Type 2 diabetes mellitus and biomarkers of neurodegeneration.
OBJECTIVE
Our objective was to investigate whether type 2 diabetes mellitus (T2DM) influences neurodegeneration in a manner similar to Alzheimer disease (AD), by promoting brain β-amyloid (Aβ) or tau.


METHODS
We studied the cross-sectional associations of T2DM with cortical thickness, brain Aβ load, and CSF levels of Aβ and tau in a sample of people from the Alzheimer's Disease Neuroimaging Initiative with diagnoses of AD dementia, mild cognitive impairment, and normal cognition. All (n=816) received MRI, and a subsample underwent brain amyloid imaging (n=102) and CSF Aβ and tau measurements (n=415). Analyses were performed across and within cognitive diagnostic strata.


RESULTS
There were 124 people with T2DM (mean age 75.5 years) and 692 without T2DM (mean age 74.1 years). After adjusting for age, sex, total intracranial volume, APO ε4 status, and cognitive diagnosis, T2DM was associated with lower bilateral frontal and parietal cortical thickness (mL) (β=-0.03, p=0.01). T2DM was not associated with 11C Pittsburgh compound B standardized uptake value ratio (AU) in any brain region or with CSF Aβ42 levels (pg/mL). T2DM was associated with greater CSF total tau (pg/mL) (β=16.06, p=0.04) and phosphorylated tau (β=5.84, p=0.02). The association between T2DM and cortical thickness was attenuated by 15% by the inclusion of phosphorylated tau.


CONCLUSIONS
T2DM may promote neurodegeneration independent of AD dementia diagnosis, and its effect may be driven by tau phosphorylation. The mechanisms through which T2DM may promote tau phosphorylation deserve further study.
From the Stroke and Ageing Research Group (C.M., T.G.P., V.S.), Vascular Brain Ageing Division, Department of Medicine, School of Clinical Sciences, Monash University, Melbourne; Neurosciences (C.M., T.G.P., V.S.), Monash Medical Centre, Monash Health, Melbourne; Caulfield General Medical Centre (C.M.), Alfred Health, Melbourne; Developmental Imaging (R.B.), Murdoch Children's Research Institute, Melbourne; School of Medicine and Pharmacology (D.G.B.), Fremantle Hospital, University of Western Australia; and Menzies Research Institute Tasmania (M.L.C., V.S.), University of Tasmania, Hobart, Australia.
Chris
C
Moran
From the Stroke and Ageing Research Group (C.M., T.G.P., V.S.), Vascular Brain Ageing Division, Department of Medicine, School of Clinical Sciences, Monash University, Melbourne; Neurosciences (C.M., T.G.P., V.S.), Monash Medical Centre, Monash Health, Melbourne; Caulfield General Medical Centre (C.M.), Alfred Health, Melbourne; Developmental Imaging (R.B.), Murdoch Children's Research Institute, Melbourne; School of Medicine and Pharmacology (D.G.B.), Fremantle Hospital, University of Western Australia; and Menzies Research Institute Tasmania (M.L.C., V.S.), University of Tasmania, Hobart, Australia.
Richard
R
Beare
From the Stroke and Ageing Research Group (C.M., T.G.P., V.S.), Vascular Brain Ageing Division, Department of Medicine, School of Clinical Sciences, Monash University, Melbourne; Neurosciences (C.M., T.G.P., V.S.), Monash Medical Centre, Monash Health, Melbourne; Caulfield General Medical Centre (C.M.), Alfred Health, Melbourne; Developmental Imaging (R.B.), Murdoch Children's Research Institute, Melbourne; School of Medicine and Pharmacology (D.G.B.), Fremantle Hospital, University of Western Australia; and Menzies Research Institute Tasmania (M.L.C., V.S.), University of Tasmania, Hobart, Australia.
Thanh G
TG
Phan
From the Stroke and Ageing Research Group (C.M., T.G.P., V.S.), Vascular Brain Ageing Division, Department of Medicine, School of Clinical Sciences, Monash University, Melbourne; Neurosciences (C.M., T.G.P., V.S.), Monash Medical Centre, Monash Health, Melbourne; Caulfield General Medical Centre (C.M.), Alfred Health, Melbourne; Developmental Imaging (R.B.), Murdoch Children's Research Institute, Melbourne; School of Medicine and Pharmacology (D.G.B.), Fremantle Hospital, University of Western Australia; and Menzies Research Institute Tasmania (M.L.C., V.S.), University of Tasmania, Hobart, Australia.
David G
DG
Bruce
From the Stroke and Ageing Research Group (C.M., T.G.P., V.S.), Vascular Brain Ageing Division, Department of Medicine, School of Clinical Sciences, Monash University, Melbourne; Neurosciences (C.M., T.G.P., V.S.), Monash Medical Centre, Monash Health, Melbourne; Caulfield General Medical Centre (C.M.), Alfred Health, Melbourne; Developmental Imaging (R.B.), Murdoch Children's Research Institute, Melbourne; School of Medicine and Pharmacology (D.G.B.), Fremantle Hospital, University of Western Australia; and Menzies Research Institute Tasmania (M.L.C., V.S.), University of Tasmania, Hobart, Australia.
Michele L
ML
Callisaya
From the Stroke and Ageing Research Group (C.M., T.G.P., V.S.), Vascular Brain Ageing Division, Department of Medicine, School of Clinical Sciences, Monash University, Melbourne; Neurosciences (C.M., T.G.P., V.S.), Monash Medical Centre, Monash Health, Melbourne; Caulfield General Medical Centre (C.M.), Alfred Health, Melbourne; Developmental Imaging (R.B.), Murdoch Children's Research Institute, Melbourne; School of Medicine and Pharmacology (D.G.B.), Fremantle Hospital, University of Western Australia; and Menzies Research Institute Tasmania (M.L.C., V.S.), University of Tasmania, Hobart, Australia. velandai.srikanth@monash.edu.
Velandai
V
Srikanth
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism; D015415:Biomarkers / Q000134:cerebrospinal fluid / Q000378:metabolism; D002540:Cerebral Cortex / Q000473:pathology*; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000473:pathology; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D016875:tau Proteins / Q000134:cerebrospinal fluid / Q000378:metabolism
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D016875:tau Proteins