Brain metal accumulation in Wilson's disease

Abstract

Introduction

Brain metal accumulation is suggested in the pathogenesis of numerous neurodegenerative disorders. In Wilson's disease (WD), only copper has been examined. The aim of the present study was to evaluate the copper, iron, manganese, and zinc concentrations in autopsy tissue samples from the brains of WD patients.

Methods

The study material consisted of 17 brains (12 WD patients, 5 controls) obtained at autopsy. Samples were taken from four different regions of each brain: frontal cortex, putamen, pons, and nucleus dentatus. The copper, manganese, and zinc content were determined using inductively coupled plasma mass spectrometry, and iron was assessed using flame atomic absorption spectroscopy. The results were analyzed according to select clinical variables.

Results

Copper content was increased homogenously in all investigated structures of the WD brains compared to controls (41.0 ± 18.6 μg/g vs.5.4 ± 1.8 μg/g; P < 0.01). The mean concentrations of iron, manganese, and zinc were similar in WD and controls, but the iron level in the nucleus dentatus was higher in WD compared to controls (56.8 ± 14.1 μg/g vs. 32.6 ± 6.0 μg/g; P < 0.05). Gender, age, and type and duration of WD treatment did not impact brain metals storage, but some correlations between the duration of the disease and copper and iron accumulation were observed.

Conclusions

During the course of WD, copper accumulates equally in different parts of the brain. Zinc and manganese do not seem to be involved in WD pathology, but increased levels of iron were found in the nucleus dentatus. Thus, additional studies of brain iron accumulation in WD are needed.

Introduction

Wilson's disease (WD) is an inherited copper metabolism disorder with pathological copper accumulation in many tissues, but mainly the brain and liver, with secondary damage to affected organs [1], [2], [3]. The disorder is caused by impairment of the copper transporting ATPase, ATP7B, in the liver, which disturbs copper transport, excretion into the bile, and incorporation into apoceruloplasmin [1], [2], [3]. These disturbances lead to decreased levels of serum ceruloplasmin (Cp), which should also cause other metal metabolism pathways to be impaired, especially iron [4], [5], [6], based on the ferroxidase activity of Cp. However, this potential effect has not yet been examined in brains. Recently, the accumulation of metals, such as iron or manganese, in the brain and or brain zinc level disturbances were suggested as a factor that impacts the clinical presentation of many neurological disorders [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. Brain iron accumulation is postulated in the etiology of neurodegeneration with brain iron accumulation (NBIA), Parkinson's disease (PD), and multiple sclerosis (MS), among others. The main suggested pathological function of iron accumulation is involvement in reactive oxygen species (ROS) production and damage to mitochondrial oxidative metabolism [13], [14], [15], [16], [17]. Manganese deposition is found in the brains of WD patients with hepatic encephalopathy [18], [19] and in other neurodegenerative disorders with extrapyramidal signs/symptoms and liver cirrhosis resulting from manganese rather than copper transporter failure [14]. Finally, zinc has been suggested to play a role in the development of neuropsychiatric disorders. Low levels of this metal were found in depressive syndromes etiology. Overtoxicity may damage neurons and astrocytes and has been proposed in the etiology of many other neurodegenerative processes [15], [16]. According to magnetic resonance imaging (MRI) studies and transcranial brain sonography examinations of WD patients, trace elements other than copper, such as iron and manganese, may accumulate in the brain over the course of WD [18], [19], [20], but no neuropathological studies have analyzed them. Therefore, we hypothesized that brain metal accumulation could be an important factor modifying the phenotypic presentation of WD. Finding the accumulation of other metals in WD patients could change and improve therapies for the disease. The aim of this study was to evaluate the brain copper, iron, manganese, and zinc levels in WD patients compared to controls and the impact of selected clinical variables on brain metal storage.