Copper neurotoxicity: Induction of cognitive dysfunction: A review

Feng, Duan; Zhao, Yu; Li, Wei; Li, Xuechao; Wan, Jixiang; Wang, Fangjun

doi:10.1097/md.0000000000036375

Cited by 6 publications

(1 citation statement)

References 83 publications

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“…Moreover, Cox17 is involved in the delivery of copper ions to mitochondria [ 68 ]. Cox17 is generally considered a key factor in the maintenance of intracellular copper homeostasis, shuttling copper ions to Sco1/2 for subsequent incorporation into Cytochrome C Oxidase [ 69 ].…”

Section: Resultsmentioning

confidence: 99%

The Role of Copper Overload in Modulating Neuropsychiatric Symptoms

Manchia,

Paribello,

Pinna

et al. 2024

IJMS

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Copper is a transition metal essential for growth and development and indispensable for eukaryotic life. This metal is essential to neuronal function: its deficiency, as well as its overload have been associated with multiple neurodegenerative disorders such as Alzheimer’s disease and Wilson’s disease and psychiatric conditions such as schizophrenia, bipolar disorder, and major depressive disorders. Copper plays a fundamental role in the development and function of the human Central Nervous System (CNS), being a cofactor of multiple enzymes that play a key role in physiology during development. In this context, we thought it would be timely to summarize data on alterations in the metabolism of copper at the CNS level that might influence the development of neuropsychiatric symptoms. We present a non-systematic review with the study selection based on the authors’ judgement to offer the reader a perspective on the most significant elements of neuropsychiatric symptoms in Wilson’s disease. We highlight that Wilson’s disease is characterized by marked heterogeneity in clinical presentation among patients with the same mutation. This should motivate more research efforts to disentangle the role of environmental factors in modulating the expression of genetic predisposition to this disorder.

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Section: Resultsmentioning

confidence: 99%

The Role of Copper Overload in Modulating Neuropsychiatric Symptoms

Manchia,

Paribello,

Pinna

et al. 2024

IJMS

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Urinary Metal Levels, Cognitive Test Performance, and Dementia in the Multi-Ethnic Study of Atherosclerosis

Domingo-Relloso,

McGraw,

Heckbert

et al. 2024

JAMA Netw Open

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ImportanceMetals are established neurotoxicants, but evidence of their association with cognitive performance at low chronic exposure levels is limited.ObjectiveTo investigate the association of urinary metal levels, individually and as a mixture, with cognitive tests and dementia diagnosis, including effect modification by apolipoprotein ε4 allele (APOE4).Design, Setting, and ParticipantsThe multicenter prospective cohort Multi-Ethnic Study of Atherosclerosis (MESA) was started from July 2000 to August 2002, with follow-up through 2018. A total of 6303 MESA participants were included. Data analysis was performed from October 12, 2023, to June 13, 2024.ExposureUrine samples were collected at baseline (2000-2002), and arsenic, cadmium, cobalt, copper, lead, manganese, tungsten, uranium, and zinc levels were measured in 2020-2022.Main Outcomes and MeasuresDigit Symbol Coding (DSC) (n = 3819) (possible score range, 0-133), Cognitive Abilities Screening Instrument (CASI) (n = 3918) (possible score range, 0-100), and Digit Span (DS) (n = 4176) (possible score range, 0-30) cognitive tests were administered in 2010-2012; higher scores of each test indicate increasing levels of positive response.ResultsA total of 6303 participants were followed up for dementia diagnosis through 2018. The median age at baseline was 60 (IQR, 53-70) years, and 3303 participants (52.4%) were female. The median cognitive scores were 51 (IQR, 38-64) for DSC, 90 (IQR, 84-95) for CASI, and 15 (IQR, 12-18) for DS. There were 559 cases of dementia through the follow-up period. Inverse associations with DSC were identified: mean differences in z scores per IQR increase in metal levels were −0.03 (95% CI, −0.07 to 0.00) for arsenic, −0.05 (95% CI, −0.09 to −0.004) for cobalt, −0.05 (95% CI, −0.07 to −0.02) for copper, −0.04 (95% CI, −0.08 to −0.001) for uranium, and −0.03 (95% CI, −0.06 to −0.01) for zinc. Among 1058 APOE4 carriers, manganese was also inversely associated with DSC. The joint mean difference of DSC comparing percentile 95th with the 25th of the 9-metal mixture was −0.30 (95% CI, −0.47 to −0.14) for APOE4 carriers and −0.10 (95% CI, −0.19 to −0.01) for noncarriers. Arsenic, cadmium, cobalt, copper, tungsten, uranium, and zinc were individually associated with dementia, with hazard ratios per IQR of metal ranging from 1.15 (95% CI, 1.03-1.29) for tungsten to 1.46 (95% CI, 1.06-2.02) for uranium. The joint hazard ratio of dementia comparing percentiles 95th with the 25th of the 9-metal mixture was 1.71 (95% CI, 1.24-3.89), with no significant difference by APOE4 status.Conclusions and RelevanceIn this study, participants with higher concentrations of metals in their urine, compared with those with lower concentrations, had worse performance on cognitive tests and greater likelihood of developing dementia. The findings of this multicenter multiethnic cohort study might inform screening and potential interventions for prevention of dementia based on individuals’ metal exposure levels and genetic profiles.

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