 by a phosphodiesterase bond 43 .…”

Section: Discussionmentioning

confidence: 99%

Porcine liver decomposition product-derived lysophospholipids promote microglial activation in vitro

Tsukahara

Haniu

Uemura

et al. 2020

Sci Rep

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cognitive impairments such as dementia are common in later life, and have been suggested to occur via a range of mechanisms, including oxidative stress, age-related changes to cellular metabolism, and a loss of phospholipids (pLs) from neuronal membranes. pLs are a class of amphipathic lipids that form plasma membrane lipid bilayers, and that occur at high concentrations in neuronal membranes. our previous study suggested that a porcine liver decomposition product (pLDp) produced via protease treatment may improve cognitive function at older ages, by acting as a rich source of pLs and lysophospholipids (LPLs); however, its specific composition remains unclear. Thus, the present study used a novel liquid chromatography electrospray ionization tandem mass spectrometric (Lc-MS/MS) protocol to identify the major PLs and LPLs in PLDP. Furthermore, it assessed the effect of identified LPLs on microglial activation in vitro, including cell shape, proliferation, and cell morphology. the results of the conducted analyses showed that pLDp and pLDp-derived LpLs concentrationdependently modulate microglial activation in vitro. in particular, lysophosphatidylcholine (Lpc) concentration-dependently promotes cell morphology, likely via effects mediated by the enzyme autotaxin (AtX), since inhibiting AtX also promoted cell morphology, while conversely, increasing AtX production (via treatment with high levels of LPC) abolished this effect. These findings suggest that Lpc is likely neuroprotective, and thus, support the importance of further research to assess its use as a therapeutic target to treat age-related cognitive impairments, including dementia.Rapid population aging and age-related disease represent an increasing global health-care burden. Dementias are the most common cause of significant late-onset cognitive decline, and affect approximately 50 million people worldwide, with nearly 10 million new cases diagnosed annually 1 . There are many different forms of dementia; for example, Alzheimer's disease is the most common form, and contributes to 60-70% of cases. Other major forms include vascular and Lewy body dementia, and a group of diseases that together comprise frontotemporal dementia 2 . Patients with mild cognitive impairment (MCI) are at risk of developing dementia; however, in some individuals, MCI reverts to normal cognition or remains stable. While clinical studies are currently being conducted to identify novel treatments to improve symptoms and/or prevent or delay the progression of MCI to dementia, no drugs or other treatments have yet been specifically approved for MCI. Lipids are increasingly recognized for their roles in neuronal function in the brain 3,4 ; for example, the lipid fraction of mammalian membranes consists of glycerophospholipids, sphingolipids, and cholesterol 4 . We previously reported that a porcine liver decomposition product (PLDP) induces a significant increase in the Hasegawa's Dementia Scale-Revised (HDS-R) score in a randomized, double-blind, placebo-controlled study in healthy hu...

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“…postsynaptic excitability or cortical gain ( Geisler and Albrecht, 1992 ; Abbott et al , 1997 ; Pi et al , 2013 ; Kanai et al., 2015 ; Mongillo et al , 2018 ). There is great interest in these neuroplastic changes because they are reminiscent of the critical period in brain development ( Schneider et al , 2019 ) and offer a potential target for interventions to promote and facilitate recovery after brain damage ( Starkstein and Robinson, 1997 ). Multiple factors may alter excitatory–inhibitory balance in perilesional tissue and enable repair ( Bansal et al , 2019 ) including changes in the uptake of neurotransmitters such as glutamate and serotonin and the release of growth factors that promote axonal sprouting in the first 2 or 3 weeks after damage.…”

Section: Introductionmentioning

confidence: 99%

Paradoxical lesions, plasticity and active inference

Sajid

Parr

Gajardo-Vidal

et al. 2020

Brain Communications

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Paradoxical lesions are secondary brain lesions that ameliorate functional deficits caused by the initial insult. This effect has been explained in several ways; particularly by the reduction of functional inhibition, or by increases in the excitatory-to-inhibitory synaptic balance within perilesional tissue. In this article, we simulate how and when a modification of the excitatory-inhibitory balance triggers the reversal of a functional deficit caused by a primary lesion. For this, we introduce in-silico lesions to an active inference model of auditory word repetition. The first in-silico lesion simulated damage to the extrinsic (between region) connectivity causing a functional deficit that did not fully resolve over 100 trials of a word repetition task. The second lesion was implemented in the intrinsic (within region) connectivity, compromising the model’s ability to rebalance excitatory-inhibitory connections during learning. We found that when the second lesion was mild, there was an increase in experience-dependent plasticity that enhanced performance relative to a single lesion. This paradoxical lesion effect disappeared when the second lesion was more severe because plasticity-related changes were disproportionately amplified in the intrinsic connectivity, relative to lesioned extrinsic connections. Finally, this framework was used to predict the physiological correlates of paradoxical lesions. This formal approach provides new insights into the computational and neurophysiological mechanisms that allow some patients to recover after large or multiple lesions.

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Sphingomyelin in Brain and Cognitive Development: Preliminary Data

Cited by 95 publications

References 48 publications

Metabolic correlates of late midlife cognitive function: findings from the 1946 British Birth Cohort

Metabolic correlates of late midlife cognitive function: findings from the 1946 British Birth Cohort

Porcine liver decomposition product-derived lysophospholipids promote microglial activation in vitro

Paradoxical lesions, plasticity and active inference

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