A Semi-Supervised Graph Convolutional Network for Early Prediction of Motor Abnormalities in Very Preterm Infants.

Approximately 32-42% of very preterm infants develop minor motor abnormalities. Earlier diagnosis soon after birth is urgently needed because the first two years of life represent a critical window of opportunity for early neuroplasticity in infants. In this study, we developed a semi-supervised graph convolutional network (GCN) model that is able to simultaneously learn the neuroimaging features of subjects and consider the pairwise similarity between them. The semi-supervised GCN model also allows us to combine labeled data with additional unlabeled data to facilitate model training. We conducted our experiments on a multisite regional cohort of 224 preterm infants (119 labeled subjects and 105 unlabeled subjects) who were born at 32 weeks or earlier from the Cincinnati Infant Neurodevelopment Early Prediction Study. A weighted loss function was applied to mitigate the impact of an imbalanced positive:negative (~1:2) subject ratio in our cohort. With only labeled data, our GCN model achieved an accuracy of 66.4% and an AUC of 0.67 in the early prediction of motor abnormalities, outperforming prior supervised learning models. By taking advantage of additional unlabeled data, the GCN model had significantly better accuracy (68.0%, p = 0.016) and a higher AUC (0.69, p = 0.029). This pilot work suggests that the semi-supervised GCN model can be utilized to aid early prediction of neurodevelopmental deficits in preterm infants.

Deletion of SUMO1 attenuates behavioral and anatomical deficits by regulating autophagic activities in Huntington disease.

The CAG expansion of huntingtin (mHTT) associated with Huntington disease (HD) is a ubiquitously expressed gene, yet it prominently damages the striatum and cortex, followed by widespread peripheral defects as the disease progresses. However, the underlying mechanisms of neuronal vulnerability are unclear. Previous studies have shown that SUMO1 (small ubiquitin-like modifier-1) modification of mHtt promotes cellular toxicity, but the in vivo role and functions of SUMO1 in HD pathogenesis are unclear. Here, we report that SUMO1 deletion in Q175DN HD-het knockin mice (HD mice) prevented age-dependent HD-like motor and neurological impairments and suppressed the striatal atrophy and inflammatory response. SUMO1 deletion caused a drastic reduction in soluble mHtt levels and nuclear and extracellular mHtt inclusions while increasing cytoplasmic mHtt inclusions in the striatum of HD mice. SUMO1 deletion promoted autophagic activity, characterized by augmented interactions between mHtt inclusions and a lysosomal marker (LAMP1), increased LC3B- and LAMP1 interaction, and decreased interaction of sequestosome-1 (p62) and LAMP1 in DARPP-32-positive medium spiny neurons in HD mice. Depletion of SUMO1 in an HD cell model also diminished the mHtt levels and enhanced autophagy flux. In addition, the SUMOylation inhibitor ginkgolic acid strongly enhanced autophagy and diminished mHTT levels in human HD fibroblasts. These results indicate that SUMO is a critical therapeutic target in HD and that blocking SUMO may ameliorate HD pathogenesis by regulating autophagy activities.

A High-fat Diet Induces a Loss of Midbrain Dopaminergic Neuronal Function That Underlies Motor Abnormalities.

Movement defects in obesity are associated with peripheral muscle defects, arthritis, and dysfunction of motor control by the brain. Although movement functionality is negatively correlated with obesity, the brain regions and downstream signaling pathways associated with movement defects in obesity are unclear. A dopaminergic neuronal pathway from the substantia nigra (SN) to the striatum is responsible for regulating grip strength and motor initiation through tyrosine hydroxylase (TH) activity-dependent dopamine release. We found that mice fed a high-fat diet exhibited decreased movement in open-field tests and an increase in missteps in a vertical grid test compared with normally fed mice. This motor abnormality was associated with a significant reduction of TH in the SN and striatum. We further found that phosphorylation of c-Jun N-terminal kinase (JNK), which modulates TH expression in the SN and striatum, was decreased under excess-energy conditions. Our findings suggest that high calorie intake impairs motor function through JNK-dependent dysregulation of TH in the SN and striatum.

A High-fat Diet Induces a Loss of Midbrain Dopaminergic Neuronal Function That Underlies Motor Abnormalities

Movement defects in obesity are associated with peripheral muscle defects, arthritis, and dysfunction of motor control by the brain. Although movement functionality is negatively correlated with obesity, the brain regions and downstream signaling pathways associated with movement defects in obesity are unclear. A dopaminergic neuronal pathway from the substantia nigra (SN) to the striatum is responsible for regulating grip strength and motor initiation through tyrosine hydroxylase (TH) activity-dependent dopamine release. We found that mice fed a high-fat diet exhibited decreased movement in open-field tests and an increase in missteps in a vertical grid test compared with normally fed mice. This motor abnormality was associated with a significant reduction of TH in the SN and striatum. We further found that phosphorylation of c-Jun N-terminal kinase (JNK), which modulates TH expression in the SN and striatum, was decreased under excess-energy conditions. Our findings suggest that high calorie intake impairs motor function through JNK-dependent dysregulation of TH in the SN and striatum.

Perverted Head-Shaking and Positional Downbeat Nystagmus in Essential Tremor.

Even though the pathophysiology is not completely understood, cerebellar dysfunction has been invoked in essential tremor (ET). We evaluated cerebellar dysfunction in ET with the presence of perverted head-shaking (pHSN) and positional downbeat nystagmus (pDBN) which are known to reflect cerebellar dysfunction. First, we reviewed the videooculography (VOG) of 185 patients with ET from March 2007 to April 2010. Seventeen of 28 patients with pHSN and pDBN were followed up for at least a 1.8-year interval from baseline to determine the clinical course. And then, we recruited 52 consecutive patients with ET and compared their ocular motor findings with 51 normal controls using VOG. Among the 185 patients with ET, 28 (15.1 %) showed pHSN (n = 23, 12.4 %) or pDBN (n = 8, 4.3 %). Seventeen of them who were followed up did not develop Parkinsonism or other neurologic deficits during the observation period. The subsequent case-control study showed a higher prevalence of pHSN or pDBN (11/52, 21.2 %, pHSN in nine and pDBN in five) in patients with ET than in the normal controls (2/51, 3.9 %, pHSN only, P = 0.015). The tremor rating scale or involved body sites did not differ between the patients with and without pHSN/pDBN. pHSN and pDBN were more common in patients with ET than in the normal controls. This result supports that cerebellar dysfunction is associated with ET.

REM sleep behavior disorder in Parkinson disease: association with abnormal ocular motor findings.

BACKGROUND: The anatomical substrates associated with generalized muscle atonia during REM sleep are located on the pontine tegmentum and medial medulla oblongata. We examined whether patients with REM sleep behavior disorder (RBD) have abnormal ocular movements suggesting brainstem or cerebellar dysfunction in Parkinson's disease (PD). METHODS: Cross-sectional survey for the existence of RBD and abnormal ocular movements. Ocular movements were examined by video-oculography (VOG). RESULTS: A total of 202 patients were included in this study. One hundred and sixteen (57.4%) of the 202 patients have clinically probable RBD, and 28 (24.1%) of the 116 with clinically probable RBD patients had abnormal VOG findings suggesting brainstem or cerebellar dysfunction; whereas 86 of the 202 patients did not have clinically probable RBD, and only 7 (8.1%) of the 86 patients had abnormal VOG findings suggesting brainstem or cerebellar dysfunction (P=0.001). CONCLUSION: This study suggests that the presence of RBD is associated with more severe or extensive brainstem pathology or different distribution of pathology in PD.