Publications by authors named "Carmela Conte"

73 Publications

An artificial neural network approach to detect presence and severity of Parkinson's disease via gait parameters.

PLoS One 2021 19;16(2):e0244396. Epub 2021 Feb 19.

Department of Medico-Surgical Sciences and Biotechnologies, University of Rome Sapienza, Latina, Italy.

Introduction: Gait deficits are debilitating in people with Parkinson's disease (PwPD), which inevitably deteriorate over time. Gait analysis is a valuable method to assess disease-specific gait patterns and their relationship with the clinical features and progression of the disease.

Objectives: Our study aimed to i) develop an automated diagnostic algorithm based on machine-learning techniques (artificial neural networks [ANNs]) to classify the gait deficits of PwPD according to disease progression in the Hoehn and Yahr (H-Y) staging system, and ii) identify a minimum set of gait classifiers.

Methods: We evaluated 76 PwPD (H-Y stage 1-4) and 67 healthy controls (HCs) by computerized gait analysis. We computed the time-distance parameters and the ranges of angular motion (RoMs) of the hip, knee, ankle, trunk, and pelvis. Principal component analysis was used to define a subset of features including all gait variables. An ANN approach was used to identify gait deficits according to the H-Y stage.

Results: We identified a combination of a small number of features that distinguished PwPDs from HCs (one combination of two features: knee and trunk rotation RoMs) and identified the gait patterns between different H-Y stages (two combinations of four features: walking speed and hip, knee, and ankle RoMs; walking speed and hip, knee, and trunk rotation RoMs).

Conclusion: The ANN approach enabled automated diagnosis of gait deficits in several symptomatic stages of Parkinson's disease. These results will inspire future studies to test the utility of gait classifiers for the evaluation of treatments that could modify disease progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244396PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894951PMC
February 2021

Effect of 1α,25(OH) Vitamin D in Mutant P53 Glioblastoma Cells: Involvement of Neutral Sphingomyelinase1.

Cancers (Basel) 2020 Oct 28;12(11). Epub 2020 Oct 28.

Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy.

Glioblastoma is one the most aggressive primary brain tumors in adults, and, despite the fact that radiation and chemotherapy after surgical approaches have been the treatments increasing the survival rates, the prognosis of patients remains poor. Today, the attention is focused on highlighting complementary treatments that can be helpful in improving the classic therapeutic approaches. It is known that 1α,25(OH) vitamin D, a molecule involved in bone metabolism, has many serendipidy effects in cells. It targets normal and cancer cells via genomic pathway by vitamin D3 receptor or via non-genomic pathways. To interrogate possible functions of 1α,25(OH) vitamin D3 in multiforme glioblastoma, we used three cell lines, wild-type p53 GL15 and mutant p53 U251 and LN18 cells. We demonstrated that 1α,25(OH) vitamin D3 acts via vitamin D receptor in GL15 cells and via neutral sphingomyelinase1, with an enrichment of ceramide pool, in U251 and LN18 cells. Changes in sphingomyelin/ceramide content were considered to be possibly responsible for the differentiating and antiproliferative effect of 1α,25(OH) vitamin D in U251 and LN18 cells, as shown, respectively, in vitro by immunofluorescence and in vivo by experiments of xenotransplantation in eggs. This is the first time 1α,25(OH) vitamin D3 is interrogated for the response of multiforme glioblastoma cells in dependence on the p53 mutation, and the results define neutral sphingomyelinase1 as a signaling effector.
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http://dx.doi.org/10.3390/cancers12113163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694157PMC
October 2020

Relationship between Fatty Acids Composition/Antioxidant Potential of Breast Milk and Maternal Diet: Comparison with Infant Formulas.

Molecules 2020 Jun 24;25(12). Epub 2020 Jun 24.

Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy.

The fatty acid composition of human breast milk is relevant for the energy, immunity and eicosanoid production in infants. Additionally, the antioxidant properties of foods are essential for human health. Therefore, in the present study we aimed to investigate the relationship between maternal diet and fatty acids composition as well as the antioxidant potential of breast milk from donors to human milk bank of Perugia's hospital, Italy. Results were compared with infant formulas. We observed increased levels of total fatty acids and, in particular, saturated and monounsaturated fatty acids in milk from mothers fed on a vegetable and fruit-rich diet compared with a Mediterranean diet. In the same milk, a reduced antioxidant potential was found. All infant formulas resulted in richer total fatty acid content than human breast milk. Only some formulas were qualitatively similar to breast milk. Of note, the antioxidant potential of the formulas was higher or lower than the human milk with the exception of one sample. The antioxidant potential of four formulas was very high. Dietary supplementation with antioxidants has been shown to have a teratogenic effect and to increase the formation of metastases in adult. There are no data on the effects of excess antioxidants in the infants, but the possibility that they can be harmful cannot be excluded.
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http://dx.doi.org/10.3390/molecules25122910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356699PMC
June 2020

Pelvic obliquity as a compensatory mechanism leading to lower energy recovery: Characterization among the types of prostheses in subjects with transfemoral amputation.

Gait Posture 2020 07 12;80:280-284. Epub 2020 Jun 12.

Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, Via Franco Faggiana 1668, 04100, Latina, Italy; Movement Analysis Laboratory, Policlinico Italia, Piazza del Campidano, 6, 00162, Rome, Italy.

Background: Subjects with transfemoral amputation (TFA) show an asymmetric gait pattern associated with a decreased ability to recover mechanical energy and an increased metabolic cost of walking.

Research Question: This study aimed to identify the spatio-temporal and kinematic gait variables correlated with mechanical energy values in subjects with TFA and to observe the ability of the identified parameters to discriminate between TFA and controls according to the type of prosthesis.

Methods: The gait of 40 subjects with TFA was evaluated with a motion 3-D optoelectronic system. Nine subjects wore a mechanical prosthesis (TFAm), seventeen a C-Leg prosthesis (TFAc), and fourteen a Genium prosthesis (TFAg). Spatio-temporal and pelvic kinematic parameters were measured. Energy recovery was measured relative to the whole-body center of mass (CoM) kinematics as the fraction of mechanical energy recovered during each walking step (R-step). Correlation tests and multiple linear regression analyses were used to evaluate the correlation and association between kinematic and energy variables, respectively. Receiver operating characteristics curves were plotted to assess the ability of the correlated parameter to distinguish subjects with TFA from controls, and optimal cutoff point values were calculated according to the type of prosthesis.

Results: Among the spatio-temporal and kinematic parameters correlated to R-step, only pelvic obliquity of the prosthetic side was significantly associated with R-step. It showed an excellent ability to discriminate between TFA and controls. Furthermore, pelvic obliquity showed an excellent discriminative ability in identifying TFAm and TFAc and a good discriminative ability in identifying TFAg from controls.

Significance: Pelvic obliquity plays an important role in energy recovery during gait for subjects using prosthetics. This information might be exploited to monitor the adaptation of subjects with TFA to prosthetic devices, to lower the energetic cost of walking potentially, and to reduce the long-term risks of secondary physical complications in prosthetic users.
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http://dx.doi.org/10.1016/j.gaitpost.2020.06.013DOI Listing
July 2020

Impairment of Global Lower Limb Muscle Coactivation During Walking in Cerebellar Ataxias.

Cerebellum 2020 Aug;19(4):583-596

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.

The aim of this study was to investigate the time-varying multi-muscle coactivation function (TMCf) in the lower limbs during gait and its relationship with the biomechanical and clinical features of patients with cerebellar ataxia. A total of 23 patients with degenerative cerebellar ataxia (16 with spinocerebellar ataxia, 7 with adult-onset ataxia of unknown etiology) and 23 age-, sex-, and speed-matched controls were investigated. The disease severity was assessed using the Scale for the Assessment and Rating of Ataxia (SARA) in all patients. During walking, simultaneous acquisition of kinematic, kinetic, and electromyography data was performed using a motion analysis system. The coactivation was processed throughout the gait cycle using the TMCf, and the following parameters were measured: synthetic coactivation index, full width at half maximum, and center of activity. Spatiotemporal (walking speed, stance duration, swing duration, first and second double-support durations, step length, step width, stride length, Center of Mass displacement), kinetic (vertical component of GRFs), and energy consumption (total energy consumption and mechanical energy recovered) parameters were also measured. The coactivation variables were compared between patients and controls and were correlated with both clinical and gait variables. A significantly increased global TMCf was found in patients compared with controls. In addition, the patients showed a significant shift of the center of activity toward the initial contact and a significant reduction in energy recovery. All coactivation parameters were negatively correlated with gait speed, whereas the coactivation index and center of activity were positively correlated with both center-of-mass mediolateral displacement values and SARA scores. Our findings suggest that patients use global coactivation as a compensatory mechanism during the earliest and most challenging subphase (loading response) of the gait cycle to reduce the lateral body sway, thus improving gait stability at the expense of effective energy recovery. This information could be helpful in optimizing rehabilitative treatment aimed at improving lower limb muscle control during gait in patients with cerebella ataxia.
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http://dx.doi.org/10.1007/s12311-020-01142-6DOI Listing
August 2020

Acid and Neutral Sphingomyelinase Behavior in Radiation-Induced Liver Pyroptosis and in the Protective/Preventive Role of rMnSOD.

Int J Mol Sci 2020 May 6;21(9). Epub 2020 May 6.

Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy.

Sphingomyelins (SMs) are a class of relevant bioactive molecules that act as key modulators of different cellular processes, such as growth arrest, exosome formation, and the inflammatory response influenced by many environmental conditions, leading to pyroptosis, a form of programmed cell death due to Caspase-1 involvement. To study liver pyroptosis and hepatic SM metabolism via both lysosomal acid SMase (aSMase) and endoplasmic reticulum/nucleus neutral SMase (nSMase) during the exposure of mice to radiation and to ascertain if this process can be modulated by protective molecules, we used an experimental design (previously used by us) to evaluate the effects of both ionizing radiation and a specific protective molecule (rMnSOD) in the brain in collaboration with the Joint Institute for Nuclear Research, Dubna (Russia). As shown by the Caspase-1 immunostaining of the liver sections, the radiation resulted in the loss of the normal cell structure alongside a progressive and dose-dependent increase of the labelling, treatment, and pretreatment with rMnSOD, which had a significant protective effect on the livers. SM metabolic analyses, performed on aSMase and nSMase gene expression, as well as protein content and activity, proved that rMnSOD was able to significantly reduce radiation-induced damage by playing both a protective role via aSMase and a preventive role via nSMase.
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http://dx.doi.org/10.3390/ijms21093281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247354PMC
May 2020

Exploring Risk of Falls and Dynamic Unbalance in Cerebellar Ataxia by Inertial Sensor Assessment.

Sensors (Basel) 2019 Dec 17;19(24). Epub 2019 Dec 17.

Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185 Rome, Italy.

Background: Patients suffering from cerebellar ataxia have extremely variable gait kinematic features. We investigated whether and how wearable inertial sensors can describe the gait kinematic features among ataxic patients.

Methods: We enrolled 17 patients and 16 matched control subjects. We acquired data by means of an inertial sensor attached to an ergonomic belt around pelvis, which was connected to a portable computer via Bluetooth. Recordings of all the patients were obtained during overground walking. From the accelerometric data, we obtained the harmonic ratio (HR), i.e., a measure of the acceleration patterns, smoothness and rhythm, and the step length coefficient of variation (CV), which evaluates the variability of the gait cycle.

Results: Compared to controls, patients had a lower HR, meaning a less harmonic and rhythmic acceleration pattern of the trunk, and a higher step length CV, indicating a more variable step length. Both HR and step length CV showed a high effect size in distinguishing patients and controls (p < 0.001 and p = 0.011, respectively). A positive correlation was found between the step length CV and both the number of falls (R = 0.672; p = 0.003) and the clinical severity (ICARS: R = 0.494; p = 0.044; SARA: R = 0.680; p = 0.003).

Conclusion: These findings demonstrate that the use of inertial sensors is effective in evaluating gait and balance impairment among ataxic patients.
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http://dx.doi.org/10.3390/s19245571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960492PMC
December 2019

In Vitro Anti-Inflammatory Effects of Phenolic Compounds from Moraiolo Virgin Olive Oil (MVOO) in Brain Cells via Regulating the TLR4/NLRP3 Axis.

Molecules 2019 Dec 10;24(24). Epub 2019 Dec 10.

Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy.

Neuroinflammation is a feature of many classic neurodegenerative diseases. In the healthy brain, microglia cells are distributed throughout the brain and are constantly surveilling the central nervous system (CNS). In response to CNS injury, microglia quickly react by secreting a wide array of apoptotic molecules. Virgin olive oil (VOO) is universally recognized as a symbol of the Mediterranean diet. In the current study, using lipopolysaccharide (LPS)-stimulated BV2 microglia, the anti-inflammatory effects of VOO phenolic extracts from Moraiolo cultivar (MVOO-PE) were investigated. The results showed that low concentration of MVOO-PE prevented microglia cell death and attenuated the LPS-induced activation of toll-like receptor 4 (TLR4)/NOD-like receptor pyrin domain-containing-3 (NLRP3) signaling cascade. The levels of TLR4 and NF-kB were diminished, as well as NLRP3 inflammasome and interleukin-1β (IL-1β) production. Cyclooxygenase-2 (COX-2) isoenzyme and ionized calcium binding adaptor molecule 1 (Iba-1) inflammatory mediator were also reduced. By modulating the TLR4/NLRP3 axis, MVOO-PE pretreatment was able to significantly down-regulate the mRNA expression of inflammatory mediators and suppress the cytokine secretion. Finally, we showed protective effect of MVOO-PE in a transwell neuron-microglia co-culture system. In conclusion, these results suggest that MVOO-PE could exerts anti-inflammatory activity on brain cells and become a promising candidate for preventing several neuroinflammatory diseases.
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http://dx.doi.org/10.3390/molecules24244523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943687PMC
December 2019

5-HT2AR and BDNF gene variants in eating disorders susceptibility.

Am J Med Genet B Neuropsychiatr Genet 2020 04 20;183(3):155-163. Epub 2019 Nov 20.

Department of Pharmaceutical Science, University of Perugia, Perugia, Italy.

Evidence from family and twin studies points to a genetic contribution to the etiology of eating disorders (EDs), confirmed by the association of several single nucleotide polymorphisms (SNPs) with this group of disorders. Previous reports have suggested that the serotonin receptor (5-HT2AR) and brain-derived neurotrophic factor (BDNF) genes could be both involved in EDs susceptibility. In order to provide further evidence about such association, we focused our attention on two SNPs located in these genes carrying out a genetic association study on a large Italian cohort composed of 556 ED patients and 355 controls (CTRs). Obtained results confirm the presence of an association between 5-HT2AR and BDNF genes and the susceptibility to EDs.
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http://dx.doi.org/10.1002/ajmg.b.32771DOI Listing
April 2020

Neutral Sphingomyelinase Modulation in the Protective/Preventive Role of rMnSOD from Radiation-Induced Damage in the Brain.

Int J Mol Sci 2019 Oct 31;20(21). Epub 2019 Oct 31.

Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy.

Studies on the relationship between reactive oxygen species (ROS)/manganese superoxide dismutase (MnSOD) and sphingomyelinase (SMase) are controversial. It has been demonstrated that SMase increases the intracellular ROS level and induces gene expression for MnSOD protein. On the other hand, some authors showed that ROS modulate the activation of SMase. The human recombinant manganese superoxide dismutase (rMnSOD) exerting a radioprotective effect on normal cells, qualifies as a possible pharmaceutical tool to prevent and/or cure damages derived from accidental exposure to ionizing radiation. This study aimed to identify neutral SMase (nSMase) as novel molecule connecting rMnSOD to its radiation protective effects. We used a new, and to this date, unique, experimental model to assess the effect of both radiation and rMnSOD in the brain of mice, within a collaborative project among Italian research groups and the Joint Institute for Nuclear Research, Dubna (Russia). Mice were exposed to a set of minor γ radiation and neutrons and a spectrum of neutrons, simulating the radiation levels to which cosmonauts will be exposed during deep-space, long-term missions. Groups of mice were treated or not-treated (controls) with daily subcutaneous injections of rMnSOD during a period of 10 days. An additional group of mice was also pretreated with rMnSOD for three days before irradiation, as a model for preventive measures. We demonstrate that rMnSOD significantly protects the midbrain cells from radiation-induced damage, inducing a strong upregulation of nSMase gene and protein expression. Pretreatment with rMnSOD before irradiation protects the brain with a value of very high nSMase activity, indicating that high levels of activity might be sufficient to exert the rMnSOD preventive role. In conclusion, the protective effect of rMnSOD from radiation-induced brain damage may require nSMase enzyme.
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http://dx.doi.org/10.3390/ijms20215431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862120PMC
October 2019

Progressive Modular Rebalancing System and Visual Cueing for Gait Rehabilitation in Parkinson's Disease: A Pilot, Randomized, Controlled Trial With Crossover.

Front Neurol 2019 29;10:902. Epub 2019 Aug 29.

Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.

The progressive modular rebalancing (PMR) system is a comprehensive rehabilitation approach derived from proprioceptive neuromuscular facilitation principles. PMR training encourages focus on trunk and proximal muscle function through direct perception, strength, and stretching exercises and emphasizes bi-articular muscle function in the improvement of gait performance. Sensory cueing, such as visual cues (VC), is one of the more established techniques for gait rehabilitation in PD. In this study, we propose PMR combined with VC for improving gait performance, balance, and trunk control during gait in patients with PD. Our assumption herein was that the effect of VC may add to improved motor performance induced by the PMR treatment. The primary aim of this study was to evaluate whether the PMR system plus VC was a more effective treatment option than standard physiotherapy in improving gait function in patients with PD. The secondary aim of the study was to evaluate the effect of this treatment on motor function severity. Two-center, randomized, controlled, observer-blind, crossover study with a 4-month washout period. Forty individuals with idiopathic PD in Hoehn and Yahr stages 1-4. Eight-week rehabilitation programs consisting of PMR plus VC (treatment A) and conventional physiotherapy (treatment B). Spatiotemporal gait parameters, joint kinematics, and trunk kinematics. UPDRS-III scale scores. The rehabilitation program was well-tolerated by individuals with PD and most participants showed improvements in gait variables and UPDRS-III scores with both treatments. However, patients who received PMR with VC showed better results in gait function with regard to gait performance (increased step length, gait speed, and joint kinematics), gait balance (increased step width and double support duration), and trunk control (increased trunk motion) than those receiving conventional physiotherapy. While crossover results revealed some differences in primary outcomes, only 37.5% of patients crossed over between the groups. As a result, our findings should be interpreted cautiously. The PMR plus VC program could be used to improve gait function and severity motor of motor deficit in individuals with PD. : www.ClinicalTrials.gov, identifier NCT03346265.
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http://dx.doi.org/10.3389/fneur.2019.00902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730596PMC
August 2019

Gentamicin Targets Acid Sphingomyelinase in Cancer: The Case of the Human Gastric Cancer NCI-N87 Cells.

Int J Mol Sci 2019 Sep 6;20(18). Epub 2019 Sep 6.

Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy.

Emerging literature implicates acid sphingomyelinase in tumor sensitivity/resistance to anticancer treatments. Gentamicin is a drug commonly used as an antimicrobial but its serendipity effects have been shown. Even though many evidences on the role of gentamicin in cancer have been reported, its mechanism of action is poorly understood. Here, we explored acid sphingomyelinase as a possible new target of gentamicin in cancer. Since gastric cancer is one of the most common cancers and represents the second cause of death in the world, we performed the study in NCI-N87 gastric cancer cell line. The effect of the drug resulted in the inhibition of cell proliferation, including a reduction of cell number and viability, in the decrease of MIB-1 proliferative index as well as in the upregulation of cyclin-dependent kinase inhibitor 1A and 1B ( and ), and growth arrest and DNA-damage 45A () genes. The cytotoxicity was apoptotic as shown by FACS analysis. Additionally, gentamicin reduced HER2 protein, indicating a minor tumor aggressiveness. To further define the involvement of sphingomyelin metabolism in the response to the drug, gene and protein expression of acid and neutral sphingomeylinase was analyzed in comparison with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and vitamin D receptor (VDR), molecules involved in cancer. Gentamicin induced a downregulation of , , and neutral sphingomyelinase and a strong upregulation of acid sphingomyelinase. Of note, we identified the same upregulation of acid sphingomyelinase upon gentamicin treatment in other cancer cells and not in normal cells. These findings provide new insights into acid sphingomyelinase as therapeutic target, reinforcing studies on the potential role of gentamicin in anticancer therapy.
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http://dx.doi.org/10.3390/ijms20184375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770866PMC
September 2019

Prediction of Responsiveness of Gait Variables to Rehabilitation Training in Parkinson's Disease.

Front Neurol 2019 2;10:826. Epub 2019 Aug 2.

Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.

Gait disorders represent one of the most disabling features of Parkinson's disease, which may benefit from rehabilitation. No consistent evidence exists about which gait biomechanical factors can be modified by rehabilitation and which clinical characteristic can predict rehabilitation-induced improvements. The aims of the study were as follows: (i) to recognize the gait parameters modifiable by a short-term rehabilitation program; (ii) to evaluate the gait parameters that can normalize after rehabilitation; and (iii) to identify clinical variables predicting improvements in gait function after rehabilitation. Thirty-six patients affected by idiopathic Parkinson's disease in Hoehn-Yahr stage 1-3 and 22 healthy controls were included in the study. Both clinical and instrumental (gait analysis) evaluations were performed before and after a 10-weeks rehabilitation treatment. Time-distance parameters, lower limb joint, and trunk kinematics were measured. At baseline evaluation with matched speed, almost all gait parameters were significantly different between patients and healthy controls. After the 10-weeks rehabilitation, most gait parameters improved, and spatial asymmetry and trunk rotation normalized. Multiple linear regression of gender combined with Unified Parkinson's Disease Rating Scale-III predicted both ΔSpeed and ΔStep length of both sides; gender combined with Unified Parkinson's Disease Rating Scale-II predicted ΔCadence; age combined with Hoehn-Yahr score and disease duration predicted Δtrunk rotation range of motion. Impaired gait parameters are susceptible to improvement by rehabilitation, and younger men with Parkinson's disease who are less severely affected and at early disease stage are more susceptible to improvements in gait function after a 10-weeks rehabilitation program.
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http://dx.doi.org/10.3389/fneur.2019.00826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688512PMC
August 2019

A Role for Neutral Sphingomyelinase in Wound Healing Induced by Keratinocyte Proliferation upon 1, 25-Dihydroxyvitamin D Treatment.

Int J Mol Sci 2019 Jul 25;20(15). Epub 2019 Jul 25.

Department of Pharmaceutical Science, University of Perugia, 06126 Perugia, Italy.

The skin has many functions, such as providing a barrier against injury and pathogens, protecting from ultraviolet light, and regulating body temperature. Mechanical causes and many different pathologies can lead to skin damage. Therefore, it is important for the skin to be always adaptable and renewable and for cells to undergo proliferation. Here, we demonstrate that 1, 25-dihydroxyvitamin D (VD3) stimulates keratinocyte proliferation, leading to wound closure in a simulation model of injury. Functionally, our results show that VD3 acts by stimulating cyclin D1, a cyclin that promotes the G1/S transition of the cell cycle. The study on the mechanism underlying cyclin D1 expression upon VD3 stimulation clearly demonstrates a key role of neutral sphingomyelinase. The enzyme, whose gene and protein expression is stimulated by VD3, is itself able to induce effects on cyclin D1 and wound healing similar to those obtained with VD3. These results could be very useful in the future to better understand wound mechanisms and improve therapeutic interventions.
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http://dx.doi.org/10.3390/ijms20153634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695647PMC
July 2019

Spatial and temporal characteristics of the spine muscles activation during walking in patients with lumbar instability due to degenerative lumbar disk disease: Evaluation in pre-surgical setting.

Hum Mov Sci 2019 May 29;66:371-382. Epub 2019 May 29.

Department of NESMOS, Sapienza University, Rome, Italy.

Our purpose was to investigate the spatial and temporal profile of the paraspinal muscle activation during gait in a group of 13 patients with lumbar instability (LI) in a pre-surgical setting compared to the results with those from both 13 healthy controls (HC) and a sample of 7 patients with failed back surgery syndrome (FBSS), which represents a chronic untreatable condition, in which the spine muscles function is expected to be widely impaired. Spatiotemporal gait parameters, trunk kinematics, and muscle activation were measured through a motion analysis system integrated with a surface EMG device. The bilateral paraspinal muscles (longissimus) at L3-L4, L4-L5, and L5-S1 levels and lumbar iliocostalis muscles were evaluated. Statistical analysis revealed significant differences between groups in the step length, step width, and trunk bending and rotation. As regard the EMG analysis, significant differences were found in the cross-correlation, full-width percentage and center of activation values between groups, for all muscles investigated. Patients with LI, showed preserved trunk movements compared to HC but a series of EMG abnormalities of the spinal muscles, in terms of left-right symmetry, top-down synchronization, and spatiotemporal activation and modulation compared to the HC group. In patients with LI some of such EMG abnormalities regarded mainly the segment involved by the instability and were strictly correlated to the pain perception. Conversely, in patients with FBSS the EMG abnormalities regarded all the spinal muscles, irrespective to the segment involved, and were correlated to the disease's severity. Furthermore, patients with FBSS showed reduced lateral bending and rotation of the trunk and a reduced gait performance and balance. Our methodological approach to analyze the functional status of patients with LI due to spine disease with surgical indications, even in more complex conditions such as deformities, could allow to evaluate the biomechanics of the spine in the preoperative conditions and, in the future, to verify whether and which surgical procedure may either preserve or improve the spine muscle function during gait.
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http://dx.doi.org/10.1016/j.humov.2019.05.013DOI Listing
May 2019

Niemann-Pick Type A Disease: Behavior of Neutral Sphingomyelinase and Vitamin D Receptor.

Int J Mol Sci 2019 May 13;20(9). Epub 2019 May 13.

Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy.

Sphingomyelinase (SMase) is responsible for the breakdown of sphingomyelin (SM) with production of ceramide. The absence of acid sphingomyelinase (aSMase) causes abnormal synapse formation in Niemann-Pick type A (NPA) disease. Because high levels of ceramide in the NPA brain were demonstrated, the involvement of other SMases were supposed. In the present study we focused the attention on the neurogenic niches in the hippocampal (GD), a brain structure essential for forming cohesive memory. We demonstrated for the first time the increase of (Sex determining region Y)-box 2 (SOX2), and the down-regulation of glial fibrillary acidic protein (GFAP) NPA mice GD. Moreover, we found that the expression of Toll like receptors (TLRs), was increased in NPA mice, particularly TLR2, TLR7, TLR8 and TLR9 members. Although no significant change in neutral sphingomyelinase (nSMase) gene expression was detected in the NPA mice hippocampus of, protein levels were enhanced, probably because of the slower protein degradation rate in this area. Many studies demonstrated that vitamin D receptor (VDR) is expressed in the hippocampus GD. Unexpectedly, we showed that NPA mice exhibited VDR gene and protein expression up-regulation. In summary, our study suggests a relation between hippocampal cell differentiation defect, nSMase and VDR increase in NPA mice.
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http://dx.doi.org/10.3390/ijms20092365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539364PMC
May 2019

Neutral sphingomyelinase increases and delocalizes in the absence of Toll-Like Receptor 4: A new insight for MPTP neurotoxicity.

Prostaglandins Other Lipid Mediat 2019 06 27;142:46-52. Epub 2019 Mar 27.

Department of Pharmaceutical Science, University of Perugia, Italy. Electronic address:

Both sphingomyelinase and Toll-Like Receptor 4 (TLR4) are implicated in neurodegenerative diseases. However, the relationship between the two molecules remains unclear. In this study, using WT and TLR4-deficient mice, treated or not with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we aimed to investigate the relation between TLR4 and neutral sphingomyelinase (nSMase) in the midbrain. We found that the lack of TLR4 caused increase in nSMase protein expression and enzyme activity in the midbrain, as well as a marked delocalization from the cell membranes. This provoked a decrease in sphingomyelin (SM) species and an increase in ceramide levels. We found that exposure of TLR4-deficient mice to MPTP reduces unsaturated SM species by increasing saturated/unsaturated SM ratio. Saturated fatty acid make SM more rigid and could contribute to reducing neural plasticity. In this study we showed that the absence of TLR4 also induced reduction of both heavy neurofilaments and glial fibrillary acidic protein (GFAP) and mice exhibited higher sensitivity to MPTP administration. We speculated about the possible association between nSMase-TLR4 complex and MPTP midbrain damage. Taken together, our findings provide for the first time indications about the role of TLR4 in change of SM metabolism in MPTP neurotoxicity.
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http://dx.doi.org/10.1016/j.prostaglandins.2019.03.004DOI Listing
June 2019

Bioadhesive polymeric films based on usnic acid for burn wound treatment: Antibacterial and cytotoxicity studies.

Colloids Surf B Biointerfaces 2019 Jun 5;178:488-499. Epub 2019 Mar 5.

Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Perugia 06123, Italy. Electronic address:

Usnic acid (UA) is a lichenic secondary metabolite useful for the treatment of burn wounds thanks to its antimicrobial activity, particularly toward strains responsible for their infections. However, the poor solubility is the main factor limiting the activity and thus its use in health care products. Adhesive polymeric films were designed to improve UA use by enhancing its bioavailability in the wounded tissues. Three different NaCMC hydrogel films, NaCMC 2% alone (F1), mixed to PVP K90 0.1% (F2) or to Carbopol 971 P 0.1% (F3), were prepared by casting method. Ex vivo experiments performed on pig skin samples showed their suitable adhesion capacity. in vitro release test, performed using the extraction cell, showed that film F2 provides the highest UA concentrations. Differential scanning calorimetry and X-ray analyses performed on the three films highlighted that UA is present in a more soluble form in F2. The in vitro antibacterial activity studies demonstrated that F2 is the most effective film against UA sensitive bacteria S. Epidermidis, E. Faecalis, B. Cereus and S. Pyogenes. In vitro cytotoxicity assays on human keratinocytes and fibroblasts showed that cells viability is not compromised.
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http://dx.doi.org/10.1016/j.colsurfb.2019.03.001DOI Listing
June 2019

Effect of phobic visual stimulation on spinal nociception.

Physiol Behav 2019 07 19;206:22-27. Epub 2019 Mar 19.

"Sapienza" University of Rome Polo Pontino, Department of Medico-Surgical Sciences and Biotechonologies, Latina, Italy.

To explore the role of strong negative emotions in spinal nociception, we evaluated the effect of fear-relevant videos of small animals on the nociceptive withdrawal reflex (NWR) and reflex-related pain perception in healthy subjects with a specific phobia of small animals. Twenty healthy subjects with a specific phobia of small animals diagnosed according to DSM-V criteria were included in this study. The NWR was evoked in the lower limb by stimulating the sural nerve and recording EMG activity in the biceps femoris. NWR pain-related perception was quantified on an 11-point numerical rating scale (NRS). Subjects were examined during 4 recording sessions. In the baseline session, no images were projected. In the other sessions, the subjects were invited to watch a video containing either neutral or phobic content. To evaluate neurovegetative responses, we measured heart rate using a pulse oximeter during each recording session. A series of clinical rating scales were administered to subjects to evaluate disgust, fear, and anxiety. The NWR amplitude was significantly increased during the phobic video session and was associated with the fear inventory scale scores. Women showed higher NWR amplitude values during the phobic video session and a lower recovery rate during the after-effect video session than did men. The NWR amplitude and related pain perception were dissociated from each other during the phobic video session, as the NRS score remained unchanged while the NWR increased in amplitude. Emotions induced by the viewing of phobic videos seem to enhance the activation of the spinal circuitries involved in nociception and the withdrawal reaction without interfering with pain processing pathways or dissociating the reflex response from related pain perception. This effect appears to differ by sex, as it was more intense and longer lasting in women than in men. Emotions induced by phobic video viewing increase the alertness devoted to the defensive reaction by emphasizing nociceptive responses independently from pain perception. The NWR may represent an interesting tool for exploring the interaction between strong negative emotions and spinal nociception. A better understanding of this mechanism may be a theoretical prerequisite for the optimization of pain management in several chronic pain syndromes.
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http://dx.doi.org/10.1016/j.physbeh.2019.03.021DOI Listing
July 2019

Common and specific gait patterns in people with varying anatomical levels of lower limb amputation and different prosthetic components.

Hum Mov Sci 2019 Mar 16;66:9-21. Epub 2019 Mar 16.

Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, INAIL, Via Fontana Candida 1, 00078 Monte Porzio Catone, Rome, Italy.

The present study's aim was to identify the kinematic and kinetic gait patterns and to measure the energy consumption in people with amputation according to both the anatomical level of amputation and the type of prosthetic components in comparison with a control group matched for the gait speed. Fifteen subjects with unilateral transtibial amputation (TTA), forty with unilateral transfemoral amputation (TFA) (9 with mechanical, 17 with CLeg and 14 with Genium prosthesis) and forty healthy subjects were recruited. We computed the time-distance gait parameters; the range of angular motion (RoM) at hip, knee and ankle joints, and at the trunk and pelvis; the values of the 2 peaks of vertical force curve; the full width at half maximum (FWHM) and center of activity (CoA) of vertical force; the mechanical behavior in terms of energy recovery (R-step) and energy consumption. The main results were: i) both TTA and TFA show a common gait pattern characterized by a symmetric increase of step length, step width, double support duration, pelvic obliquity, trunk lateral bending and trunk rotation RoMs compared to control groups. They show also an asymmetric increase of stance duration and of Peak1 in non-amputated side and a decrease of ankle RoM in amputated side; ii) only TFA show a specific gait pattern, depending on the level of amputation, characterized by a symmetric reduction of R-step and an asymmetric decrease of stance duration, CoA and FWHM and an increase of Peak1 in the amputated side and of hip and knee RoM, CoA and FWHM in the non-amputated side; iii) people with amputation with Genium prosthesis show a longer step length and increased hip and knee RoMs compared to people with amputation with mechanical prosthesis who conversely show an increased pelvic obliquity: these are specific gait patterns depending of the type of prosthesis. In conclusion, we identified both common and specific gait patterns in people with amputation, either regardless of, or according to their level of amputation and the type of prosthetic component.
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http://dx.doi.org/10.1016/j.humov.2019.03.008DOI Listing
March 2019

Nuclear Lipid Microdomains Regulate Daunorubicin Resistance in Hepatoma Cells.

Int J Mol Sci 2018 Nov 1;19(11). Epub 2018 Nov 1.

Department of Experimental Medicine, University of Perugia, 06126 Perugia, Italy.

Daunorubicin is an anticancer drug, and cholesterol is involved in cancer progression, but their relationship has not been defined. In this study, we developed a novel experimental model that utilizes daunorubicin, cholesterol, and daunorubicin plus cholesterol in the same cells (H35) to search for the role of nuclear lipid microdomains, rich in cholesterol and sphingomyelin, in drug resistance. We find that the daunorubicin induces perturbation of nuclear lipid microdomains, localized in the inner nuclear membrane, where active chromatin is anchored. As changes of sphingomyelin species in nuclear lipid microdomains depend on neutral sphingomyelinase activity, we extended our studies to investigate whether the enzyme is modulated by daunorubicin. Indeed the drug stimulated the sphingomyelinase activity that induced reduction of saturated long chain fatty acid sphingomyelin species in nuclear lipid microdomains. Incubation of untreated-drug cells with high levels of cholesterol resulted in the inhibition of sphingomyelinase activity with increased saturated fatty acid sphingomyelin species. In daunodubicin-treated cells, incubation with cholesterol reversed the action of the drug by acting via neutral sphingomyelinase. In conclusion, we suggest that cholesterol and sphingomyelin-forming nuclear lipid microdomains are involved in the drug resistance.
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http://dx.doi.org/10.3390/ijms19113424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274808PMC
November 2018

Botulinum toxin A modifies nociceptive withdrawal reflex in subacute stroke patients.

Brain Behav 2018 09 23;8(9):e01069. Epub 2018 Aug 23.

Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.

Objectives: The aims of this study were to evaluate the pattern of the nociceptive withdrawal reflex (NWR) of the upper limb at rest and after injection of Botulinum toxin type A (BoNT-A) in poststroke subacute hemiparetic patients.

Methods: Fourteen patients with poststroke subacute hemiparesis underwent clinical and instrumental evaluation and BoNT-A injection. Painful electrical stimulation was applied to induce the NWR. Baseline EMG activity and NWR recordings (EMG and kinematic response) were performed at T0, one month (T1), and three months (T2) after the BoNT-A injection, as were Modified Ashworth Scale (MAS) and Functional Independence Measure (FIM) scores.

Results: Comparison of results at T0, T1, and T2 revealed significant changes in the MAS score for the elbow (p < 0.001) and wrist joints (p < 0.001) and in the FIM score at T0 and T2. BoNT-A injection had a significant effect on both NWR amplitude and baseline EMG activity in the posterior deltoid (PD) and flexor carpi radialis (FCR) muscles as well as in all averaged muscles. Analysis of elbow kinematics before and after treatment revealed that the reflex probability rates were significantly higher at T1 and T2 than at T0.

Conclusion: Injection of BoNT-A in the subacute phase of stroke can modify both the baseline EMG activity and the NWR-related EMG responses in the upper limb muscles irrespective of the site of injection; furthermore, the reflex-mediated defensive mechanical responses, that is, shoulder extension and abduction and elbow flexion, increased after treatment. BoNT-A injection may be a useful treatment in poststroke spasticity with a potential indirect effect on spinal neurons.
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http://dx.doi.org/10.1002/brb3.1069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160647PMC
September 2018

Alpha-Mannosidosis: Therapeutic Strategies.

Int J Mol Sci 2018 May 17;19(5). Epub 2018 May 17.

Department of Pharmaceutical Sciences; University of Perugia, Via Fabretti 48, 06123 Perugia, Italy.

Alpha-mannosidosis (α-mannosidosis) is a rare lysosomal storage disorder with an autosomal recessive inheritance caused by mutations in the gene encoding for the lysosomal α-d-mannosidase. So far, 155 variants from 191 patients have been identified and in part characterized at the biochemical level. Similarly to other lysosomal storage diseases, there is no relationship between genotype and phenotype in alpha-mannosidosis. Enzyme replacement therapy is at the moment the most effective therapy for lysosomal storage disease, including alpha-mannosidosis. In this review, the genetic of alpha-mannosidosis has been described together with the results so far obtained by two different therapeutic strategies: bone marrow transplantation and enzyme replacement therapy. The primary indication to offer hematopoietic stem cell transplantation in patients affected by alpha-mannosidosis is preservation of neurocognitive function and prevention of early death. The results obtained from a Phase I⁻II study and a Phase III study provide evidence of the positive clinical effect of the recombinant enzyme on patients with alpha-mannosidosis.
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http://dx.doi.org/10.3390/ijms19051500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983820PMC
May 2018

Biomechanical characterization of the Junzuki karate punch: indexes of performance.

Eur J Sport Sci 2018 Jul 3;18(6):796-805. Epub 2018 Apr 3.

b Rehabilitation Centre , Policlinico Italia , Rome , Italy.

The aims of this study were: (i) to determine kinematic, kinetic, and electromyographic characteristics of Junzuki karate punch in professional karate athletes; (ii) to identify biomechanical parameters that correlate with punch force and lead to a higher punching performance; (iii) to verify the presence of muscle co-activation in the upper limb, trunk, and lower limb muscles. Data were collected from nine experienced karatekas from the Accademia Italiana Karate e Arti Marziali during the execution of the specific punch. Mean punch forces (181.2 N) delivered to the target, the range of motion of both right and left knees (1.13 and 0.82 rad) and right elbow (1.49 rad) joints, and the angles at impact (knee: 0.81 and 0.91 rad; elbow: 1.19 rad) in the sagittal plane were computed. Furthermore, the trunk rotational angular acceleration (63.1 rads), force related to the lower limbs (550.2 and 425.1 N), and co-activation index for the upper limb (36.1% and 34.7%), trunk (24.5% and 16%), and lower limbs (16.0% and 16.1%) muscles were evaluated bilaterally. Significant positive correlations were found between the punch force and both right and left knee flexion at the instant of impact and right and left leg force. Significant negative correlation was found between the punch force and maximum trunk angular acceleration. Significant differences (p = .03) in the co-activation index among the upper limb, trunk, and lower limbs muscles highlighted a rostro-caudal gradient on both body sides. This research could be of use to performers and coaches when considering training preparations.
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http://dx.doi.org/10.1080/17461391.2018.1455899DOI Listing
July 2018

The Potential Role of Toll-Like Receptor 4 in Mediating Dopaminergic Cell Loss and Alpha-Synuclein Expression in the Acute MPTP Mouse Model of Parkinson's Disease.

J Mol Neurosci 2018 Apr 27;64(4):611-618. Epub 2018 Mar 27.

Department of Pharmaceutical Sciences, University of Perugia, 06126, Perugia, Italy.

Toll-like receptors (TLRs) may have a role in Parkinson's disease (PD). In this study, we aimed at investigating the dopaminergic cell loss and alpha-synuclein (α-SYN) expression in TLR4-deficient mice (TLR4) acutely exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a pharmacological PD model. TLR4 ablation restrained the number of dopaminergic neurons in the substantia nigra (SN), as assessed by tyrosine hydroxylase (TH) protein expression. Intriguingly, TLR4 mice showed massive α-SYN protein accumulation in the midbrain along with high α-SYN mRNA levels in cerebral cortex, striatum, hippocampus, and cerebellum. Contrary to expectations, the high levels of α-SYN do not correlate with greater dopaminergic neuronal loss. The levels of nigral α-SYN protein in TLR4 mice further, but not significantly, increased during MPTP treatment. Contrariwise, MPTP treatment significantly induced the mRNA expression of α-SYN in examined brain regions of WT and TLR4 mice. Protein levels of GATA2, a transcription factor proposed to control α-SYN gene expression, did not change in TLR4 mice at baseline and after MPTP treatment. These findings suggest a role for TLR4 in mediating dopaminergic cell loss and in the constitutive expression of brain α-SYN. However, further exploration is needed in order to establish the actual role of α-SYN in the relative absence of TLR4.
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http://dx.doi.org/10.1007/s12031-018-1057-7DOI Listing
April 2018

Effect of Vitamin D in HN9.10e Embryonic Hippocampal Cells and in Hippocampus from MPTP-Induced Parkinson's Disease Mouse Model.

Front Cell Neurosci 2018 7;12:31. Epub 2018 Feb 7.

Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.

It has long been proven that neurogenesis continues in the adult brains of mammals in the dentatus gyrus of the hippocampus due to the presence of neural stem cells. Although a large number of studies have been carried out to highlight the localization of vitamin D receptor in hippocampus, the expression of vitamin D receptor in neurogenic dentatus gyrus of hippocampus in Parkinson's disease (PD) and the molecular mechanisms triggered by vitamin D underlying the production of differentiated neurons from embryonic cells remain unknown. Thus, we performed a preclinical study by inducing PD in mice with MPTP and showed a reduction of glial fibrillary acidic protein ( in the dentatus gyrus of hippocampus. Then, we performed an study by inducing embryonic hippocampal cell differentiation with vitamin D. Interestingly, vitamin D stimulates the expression of its receptor. Vitamin D receptor is a transcription factor that probably is responsible for the upregulation of microtubule associated protein 2 and neurofilament heavy polypeptide genes. The latter increases heavy neurofilament protein expression, essential for neurofilament growth. Notably N-cadherin, implicated in activity for dendritic outgrowth, is upregulated by vitamin D.
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http://dx.doi.org/10.3389/fncel.2018.00031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808335PMC
February 2018

Dataset on gait patterns in degenerative neurological diseases.

Data Brief 2018 Feb 12;16:806-816. Epub 2017 Dec 12.

Department of Mechanical and Aerospace Engineering, "Sapienza" University of Rome, Via Eudossiana 18 - 00184 Roma, Italy.

We collected the gait parameters and lower limb joint kinematics of patients with three different types of primary degenerative neurological diseases: (i) cerebellar ataxia (19 patients), (ii) hereditary spastic paraparesis (26 patients), and (iii) Parkinson's disease (32 patients). Sixty-five gender-age matched healthy subjects were enrolled as control group. An optoelectronic motion analysis system was used to measure time-distance parameters and lower limb joint kinematics during gait in both patients and healthy controls.
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http://dx.doi.org/10.1016/j.dib.2017.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773445PMC
February 2018

Identification of specific gait patterns in patients with cerebellar ataxia, spastic paraplegia, and Parkinson's disease: A non-hierarchical cluster analysis.

Hum Mov Sci 2018 Feb 28;57:267-279. Epub 2017 Sep 28.

Department of Mechanical and Aerospace Engineering, "Sapienza" University of Rome, Via Eudossiana 18, 00184 Roma, Italy.

Background: Patients with degenerative neurological diseases such as cerebellar ataxia, spastic paraplegia, and Parkinson's disease often display progressive gait function decline that inexorably impacts their autonomy and quality of life. Therefore, considering the related social and economic costs, one of the most important areas of intervention in neurorehabilitation should be the treatment of gait abnormalities. This study aims to determine whether an entire dataset of gait parameters recorded in patients with degenerative neurological diseases can be clustered into homogeneous groups distinct from each other and from healthy subjects. Patients affected by three different types of primary degenerative neurological diseases were studied. These diseases were: i) cerebellar ataxia (28 patients), ii) hereditary spastic paraplegia (31 patients), and iii) Parkinson's disease (70 patients). Sixty-five gender-age-matched healthy subjects were enrolled as a control group. An optoelectronic motion analysis system was used to measure time-distance parameters and lower limb joint kinematics during gait in both patients and healthy controls. When clustering single parameters, step width and ankle joint range of motion (RoM) in the sagittal plane differentiated cerebellar ataxia group from the other groups. When clustering sets of two, three, or four parameters, several pairs, triples, and quadruples of clusters differentiated the cerebellar ataxia group from the other groups. Interestingly, the ankle joint RoM parameter was present in 100% of the clusters and the step width in approximately 50% of clusters. In addition, in almost all clusters, patients with cerebellar ataxia showed the lowest ankle joint RoM and the largest step width values compared to healthy controls, patients with hereditary spastic paraplegia, and Parkinson's disease subjects. This study identified several clusters reflecting specific gait patterns in patients with degenerative neurological diseases. In particular, the specific gait pattern formed by the increased step width, reduced ankle joint RoM, and increased gait variability, can differentiate patients with cerebellar ataxia from healthy subjects and patients with spastic paraplegia or Parkinson's disease. These abnormal parameters may be adopted as sensitive tools for evaluating the effect of pharmacological and rehabilitative treatments.
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http://dx.doi.org/10.1016/j.humov.2017.09.005DOI Listing
February 2018