Quantitative iron-neuromelanin MRI associates with motor severity in Parkinson's disease and matches radiological disease classification.

Background: Neuromelanin- and iron-sensitive MRI studies in Parkinson's disease (PD) are limited by small sample sizes and lack detailed clinical correlation. In a large case-control PD cohort, we evaluated the diagnostic accuracy of quantitative iron-neuromelanin MRI parameters from the substantia nigra (SN), their radiological utility, and clinical association. Methods: PD patients and age-matched controls were prospectively recruited for motor assessment and midbrain neuromelanin- and iron-sensitive [quantitative susceptibility mapping (QSM) and susceptibility map-weighted imaging (SMWI)] MRI. Quantitative neuromelanin-iron parameters from the SN were assessed for their discriminatory performance in PD classification using ROC analysis compared to those of qualitative visual classification by radiological readers of differential experience and used to predict motor severity. Results: In total, 191 subjects (80 PD, mean age 65.0 years; 111 controls, 65.6) were included. SN masks showed (a) higher mean susceptibility (p < 0.0001) and smaller sizes after thresholding for low susceptibility (p < 0.0001) on QSM and (b) lower contrast range (p < 0.0001) and smaller sizes after thresholding for high-signal voxels (p < 0.0001) on neuromelanin-sensitive MRI in patients than in controls. Quantitative iron and neuromelanin parameters showed a moderate correlation with motor dysfunction (87.5%: 0.4< | r | <0.6, p < 0.0001), respectively. A composite quantitative neuromelanin-iron marker differentiated the groups with excellent performance (AUC 0.94), matching the diagnostic accuracy of the best-performing reader (accuracy 97%) using SMWI. Conclusion: Quantitative neuromelanin-iron MRI is associated with PD motor severity and matched best-performing radiological PD classification using SMWI, with the potential to improve diagnostic confidence in the clinics and track disease progression and response to neuroprotective therapies.

The association between Parkinson's disease and Sexual dysfunction: Clinical correlation and therapeutic implications.

Sexual function which comprises of desire, arousal, orgasm and satisfaction and pain, involves coordinated physiologic responses from multiple different pathways. Sexual dysfunction (SD) occurs when these domains of the sexual response cycle are affected. SD is a common but under-recognized non-motor feature in Parkinson's disease (PD), a common age-related neurodegenerative disorder. SD significantly affects the quality of life of PD patients and their partners. Advanced age, gender, hormone deficiency, neuropsychiatric and medical comorbidities contribute to SD in PD. Possible potential pathological mechanisms include vasculogenic, endocrinologic, neurogenic and psychogenic factors. Various therapeutic interventions, both pharmacological and non-pharmacological modalities have been suggested to improve SD in PD. However, erectile dysfunction (ED) is the only SD with evidence-based treatment available. Non-pharmacological therapies are also offering promising evidence in the improvement of SD. A multidisciplinary approach in the assessment, investigation, and treatment is needed to address the real life complex issues (gender and comorbidities, neurobiological, vasoactive, hormonal as well as psychosocial aspects). Future clinical studies with validated and standardized methods in assessing SD as well as experimental models will be necessary for better insight into the pathophysiology. This would facilitate appropriate therapy and improve sexual rehabilitation in PD patients.

Clinical correlates of white matter lesions in Parkinson's disease using automated multi-modal segmentation measures.

BACKGROUND: Age-related white matter lesions (WML) are common, impact neuronal connectivity, and affect motor function and cognition. In addition to pathological nigrostriatal losses, WML are also common co-morbidities in Parkinson's disease (PD) that affect postural stability and gait. Automated brain volume measures are increasingly incorporated into the clinical reporting workflow to facilitate precision in medicine. Recently, multi-modal segmentation algorithms have been developed to overcome challenges with WML quantification based on single-modality input. OBJECTIVE: We evaluated WML volumes and their distribution in a case-control cohort of PD patients to predict the domain-specific clinical severity using a fully automated multi-modal segmentation algorithm. METHODS: Fifty-five subjects comprising of twenty PD patients and thirty-five age- and gender-matched control subjects underwent standardized motor/gait and cognitive assessments and brain MRI. Spatially differentiated WML obtained using automated segmentation algorithms on multi-modal MPRAGE and FLAIR images were used to predict domain-specific clinical severity. Preliminary statistical analysis focused on describing the relationship between WML and clinical scores, and the distribution of WML by brain regions. Subsequent stepwise regressions were performed to predict each clinical score using WML volumes in different brain regions, while controlling for age. RESULTS: WML volume strongly correlates with both motor and cognitive dysfunctions in PD patients (p < 0.05), with differential impact in the frontal lobe and periventricular regions on cognitive domains (p < 0.01) and severity of motor deficits (p < 0.01), respectively. CONCLUSION: Automated multi-modal segmentation algorithms may facilitate precision medicine through regional WML load quantification, which show potential as imaging biomarkers for predicting domain-specific disease severity in PD.

Remote Prescription During Pandemic: Challenges and Solutions.

The current COVID-19 pandemic has created an awareness and at the same time provides an impetus to transform digitalisation of healthcare delivery. Remote prescription is one key component of telemedicine, but it is the easiest and already practised in most places during the current pandemic even without the framework of virtual medicine in place. However, remote prescription, with its antecedent problems cannot be properly and safely executed in isolation. To ensure patients' safety and health outcomes, specific guidelines will need to be developed to cater for specific medical conditions to address individual drug prescriptions and concerns. There is a need for a robust governance to ensure that patient's safety is the foremost priority, and provisions should be made for requirements of remote prescription in the different medical subspecialities. The pandemic provides an enormous opportunity for stakeholders and policymakers to come together to create a seamless and user friendly and yet innovative healthcare ecosystem to transform clinical healthcare delivery with patient safety as the core driver in the implementation.

Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.

Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity. Herein we describe a new disease caused by high-penetrance heterozygous germline mutations in TNFAIP3, which encodes the NF-κB regulatory protein A20, in six unrelated families with early-onset systemic inflammation. The disorder resembles Behçet's disease, which is typically considered a polygenic disorder with onset in early adulthood. A20 is a potent inhibitor of the NF-κB signaling pathway. Mutant, truncated A20 proteins are likely to act through haploinsufficiency because they do not exert a dominant-negative effect in overexpression experiments. Patient-derived cells show increased degradation of IκBα and nuclear translocation of the NF-κB p65 subunit together with increased expression of NF-κB-mediated proinflammatory cytokines. A20 restricts NF-κB signals via its deubiquitinase activity. In cells expressing mutant A20 protein, there is defective removal of Lys63-linked ubiquitin from TRAF6, NEMO and RIP1 after stimulation with tumor necrosis factor (TNF). NF-κB-dependent proinflammatory cytokines are potential therapeutic targets for the patients with this disease.