Towards improved cognitive health: role of metabolomic guidance - - PowerPoint PPT Presentation

Host Institution

Towards improved cognitive health: role of metabolomic guidance

Garth J S Cooper Centre for Advanced Discovery & Experimental Therapeutics (CADET) University of Manchester

13-14 April 2016

Approach

Metabolomics

• Gas-chromatography mass-

spectrometry (GC-MS)

• Liquid-chromatography mass-

spectrometry (LC-MS) Proteomics (enzymes, transporters, structural proteins, etc.)

• Protein mass spectrometry

Metabolites

• Small metabolites
• Mass: 70 Da~300 Da
• N = ~50-90
• Structural Lipids etc
• Mass: ~100-700 Da
• N ~600-1000

Proteins (from peptide digests)

• Hundreds to several

thousands

Representative GC-MS metabolomic profile of human brain (entorhinal cortex)

Xu J…Cooper GJS Biochim Biophys Acta, 2016

Background

Metabolomics-based characterisation of complex metabolic states

Prediction of a complex metabolic disorder by metabolomic analysis of plasma

Yellow, preeclampsia; blue, control

Method now under development for entry into multi-centre trials in the UK for application in routine pregnancy screening

Plasma metabolomics identifies multiple defects in lipid regulation that occur prior to defective glucose regulation in diabetes

Brain metabolomics

Discovery of defects in common metabolic pathways as the probable cause of dementia in Alzheimer’s disease and Huntington’s disease: windows on cognitive health

Proteomics-based discovery of diabetes-like metabolic defects in Alzheimer’s brain

…and in Huntington’s brain

Metabolomic analysis of human brain identifies toxigenic urea levels as a probable cause of neurodegeneration in Huntington’s

Global GC-MS metabolomics identifies toxigenic elevations of glucose and polyol pathway intermediates in the putamen of Huntington’s brain

Patassini S…Cooper GJS 2016, in the press Note that the putamen is the region where neurodegeneration is thought to begin in HD brain

Severe elevation of polyol pathway metabolites in Alzheimer’s brain are at toxigenic levels

Metabolomic analysis of the peripheral nervous system in the diabetic rat

Freeman OJ…Cooper GJS, Gardiner N Diabetes, 2016

Human Alzheimer’s brain

Xu J…Cooper GJS Biochim Biophys Acta, 2016

Conclusions

• Metabolomic analysis of plasma can be used to predict onset and monitor

progression of complex metabolic disorders

• Common causes of dementia display toxigenic levels of well known

metabolites in brain regions known to undergo neurodegeneration in cognitive impairment

• These recently identified defects provide the probable cause of

neurodegeneration and dementia in Alzheimer’s disease and Huntington’s disease

• Relatively small delays in onset and progression may convey major benefit at

the population level

• The pathways implicated in cognitive impairment by metabolomic analysis are

well known to be amenable to nutritional/life-style modification and could serve as targets for focussed nutritional interventions aimed at improving cognitive health

• Development of nutritional interventions to address these recently discovered

mechanisms is encouraged