Grazia Daniela Femminella1, Nicholas R Livingston1, Sanara Raza1, Thalia van der Doef1, Eleni Frangou2, Sharon Love2, Gail Busza1, Valeria Calsolaro1, Stefan Carver1, Clive Holmes3, Craig W Ritchie4, Robert M Lawrence5, Brady McFarlane6, George Tadros7, Basil H Ridha8, Carol Bannister9, Zuzana Walker10, Hilary Archer11, Elizabeth Coulthard11, Ben Underwood12, Aparna Prasanna13, Paul Koranteng14, Salman Karim15, Kehinde Junaid16, Bernadette McGuinness17, Anthony Peter Passmore17, Ramin Nilforooshan18, Ajayverma Macharouthu19, Andrew Donaldson20, Simon Thacker21, Gregor Russell22, Naghma Malik23, Vandana Mate24, Lucy Knight25, Sajeev Kshemendran26, Tricia Tan1, Christian Holscher27, John Harrison28, David J Brooks29, Clive Ballard30, Paul Edison31. 1. Division of Neurology, Neurology Imaging Unit, Department of Brain Sciences, Imperial College London, 1st Floor B Block, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK. 2. University of Oxford, Oxford, UK. 3. University of Southampton, Southampton, UK. 4. University of Edinburgh, Edinburgh, UK. 5. South West London and St George's Mental Health NHS Trust, London, UK. 6. Southern Health NHS Foundation Trust, Southampton, UK. 7. Heart of England NHS Foundation Trust, Birmingham, UK. 8. Brighton and Sussex University Hospital Trust, Brighton, UK. 9. King's College London, London, UK. 10. Mental Health Unit, St. Margaret's Hospital, Epping, Essex, UK. 11. North Bristol NHS Trust, Bristol, UK. 12. Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK. 13. Black Country Partnership NHS Foundation Trust, Wolverhampton, UK. 14. Northamptonshire Healthcare NHS Foundation Trust, Northampton, UK. 15. Lancashire Care NHS Foundation Trust, Preston, UK. 16. Nottinghamshire Healthcare NHS Foundation Trust, Nottingham, UK. 17. Queen's University Belfast, Belfast, UK. 18. Surrey and Borders Partnership NHS Foundation Trust, Chertsey, UK. 19. NHS Ayrshire and Arran, Kilmarnock, UK. 20. NHS Lanarkshire, Airdrie, UK. 21. Derbyshire Healthcare NHS Foundation Trust, Derby, UK. 22. Bradford District Care NHS Foundation Trust, Bradford, UK. 23. North West Boroughs Partnership NHS Foundation Trust, Warrington, UK. 24. Cornwall Partnership NHS Foundation Trust, Redruth, UK. 25. Somerset Partnership NHS Foundation Trust, South Petherton, UK. 26. South Staffordshire and Shropshire Healthcare NHS Foundation Trust, Shrewsbury, UK. 27. Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, China. 28. Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands. 29. Newcastle University, Newcastle upon Tyne, UK. 30. University of Exeter Medical School, Exeter, UK. 31. Division of Neurology, Neurology Imaging Unit, Department of Brain Sciences, Imperial College London, 1st Floor B Block, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK. paul.edison@imperial.ac.uk.
Abstract
BACKGROUND: Type 2 diabetes is a risk factor for Alzheimer's disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabetic patients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter lesions (WMLs) in non-diabetic AD subjects. METHODS: In total, 130 non-diabetic AD subjects underwent MRI and [18F]FDG PET scans with arterial cannula insertion for radioactivity measurement. T1 Volumetric and FLAIR sequences were acquired on a 3-T MRI scanner. These subjects also had measurement of glucose and insulin levels after a 4-h fast on the same day of the scan. Insulin resistance was calculated by the updated homeostatic model assessment (HOMA2). For [18F]FDG analysis, cerebral glucose metabolic rate (rCMRGlc) parametric images were generated using spectral analysis with arterial plasma input function. RESULTS: In this non-diabetic AD population, HOMA2 was negatively associated with hippocampal rCMRGlc, along with total grey matter volumes. No significant correlation was observed between HOMA2, hippocampal volume and WMLs. CONCLUSIONS: In non-diabetic AD, peripheral insulin resistance is independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, suggesting that peripheral insulin resistance might influence AD pathology by its action on cerebral glucose metabolism and on neurodegeneration.
BACKGROUND:Type 2 diabetes is a risk factor for Alzheimer's disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabeticpatients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter lesions (WMLs) in non-diabetic AD subjects. METHODS: In total, 130 non-diabetic AD subjects underwent MRI and [18F]FDG PET scans with arterial cannula insertion for radioactivity measurement. T1 Volumetric and FLAIR sequences were acquired on a 3-T MRI scanner. These subjects also had measurement of glucose and insulin levels after a 4-h fast on the same day of the scan. Insulin resistance was calculated by the updated homeostatic model assessment (HOMA2). For [18F]FDG analysis, cerebral glucose metabolic rate (rCMRGlc) parametric images were generated using spectral analysis with arterial plasma input function. RESULTS: In this non-diabetic AD population, HOMA2 was negatively associated with hippocampal rCMRGlc, along with total grey matter volumes. No significant correlation was observed between HOMA2, hippocampal volume and WMLs. CONCLUSIONS: In non-diabetic AD, peripheral insulin resistance is independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, suggesting that peripheral insulin resistance might influence AD pathology by its action on cerebral glucose metabolism and on neurodegeneration.
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