Value of serum nonceruloplasmin copper for prediction of mild cognitive impairment conversion to Alzheimer disease
Corresponding Author
Rosanna Squitti PhD
Department of Neuroscience, Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome
Laboratory of Neurodegeneration, IRCCS “San Raffaele Pisana”, Rome
Address correspondence to Dr Squitti, Department of Neuroscience, AFaR-Osp. Fatebenefratelli, 00186, Rome, Italy. E-mail [email protected]Search for more papers by this authorRoberta Ghidoni PhD
Proteomics Unit, IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli, Brescia
Search for more papers by this authorMariacristina Siotto PhD
Don Carlo Gnocchi Foundation, ONLUS, Milan
Search for more papers by this authorMariacarla Ventriglia PhD
Department of Neuroscience, Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome
Search for more papers by this authorLuisa Benussi PhD
NeuroBioGen Laboratory–Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli, Brescia
Search for more papers by this authorAnna Paterlini PhD
Proteomics Unit, IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli, Brescia
Search for more papers by this authorMariachiara Magri PhD
Medical Statistics and Information Technology, Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome
Search for more papers by this authorGiuliano Binetti MD
NeuroBioGen Laboratory–Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli, Brescia
Search for more papers by this authorEmanuele Cassetta MD
Department of Neuroscience, Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome
Search for more papers by this authorDeborah Caprara PhD
Department of Neuroscience, Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome
Search for more papers by this authorFabrizio Vernieri MD
Department of Neurology, University “Campus Biomedico,”, Rome
Search for more papers by this authorPaolo M. Rossini MD
IRCCS “San Raffaele Pisana”, Rome
Institute of Neurology, Catholic University, Rome
Search for more papers by this authorPatrizio Pasqualetti PhD
Medical Statistics and Information Technology, Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome
Unit of Clinical and Molecular Epidemiology, IRCCS “San Raffaele Pisana”, Rome, Italy
Search for more papers by this authorCorresponding Author
Rosanna Squitti PhD
Department of Neuroscience, Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome
Laboratory of Neurodegeneration, IRCCS “San Raffaele Pisana”, Rome
Address correspondence to Dr Squitti, Department of Neuroscience, AFaR-Osp. Fatebenefratelli, 00186, Rome, Italy. E-mail [email protected]Search for more papers by this authorRoberta Ghidoni PhD
Proteomics Unit, IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli, Brescia
Search for more papers by this authorMariacristina Siotto PhD
Don Carlo Gnocchi Foundation, ONLUS, Milan
Search for more papers by this authorMariacarla Ventriglia PhD
Department of Neuroscience, Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome
Search for more papers by this authorLuisa Benussi PhD
NeuroBioGen Laboratory–Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli, Brescia
Search for more papers by this authorAnna Paterlini PhD
Proteomics Unit, IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli, Brescia
Search for more papers by this authorMariachiara Magri PhD
Medical Statistics and Information Technology, Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome
Search for more papers by this authorGiuliano Binetti MD
NeuroBioGen Laboratory–Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli, Brescia
Search for more papers by this authorEmanuele Cassetta MD
Department of Neuroscience, Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome
Search for more papers by this authorDeborah Caprara PhD
Department of Neuroscience, Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome
Search for more papers by this authorFabrizio Vernieri MD
Department of Neurology, University “Campus Biomedico,”, Rome
Search for more papers by this authorPaolo M. Rossini MD
IRCCS “San Raffaele Pisana”, Rome
Institute of Neurology, Catholic University, Rome
Search for more papers by this authorPatrizio Pasqualetti PhD
Medical Statistics and Information Technology, Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome
Unit of Clinical and Molecular Epidemiology, IRCCS “San Raffaele Pisana”, Rome, Italy
Search for more papers by this authorAbstract
Objective
Meta-analyses show that nonbound ceruloplasmin (non-Cp) copper (also known as free or labile copper) in serum is higher in patients with Alzheimer disease (AD). It differentiates subjects with mild cognitive impairment (MCI) from healthy controls. However, a longitudinal study on an MCI cohort has not yet been performed to assess the accuracy of non-Cp copper for the prediction of conversion from MCI to AD during a long-term follow-up.
Methods
The study included 42 MCI converters and 99 stable MCI subjects. We assessed levels of copper, ceruloplasmin, non-Cp copper, iron, transferrin, ferritin, and APOE genotype. A multiple Cox regression analysis—with age, sex, baseline Mini-Mental State Examination, APOE4, iron, non-Cp copper, transferrin, ferritin, hypercholesterolemia, and hypertension as covariates—was applied to predict the conversion from MCI to AD.
Results
Among the evaluated parameters, the only significant predictor of conversion to AD was non-Cp copper (hazard ratio = 1.23, 95% confidence interval = 1.03–1.47, p = 0.022); for each additional micromole per liter unit (μmol/l) of non-Cp copper, the hazard increased by ∼20%. Subjects with non-Cp copper levels >1.6μmol/l had a hazard conversion rate (50% of conversion in 4 years) that was ∼3× higher than those with values ≤1.6μmol/l (<20% in 4 years). The rate of conversion was similar between APOE4 carriers and noncarriers (p = 0.321), indicating that the non-Cp copper association was independent of APOE4.
Interpretation
Non-Cp copper appears to predict conversion from MCI to AD. These results encourage healthy life style choices and dietary intervention to modify this risk. ANN NEUROL 2014;75:574–580
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