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. 2025 Jul 1;7(1):47.
doi: 10.1186/s42466-025-00401-3.

Atrophy related neuroimaging biomarkers for neurological and cognitive function in Wilson disease

Ann Carolin Hausmann  1 , Christian Rubbert  2 , Silja K Querbach  1 , Vivien Lorena Ivan  2 , Alfons Schnitzler  1   3 , Christian Johannes Hartmann  4   5 , Julian Caspers  2
Affiliations

Atrophy related neuroimaging biomarkers for neurological and cognitive function in Wilson disease

Ann Carolin Hausmann et al. Neurol Res Pract. .

Abstract

Background: Although brain atrophy is a prevalent finding in Wilson disease (WD), its role as a contributing factor to clinical symptoms, especially cognitive decline, remains unclear. The objective of this study was to investigate different neuroimaging biomarkers related to grey matter atrophy and their relationship with neurological and cognitive impairment in WD.

Methods: In this study, 30 WD patients and 30 age- and sex-matched healthy controls were enrolled prospectively and underwent structural magnetic resonance imaging (MRI). Regional atrophy was evaluated using established linear radiological measurements and the automated workflow volumetric estimation of gross atrophy and brain age longitudinally (veganbagel) for age- and sex-specific estimations of regional brain volume changes. Brain Age Gap Estimate (BrainAGE), defined as the discrepancy between machine learning predicted brain age from structural MRI and chronological age, was assessed using an established model. Atrophy markers and clinical scores were compared between 19 WD patients with a neurological phenotype (neuro-WD), 11 WD patients with a hepatic phenotype (hep-WD), and a healthy control group using Welch's ANOVA or Kruskal-Wallis test. Correlations between atrophy markers and neurological and neuropsychological scores were investigated using Spearman's correlation coefficients.

Results: Patients with neuro-WD demonstrated increased third ventricle width and bicaudate index, along with significant striatal-thalamic atrophy patterns that correlated with global cognitive function, mental processing speed, and verbal memory. Median BrainAGE was significantly higher in patients with neuro-WD (8.97 years, interquartile range [IQR] = 5.62-15.73) compared to those with hep-WD (4.72 years, IQR = 0.00-5.48) and healthy controls (0.46 years, IQR = - 4.11-4.24). Striatal-thalamic atrophy and BrainAGE were significantly correlated with neurological symptom severity.

Conclusions: Our findings indicate advanced predicted brain age and substantial striatal-thalamic atrophy patterns in patients with neuro-WD, which serve as promising neuroimaging biomarkers for neurological and cognitive functions in treated, chronic WD.

Keywords: BrainAGE; Atrophy; Cognition; Magnetic resonance imaging; Wilson disease.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was part of a larger observational imaging study on neurodegenerative diseases (DRKS00034050; retrospectively registered February 10th, 2025) and has been approved by the ethics committee of the Medical Faculty at the Heinrich-Heine University Düsseldorf, Germany (IRB00001579), under the study number 2019-470_4. It has been performed in accordance with the Declaration of Helsinki. All subjects provided written informed consent prior to participation. Consent for publication: Not applicable. Competing interests: CJH received honoraria and travel support from Alexion Pharma Germany GmbH, Orphalan SA, and Univar Solutions B.V. He received speaker fees from AbbVie and Abbott. The remaining authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Striatal-thalamic atrophy patterns in patients with Wilson disease. As an illustration of the striatal-thalamic atrophy patterns observed in most atrophy maps of patients with neurological Wilson disease, the native T1-weighted image and two corresponding representative slices of veganbagel-generated atrophy maps of three patients are presented. For instance, A shows a patient with comparatively mild striatal-thalamic atrophy, B shows a patient with severe striatal atrophy, and C shows a patient with marked striatal atrophy and additional thalamic atrophy. Color-coding indicates deviations of grey matter volumes compared to respective age- and sex-specific normative templates (blue indicating z-scores < − 2.5, red indicating z-scores > 2.5). Visual assessment indicated that atrophy was most pronounced in the putamen, and that the mediodorsal and anterior nuclei appeared to be the predominant regions of thalamic volume loss
Fig. 2
Fig. 2
BrainAGE of patients with Wilson disease and controls. Medians and interquartile ranges of BrainAGE scores in the control group, hep-WD group, and neuro-WD group are shown. A Kruskal–Wallis test revealed that BrainAGE significantly differed among the three groups (p <.001). Significant post-hoc comparisons are indicated. BrainAGE = Brain Age Gap Estimate; Hep-WD = hepatic Wilson disease; Neuro-WD = neurological Wilson disease; * p-value <0.050; ** p-value <0.001
Fig. 3
Fig. 3
Clinical correlations of striatal-thalamic atrophy and BrainAGE. Significant correlations between clinical scores, striatal-thalamic atrophy scores, and BrainAGE (in years) in the total sample of WD patients are shown (Bonferroni-Holm corrected p ≤0.05). Striatal-thalamic atrophy scores demonstrated a significant correlation with neurological scores and the majority of cognitive scores, including MMSE, RBMT-S, and SDMT. BrainAGE was also significantly correlated with neurological scores; however, except for SDMT scores, the associations between BrainAGE and neuropsychological scores lost statistical significance following multiple comparison correction. A comparison of the variance explained in UWDRS-N scores by the novel neuroimaging biomarkers in addition to common radiological measurements can be found in Additional File 1. UWDRS-N = Unified Wilson’s Disease Rating Scale-neurological subscale; BrainAGE = Brain Age Gap Estimate; MMSE = Mini-Mental State Examination; SDMT = Symbol Digit Modalities Test; RBMT-S = Rivermead Behavioural Memory Test-story subtest; WD = Wilson disease; rs = Spearman’s correlation coefficients; * p-value <0.050
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