Genomics and CSF analyses implicate thyroid hormone in hippocampal sclerosis of aging.
We report evidence of a novel pathogenetic mechanism in which thyroid hormone dysregulation contributes to dementia in elderly persons. Two single nucleotide polymorphisms (SNPs) on chromosome 12p12 were the initial foci of our study: rs704180 and rs73069071. These SNPs were identified by separate research groups as risk alleles for non-Alzheimer's neurodegeneration. We found that the rs73069071 risk genotype was associated with hippocampal sclerosis (HS) pathology among people with the rs704180 risk genotype (National Alzheimer's Coordinating Center/Alzheimer's Disease Genetic Consortium data; n = 2113, including 241 autopsy-confirmed HS cases). Furthermore, both rs704180 and rs73069071 risk genotypes were associated with widespread brain atrophy visualized by MRI (Alzheimer's Disease Neuroimaging Initiative data; n = 1239). In human brain samples from the Braineac database, both rs704180 and rs73069071 risk genotypes were associated with variation in expression of ABCC9, a gene which encodes a metabolic sensor protein in astrocytes. The rs73069071 risk genotype was also associated with altered expression of a nearby astrocyte-expressed gene, SLCO1C1. Analyses of human brain gene expression databases indicated that the chromosome 12p12 locus may regulate particular astrocyte-expressed genes induced by the active form of thyroid hormone, triiodothyronine (T3). This is informative biologically, because the SLCO1C1 protein transports thyroid hormone into astrocytes from blood. Guided by the genomic data, we tested the hypothesis that altered thyroid hormone levels could be detected in cerebrospinal fluid (CSF) obtained from persons with HS pathology. Total T3 levels in CSF were elevated in HS cases (p < 0.04 in two separately analyzed groups), but not in Alzheimer's disease cases, relative to controls. No change was detected in the serum levels of thyroid hormone (T3 or T4) in a subsample of HS cases prior to death. We conclude that brain thyroid hormone perturbation is a potential pathogenetic factor in HS that may also provide the basis for a novel CSF-based clinical biomarker.
University of Kentucky, Lexington, KY, USA. pnels2@email.uky.edu.
Peter T
PT
Nelson
University of Kentucky, Lexington, KY, USA.
Yuriko
Y
Katsumata
University of Indiana, Indianapolis, IN, USA.
Kwangsik
K
Nho
University of Kentucky, Lexington, KY, USA.
Sergey C
SC
Artiushin
University of Kentucky, Lexington, KY, USA.
Gregory A
GA
Jicha
University of Kentucky, Lexington, KY, USA.
Wang-Xia
WX
Wang
University of Kentucky, Lexington, KY, USA.
Erin L
EL
Abner
University of Indiana, Indianapolis, IN, USA.
Andrew J
AJ
Saykin
University of Washington, Seattle, WA, USA.
Walter A
WA
Kukull
University of Kentucky, Lexington, KY, USA.
David W
DW
Fardo
D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D023281:Genomics / Q000379:methods*; D005838:Genotype; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D027361:Organic Anion Transporters / Q000134:cerebrospinal fluid / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012598:Sclerosis / Q000209:etiology; D064233:Sulfonylurea Receptors / Q000235:genetics / Q000378:metabolism; D014284:Triiodothyronine / Q000097:blood / Q000134:cerebrospinal fluid*
C577510:ABCC9 protein, human; D027361:Organic Anion Transporters; C503526:SLCO2A1 protein, human; D064233:Sulfonylurea Receptors; D014284:Triiodothyronine
Braineac; CARTS; HS-Aging; KATP; SUR2; TDP-43