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From the Bloomfield Centre for Research in Aging (Drs. Schipper, Chertkow, and Mehindate, and D. Frankel), Lady Davis Institute for Medical Research; the Departments of Clinical Neurosciences (Drs. Schipper, Chertkow, and Melmed) and Medicine, Division of Geriatrics (Drs. Schipper, Chertkow, and Bergman), Sir Mortimer B. Davis Jewish General Hospital, Montreal; the Department of Neurology and Neurosurgery (Drs. Schipper, Chertkow, and Melmed), McGill University, Montreal; and the Research Centre (Dr. Chertkow), Centre Hospitalier Côte-des-Neiges, Montreal, Canada.
Address correspondence and reprint requests to Dr. Hyman Schipper, Lady Davis Institute, Jewish General Hospital, 3755 Cote Ste. Catherine Road, Montreal, Quebec, Canada H3T 1E2.
BACKGROUND: Heme oxygenase-1 (HO-1) is a 32-kDa stress protein that catalyzes the degradation of heme to biliverdin. HO-1 immunoreactivity is greatly increased in neurons and astrocytes of the hippocampus and cerebral cortex of individuals with AD and colocalizes to senile plaques and neurofibrillary tangles.
METHODS: We investigated whether systemic HO-1 regulation is also deranged in AD patients and whether blood HO-1 measurements provide a peripheral biomarker of the disease. Plasma HO-1 protein levels were measured by competitive ELISA and lymphocyte HO-1 mRNA levels were determined by Northern analysis in patients with early probable sporadic AD, normal elderly controls (NEC), normal younger controls, individuals with age-associated cognitive decline (AACD) not meeting AD criteria, and patients with non-Alzheimer dementia, nondementing neurologic illness, and chronic medical disorders. CSF HO-1 protein concentrations were also determined by ELISA in pathologically confirmed AD and control cases.
RESULTS: Mean plasma HO-1 protein concentrations were significantly lower in AD patients (0.85 ± 0.14 µg/mL) compared with NEC (1.77 ± 0.34 µg/mL; p < 0.05) and control patients. The AACD group exhibited plasma HO-1 concentrations (1.06 ± 0.33 µg/mL) intermediate between, but not different from, those of the AD patients and NEC. Lymphocyte HO-1 mRNA levels were lower in the AD cohort relative to NEC (p < 0.001) and individuals with AACD, non-Alzheimer dementia, nondementing neurologic illness, and chronic medical conditions. Lymphocyte HO-1 mRNA levels were also lower in the AACD group relative to NEC (p < 0.05). In comparison with all groups excluding AACD, the sensitivity and specificity of lymphocyte HO-1 mRNA measurement for diagnosis of early sporadic AD are 88% and 75%. Mean CSF HO-1 protein concentrations were lower (p < 0.01) in AD cases (19.07 ng/mL) relative to control values (32.48 ng/mL).
CONCLUSIONS: Plasma and CSF HO-1 protein and lymphocyte HO-1 mRNA levels are decreased in subjects with sporadic AD. Quantitative assay for lymphocyte HO-1 mRNA expression may serve as a useful biologic marker in early sporadic AD.
Key words: Aging—AD—Biologic marker—Dementia—Diagnosis—Heme oxygenase-1.
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