Objective: To provide an overview of brain regions involved in cognitive impairment (CI) in Wilson disease (WD) with the aim of understanding pathomechanisms.

Background: WD patients frequently show mild to moderate CI in multiple domains, e.g., memory and attention. However, knowledge about underlying neural mechanisms is limited.

Method: A systematic review was conducted by searching electronic databases. All studies investigating correlations between CI and neuroimaging abnormalities in WD were included. A total of eight articles were reviewed as, to date, evidence is sparse.

Results: CI was associated with the severity of T2 hyperintense lesions in the entire brain [1] and in the globus pallidus [2]. Furthermore, a positive relation between signal changes in the putamen and the amount of affected cognitive domains was observed [3]. Thus, basal ganglia (BG) abnormalities might play a crucial role in memory deficits, although patients with multifocal cortico-subcortical pathologies tend to exhibit more severe CI [4]. Multimodal neuroimaging studies found no direct influence of grey matter (GM) atrophy [5]. Instead, neural circuits from the atrophic BG to the right orbitofrontal gyrus (ORB) were found to contribute to prospective memory (PM) deficits, with reduced cortical thickness of the ORB operating as a promising neural biomarker [6]. PM was further associated with decreased functional connectivity (FC) between atrophic CH4 cells of the basal forebrain (BF) and the ORB, indicating an indirect relation between PM dysfunction and degenerative changes of BF [7]. Moreover, an indirect effect of increased GM volume of the visual association cortex (VAC1) on global cognitive dysfunction is reported due to disturbed FC of VAC1 with left thalamus and hippocampus [5]. There is also evidence for a relation between abnormal white matter changes, e.g., in association fibers, and PM, verbal intelligence, and memory speed [5, 8]. Scientific merit of the included studies varied greatly. Main limitations were small sample sizes (median n = 21), exclusive use of descriptive statistics (25%), partly missing control group data (75%), and lack of diversity of CI studied.

Conclusion: The involvement of cortical and subcortical brain regions in CI in WD seems to be manifold. Further research with more comprehensive neuroimaging and neuropsychological testing is needed.

References: [1] Frota, N. A. F., Barbosa, E. R., Porto, C. S., Lucato, L. T., Ono, C. R., Buchpiguel, C. A., & Caramelli, P. (2013). Cognitive impairment and magnetic resonance imaging correlations in Wilson’s disease. Acra Neurologica Scandinavia, 127, 391-398. doi: 10.1111/ane.12037.
[2] Frota, N. A. F., Barbosa, E. R., Porto, C. S., Lucato, L. T., Ono, C. A., Buchpiguel, C. A., Machado, A. A. C., & Caramelli, P. (2016). Which factors are associated with global cognitive impairment in Wilson’s disease? Dementia & Neuropsychologica, 10(4), 320-326. doi: 10.1590/s1980-5764-2016dn1004011.
[3] Hedge, S., Sinha, S., Raio, S. L., Taly, A. B., & Vasudev, M. K. (2010). Cognitive profile and structural findings in Wilson’s disease: A neuropsychological and MRI-based study. Neurology India, 58(5), 708-713. doi: 10.4103/0028-3886.72172.
[4] Seniów, J., Bak, T., Gajda, J., Poniatowska , R., & Czlonkowska, A. (2002). Cognitive functioning in neurologically symptomatic and asymptomatic forms of Wilson’s disease. Movement Disorders, 17(5), 1077-1083. doi: 10.1002/mds.10195.
[5] Hu, S., Xu, C., Dong, T., Wu, H., Wang, Y., Wang, A., Kan, H., & Li, C. (2021). Structural and functional changes are related to cognitive status in Wilson’s disease. Frontiers in Human Neuroscience, 15, 610947. doi: 10.3389/fnhum.2021.610947.
[6] Hu, S., Xu, C., Wang, Y., Dong, T., Wu, H., Wang, A., Li, C., & Qiu, B. (2022). Basal ganglia-orbitofrontal circuits are associated with prospective memory deficits in Wilson’s disease. Brain Imaging and Behavior, 16:141-150. doi: 10.1007/s11682-021-00485-w.
[7] Wu, Y., Hu, S., Wang, Y., Dong, T., Hongli, W., Zhang, Y., Qu, Q., Wang, A., Yang, Y., & Li, C. (2020). The degeneration changes of basal forebrain are associated with prospective memory impairment in patients with Wilson’s disease. Brain and Behavior, 11:e2239. doi: 10.1002/brb3.2239
[8] Dong, E., Yang, W., Wu, M., Zhang, J., Huang, P., Xu, C., Wang, A., Kuang, C., & Gao, Z. (2019). Microstructure changes in white matter relate to cognitive impairment in Wilson’s disease. Bioscience Reports, 39, BSR20181651. doi: 10.1042/BSR20181651.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/correlations-between-cognitive-impairments-and-brain-abnormalities-in-wilson-disease-a-systematic-review/