Brain Hemisphere Dissimilarity, a Self-Supervised Learning Approach for alpha-synucleinopathies prediction with FDG PET.

Idiopathic Rem sleep Behavior Disorder (iRBD) is a significant biomarker for the development of alpha-synucleinopathies, such as Parkinson's disease (PD) or Dementia with Lewy bodies (DLB). Methods to identify patterns in iRBD patients can help in the prediction of the future conversion to these diseases during the long prodromal phase when symptoms are non-specific. These methods are essential for disease management and clinical trial recruitment. Brain PET scans with 18F-FDG PET radiotracers have recently shown promise, however, the scarcity of longitudinal data and PD/DLB conversion information makes the use of representation learning approaches such as deep convolutional networks not feasible if trained in a supervised manner. In this work, we propose a self-supervised learning strategy to learn features by comparing the brain hemispheres of iRBD non-convertor subjects, which allows for pre-training a convolutional network on a small data regimen. We introduce a loss function called hemisphere dissimilarity loss (HDL), which extends the Barlow Twins loss, that promotes the creation of invariant and non-redundant features for brain hemispheres of the same subject, and the opposite for hemispheres of different subjects. This loss enables the pre-training of a network without any information about the disease, which is then used to generate full brain feature vectors that are fine-tuned to two downstream tasks: follow-up conversion, and the type of conversion (PD or DLB) using baseline 18F-FDG PET. In our results, we find that the HDL outperforms the variational autoencoder with different forms of inputs.

Management of systemic prostate cancer: current algorithm from castration sensitive to castration resistant setting.

In recent years, the advanced knowledge of clinical, biological and molecular features of prostate cancer have led to the introduction of new drugs and have allowed the relocation of old drugs in different settings. In this way, the new concepts of systemic disease arise: high risk or high volume vs. low risk and low volume disease castration sensitive prostate cancer (CSPC), diversifying the use of previously approved drugs (CRPC) and opening new scenarios for sequence therapy. The aim of this review is to integrate new developments into the medical management of systemic prostate cancer.

Penile cancer: prognostic and predictive factors in clinical decision-making.

Penile cancer (PC) is a typical tumor of non-industrialized countries. The incidence is 20-30 times higher in Africa and South America, considering the elevated prevalence of sexually transmitted diseases. Histologically, PC includes squamous cell carcinoma (SCPC), the most frequent, and nonsquamous carcinoma (NSCPC). Early diagnosis is the goal, whereas later diagnosis relates to poor functional outcomes and worse prognosis. The 5-year survival rate is 85% for patients with histologically regional negative lymph nodes, compared to 29%-40% for those with histologically regional positive lymph nodes. To date no new drugs are approved, and there are few new data about molecular mechanisms underlying tumorigenesis. The SCPC remains a rare tumor and the current therapeutic algorithm is based principally on retrospective analysis and less on prospective trials. In this review article, biomarkers of prognosis and efficacy of current treatments are summarized with a focus on those that have the potential to affect treatment decision-making in SCPC.

Advanced/metastatic bladder cancer: current status and future directions.

In 2015 bladder cancer was the fourth most frequent malignancy and the eighth cause of death for cancer. At diagnosis, about 30% of bladder cancer (BC) patients present a muscle-invasive bladder cancer (MIBC) and 5% a metastatic bladder carcinoma (MBC). For fit MBC patients, combination chemotherapy (CC) is the standard of care for first-line treatment. CC includes both the treatment with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) either the classical or the dose-dense MVAC regimen, and the doublet therapy with cisplatin and gemcitabine (CG). Median progression free survival (PFS) was 7 months and median overall survival (OS) was 15 months. The present review provides an update on the management of MBC, with focus on target therapies, immune checkpoint inhibition, looking for prognostic and predictive factors.

Preliminary evidence that vortioxetine may improve sleep quality in depressed patients with insomnia: a retrospective questionnaire analysis.

Insomnia is a frequent symptom in depressed patients. It can present with difficulty in initiating and/or maintaining sleep. We retrospectively evaluated a group of 15 patients affected by major depressive disorder and complaining of insomnia, who started vortioxetine (VOR) treatment for their depressive symptoms. The following questionnaires were captured at baseline and follow-up: Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Beck Depression Inventory. Pittsburgh Sleep Quality Index total score significantly decreased between follow-up and baseline (P < 0.01), and in several subitems related to sleep quality and continuity. Moreover, Epworth Sleepiness Scale decreased between follow-up and baseline (P < 0.01). Finally, Beck Depression Inventory reduction was also evident between follow-up and baseline (P < 0.01). This retrospective analysis showing the significant effect of VOR on both depressive symptoms and insomnia in patients showing comorbid major depressive disorder and insomnia invites further research in order to confirm this preliminary evidence. We hypothesize that the VOR mechanism of action may explain the improvement of subjective sleep, other than depressive symptoms.

Subthalamic nucleus deep brain stimulation on motor-symptoms of Parkinson's disease: Focus on neurochemistry.

Deep brain stimulation (DBS) has become a standard therapy for Parkinson's disease (PD) and it is also currently under investigation for other neurological and psychiatric disorders. Although many scientific, clinical and ethical issues are still unresolved, DBS delivered into the subthalamic nucleus (STN) has improved the quality of life of several thousands of patients. The mechanisms underlying STN-DBS have been debated extensively in several reviews; less investigated are the biochemical consequences, which are still under scrutiny. Crucial and only partially understood, for instance, are the complex interplays occurring between STN-DBS and levodopa (LD)-centred therapy in the post-surgery follow-up. The main goal of this review is to address the question of whether an improved motor control, based on STN-DBS therapy, is also achieved through the additional modulation of other neurotransmitters, such as noradrenaline (NA) and serotonin (5-HT). A critical issue is to understand not only acute DBS-mediated effects, but also chronic changes, such as those involving cyclic nucleotides, capable of modulating circuit plasticity. The present article will discuss the neurochemical changes promoted by STN-DBS and will document the main results obtained in microdialysis studies. Furthermore, we will also examine the preliminary achievements of voltammetry applied to humans, and discuss new hypothetical investigational routes, taking into account novel players such as glia, or subcortical regions such as the pedunculopontine (PPN) area. Our further understanding of specific changes in brain chemistry promoted by STN-DBS would further disseminate its utilisation, at any stage of disease, avoiding an irreversible lesioning approach.

CSF lactate levels, τ proteins, cognitive decline: a dynamic relationship in Alzheimer's disease.

OBJECTIVES: To investigate, in patients with Alzheimer's Disease (AD), the possible interplay linking alteration of neuronal energy metabolism, as measured via cerebrospinal fluid (CSF) lactate concentration, to severity of AD neurodegenerative processes and impairment of cognitive abilities. METHODS: In this study we measured and correlated CSF lactate concentrations, AD biomarker levels (τ-proteins and ß-amyloid) and Mini-Mental State Examination (MMSE) score in a population of drug-naïve patients with AD ranging from mild (MMSE≥21/30) to moderate-severe (MMSE<21/30) cognitive decline. They were compared to healthy controls and patients with vascular dementia (VaD). RESULTS: Patients with AD (n=145) showed a significant increase of CSF lactate concentration compared to controls (n=80) and patients with VaD (n=44), which was higher in mild (n=67) than in patients with moderate-severe AD (n=78). Moreover, we found, in either the whole AD population or both subgroups, a CSF profile in which higher CSF levels of t-τ and p-τ proteins corresponded to lower concentrations of lactate. CONCLUSIONS: We verified the occurrence of high CSF lactate levels in patients with AD, which may be ascribed to mitochondria impairment. Hypothesising that τ proteins may exert a detrimental effect on the entire cellular energy metabolism, the negative correlation found between lactate and τ-protein levels may allow speculation that τ toxicity, already demonstrated to have affected mitochondria, could also impair glycolytic metabolism with a less evident increase of lactate levels in more severe AD. Thus, we suggest a dynamic relationship between neuronal energy metabolism, τ proteins and cognitive decline in AD and propose the clinical potential of assessing CSF lactate levels in patients with AD to better define the neuronal brain metabolism damage.

Restless legs syndrome and post polio syndrome: a case-control study.

BACKGROUND AND PURPOSE: The aim was to investigate the prevalence of restless legs syndrome (RLS), fatigue and daytime sleepiness in a large cohort of patients affected by post polio syndrome (PPS) and their impact on patient health-related quality of life (HRQoL) compared with healthy subjects. METHODS: PPS patients were evaluated by means of the Stanford Sleepiness Scale and the Fatigue Severity Scale (FSS). The Short Form Health Survey (SF-36) questionnaire was utilized to assess HRQoL in PPS. RLS was diagnosed when standard criteria were met. Age and sex matched healthy controls were recruited amongst spouses or friends of PPS subjects. RESULTS: A total of 66 PPS patients and 80 healthy controls were enrolled in the study. A significantly higher prevalence of RLS (P < 0.0005; odds ratio 21.5; 95% confidence interval 8.17-57) was found in PPS patients (PPS/RLS+ 63.6%) than in healthy controls (7.5%). The FSS score was higher in PPS/RLS+ than in PPS/RLS- patients (P = 0.03). A significant decrease of SF-36 scores, including the physical function (P = 0.001), physical role (P = 0.0001) and bodily pain (P = 0.03) domains, was found in PPS/RLS+ versus PPS/RLS- patients. Finally, it was found that PPS/RLS+ showed a significant correlation between International Restless Legs Scale score and FSS (P < 0.0001), as well as between International Restless Legs Scale score and most of the SF-36 items (physical role P = 0.0018, general health P = 0.0009, vitality P = 0.0022, social functioning P = 0.002, role emotional P = 0.0019, and mental health P = 0.0003). CONCLUSION: Our findings demonstrate a high prevalence of RLS in PPS, and that RLS occurrence may significantly influence the HRQoL and fatigue of PPS patients. A hypothetical link between neuroanatomical and inflammatory mechanisms in RLS and PPS is suggested.

Cerebrospinal-fluid orexin levels and daytime somnolence in frontotemporal dementia.

Daytime somnolence and sleep-wake cycle disturbances are commonly encountered symptoms in Frontotemporal Dementia (FTD). Orexin-A (Hypocretin-1) is a hypothalamic neuropeptide regulating the sleep-wake rhythm. We investigated the cerebrospinal-fluid (CSF) orexin levels in a population of FTD patients and evaluated whether there is a relationship between daytime somnolence and CSF orexin concentrations. CSF orexin levels were measured in a sample of FTD patients (n = 11) compared to a population of non-demented controls (n = 13) similar for age and sex. Moreover, CSF orexin concentrations were correlated with daytime somnolence investigated by means of the Epworth Sleepiness Scale (ESS) in both FTD patients and controls. FTD patients showed CSF orexin concentrations (164.3 ± 66.45 vs 170.81 ± 42.73 pg/mL) and ESS scores (7.45 ± 4.36 vs 3.84 ± 1.82) not different from controls. However, three FTD patients showed pathological daytime sleepiness (ESS > 10) coupled with the lowest CSF orexin levels. In addition, we found a significant negative correlation between CSF orexin levels and ESS scores in the FTD population (R = -0.91; p < 0.0001), which was not evident in the control group (R = 0.16; p > 0.05). This is the first study investigating CSF orexin concentrations in FTD. We did not find differences in CSF orexin concentrations between FTD patients and controls. However, a significant negative correlation between daytime somnolence and CSF orexin levels was evident in FTD patients. Moreover, we have found that pathological daytime somnolence was evident in those FTD patients with the lowest CSF orexin levels. Based on these findings, we argued that lower orexin levels may be permissive for increased daytime somnolence in FTD.

Sleep disorders in myotonic dystrophy type 2: a controlled polysomnographic study and self-reported questionnaires.

BACKGROUND AND PURPOSE: There is a paucity of data available regarding the occurrence of sleep disorders in myotonic dystrophy type 2 (DM2). In this study the sleep-wake cycle and daytime sleepiness were investigated in DM2 patients and compared with results from healthy subjects and myotonic dystrophy type 1 (DM1) patients. METHODS: Twelve DM2 outpatients, 12 age- and sex-matched healthy controls and 18 DM1 patients were recruited. Subjective quality of sleep was assessed by means of the Pittsburgh Sleep Quality Index (PSQI). Both the Epworth Sleepiness Scale and the Daytime Sleepiness Scale were performed in order to evaluate excessive daytime sleepiness (EDS). All participants underwent polysomnographic monitoring over 48 h as well as the Multiple Sleep Latency Test. RESULTS: Sleep efficiency was < 90% in 12/12 DM2 patients, and significantly reduced when compared with controls or with DM1. Decreased sleep efficiency was associated with sleep-disordered breathing in seven out of 12 DM2 patients and/or periodic limbs movements of sleep (PLMS) in three out of eight patients. Six DM2 patients showed REM sleep without atonia, whereas none of the controls or DM1 patients showed REM sleep dysregulation. The global PSQI score was higher in DM2 patients than in controls and DM1 patients. CONCLUSIONS: Sleep quality in DM2 patients is poorer than in DM1 patients and controls. Sleep apnea is the most common sleep disorder in DM2 patients. Obstructive sleep apnea and sleep fragmentation may represent the main cause of EDS, whereas PLMS is a frequent finding in DM1.

Lacosamide as add-on treatment of focal symptomatic epilepsy in a patient with alcoholic liver cirrhosis.

The occurrence of epileptic seizures in the presence of hepatic disease is not uncommon in clinical practice. Selecting an appropriate AED for patients affected by liver failure who have new-onset epileptic seizures can be challenging. We describe a 64-year-old man affected by liver cirrhosis. The patient developed partial epilepsy with secondary generalization because of an intracerebral hemorrhage in the left parieto-occipital regions. After the neurosurgery procedure, seizures reappeared and were initially managed with levetiracetam. After one month, the patient experienced clusters of seizures while on stable treatment with levetiracetam. Pregabalin as add-on was not tolerated; therefore, he received a low dose of phenobarbital as add-on treatment. The patient developed hepatic encephalopathy. Phenobarbital was immediately stopped, and oral lacosamide was added. A rapid recovery of encephalopathy with a 6-month seizure freedom was obtained. The patient died 6 months later because of progressive impairment of liver function. Lacosamide may represent an alternative to other AEDs in patients with liver failure; however, further prospective evaluation of its efficacy and safety in this clinical setting is needed.

Estimation of liver iron concentration by dual energy CT images: influence of X-ray energy on sensitivity.

In hemochromatosis an abnormal accumulation of iron is present in parenchymal organs and especially in liver. Among the several techniques employed to diagnose the iron overload, magnetic resonance imaging (MRI) and Computed Tomography (CT) are the most promising non-invasive ones. MRI is largely used but shows limitation including an overestimation of iron and inability to quantify iron at very high concentrations. Therefore, some research groups are focusing on the estimation of iron concentration by CT images. Single X-ray CTs are not able to accurately perform this task in case of the presence of confounding factors (e.g., fat). A potential solution to overcome this concern is the employment of Dual-Energy CT (DECT). The aim of this work is to investigate influence of the kVp and mAs on CT number sensitivity to iron concentration. A phantom with test tubes filled with homogenized porcine liver at different iron concentrations, has been scanned with DECT at different mAs. The images have been analyzed using an ad-hoc developed algorithm which allows minimizing the influence of air bubbles present in the homogenized. Data show that the sensitivity is strongly influenced by kVp (its value almost halves from 80 kVp to 140 kVp; e.g. 0.41 g·µmol(-1) and 0.19 g·µmol(-1) at 80 kVp/120 mAs and 140 kVp/60 mAs respectively), on the other hand the influence of mAs value is negligible.

Sleep-Wake Cycle and Daytime Sleepiness in the Myotonic Dystrophies.

Myotonic dystrophy is the most common type of muscular dystrophy in adults and is characterized by progressive myopathy, myotonia, and multiorgan involvement. Two genetically distinct entities have been identified, myotonic dystrophy type 1 (DM1 or Steinert's Disease) and myotonic dystrophy type 2 (DM2). Myotonic dystrophies are strongly associated with sleep dysfunction. Sleep disturbances in DM1 are common and include sleep-disordered breathing (SDB), periodic limb movements (PLMS), central hypersomnia, and REM sleep dysregulation (high REM density and narcoleptic-like phenotype). Interestingly, drowsiness in DM1 seems to be due to a central dysfunction of sleep-wake regulation more than SDB. To date, little is known regarding the occurrence of sleep disorders in DM2. SDB (obstructive and central apnoea), REM sleep without atonia, and restless legs syndrome have been described. Further polysomnographic, controlled studies are strongly needed, particularly in DM2, in order to clarify the role of sleep disorders in the myotonic dystrophies.

Spasticity as an ictal pattern due to excitotoxic upper motor neuron damage.

We describe the case of a man who presented with spasticity and aphasia related to continuous electroencephalographic epileptic activity in the left frontal-temporal regions. Magnetic resonance imaging (MRI) documented in diffusion-weighted images (DWI) two areas of restricted diffusion in the left frontal and temporal cortex. After starting treatment with levetiracetam 3000 mg/day there was progressive recovery of the clinical picture as well as the gradual disappearance of the electroencephalographic seizure activity and the vanishing of areas of restricted diffusion in brain MRI. Based on the clinical, EEG and MRI data, we hypothesized that both aphasia and spasticity represented ictal signs. To our knowledge, this is the first case report of ictal spasticity.