The Cerebellum Is a Common Key for Visuospatial Execution and Attention in Parkinson’s Disease

Cognitive decline affects the clinical course in patients with Parkinson’s disease (PD) and contributes to a poor prognosis. However, little is known about the underlying network-level abnormalities associated with each cognitive domain. We aimed to identify the networks related to each cognitive domain in PD using resting-state functional magnetic resonance imaging (MRI). Forty patients with PD and 15 normal controls were enrolled. All subjects underwent MRI and the Mini-Mental State Examination. Furthermore, the cognitive function of patients with PD was assessed using the Montreal Cognitive Assessment (MoCA). We used independent component analysis of the resting-state functional MRI for functional segmentation, followed by reconstruction to identify each domain-related network, to predict scores in PD using multiple regression models. Six networks were identified, as follows: the visuospatial-executive-domain-related network (R2 = 0.54, p < 0.001), naming-domain-related network (R2 = 0.39, p < 0.001), attention-domain-related network (R2 = 0.86, p < 0.001), language-domain-related network (R2 = 0.64, p < 0.001), abstraction-related network (R2 = 0.10, p < 0.05), and orientation-domain-related network (R2 = 0.64, p < 0.001). Cerebellar lobule VII was involved in the visuospatial-executive-domain-related and attention-domain-related networks. These two domains are involved in the first three listed nonamnestic cognitive impairment in the diagnostic criteria for PD with dementia (PDD). Furthermore, Brodmann area 10 contributed most frequently to each domain-related network. Collectively, these findings suggest that cerebellar lobule VII may play a key role in cognitive impairment in nonamnestic types of PDD

Testosterone Recovery after Neoadjuvant Gonadotropin-Releasing Hormone Antagonist versus Agonist on Permanent Iodine-125 Seed Brachytherapy in Prostate Cancer Patients: A Propensity Score Analysis

Optimal neoadjuvant hormone therapy (NHT) for reducing prostate cancer (PC) patients’ prostate volume pre-brachytherapy is controversial. We evaluated the differential impact of neoadjuvant gonadotropin-releasing hormone (GnRH) antagonist versus agonist on post-brachytherapy testosterone recovery in 112 patients treated pre-brachytherapy with NHT (GnRH antagonist, n=32; GnRH agonists, n=80) (Jan. 2007-June 2019). We assessed the effects of patient characteristics and a GnRH analogue on testosterone recovery with logistic regression and a propensity score analysis (PSA). There was no significant difference in the rate of testosterone recovery to normal levels (> 300 ng/dL) between the GnRH antagonist and agonists (p=0.07). The GnRH agonists induced a significantly more rapid testosterone recovery rate at 3 months post-brachytherapy versus the GnRH antagonist (p<0.0001); there was no difference in testosterone recovery at 12 months between the GnRH antagonist/agonists (p=0.8). In the multivariate analysis, no actor was associated with testosterone recovery. In the PSA, older age and higher body mass index (BMI) were significantly associated with longer testosterone recovery. Post-brachytherapy testosterone recovery was quicker with the neoadjuvant GnRH agonists than the antagonist, and the testosterone recovery rate was significantly associated with older age and higher BMI. Long-term follow-ups are needed to determine any differential effects of GnRH analogues on the quality of life of brachytherapy-treated PC patients

Conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in ERK signalling

The phosphorylation cascade in the extracellular signal-regulated kinase (ERK) pathway is a versatile reaction network motif that can potentially act as a switch, oscillator or memory. Nevertheless, there is accumulating evidence that the phosphorylation response is mostly linear to extracellular signals in mammalian cells. Here we find that subsequent nuclear translocation gives rise to a switch-like increase in nuclear ERK concentration in response to signal input. The switch-like response disappears in the presence of ERK inhibitor, suggesting the existence of autoregulatory mechanisms for ERK nuclear translocation involved in conversion from a graded to a switch-like response. In vitro reconstruction of ERK nuclear translocation indicates that ERK-mediated phosphorylation of nucleoporins regulates ERK translocation. A mathematical model and knockdown experiments suggest a contribution of nucleoporins to regulation of the ERK nuclear translocation response. Taken together, this study provides evidence that nuclear translocation with autoregulatory mechanisms acts as a switch in ERK signalling