Chair: Anna Członkowska (Institute of Psychiatry and Neurology, Warsaw, Poland) and Susan Gaskin (Institute of Psychiatry and Neurology, McGill University, Montreal, Canada)

Symposium 5: Copper in the brain

Copper is essential for all living organisms, however an excessive exposure or a deficiency may lead to adverse effects on human health. A copper imbalance may be caused by environmental factors, but there are also several mainly genetic diseases, in which impaired copper metabolism leading to brain injury.


Anna Czlonkowska, Institute of Psychiatry and Neurology, Warsaw, Poland

Wilson Disease – genetics, clinic, diagnosis and treatment

Wilson Disease is a rare autosomal recessive disorder (30-50 cases per million) caused by mutation(s) in the ATP7B gene. Impaired function of the ATPase in liver cells leads to impaired incorporation of copper onto ceruloplasmin and its excretion in the bile, leading to accumulation primarily in the liver and the brain. Clinical symptoms are highly variable in age of onset, dominant organ symptoms and their intensity. Diagnosis is based on clinical signs (hepatic, neurological, psychiatric), measurement of serum ceruloplasmin, urine copper excretion and mutation analysis of ATP7B. Pre-symptomatic diagnosis is possible. Copper depleting treatment (chelation or inhibition of copper absorption) is successful, but must be lifelong. Gene therapy is under development.

References:
1. Roberts EA, et al. Current and Emerging Issues in Wilson’s Disease. N Eng J Med., 2023. doi: 10.1056/NEJMra1903585
2. Czlonkowska A, et al. Seven decades of clinical experience with Wilson’s disease: Report from the national reference centre in Poland. Eur J Neurol, 2022. doi: 10.1111/ene.15646


Susan Gaskin, Ph.D., Eng., McGill University, Montreal, Canada

Copper toxicity in the brain – exposure, mechanisms and manifestations

Copper toxicity disrupts normal brain function through catecholamine imbalance, abnormal myelination of neurons and loss of normal brain architecture, manifesting in a wide spectrum of neurologic and/or psychiatric symptoms1. In the brain, copper is tightly regulated to prevent oxidative stress, which decreases neuronal viability by disrupting signalling pathways regulating the regeneration, survival and repair of neurons. Increased copper enters the brain via the endothelial cell layer of the blood-brain-barrier, which is vulnerable to impaired mitochondrial respiration from cuprotosis, resulting in leakiness even at modest circulating labile copper levels2. The latter can result from environmental exposure via ingestion of copper salts, e.g. pesticide residues, absorbed directly into the blood stream.

References:
1. Lutsenko S, et al. Copper and the brain noradrenergic system. J Biol Inorg Chem., 2019. doi: 10.1007/s00775-019-01737-3.
2. Borchard S, et al. The exceptional sensitivity of brain mitochondria to copper. Toxicology in vitro, 2018 doi: 10.1016/j.tiv.2018.04.012


Tomasz Litwin, MD, Ph.D., Institute of Psychiatry and Neurology, Warsaw, Poland

Copper and other neurological disorders

Copper, a trace element, is an essential a cofactor for many cuproenzymes involved in neuronal development, myelination, neurotransmitter synthesis, oxidative metabolism and antioxidant defense (e.g. cytochrome C oxidase, superoxide dismutase and dopamine-beta hydroxylase)1.

Wilson’s disease, the best-known disorder of copper metabolism, has pathological copper accumulation in different organ systems2. Other less frequent neurodegenerative disorders with copper metabolism disturbances, falling within the broad range of Wilson’s disease phenotypes, include Menkes disease, Mednik disease, apoceruloplasminemia (with copper and iron metabolism disturbances), Huppke-Brendel syndrome, MDR3 deficiency, manganese transport defects and congenital glycosylation disorders1,2. These syndromes document how aspects of copper metabolism may be altered, other than the defect in ATP7B of Wilson’s disease2.

References:
1. Gale J, et al. The physiological and pathophysiological roles of copper in the nervous system. Eur J Neurosci., 2024. doi: 10.1111/ejn.16370
2. Bandmann O, et al. Wilson’s disease and other neurological copper disorders. Lancet Neurology, 2015. doi: 10.1016/S1474-4422(14)70190-5


Petr Dusek, MD, Ph.D., Charles University and General University Hospital in Prague, Prague, Czech Republik

Neuroimaging of copper disorders

Neuroimaging techniques, including MRI and PET scans, are valuable tools for studying brain changes in disorders associated with abnormal copper metabolism, such as Wilson’s disease. Neuropathology in these disorders often includes demyelination, gliosis, basal ganglia lesions, white matter abnormalities, and atrophy, all of which can be detected on structural MRI1. Concomitant abnormalities of other metals are common. Advanced techniques like diffusion tensor imaging (DTI) and spectroscopy further reveal microstructural damage and metabolic disruptions. PET imaging, using radiolabeled copper isotopes such as 64Cu, allows researchers to visualize copper uptake, distribution, and clearance in the brain over time2. Neuroimaging is instrumental in understanding the pathophysiology of copper disorders, monitoring disease progression, and assessing the efficacy of treatments.

References:
1. Dusek P, et al. Semiquantitative Scale for Assessing Brain MRI Abnormalities in Wilson Disease: A Validation Study. Mov Disord., 2020. doi: 10.1002/mds.28018
2. Munk DE, et al. Distribution of non-ceruloplasmin-bound copper after i.v. 64Cu injection studied with PET/CT in patients with Wilson disease. JHEP Rep., 2023. doi: 10.1016/j.jhepr.2023.100916

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