Therapeutic interventions and adjustments in the management of Parkinson disease: role of combined carbidopa/levodopa/entacapone (Stalevo®)

Parkinson disease (PD) is a neurodegenerative disorder characterized by 3 cardinal motor symptoms: resting tremor, rigidity, and bradykinesia. Since its introduction 40 years ago, levodopa has represented the gold standard for dopaminergic stimulation therapy in patients with PD. Levodopa is routinely combined with a dopa-decarboxylase inhibitor (DDCI) to prevent the conversion of levodopa into dopamine in peripheral circulation. However, up to 80% of patients treated with continuous levodopa manifest the onset of disabling motor complications capable of producing an adverse effect on quality of life as the disease progresses. In recent years, a new, safe, and efficacious armamentarium of treatment options has been provided by the marketing of the catechol-O-methyltransferase (COMT) inhibitor, entacapone, a peripheral blocker of dopa to 3-0-methyldopa metabolism, which increments levodopa brain availability. When administered with levodopa, entacapone conjugates the rapid onset of levodopa-induced effects with a protracted efficiency, thus providing additional benefits to classic levodopa treatment by increasing “on” time in fluctuating PD patients, and theoretically providing a more continuous and physiological-like stimulation of dopamine receptors implying a reduced risk of motor complications. In this context, the use of a single administration of combined carbidopa/ levodopa/entacapone (Stalevo®) in the treatment of PD affords clinical improvements similar to those obtained by 2 separate tablets (ie, levodopa/DDCI and entacapone), although the former produces a more positive effect on quality of life than the latter. Additionally, the STalevo Reduction In Dyskinesia Evaluation (STRIDE-PD) study was designed with the aim of demonstrating that the combination of levodopa, carbidopa, and entacapone, used as initial levodopa therapy, significantly delays the onset of dyskinesias compared with the conventional levodopa/carbidopa formulation. Unfortunately, STRIDEPD failed to prove the benefit of continuous dopaminergic stimulation with triple therapy in a clinical setting. Recently, the effect of combined COMT inhibitor with levodopa administration in reducing homocysteine synthesis has been described. To this regard, clear evidence has been presented indicating homocysteine as a risk factor for vascular diseases, cognitive impairment, and dementia. Several studies have discussed the potential of entacapone as adjunct to levodopa/ DDCI in reducing plasma homocysteine levels with contrasting results

Changes in MEG resting-state networks are related to cognitive decline in type 1 diabetes mellitus patients

OBJECTIVE: Integrity of resting-state functional brain networks (RSNs) is important for proper cognitive functioning. In type 1 diabetes mellitus (T1DM) cognitive decrements are commonly observed, possibly due to alterations in RSNs, which may vary according to microvascular complication status. Thus, we tested the hypothesis that functional connectivity in RSNs differs according to clinical status and correlates with cognition in T1DM patients, using an unbiased approach with high spatio-temporal resolution functional network.; METHODS: Resting-state magnetoencephalographic (MEG) data for T1DM patients with (n=42) and without (n=41) microvascular complications and 33 healthy participants were recorded. MEG time-series at source level were reconstructed using a recently developed atlas-based beamformer. Functional connectivity within classical frequency bands, estimated by the phase lag index (PLI), was calculated within eight commonly found RSNs. Neuropsychological tests were used to assess cognitive performance, and the relation with RSNs was evaluated.; RESULTS: Significant differences in terms of RSN functional connectivity between the three groups were observed in the lower alpha band, in the default-mode (DMN), executive control (ECN) and sensorimotor (SMN) RSNs. T1DM patients with microvascular complications showed the weakest functional connectivity in these networks relative to the other groups. For DMN, functional connectivity was higher in patients without microangiopathy relative to controls (all p<0.05). General cognitive performance for both patient groups was worse compared with healthy controls. Lower DMN alpha band functional connectivity correlated with poorer general cognitive ability in patients with microvascular complications.; DISCUSSION: Altered RSN functional connectivity was found in T1DM patients depending on clinical status. Lower DMN functional connectivity was related to poorer cognitive functioning. These results indicate that functional connectivity may play a key role in T1DM-related cognitive dysfunction

Functional outcomes after transoral CO2 laser treatment for posterior glottic stenosis: a bicentric case series

Purpose The aim of this study is to evaluate functional outcomes in terms of decannulation rate and quality of life of patients affected by PGS (Grades I-IV) treated only by transoral CO2 laser microsurgery (TOLMS) in two tertiary centers. Methods An observational retrospective study was carried out, enrolling 22 patients affected by PGS who were treated by a transoral approach at two tertiary referral centers. Surgical treatment included TOLMS with tailored laser resection of the scar tissue combined with posterior cordotomy, resurfacing of the raw area with mucosal microflap, or placement of a Montgomery T-tube or Keel stent. All patients were evaluated and staged preoperatively and postoperatively, at least 6 months after the surgery. Functional outcomes were objectively evaluated by the Airway-Dysphonia-Voice-Swallowing (ADVS) staging system, Voice Handicap Index-30 (VHI-30), and Eating Assessment Tool-10 (EAT-10) questionnaires. Results Quality of life significantly improved as measured by the VHI-30 questionnaire with a median variation of - 31.0 (p = 0.003), the EAT-10 with a median variation of - 4.0 (p = 0.042), and the ADVS with a median variation of - 3.5 (p < 0.001). No significant changes were observed in swallowing scores. We were able to decannulate 7 of 9 patients (almost 80%) with previous tracheotomy. Conclusion In conclusion, even if there is still no general agreement on an exact therapeutic algorithm to treat PGS, our results confirm that transoral surgery, in terms of scar tissue removal, combined in selected patients with posterior cordotomy and pedicled local flaps and/or placement of stents, represents a safe and effective surgical approach even for more severe PGS

Case Report: Modulation of Effective Connectivity in Brain Networks after Prosthodontic Tooth Loss Repair

INTRODUCTION. Recent neuroimaging studies suggest that dental loss replacements induce changes in neuroplasticity as well as in correlated connectivity between brain networks. However, as the typical temporal delay in detecting brain activity by neuroimaging cannot account for the influence one neural system exerts over another in a context of real activation (“effective” connectivity), it seems of interest to approach this dynamic aspect of brain networking in the time frame of milliseconds by exploiting electroencephalographic (EEG) data. MATERIAL AND METHODS. The present study describes one subject who received a new prosthodontic provisional implant in substitution for previous dental repairs. Two EEG sessions led with a portable device were recorded before and after positioning the new dental implant. By following MATLAB-EEGLAB processing supported by the plugins FIELDTRIP and SIFT, the independent component analysis (ICA) derived from EEG raw signals was rendered as current density fields and interpolated with the dipoles generated by each electrode for a dynamic study of the effective connectivity. One more recording session was undertaken six months after the placement of the final implant. RESULTS. Compared to the baseline, the new prosthodontic implant induced a novel modulation of the neuroplasticity in sensory-motor areas which was maintained following the definitive implant after six months, as revealed by changes in the effective connectivity from the basal strong enslavement of a single brain area over the others, to an equilibrate inter-related connectivity evenly distributed along the frontotemporal regions of both hemispheres. CONCLUSIONS. The rapid shift of the effective connectivity after positioning the new prosthodontic implant and its substantial stability after six months suggest the possibility that synaptic modifications, induced by novel sensory motor conditions, modulate the neuroplasticity and reshape the final dynamic frame of the interarea connectivity. Moreover, given the viability of the EEG practice, this approach could be of some interest in assessing the association between oral pathophysiology and neuronal networking

Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment

Acknowledgments This study is supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London (FM and HZ), the Medical Research Council grant (grant reference MR/L013142/1, FM), SMA-Europe grant (FM and HZ) and Great Ormond Street Hospital Children’s Charity grants (FM and HZ). JEM is supported by Great Ormond Street Hospital Children’s Charity. PS is supported by Bill Marshall Fellowship and The CP Charitable Trust at Great Ormond Street Hospital and UCL. SHP is supported by SMA Trust and Euan MacDonald Centre for Motor Neurone Disease Research.Peer reviewedPublisher PD

Neuroimaging, Networking and Systems Biology: The New Way to Investigate Pathologies with Neurological System Implications. The example of Tourette Syndrome as a Pilot Study

Purpose: Recently, many academic research groups have focused their attention on changes in human brain networks related to several kinds of pathologies and diseases, generating the new discipline termed “Network Medicine”. Purpose of this paper is to investigate the ability of the Network Medicine to give deeper insights in the functionality of brain activity. Material and Methods: In the proposed study of Tourette syndrome, we have investigated with the functional magnetic resonance imaging the possibility that the mechanisms associated with the monitoring and internal control of movements were compromised in individuals with Tourette syndrome; we enrolled 20 Tourette Syndrome patients in comparison with a healthy Controls group of 15 subjects matching for age and sex distribution. We proposed, for the fMRI analysis, a novel task based on the execution of switching between complex movements on demand. Results: The elementary activation model found that the effort related to the task in comparing Tourettic vs Controls mainly concerns the areas of the Gyrus of the Cingulum, the precuneus and the thalamic area of the ventral-lateral nucleus. In particular, the BA11 plays an essential role in the Tourette Patients related to the continue tentative to correct the TIC. Considering the status of the pilot study of this work, we remark the power of proposed methods to investigate the complex interaction of the brain networks. Conclusion: Alteration in brain activity for a population of Tourette Syndrome patients is evaluable by the use of complex indexes, results confirm the literature about this pathology and these medical physics methods can be applied to all neurological diseases investigation by opportune task-driven experiments or by resting state fc-MRI experiments

Prevalence of Anisakis spp. and Hysterothylacium spp. larvae in teleosts and cephalopods sampled from waters off Sardinia.

A study was carried out on the presence of Anisakis and Hysterothylacium larvae in fish and cephalopods caught in Sardinian waters. A total of 369 specimens of 24 different species of teleosts and 5 species of cephalopods were collected from different fishing areas of Sardinia. Larvae were detected and isolated by both visual inspection and enzymatic digestion. These methods allowed Anisakis type I and type II third-stage larvae and Hysterothylacium third-and fourth-stage larvae to be detected. The prevalence, mean intensity, and mean abundance were calculated. The results obtained showed the highest prevalence of Anisakidae in Zeus faber (100%) and of Anisakis in Micromesistius poutassou (87.5%). The highest prevalence of Anisakis type I larvae was in M. poutassou (81.2%), and that of Anisakis type II larvae was in Todarodes sagittatus (20%). The highest values for prevalence, mean intensity, and mean abundance for Hysterothylacium were found in Z. faber. These prevalences and the mean intensity and abundance were higher than those reported by different authors in other Mediterranean areas. This may be because the enzymatic digestive method used in this research resulted in higher recovery levels. The data suggest that Sardinia may be a high-risk area for zoonotic diseases and that measures such as information campaigns, aimed at both sanitary service personnel and consumers, should be employed to limit the spread of such zoonosis. Copyright © International Association for Food Protection

The implication of neuroactive steroids in Tourette syndrome pathogenesis: a role for 5α-reductase?

This is the peer reviewed version of the following article: Bortolato, M., Frau, R., Godar, S. C., Mosher, L. J., Paba, S., Marrosu, F. and Devoto, P. (2013), The Implication of Neuroactive Steroids in Tourette's Syndrome Pathogenesis: A Role for 5α-Reductase?. J Neuroendocrinol, 25: 1196–1208. doi:10.1111/jne.12066, which has been published in final form at http://doi.org/10.1111/jne.12066. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Tourette syndrome (TS) is a neurodevelopmental disorder characterized by recurring motor and phonic tics. The pathogenesis of TS is thought to reflect dysregulations in the signaling of dopamine (DA) and other neurotransmitters, which lead to excitation/inhibition imbalances in cortico-striato-thalamocortical circuits. The causes of these deficits may reflect complex gene × environment × sex (G×E×S) interactions; indeed, the disorder is markedly predominant in males, with a male-to-female prevalence ratio of ~4:1. Converging lines of evidence point to neuroactive steroids as likely molecular candidates to account for GxExS interactions in TS. Building on these premises, our group has begun examining the possibility that alterations in the steroid biosynthetic process may be directly implicated in TS pathophysiology; in particular, our research has focused on 5α-reductase (5αR), the enzyme catalyzing the key rate-limiting step in the synthesis of pregnane and androstane neurosteroids. In clinical and preclinical studies, we found that 5αR inhibitors exerted marked anti-DAergic and tic-suppressing properties, suggesting a central role for this enzyme in TS pathogenesis. Based on these data, we hypothesize that enhancements in 5αR activity in early developmental stages may lead to an inappropriate activation of the “backdoor” pathway for androgen synthesis from adrenarche until the end of puberty. We predict that the ensuing imbalances in steroid homeostasis may impair the signaling of DA and other neurotransmitters, ultimately resulting in the facilitation of tics and other behavioral abnormalities in TS

An unusual delusion of duplication in a patient affected by Dementia with Lewy bodies

Background: Dementia with Lewy bodies (DLB) is the second most frequent diagnosis of progressive degenerative dementia in older people. Delusions are common features in DLB and, among them, Capgras syndrome represents the most frequent disturbance, characterized by the recurrent and transient belief that a familiar person, often a close family member or caregiver, has been replaced by an identical-looking imposter. However, other delusional conditions near to misidentification syndromes can occur in DLB patients and may represent a major psychiatric disorder, although rarely studied systematically. Case presentation: We reported on a female patient affected by DLB who presented with an unusual delusion of duplication. Referring to the female professional caregiver engaged by her relatives for her care, the patient constantly described the presence of two different female persons, with a disorder framed in the context of a delusion of duplication. A brain 99Tc-hexamethylpropyleneamineoxime SPECT was performed showing moderate hypoperfusion in both occipital lobes, and associated with marked decreased perfusion in parieto-fronto-temporal lobes bilaterally. Conclusions: An occipital hypoperfusion was identified, although in association with a marked global decrease of perfusion in the remaining lobes. The role of posterior lobes is certainly important in all misidentification syndromes where a natural dissociation between recognition and identification is present. Moreover, the concomitant presence of severe attentional and executive deficits evocative for a frontal syndrome and the marked global decrease of perfusion in the remaining lobes at the SPECT scan also suggest a possible dysfunction in an abnormal connectivity between anterior and posterior areas