Digital assessments enable objective measurements of ataxia severity and provide informative features that expand upon the information obtained during a clinical examination. In this study, we demonstrate the feasibility of using finger tapping videos to distinguish participants with Ataxia (N = 169) from participants with parkinsonism (N = 78) and from controls (N = 58), and predict their upper extremity and overall disease severity. Features were extracted from the time series representing the distance between the index and thumb and its derivatives. Classification models in ataxia archived areas under the receiver-operating curve of around 0.91, and regression models estimating disease severity obtained correlation coefficients around r = 0.64. Classification and prediction model coefficients were examined and they not only were in accordance, but were in line with clinical observations of ataxia phenotypes where rate and rhythm are altered during upper extremity motor movement.
Abstract Objective Late‐onset GM2 gangliosidosis (LOGG) subtypes late‐onset Tay‐Sachs (LOTS) and Sandhoff disease (LOSD) are ultra‐rare neurodegenerative lysosomal storage disorders presenting with weakness, ataxia, and neuropsychiatric symptoms. Previous studies considered LOTS and LOSD clinically indistinguishable; recent studies have challenged this. We performed a scoping review to ascertain whether imaging and clinical features may differentiate these diseases. Methods We examined MEDLINE/non‐MEDLINE databases up to May 2022. Articles reporting brain imaging findings in genetically/enzymatically confirmed LOGG, symptom onset at age ≥ 10 years (or evaluated at least once ≥18 years) were included, yielding 170 LOGG patients (LOTS = 127, LOSD = 43) across 68 papers. We compared LOTS versus LOSD and performed regression analyses. Results were corrected for multiple comparisons. Results Age of onset was lower in LOTS versus LOSD (17.9 ± 8.2 vs. 23.9 ± 14.4 years, p = 0.017), although disease duration was similar ( p = 0.34). LOTS more commonly had psychosis/bipolar symptoms (35.0% vs. 9.30%, p = 0.011) but less frequent swallowing problems (4.10% vs. 18.60%, p = 0.041). Cerebellar atrophy was more common in LOTS (89.0%) versus LOSD (60.5%), p < 0.0001, with more severe atrophy in LOTS ( p = 0.0005). Brainstem atrophy was documented only in LOTS (14.2%). Independent predictors of LOTS versus LOSD (odds ratio [95% confidence interval]) included the presence of psychosis/bipolar symptoms (4.95 [1.59–19.52], p = 0.011), no swallowing symptoms (0.16 [0.036–0.64], p = 0.011), and cerebellar atrophy (5.81 [2.10–17.08], p = 0.0009). Lower age of onset (0.96 [0.93–1.00], p = 0.075) and tremor (2.50 [0.94–7.43], p = 0.078) were marginally statistically significant but felt relevant to include in the model. Interpretation These data suggest significant differences in symptomatology, disease course, and imaging findings between LOTS and LOSD.
The incidence of cutaneous squamous cell carcinoma (cSCC) is rising. Whilst the majority are cured surgically, aggressive metastatic cSCC carry a poor prognosis. Inactivating mutations in transforming growth factor beta (TGF-β) receptors have been identified amongst genetic drivers of sporadic tumours and murine models of cSCC, suggesting a tumour suppressor function for TGF-β in normal skin. However, paradoxically, TGF-β acts as a tumour promoter in some murine model systems. Few studies have analysed the role of TGF-β/activin signalling in human normal skin, hyper-proliferative skin disorders and cSCC. Antibodies recognising phospho-SMAD proteins which are activated during canonical TGF-β/activin signalling were validated for use in immunohistochemistry. A tissue microarray comprising FFPE lesional and perilesional tissue from human primary invasive cSCC (n=238), cSCC in-situ (n=2) and keratocanthoma (n=9) were analysed in comparison with tissues from normal human scalp (n=10). Phosphorylated SMAD2 and SMAD3 were detected in normal interfollicular epidermal keratinocytes and were also highly localised to inner root sheath, matrix cells and Keratin 15 positive cells. Lesional cSCC tissue had significantly reduced activated SMAD2/3 compared to perilesional tissue, consistent with a tumour suppressor role for SMAD2/3 activators in cSCC. Increased cSCC tumour thickness inversely correlated with the presence of phospho-SMADs in tumour tissue suggesting that a reduction in canonical TGF-β/activin signalling may be associated with disease progression.
Abstract Eye movements are disrupted in many neurodegenerative diseases and are frequent and early features in conditions affecting the cerebellum. Characterizing eye movements is important for diagnosis and may be useful for tracking disease progression and response to therapies. Assessments are limited as they require an in-person evaluation by a neurology subspecialist or specialized and expensive equipment. We tested the hypothesis that important eye movement abnormalities in cerebellar disorders (i.e., ataxias) could be captured from iPhone video. Videos of the face were collected from individuals with ataxia (n = 102) and from a comparative population (Parkinson’s disease or healthy participants, n = 61). Computer vision algorithms were used to track the position of the eye which was transformed into high temporal resolution spectral features. Machine learning models trained on eye movement features were able to identify abnormalities in smooth pursuit (a key eye behavior) and accurately distinguish individuals with abnormal pursuit from controls (sensitivity = 0.84, specificity = 0.77). A novel machine learning approach generated severity estimates that correlated well with the clinician scores. We demonstrate the feasibility of capturing eye movement information using an inexpensive and widely accessible technology. This may be a useful approach for disease screening and for measuring severity in clinical trials.
Despite advancements in the assessment and management of functional neurological disorder (FND), the feasibility of implementing a new standard of care remains unclear. Chart reviews were performed for 100 patients with motor FND to investigate factors related to treatment adherence and clinical improvement over an average follow-up of 7 months. Of 81 patients who returned for follow-up, a history of chronic pain disorder inversely correlated with improvement. Of the 50 individuals newly referred for treatment, adherence correlated with improvement, while having abnormal neuroimaging inversely correlated with improvement. This study supports the feasibility of applying a new standard of care for FND.
Dupuytren’s disease is an acquired condition of the hand associated with fibrosis and contraction of the fascia of the palm, leading to stiffness and inability to properly flex and extend the digits. The disease is caused by both genetic and environmental factors. There is some evidence that Angiotensin II (ANGT II) may be associated with this disorder and that blockers of ANGT II may help in treating this disease. This study was designed to investigate the presence of ANGT II receptors 1 (AT1) and 2 (AT2) in myofibroblasts derived from primary tissue of 11 patients who had the disease. My hypothesis is that myofibroblasts will express angiotensin receptors and that these will primarily be of the AT1 receptor subtype.
Initially, the tissues were excised from patients who were undergoing surgery for Dupuytren’s disease in the Department of Plastic Surgery at Royal Preston Hospital. The tissue from each patient was dissociated into myofibroblasts using collagenase. The myofibroblasts from each patient were cultured in a growth medium over a period of 8-10 days. The results show that it was possible to obtain successful growth curves for the myofibroblast following 8-10 days of cell culture. Some cultures produced better yields than others. The myofibroblasts were then stained and treated with specific polyclonal antibodies for the identification of AT1 and AT2 receptors. The results show that both AT1 and AT2 receptors were presented in myofibroblasts taken from all 11 patients. The results show a wider distribution of AT2 receptors compared with AT1 receptors. Samples of the myofibroblasts were employed to measure the contractile response and intracellular free calcium (Ca2+) concentrations. After numerous attempts using a collagen gel model to measure contraction, it was not possible to obtain any successful results. Similarly, fura loaded myofibroblasts show no signs of Ca2+ using a microspectoflurometer to measure intracellular calcium. In conclusion, the results presented in this thesis have shown that it is possible to isolate tissues from patients with Dupuytren’s disease and culture myofibroblasts successfully. Moreover, these myofibroblasts contain both AT1 and AT2 receptors. Further experiments are required to study the role of blocking AT1 and AT2 receptors excitation-contraction coupling process of the myofibroblasts.
To ascertain demographic and clinical features of Parkinson disease (PD) associated with functional neurological features.A standardised form was used to extract data from electronic records of 53 PD patients with associated functional neurological disorders (PD-FND) across eight movement disorders centres in the USA, Canada and Europe. These subjects were matched for age, gender and disease duration to PD patients without functional features (PD-only). Logistic regression analysis was used to compare both groups after adjusting for clustering effect.Functional symptoms preceded or co-occurred with PD onset in 34% of cases, nearly always in the most affected body side. Compared with PD-only subjects, PD-FND were predominantly female (68%), had longer delay to PD diagnosis, greater prevalence of dyskinesia (42% vs 18%; P=0.023), worse depression and anxiety (P=0.033 and 0.025, respectively), higher levodopa-equivalent daily dose (972±701 vs 741±559 mg; P=0.029) and lower motor severity (P=0.019). These patients also exhibited greater healthcare resource utilisation, higher use of [(123)I]FP-CIT SPECT and were more likely to have had a pre-existing psychiatric disorder (P=0.008) and family history of PD (P=0.036).A subtype of PD with functional neurological features is familial in one-fourth of cases and associated with more psychiatric than motor disability and greater use of diagnostic and healthcare resources than those without functional features. Functional manifestations may be prodromal to PD in one-third of patients.
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