Botulinum neurotoxin as early treatment in acute-onset lesional hemiballism.

BACKGROUND: Hemiballism (HB) and hemichorea (HC) are the most frequent secondary movement disorders, usually caused by cerebrovascular diseases. In only a minority of cases, these involuntary movements are not self-limited, and they may severely compromise patients' quality of life, so that symptomatic treatments are required. Typical and atypical neuroleptics as well as tetrabenazine are considered therapies of choice. However, anecdotal reports of antiseizures medications and botulinum neurotoxin injection effectiveness have been described. METHODS: We described a case of severely disabling acute-onset lesional HB/HC, where high dosage of first- and second-line therapies was contraindicated due to patient's comorbidities. RESULTS: After botulin neurotoxin (BoNT) injections in his left upper limb muscles (biceps brachii, triceps brachii, teres major, and deltoid), the patient experienced gradual reduction of hyperkinetic movements. The gradual discontinuation of topiramate (TPM) did not worsen the clinical picture. DISCUSSION: The reduction of hyperkinetic movements led to rhabdomyolysis resolution as well as cutaneous injuries healing with renal function improvement, so that the patient was able to be eligible for rehabilitation, which was prevented by HB/HC itself. The clinical improvement was consistent with BoNT pharmacokinetic. The administration of BoNT early after the onset of lesional HB/HC remarkably modified the clinical management and drove toward comorbidities resolution and rehabilitation. CONCLUSION: The present case highlights the effectiveness of unconventional therapeutic options in disabling acute onset lesional HB/HC when first-line therapies are contraindicated. Particularly, this report may encourage BoNT application in the early stage of movement disorder emergencies.

Involvement of Mitochondria in the Selective Response to Microsecond Pulsed Electric Fields on Healthy and Cancer Stem Cells in the Brain.

In the last few years, pulsed electric fields have emerged as promising clinical tools for tumor treatments. This study highlights the distinct impact of a specific pulsed electric field protocol, PEF-5 (0.3 MV/m, 40 µs, 5 pulses), on astrocytes (NHA) and medulloblastoma (D283) and glioblastoma (U87 NS) cancer stem-like cells (CSCs). We pursued this goal by performing ultrastructural analyses corroborated by molecular/omics approaches to understand the vulnerability or resistance mechanisms triggered by PEF-5 exposure in the different cell types. Electron microscopic analyses showed that, independently of exposed cells, the main targets of PEF-5 were the cell membrane and the cytoskeleton, causing membrane filopodium-like protrusion disappearance on the cell surface, here observed for the first time, accompanied by rapid cell swelling. PEF-5 induced different modifications in cell mitochondria. A complete mitochondrial dysfunction was demonstrated in D283, while a mild or negligible perturbation was observed in mitochondria of U87 NS cells and NHAs, respectively, not sufficient to impair their cell functions. Altogether, these results suggest the possibility of using PEF-based technology as a novel strategy to target selectively mitochondria of brain CSCs, preserving healthy cells.

Interplay between speech and gait variables in Parkinson's disease patients treated with subthalamic nucleus deep brain stimulation: A long-term instrumental assessment.

OBJECTIVE: To evaluate correlations between speech and gait parameters in the long term and under different medication and subthalamic nucleus deep brain stimulation (STN-DBS) conditions in a cohort of advanced Parkinson's disease (PD) patients. METHODS: This observational study included consecutive PD patients treated with bilateral STN-DBS. Axial symptoms were evaluated using a standardized clinical-instrumental approach. Speech and gait were assessed by perceptual and acoustic analyses and by the instrumented Timed Up and Go (iTUG) test, respectively. Disease motor severity was evaluated with the total score and subscores of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III. Different stimulation and drug treatment conditions were assessed: on-stimulation/off-medication, off-stimulation/off-medication, and on-stimulation/on-medication. RESULTS: Twenty-five PD patients with a 5-year median follow-up after surgery (range 3-7 years) were included (18 males; disease duration at surgery: 10.44 [SD 4.62] years; age at surgery: 58.40 [SD 5.73] years). In the off-stimulation/off-medication and on-stimulation/on-medication conditions, patients who spoke louder had also the greater acceleration of the trunk during gait; whereas in the on-stimulation/on-medication condition only, patients with the poorer voice quality were also the worst to perform the sit to stand and gait phases of the iTUG. Conversely, patients with the higher speech rate performed well in the turning and walking phases of the iTUG. CONCLUSIONS: This study underlines the presence of different correlations between treatment effects of speech and gait parameters in PD patients treated with bilateral STN-DBS. This may allow us to better understand the common pathophysiological basis of these alterations and to develop a more specific and tailored rehabilitation approach for axial signs after surgery.

3D Cell Models in Radiobiology: Improving the Predictive Value of In Vitro Research.

Cancer is intrinsically complex, comprising both heterogeneous cellular composition and extracellular matrix. In vitro cancer research models have been widely used in the past to model and study cancer. Although two-dimensional (2D) cell culture models have traditionally been used for cancer research, they have many limitations, such as the disturbance of interactions between cellular and extracellular environments and changes in cell morphology, polarity, division mechanism, differentiation and cell motion. Moreover, 2D cell models are usually monotypic. This implies that 2D tumor models are ineffective at accurately recapitulating complex aspects of tumor cell growth, as well as their radiation responses. Over the past decade there has been significant uptake of three-dimensional (3D) in vitro models by cancer researchers, highlighting a complementary model for studies of radiation effects on tumors, especially in conjunction with chemotherapy. The introduction of 3D cell culture approaches aims to model in vivo tissue interactions with radiation by positioning itself halfway between 2D cell and animal models, and thus opening up new possibilities in the study of radiation response mechanisms of healthy and tumor tissues.

Genetic diversity of Staphylococcus aureus influences disease phenotype of systemic lupus erythematosus.

OBJECTIVE: We investigated the genetic diversity, molecular epidemiology and evolutionary dynamics of Staphylococcus aureus (SA) isolated from SLE patients by means of phylogenetic analysis. METHODS: Consecutive SLE patients (ACR 1997 criteria) were enrolled: clinical/laboratory data were collected and nasal swab for SA identification was performed. On the basis of the translation elongation factor (tuf) gene, a phylogenetic analysis was performed to investigate relationships and to assess significant clades. Selective pressure analysis was used to investigate the evolution of the SA tuf gene. The gene sequences from non-SLE individuals, downloaded from the GenBank database, were compared through phylogenetic analysis with the tuf gene from SLE patients. RESULTS: We enrolled 118 patients [M/F 10/108; median (interquartile range (IQR)) age 45.5 (13.2) years; median (IQR) disease duration 120 (144) months]. Twenty-four patients (20.3%) were SA carriers (SA+), three of them MRSA. SA+ SLE showed significantly higher SLEDAI-2k values [SA+: median (IQR) 2 (3.75); SA-: 0 (2); P = 0.04]. The phylogenetic analysis, restricted to 21 non-MRSA SA+, revealed a statistically supported larger clade (A, n = 17) and a smaller one (B, n = 4). Patients located in clade A showed a significantly higher prevalence of joint involvement (88.2%) in comparison with clade B (50.0%, P < 0.0001) and SA- (62.7%, P < 0.0001). Haematological manifestations were significantly more frequent in clade A (64.7%) compared with B (50.0%, P = 0.004). CONCLUSION: We suggest a possible role of SA nasal carriage status in SLE disease activity. Moreover, our findings support the hypothesis that bacterial genetic variants may be associated with specific disease features.

Parkinson's disease patients' needs during the COVID-19 pandemic in a red zone: A framework analysis of open-ended survey questions.

BACKGROUND AND PURPOSE: During the first phase of the COVID-19 pandemic, a lockdown was imposed in Italy. The aim of this study was to investigate the perceptions, feelings and unmet needs of Parkinson's disease (PD) patients who experienced the 2-month lockdown in a "red zone" in the northern part of Italy during the COVID-19 outbreak. METHODS: The study had a descriptive design that used a cross-sectional online survey which included open-ended questions to elicit responses on the participant's feelings concerning their risk of contracting coronavirus, how their physical activity had changed, and their personal needs, dictated by their condition, which were not met in this pandemic period as compared to previous periods. Demographic data were analysed using descriptive frequencies, while the open-ended questions were analysed using thematic framework analysis. RESULTS: The study included 103 participants (63 men/40 women [61.17 vs. 38.83%]). Framework analysis led to the identification of four main themes: (i) fearing the risk of contracting coronavirus; (ii) reduction of physical activity; (iii) perception of the risk of not being able to access outpatient clinics or support services; and (iv) negative experiences of the important reduction in socialization. The perceptions of unmet needs appeared to be greater than the actual experience, particularly for the reduction in physical activity and the interruption of contacts with the neurologist and other specialists. CONCLUSIONS: This study highlights how perceptions and actual experience shape the meaning of living with PD during the pandemic. Worth noting is the divergence between perceptions and real impact in some aspects of the COVID-19 outbreak.

Long-Term Effects of Ionizing Radiation on the Hippocampus: Linking Effects of the Sonic Hedgehog Pathway Activation with Radiation Response.

Radiation therapy represents one of the primary treatment modalities for primary and metastatic brain tumors. Although recent advances in radiation techniques, that allow the delivery of higher radiation doses to the target volume, reduce the toxicity to normal tissues, long-term neurocognitive decline is still a detrimental factor significantly affecting quality of life, particularly in pediatric patients. This imposes the need for the development of prevention strategies. Based on recent evidence, showing that manipulation of the Shh pathway carries therapeutic potential for brain repair and functional recovery after injury, here we evaluate how radiation-induced hippocampal alterations are modulated by the constitutive activation of the Shh signaling pathway in Patched 1 heterozygous mice (Ptch1+/-). Our results show, for the first time, an overall protective effect of constitutive Shh pathway activation on hippocampal radiation injury. This activation, through modulation of the proneural gene network, leads to a long-term reduction of hippocampal deficits in the stem cell and new neuron compartments and to the mitigation of radio-induced astrogliosis, despite some behavioral alterations still being detected in Ptch1+/- mice. A better understanding of the pathogenic mechanisms responsible for the neural decline following irradiation is essential for identifying prevention measures to contain the harmful consequences of irradiation. Our data have important translational implications as they suggest a role for Shh pathway manipulation to provide the therapeutic possibility of improving brain repair and functional recovery after radio-induced injury.

Out-of-Field Hippocampus from Partial-Body Irradiated Mice Displays Changes in Multi-Omics Profile and Defects in Neurogenesis.

The brain undergoes ionizing radiation exposure in many clinical situations, particularly during radiotherapy for brain tumors. The critical role of the hippocampus in the pathogenesis of radiation-induced neurocognitive dysfunction is well recognized. The goal of this study is to test the potential contribution of non-targeted effects in the detrimental response of the hippocampus to irradiation and to elucidate the mechanisms involved. C57Bl/6 mice were whole body (WBI) or partial body (PBI) irradiated with 0.1 or 2.0 Gy of X-rays or sham irradiated. PBI consisted of the exposure of the lower third of the mouse body, whilst the upper two thirds were shielded. Hippocampi were collected 15 days or 6 months post-irradiation and a multi-omics approach was adopted to assess the molecular changes in non-coding RNAs, proteins and metabolic levels, as well as histological changes in the rate of hippocampal neurogenesis. Notably, at 2.0 Gy the pattern of early molecular and histopathological changes induced in the hippocampus at 15 days following PBI were similar in quality and quantity to the effects induced by WBI, thus providing a proof of principle of the existence of out-of-target radiation response in the hippocampus of conventional mice. We detected major alterations in DAG/IP3 and TGF-ß signaling pathways as well as in the expression of proteins involved in the regulation of long-term neuronal synaptic plasticity and synapse organization, coupled with defects in neural stem cells self-renewal in the hippocampal dentate gyrus. However, compared to the persistence of the WBI effects, most of the PBI effects were only transient and tended to decrease at 6 months post-irradiation, indicating important mechanistic difference. On the contrary, at low dose we identified a progressive accumulation of molecular defects that tended to manifest at later post-irradiation times. These data, indicating that both targeted and non-targeted radiation effects might contribute to the pathogenesis of hippocampal radiation-damage, have general implications for human health.

SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the α-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. OBJECTIVES: The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. METHODS: Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. RESULTS: In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P < .001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P < .0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. CONCLUSIONS: These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society.

Multi-drug resistant Pseudomonas aeruginosa nosocomial strains: Molecular epidemiology and evolution.

Pseudomonas aeruginosa causes a wide variety of nosocomial infections. In the study, phylogenetic, selective pressure analysis and homology modelling were applied to oprD efflux pump gene with the aim to characterize multi-drug resistant strains circulating in the nosocomial setting, their transmission dynamics and ongoing evolution. One hundred ninety-three consecutive inpatients with Pseudomonas aeruginosa infection were enrolled at the University Campus Bio-Medico of Rome, between January 2015 and December 2016. oprD gene was sequenced in 20 nosocomial multi-drug resistant P. aeruginosa strains. Phylogeographic, selective pressure, residue conservation analysis and homology modelling were performed. Clinical epidemiological data were extracted from patient medical records. Multi-drug resistant strains accounted for the 36% of total strains and were responsible of 20 cases of nosocomial infections. P. aeruginosa infections occurred prevalently in the West area, especially at the location IIIW and in the Geriatric ward. The time of the most recent common ancestor indicated that strains could have been introduced in the hospital since the end of the year 2009 with the most probable location in general surgery ward. By selective pressure analysis, 29 positions under diversifying selection have been identified and mapped onto the OprD model. Most of the observed residue substitutions are predicted to be destabilizing and some of them occurred in the Loops 2 and 3 that are involved in solute selection and carbapenem susceptibility. The molecular and evolutionary analysis of Multi-drug resistant strains circulating in the nosocomial setting may provide useful insights into the epidemiology and the mechanisms leading to resistance, contributing to infection control improvement.

The Patched 1 tumor-suppressor gene protects the mouse lens from spontaneous and radiation-induced cataract.

Age-related cataract is the most common cause of visual impairment. Moreover, traumatic cataracts form after injury to the eye, including radiation damage. We report herein that sonic hedgehog (Shh) signaling plays a key role in cataract development and in normal lens response to radiation injury. Mice heterozygous for Patched 1 (Ptch1), the Shh receptor and negative regulator of the pathway, develop spontaneous cataract and are highly susceptible to cataract induction by exposure to ionizing radiation in early postnatal age, when lens epithelial cells undergo rapid expansion in the lens epithelium. Neonatally irradiated and control Ptch1(+/-) mice were compared for markers of progenitors, Shh pathway activation, and epithelial-to-mesenchymal transition (EMT). Molecular analyses showed increased expression of the EMT-related transforming growth factor ß/Smad signaling pathway in the neonatally irradiated lens, and up-regulation of mesenchymal markers Zeb1 and Vim. We further show a link between proliferation and the stemness property of lens epithelial cells, controlled by Shh. Our results suggest that Shh and transforming growth factor ß signaling cooperate to promote Ptch1-associated cataract development by activating EMT, and that the Nanog marker of pluripotent cells may act as the primary transcription factor on which both signaling pathways converge after damage. These findings highlight a novel function of Shh signaling unrelated to cancer and provide a new animal model to investigate the molecular pathogenesis of cataract formation.

Hyperexcitable C nociceptors in fibromyalgia.

OBJECTIVE: To test the hypothesis that peripheral C nociceptor function may be abnormal in fibromyalgia and that C nociceptor dysfunction may contribute to the symptoms reported by these patients. METHODS: Microneurography was used to record C nociceptors of 30 female patients meeting criteria for fibromyalgia and compared with recordings from 17 female patients with small-fiber neuropathy and 9 female controls. RESULTS: We obtained stable recordings of 186 C nociceptors in the fibromyalgia group, 114 from small-fiber neuropathy patients, and 66 from controls. The mechanosensitive nociceptors in the fibromyalgia patients behaved normally, but the silent nociceptors in 76.6% of fibromyalgia patients exhibited abnormalities. Spontaneous activity was detected in 31% of silent nociceptors in fibromyalgia, 34% in small-fiber neuropathy, and 2.2% in controls. Sensitization to mechanical stimulation was found in 24.2% of silent nociceptors in fibromyalgia, 22.7% in small-fiber neuropathy, and 3.7% in controls. Abnormally high slowing of conduction velocity when first stimulated at 0.25Hz was more common in fibromyalgia. INTERPRETATION: We show for the first time that the majority of fibromyalgia patients have abnormal C nociceptors. Many silent nociceptors exhibit hyperexcitability resembling that in small-fiber neuropathy, but high activity-dependent slowing of conduction velocity is more common in fibromyalgia patients, and may constitute a distinguishing feature. We infer that abnormal peripheral C nociceptor ongoing activity and increased mechanical sensitivity could contribute to the pain and tenderness suffered by patients with fibromyalgia.

Dopamine-agonists and impulsivity in Parkinson's disease: impulsive choices vs. impulsive actions.

The control of impulse behavior is a multidimensional concept subdivided into separate subcomponents, which are thought to represent different underlying mechanisms due to either disinhibitory processes or poor decision-making. In patients with Parkinson's disease (PD), dopamine-agonist (DA) therapy has been associated with increased impulsive behavior. However, the relationship among these different components in the disease and the role of DA is not well understood. In this imaging study, we investigated in PD patients the effects of DA medication on patterns of brain activation during tasks testing impulsive choices and actions. Following overnight withdrawal of antiparkinsonian medication, PD patients were studied with a H2 ((15)) O PET before and after administration of DA (1 mg of pramipexole), while they were performing the delay discounting task (DDT) and the GoNoGo Task (GNG). We observed that pramipexole augmented impulsivity during DDT, depending on reward magnitude and activated the medial prefrontal cortex and posterior cingulate cortex and deactivated ventral striatum. In contrast, the effect of pramipexole during the GNG task was not significant on behavioral performance and involved different areas (i.e., lateral prefrontal cortex). A voxel-based correlation analysis revealed a significant negative correlation between the discounting value (k) and the activation of medial prefrontal cortex and posterior cingulate suggesting that more impulsive patients had less activation in those cortical areas. Here we report how these different subcomponents of inhibition/impulsivity are differentially sensitive to DA treatment with pramipexole influencing mainly the neural network underlying impulsive choices but not impulsive action.

Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment.

BACKGROUND: Mutations in Janus kinase 3 (JAK3) are a cause of severe combined immunodeficiency, but hypomorphic JAK3 defects can result in a milder clinical phenotype, with residual development and function of autologous T cells. Maternal T-cell engraftment is a common finding in infants with severe combined immunodeficiency but is not typically observed in patients with residual T-cell development. OBJECTIVE: We sought to study in detail the molecular, cellular, and humoral immune phenotype and function of 3 patients with hypomorphic JAK3 mutations. METHODS: We analyzed the distribution and function of T and B lymphocytes in 3 patients and studied the in vitro and in vivo responses of maternal T lymphocytes in 1 patient with maternal T-cell engraftment and residual production of autologous T lymphocytes. RESULTS: B cells were present in normal numbers but with abnormal distribution of marginal zone-like and memory B cells. B-cell differentiation to plasmablasts in vitro in response to CD40 ligand and IL-21 was abolished. In 2 patients the T-cell repertoire was moderately restricted. Surprisingly, 1 patient showed coexistence of maternal and autologous T lymphocytes. By using an mAb recognizing the maternal noninherited HLA-A2 antigen, we found that autologous cells progressively accumulated in vivo but did not compete with maternal cells in vitro. CONCLUSION: The study of 3 patients with hypomorphic JAK3 mutations suggests that terminal B-cell maturation/differentiation requires intact JAK3 function, even if partially functioning T lymphocytes are present. Maternal T-cell engraftment can occur in patients with JAK3 mutations despite the presence of autologous T cells.

Role of Apolipoprotein E in the Hippocampus and Its Impact following Ionizing Radiation Exposure.

Apolipoprotein E (ApoE) is a lipid carrier in both the peripheral and the central nervous systems (CNSs). Lipid-loaded ApoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and brain injury repair. In the brain, ApoE is produced predominantly by astrocytes, but it is also abundantly expressed in most neurons of the CNS. In this study, we addressed the role of ApoE in the hippocampus in mice, focusing on its role in response to radiation injury. To this aim, 8-week-old, wild-type, and ApoE-deficient (ApoE-/-) female mice were acutely whole-body irradiated with 3 Gy of X-rays (0.89 Gy/min), then sacrificed 150 days post-irradiation. In addition, age-matching ApoE-/- females were chronically whole-body irradiated (20 mGy/d, cumulative dose of 3 Gy) for 150 days at the low dose-rate facility at the Institute of Environmental Sciences (IES), Rokkasho, Japan. To seek for ApoE-dependent modification during lineage progression from neural stem cells to neurons, we have evaluated the cellular composition of the dentate gyrus in unexposed and irradiated mice using stage-specific markers of adult neurogenesis. Our findings indicate that ApoE genetic inactivation markedly perturbs adult hippocampal neurogenesis in unexposed and irradiated mice. The effect of ApoE inactivation on the expression of a panel of miRNAs with an established role in hippocampal neurogenesis, as well as its transcriptional consequences in their target genes regulating neurogenic program, have also been analyzed. Our data show that the absence of ApoE-/- also influences synaptic functionality and integration by interfering with the regulation of mir-34a, mir-29b, and mir-128b, leading to the downregulation of synaptic markers PSD95 and synaptophysin mRNA. Finally, compared to acute irradiation, chronic exposure of ApoE null mice yields fewer consequences except for the increased microglia-mediated neuroinflammation. Exploring the function of ApoE in the hippocampus could have implications for developing therapeutic approaches to alleviate radiation-induced brain injury.

Comparing the effects of irradiation with protons or photons on neonatal mouse brain: Apoptosis, oncogenesis and hippocampal alterations.

BACKGROUND AND PURPOSE: Medulloblastoma (MB) is a common primary brain cancer in children. Proton therapy in pediatric MB is intensively studied and widely adopted. Compared to photon, proton radiations offer potential for reduced toxicity due to the characteristic Bragg Peak at the end of their path in tissue. The aim of this study was to compare the effects of irradiation with the same dose of protons or photons in Patched1 heterozygous knockout mice, a murine model predisposed to cancer and non-cancer radiogenic pathologies, including MB and lens opacity. MATERIALS AND METHODS: TOP-IMPLART is a pulsed linear proton accelerator for proton therapy applications. We compared the long-term health effects of 3 Gy of protons or photons in neonatal mice exposed at postnatal day 2, during a peculiarly susceptible developmental phase of the cerebellum, lens, and hippocampus, to genotoxic stress. RESULTS: Experimental testing of the 5 mm Spread-Out Bragg Peak (SOBP) proton beam, through evaluation of apoptotic response, confirmed that both cerebellum and hippocampus were within the SOBP irradiation field. While no differences in MB induction were observed after irradiation with protons or photons, lens opacity examination confirmed sparing of the lens after proton exposure. Marked differences in expression of neurogenesis-related genes and in neuroinflammation, but not in hippocampal neurogenesis, were observed after irradiation of wild-type mice with both radiation types. CONCLUSION: In-vivo experiments with radiosensitive mouse models improve our mechanistic understanding of the dependence of brain damage on radiation quality, thus having important implications in translational research.

Prefrontal dopaminergic receptor abnormalities and executive functions in Parkinson's disease.

The main pattern of cognitive impairments seen in early to moderate stages of Parkinson's disease (PD) includes deficits of executive functions. These nonmotor complications have a significant impact on the quality of life and day-to-day activities of PD patients and are not effectively managed by current therapies, a problem which is almost certainly due to the fact that the disease extends beyond the nigrostriatal system. To investigate the role of extrastriatal dopamine in executive function in PD, PD patients and a control group were studied with positron-emission-tomography using a high-affinity dopamine D2/D3 receptor tracer, [(11) C]FLB-457. All participants were scanned twice while performing an executive task and a control task. Patients were off medication for at least 12 h. The imaging analysis revealed that parkinsonian patients had lower [(11) C]FLB-457 binding than control group independently of task conditions across different brain regions. Cognitive assessment measures were positively correlated with [(11) C]FLB-457 binding in the bilateral dorsolateral prefrontal cortex and anterior cingulate cortex only in control group, but not in PD patients. Within the control group, during the executive task (as compared to control task), there was evidence of reduced [(11) C]FLB-457 binding (indicative of increased dopamine release) in the right orbitofrontal cortex. In contrast, PD patients did not show any reduction in binding during the executive task (as compared with control task). These findings suggest that PD patients present significant abnormalities in extrastriatal dopamine associated with executive processing. These observations provide important insights on the pathophysiology of cognitive dysfunction in PD.

A study on the correlations between acoustic speech variables and bradykinesia in advanced Parkinson's disease.

Background: Very few studies have assessed the presence of a possible correlation between speech variables and limb bradykinesia in patients with Parkinson's disease (PD). The objective of this study was to find correlations between different speech variables and upper extremity bradykinesia under different medication conditions in advanced PD patients. Methods: Retrospective data were collected from a cohort of advanced PD patients before and after an acute levodopa challenge. Each patient was assessed with a perceptual-acoustic analysis of speech, which included several quantitative parameters [i.e., maximum phonation time (MPT) and intensity (dB)]; the Unified Parkinson's Disease Rating Scale (UPDRS) (total scores, subscores, and items); and a timed test (a tapping test for 20 s) to quantify upper extremity bradykinesia. Pearson's correlation coefficient was applied to find correlations between the different speech variables and the tapping rate. Results: A total of 53 PD patients [men: 34; disease duration: 10.66 (SD 4.37) years; age at PD onset: 49.81 years (SD 6.12)] were included. Levodopa intake increased the MPT of sustained phonation (p < 0.01), but it reduced the speech rate (p = 0.05). In the defined-OFF condition, MPT of sustained phonation positively correlated with both bilateral mean (p = 0.044, r-value:0.299) and left (p = 0.033, r-value:0.314) tapping. In the defined-ON condition, the MPT correlated positively with bilateral mean tapping (p = 0.003), left tapping (p = 0.003), and right tapping (p = 0.008). Conclusion: This study confirms the presence of correlations between speech acoustic variables and upper extremity bradykinesia in advanced PD patients. These findings suggest common pathophysiological mechanisms.

Longitudinal Neuropsychological Assessment of Symptomatic Edema after Subthalamic Nucleus Deep Brain Stimulation Surgery: A Case Series Study.

Severe non-infectious or non-haemorrhagic brain edema surrounding the electrode represents a rare complication of subthalamic nucleus deep brain stimulation (STN-DBS) surgery. The aim of this study is to report three patients with advanced Parkinson's Disease (PD) who developed symptomatic brain edema after STN-DBS surgery treated with intravenous steroids with a specific profile of reversible cognitive alterations. Patients were both assessed with a comprehensive neuropsychological battery including attention, memory, visuo-spatial and executive tasks. They were also briefly assessed for emotional and behavioural alterations, and for possible limitations in the activities of daily living. Normative data for an Italian population were available for all neuropsychological tests. The patients were firstly assessed before the surgery (baseline) as soon as they became symptomatic for the post-surgery edema and a few more times in follow-up up to ten months. In all patients we observed the resolution of cognitive deficits within six months after surgery with the corresponding reabsorption of edema at brain CT scans. The appearance of post-DBS edema is a fairly frequent and clinically benign event. However, in some rare cases it can be very marked and lead to important clinical-albeit transient-disturbances. These events can compromise, at least from a psychological point of view, the delicate path of patients who undergo DBS and can prolong the post-operative hospital stay. In this setting it could be helpful to perform a brain CT scan in 2-3 days with the aim of detecting the early appearance of edema and treating it before it can constitute a relevant clinical problem.

Long-term effects of subthalamic nucleus deep brain stimulation on speech in Parkinson's disease.

Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment in advanced Parkinson's Disease (PD). However, the effects of STN-DBS on speech are still debated, particularly in the long-term follow-up. The objective of this study was to evaluate the long-term effects of bilateral STN-DBS on speech in a cohort of advanced PD patients treated with bilateral STN-DBS. Each patient was assessed before surgery through a neurological evaluation and a perceptual-acoustic analysis of speech and re-assessed in the long-term in different stimulation and drug conditions. The primary outcome was the percentage change of speech intelligibility obtained by comparing the postoperative on-stimulation/off-medication condition with the preoperative off-medication condition. Twenty-five PD patients treated with bilateral STN-DBS with a 5-year follow-up were included. In the long-term, speech intelligibility stayed at the same level as preoperative values when compared with preoperative values. STN-DBS induced a significant acute improvement of speech intelligibility (p < 0.005) in the postoperative assessment when compared to the on-stimulation/off-medication and off-stimulation/off-medication conditions. These results highlight that STN-DBS may handle speech intelligibility even in the long-term.