Activity-based photoacoustic probe for biopsy-free assessment of copper in murine models of Wilson's disease and liver metastasis.

The development of high-performance photoacoustic (PA) probes that can monitor disease biomarkers in deep tissue has the potential to replace invasive medical procedures such as a biopsy. However, such probes must be optimized for in vivo performance and exhibit an exceptional safety profile. In this study, we have developed PACu-1, a PA probe designed for biopsy-free assessment (BFA) of hepatic Cu via photoacoustic imaging. PACu-1 features a Cu(I)-responsive trigger appended to an aza-BODIPY dye platform that has been optimized for ratiometric sensing. Owing to its excellent performance, we were able to detect basal levels of Cu in healthy wild-type mice as well as elevated Cu in a Wilson's disease model and in a liver metastasis model. To showcase the potential impact of PACu-1 for BFA, we conducted two blind studies in which we were able to successfully identify Wilson's disease animals from healthy control mice in each instance.

Study on Lesion Assessment of Cerebello-Thalamo-Cortical Network in Wilson's Disease with Diffusion Tensor Imaging.

Wilson's disease (WD) is a genetic disorder of copper metabolism with pathological copper accumulation in the brain and any other tissues. This article aimed to assess lesions in cerebello-thalamo-cortical network with an advanced technique of diffusion tensor imaging (DTI) in WD. 35 WD patients and 30 age- and sex-matched healthy volunteers were recruited to accept diffusion-weighted images with 15 gradient vectors and conventional magnetic resonance imaging (MRI). The DTI parameters, including fractional anisotropy (FA) and mean diffusion (MD), were calculated by diffusion kurtosis estimator software. After registration, patient groups with FA mappings and MD mappings and normal groups were compared with 3dttest and receiver-operating characteristic (ROC) curve analysis, corrected with FDR simulations (p = 0.001, α = 0.05, cluster size = 326). We found that the degree of FA increased in the bilateral head of the caudate nucleus (HCN), lenticular nucleus (LN), ventral thalamus, substantia nigra (SN), red nucleus (RN), right dentate nucleus (DN), and decreased in the mediodorsal thalamus and extensive white matter. The value of MD increased in HCN, LN, SN, RN, and extensive white matter. The technique of DTI provides higher sensitivity and specificity than conventional MRI to detect Wilson's disease. Besides, lesions in the basal ganglia, thalamus, and cerebellum might disconnect the basal ganglia-thalamo-cortical circuits or dentato-rubro-thalamic (DRT) track and disrupt cerebello-thalamo-cortical network finally, which may cause clinical extrapyramidal symptoms.

Microstructure assessment of the thalamus in Wilson's disease using diffusion tensor imaging.

AIM: To assess diffusion changes of the thalamus in Wilson's disease using diffusion tensor imaging (DTI). MATERIALS AND METHODS: Fifteen patients with Wilson's disease and an abnormal signal in the thalamus (designated as group 1) and 18 patients with Wilson's disease with a normal-appearing thalamus (designated as group 2) at conventional magnetic resonance imaging (MRI) were recruited. Fifteen age-matched and sex-matched healthy volunteers were also enrolled as the control group (designated as group 3). The fractional anisotropy (FA), primary eigenvalue (λ1), second eigenvalue (λ2), and third eigenvalue (λ3) of the thalamus were measured and the differences were compared. RESULTS: The FA values of the thalamus were different in the three groups (group 1: 0.36 ± 0.02; group 2: 0.38 ± 0.02; group 3: 0.43 ± 0.02; F = 54.51, p < 0.001). A statistically significant difference was observed between group 1 and group 2 (p = 0.003), group 1 and group 3 (p = 0.001), and group 2 and group 3 (p < 0.001). The λ1, λ2, and λ3 values of the thalamus were different in the three groups (1.11 ± 0.06 mm(2)/s, 1.11 ± 0.06 mm(2)/s, and 1.10 ± 0.04 mm(2)/s of λ1 in group 1, group 2, and group 3, respectively; 0.82 ± 0.08 mm(2)/s, 0.78 ± 0.05 mm(2)/s, and 0.72 ± 0.02 mm(2)/s of λ2 in group 1, group 2, and group 3, respectively; 0.52 ± 0.05 mm(2)/s, 0.49 ± 0.06 mm(2)/s, and 0.42 ± 0.06 mm(2)/s of λ3 in group 1, group 2, and group 3, respectively; F = 1.65, p = 0.203 of λ1; F = 10.55, p < 0.001 of λ2; F = 4.21, p = 0.021 of λ3; respectively). A statistically significant difference in the λ2 value was observed between group 1 and group 3 (p < 0.001) and group 2 and group 3 (p = 0.005). A statistically significant difference in the λ3 value was also observed between group 1 and group 3 (p = 0.007). No significant difference in the λ1 value was noted between each of the two groups. CONCLUSIONS: Damage of the thalamus in Wilson's disease patients can be detected using DTI. DTI may provide information regarding thalamus damage in patients with Wilson's disease before abnormal signals on conventional MRI.

Constantin von Economo's contribution to the understanding of movement disorders.

Constantin von Economo's (CvE) main scientific achievements were his studies on the cytoarchitectonics of the cerebral cortex, sleep, and encephalitis lethargica (EL). He found a close relationship between motor symptoms and psychiatric and behavioral disorders in EL and postencephalitic Parkinsonism and identified the underlying neuropathology in the diencephalon and the brainstem. In agreement with Tretiakoff's findings in Parkinson's disease, CvE related postencephalitic Parkinsonism to neuronal loss in the substantia nigra. Several of CvE's early, less well-known publications also deal with the basal ganglia and movement disorders. He demonstrated in rabbits that the substantia nigra modulates automatization, coordination, and succession of masticatory movements and swallowing. In a study on the effects of experimental lesions of the cerebral peduncle in cats and monkeys, CvE hypothesized a corticotegmental pathway that maintains motor functions after pyramidal tract lesions. Recent studies have identified this pathway, which ends in the pedunculopontine nucleus. In a study on posthemiplegic chorea, CvE discussed various pathophysiological hypotheses that partly resemble modern concepts of chorea. In a clinicopathological study on Wilson's disease, CvE traced the striofugal fibers and visualized the basal ganglia outflow pathways. CvE was an outstanding multidisciplinary movement disorder specialist who contributed substantially to modern basal ganglia research.

Clinical assessment of 31 patients with Wilson's disease. Correlations with structural changes on magnetic resonance imaging.

Thirty-one patients with Wilson's disease were evaluated with detailed neurologic and medical examinations. Mean age (+/- SD) at onset was 21 +/- 5 years and at examination was 28 +/- 6 years. Of the 90% of patients who were first treated with penicillamine, 31% deteriorated initially despite therapy, and half never recovered to pretherapy baseline. At the time of our evaluations, the most common neurologic findings were dysarthria (97%), dystonia (65%), dysdiadochokinesia (58%), rigidity (52%), gait and postural abnormalities (42%), and tremor (32%). Chorea and dementia were rare. Twenty-two patients underwent magnetic resonance imaging. All but one of the 19 symptomatic patients had abnormal scans. The three asymptomatic patients had normal scans. Most lesions were seen in the caudate, putamen, subcortical white matter, midbrain, and pons. Generalized brain atrophy was also common. Lesions were less common in the thalamus, cerebellar vermis, midbrain tegmentum, globus pallidus, red nucleus, and dentate nucleus. Dystonia and bradykinesia correlated with putamen lesions, and dysarthria correlated with both putamen and caudate lesions.