Role of expectations in clinical outcomes after deep brain stimulation in patients with Parkinson's disease: a systematic review.

Deep brain stimulation (DBS) is a well-established treatment that significantly improves the motor symptoms of patients with Parkinson's disease (PD); however, patients may experience post-operative psychological distress and social maladjustments. This phenomenon has been shown to be related to patients' pre-operative cognitive representations, such as expectations. In this systematic review, we discuss the findings on the role of the expectations of patients with PD regarding the clinical outcomes of DBS to identify areas of intervention to improve pre-operative patient education and promote successful post-operative psychosocial adjustment. PubMed was searched for relevant articles published up to 16 January 2023. Of the 84 identified records, 10 articles focusing on the treatment expectations of patients with PD undergoing DBS were included in this review. The selected studies were conducted among cohorts of patients with different DBS targets, among which the most common was the bilateral subthalamic nucleus. Overall, the data showed that patients' expectations contribute to treatment efficacy. Experiments investigating the placebo effect itself have shown clinical improvement after the induction of positive therapeutic expectations; conversely, unrealistic treatment expectations can affect patient satisfaction after surgery, clinical outcomes, and subjective well-being. This review highlights the need for routine clinical practice to better investigate and manage patients' pre-operative expectations, as well as multidisciplinary education to improve patient satisfaction and psychosocial adjustment after DBS.

Lower semantic fluency scores and a phonemic-over-semantic advantage predict abnormal CSF P-tau181 levels in Aß + patients within the Alzheimer's disease clinical spectrum.

BACKGROUND: The present study aimed to determine whether patients with mild cognitive impairment (MCI) and dementia due to Alzheimer's disease (AD), semantic verbal fluency (SVF), and the semantic-phonemic discrepancy (SPD) could predict abnormal cerebrospinal fluid (CSF) phosphorylated tau (P-tau181) and total tau (T-tau) levels. METHODS: Phonemic verbal fluency (PVF) and SVF scores of N = 116 Aß-positive patients with either MCI due to AD (N = 39) or probable AD dementia (ADD; N = 77) were retrospectively collected. The SPD was computed by subtracting PVF scores from SVF ones (positive and negative values corresponding to a semantic and phonemic advantage, respectively). Patients were cognitively phenotyped via a thorough test battery and profiled according to the amyloidosis/tauopathy/neurodegeneration (ATN) framework via CSF analyses. Two separate sets of logistic regressions were run to predict normal vs. abnormal P-tau181 and T-tau levels by encompassing as predictors SVF + PVF and SPD and covarying for demographic, disease-related features, and cognitive profile. RESULTS: Lower SVF, but not PVF, scores, as well as a greater phonemic advantage (i.e., negative SPD values), predicted abnormal CSF P-tau181 levels (p ≤ .01). Moreover, lower SVF scores were selectively predictive of abnormal CSF T-tau levels too (p = .016), while the SPD was not. DISCUSSION: SVF and the SPD are able to predict tauopathy across the AD spectrum, thus supporting their status of valid, and sufficiently specific, cognitive markers of AD.

Fluid structure interaction analysis to stratify the behavior of different atheromatous carotid plaques.

BACKGROUND: In asymptomatic carotid stenosis (ACS), different plaque types, i.e. lipidic (LP), fibrous (FP), and calcific (CP), could have different hemodynamic and structural behaviors. METHODS: Different carotid plaques, reconstructed from medical imaging of ACS >70%, were analyzed by computing fluid structure interaction (FSI), modeling the spatial distribution of wall shear stresses (WSS), plaque displacements (D), von Mises stresses (VMS), and absorbed elastic energy (AEE) together with their maximum-in-space values at the systole (WSSsyst, Dsyst, VMSsyst and AEEsyst). RESULTS: WSS resulted significantly higher in CP, whereas D and VMS showed the highest values for LP. Regarding AEEsyst stored by the plaques, LP absorbed in average 2320 J/m3, FP 408 J/m3 (470%) and CP 99 J/m3 (2240%), (P<0.01, P<0.01, and P<0.01, respectively). CONCLUSIONS: Depending upon their nature, plaques store different deformations and inner distributions of forces, thus potentially influencing their vulnerability.

Pallidal functional connectivity changes are associated with disgust recognition in pure motor amyotrophic lateral sclerosis.

In the present study, we aimed to investigate the resting-state functional connectivity (RS-FC) of the globus pallidus (GP) in patients with amyotrophic lateral sclerosis (ALS) compared to healthy controls, and the relationship between RS-FC changes and disgust recognition. Twenty-six pure-motor ALS patients and 52 healthy controls underwent RS functional MRI and a neuropsychological assessment including the Comprehensive Affect Testing System. A seed-based RS-FC analysis was performed between the left and right GP and the rest of the brain and compared between groups. Correlations between RS-FC significant changes and subjects' performance in recognizing disgust were tested. Compared to controls, patients were significantly less able to recognize disgust. In ALS compared to controls, the seed-based analysis showed: reduced RS-FC between bilateral GP and bilateral middle and superior frontal and middle cingulate gyri, and increased RS-FC between bilateral GP and bilateral postcentral, supramarginal and superior temporal gyri and Rolandic operculum. Decreased RS-FC was further observed between left GP and left middle and inferior temporal gyri and bilateral caudate; and increased RS-FC was also shown between right GP and left lingual and fusiform gyri. In patients and controls, lower performance in recognizing disgust correlated with reduced RS-FC between left GP and left middle and inferior temporal gyri. In pure-motor ALS patients, we demonstrated altered RS-FC between GP and the rest of the brain. The reduced left pallidum-temporo-striatal RS-FC may have a role in the lower ability of patients in recognizing disgust.

A + T ± status across MCI and dementia due to AD: a clinic-based, retrospective study.

BACKGROUND: This study aimed at comparing, within the 2018 NIA-AA amyloidosis/tauopathy/neurodegeneration (ATN) framework, the distribution of T ± profiles across A + patients with MCI and dementia in a retrospective, single-center, clinic-based cohort. METHODS: We retrospectively collected data on N = 168 A + patients with either MCI due to AD (N = 50) or probable AD dementia (ADD; N = 118). ATN status was assigned, according to the 2018 NIA-AA framework, based on cerebrospinal fluid (CSF) biomarker concentrations. A χ2-test for independent samples was run to compare the distribution of A + T + vs. A + T- profiles, regardless of N status, across MCI and dementia patients. RESULTS: The most represented ATN profile in both groups was A + T + N + (MCI: 54%; dementia: 70.3%); 3.4% of dementia patients and none within the MCI cohort presented with an A + T-N + profile. When grouping ATN profiles solely based on A and T dimensions, the prevalence of A + T + was of 76.3% and 66% in dementia and MCI patients, respectively. No association between clinical diagnoses (i.e., MCI vs. dementia status) and AT profiles (i.e., A + T + vs. A + T-) was detected. DISCUSSION: The distribution of A + T + vs. A + T- does not differ between MCI and ADD, with A + T + profiles being predominant in both clinical categories. This does not support the common notion of A + T- profiles being relatively more prevalent in MCI patients, as indexing an earlier and/or less severe disease. Hence, caution should be exerted in attributing a case of MCI to prodromal AD solely based on A-positivity in the presence of a T-negative profile.

Role of risk scoring systems in predicting life expectancy after carotid endarterectomy in asymptomatic patients.

OBJECTIVE: The aim of this study is to compare and to test the performance of all available risk scoring systems (RSSs) designed to predict long-term survival rate in asymptomatic candidate patients for carotid endarterectomy (CEA) for significant carotid artery stenosis. METHODS: Data on asymptomatic patients who underwent CEA in three high-volume centers were prospectively recorded. Through literature research using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, six RSSs were identified for the intent of the study. Primary endpoints were 3- and 5-year survival rates after CEA. All items used as variables to compose multiple RSSs were applied to every patient in the study population. The 3- and 5-year mortality prediction rates for each score were assessed by sensitivity, specificity, and predictive negative and positive value calculation, as well as univariable Cox proportional hazard models with the Harrell C index. RESULTS: During the study period, 825 CEAs in 825 asymptomatic patients were analyzed. All items used in RSSs were available in the dataset, with some concerns regarding their definition and application among RSSs. The 3- and 5-year survival rates of the study cohort were 94.5% and 90.3%, respectively. Among the six RSSs analyzed, no RSS demonstrated optimal results in terms of mortality rate prediction accuracy, although some scores had good diagnostic and risk of death precision. CONCLUSIONS: RSSs, when used alone, fail to optimally detect postoperative life expectancy in asymptomatic CEA patient candidates. Further prospective controlled studies are needed to compose and validate RSSs with better calibration to predict outcomes.

COVID-19 and supra-aortic trunks disease: review of literature about critical phase and sequelae.

The acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 disease, a global pandemic. A strong association has been documented between COVID-19 and cardiovascular events, although the exact pathophysiological mechanism is still unclear. Carotid atherothrombosis and ischemic stroke represents one of the possible severe manifestations of COVID-19, as a leading cause of long-term disability and death. Different complex intertwined mechanisms seem to underlie the endothelitis which is the cause of multiple cardiovascular manifestations. To date, few case series describing COVID-19 and acute ischemic stroke caused by cervical carotid thrombosis have been published. All the patients shared common similar radiographic features, comorbidities, and biomarker profiles. The aim of this brief review was to analyze the impact of COVID-19 pandemic in the management of a Vascular Surgery Department, changing the daily vascular practice, as well as to provide practical suggestions for symptomatic carotid stenosis, while reviewing published literature.

Impaired recognition of disgust in amyotrophic lateral sclerosis is related to basal ganglia involvement.

In the present study we investigated emotion recognition in pure motor amyotrophic lateral sclerosis (ALS) patients and its relationship with the integrity of basal ganglia, hippocampus and amygdala. Twenty ALS patients without either cognitive or behavioural impairment, and 52 matched healthy controls performed a neuropsychological assessment including the Comprehensive Affect Testing System (CATS) investigating emotion recognition. All participants underwent also a 3T brain MRI. Volumes of basal ganglia, hippocampus and amygdala bilaterally were measured using FIRST in FSL. Sociodemographic, cognitive and MRI data were compared between groups. In ALS patients, correlations between CATS significant findings, brain volumes, cognition, mood and behaviour were explored. ALS patients showed altered performances at the CATS total score and, among the investigated emotions, patients were significantly less able to recognize disgust compared with controls. No brain volumetric differences were observed between groups. In ALS patients, a lower performance in disgust recognition was related with a reduced volume of the left pallidum and a lower performance on the Edinburgh Cognitive and Behavioural ALS Screen. Cognitively/behaviourally unimpaired ALS patients showed impaired disgust recognition, which was associated with pallidum volume. The association with cognitive alterations may suggest impaired disgust recognition as an early marker of cognitive decline.

SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution.

The nuclear RNA-binding protein TDP-43 forms abnormal cytoplasmic aggregates in the brains of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients and several molecular mechanisms promoting TDP-43 cytoplasmic mislocalization and aggregation have been proposed, including defects in nucleocytoplasmic transport, stress granules (SG) disassembly and post-translational modifications (PTM). SUMOylation is a PTM which regulates a variety of cellular processes and, similarly to ubiquitination, targets lysine residues. To investigate the possible regulatory effects of SUMOylation on TDP-43 activity and trafficking, we first assessed that TDP-43 is SUMO-conjugated in the nuclear compartment both covalently and non-covalently in the RRM1 domain at the predicted lysine 136 and SUMO-interacting motif (SIM, 106-110 residues), respectively. By using the SUMO-mutant TDP-43 K136R protein, we demonstrated that SUMOylation modifies TDP-43 splicing activity, specifically exon skipping, and influences its sub-cellular localization and recruitment to SG after oxidative stress. When promoting deSUMOylation by SENP1 enzyme over-expression or by treatment with the cell-permeable SENP1 peptide TS-1, the cytoplasmic localization of TDP-43 increased, depending on its SUMOylation. Moreover, deSUMOylation by TS-1 peptide favoured the formation of small cytoplasmic aggregates of the C-terminal TDP-43 fragment p35, still containing the SUMO lysine target 136, but had no effect on the already formed p25 aggregates. Our data suggest that TDP-43 can be post-translationally modified by SUMOylation which may regulate its splicing function and trafficking, indicating a novel and druggable mechanism to explore as its dysregulation may lead to TDP-43 pathological aggregation in ALS and FTD.

Epileptic Capgras-Like Delusions in a Patient with Right Frontal Meningioma: Case Report.

Capgras syndrome is a condition characterized by the belief that a relative has been replaced by an almost identical imposter. The disorder has been reported in several neurological diseases. We describe the uncommon case of a transient Capgras syndrome manifesting as focal temporal seizures in a woman with a right frontal meningioma. Our patient represents an exceptional case of Capgras syndrome for several reasons, namely, the association with meningioma, very rarely reported before, the transient manifestation of symptoms, and, most importantly, the epileptic etiology of reduplicative paramnesias. Lastly, our report also confirms the importance of frontal and right hemisphere dysfunction in generating Capgras syndrome-like delusions.

Fiberoptic endoscopic evaluation of swallowing in early-to-advanced stage Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor disturbances, cognitive decline, and behaviour changes. A well-recognized feature of advanced HD is dysphagia, which leads to malnutrition and aspiration pneumonia, the latter being the primary cause of death in HD. Previous studies have underscored the importance of dysphagia in HD patients with moderate-to-advanced stage disease, but it is unclear whether dysphagia affects patients already at an early stage of disease and whether genetic or clinical factors can predict its severity. We performed fiberoptic endoscopic evaluation of swallowing (FEES) in 61 patients with various stages of HD. Dysphagia was found in 35% of early-stage, 94% of moderate-stage, and 100% of advanced-stage HD. Silent aspiration was found in 7.7% of early-stage, 11.8% of moderate-stage, and 27.8% of advanced-stage HD. A strong correlation was observed between disease progression and dysphagia severity: worse dysphagia was associated with worsening of motor symptoms. Dysphagia severity as assessed by FEES correlated with Huntington's Disease Dysphagia Scale scores (a self-report questionnaire specific for evaluating swallowing in HD). The present findings add to our understanding of dysphagia onset and progression in HD. A better understanding of dysphagia onset and progression in HD may inform guidelines for standard clinical care in dysphagia, its recognition, and management.

Carotid artery stenting is safe and effective for symptomatic patients with acute coronary syndrome.

BACKGROUND: Patients with symptomatic carotid stenosis recently treated with percutaneous transluminal coronary angioplasty (PTCA) for acute coronary syndrome (ACS) are always classified as at high risk for surgery, given that they are required uninterrupted dual antiplatelet therapy. In this regard, carotid artery stenting (CAS) may represent a valid alternative. OBJECTIVE: The purpose of this study is to overview CAS outcomes in symptomatic patients with and without ACS. METHODS: One hundred fifty-one consecutive symptomatic patients who underwent CAS between 2010 and 2017 in a single institution were included in this study, of which 66 (43.7%) were identified as having ACS. All patients were followed-up with carotid duplex ultrasound scan and a neurological assessment of symptoms status at 30-day postprocedure and at 3, 6, and 12 months, with annual follow-up after that for 3 years. RESULTS: Among symptomatic ACS patients, common risks factors were active smoking, metabolic syndrome, diabetes, and hypertension. In the short-term follow-up, no significant differences were observed among rates of death, stroke, myocardial infarction (MI), and restenosis, between patients with and without ACS. Mean clinical follow-up was 28.2 (12.3) months. In the long-term follow-up, higher rates of death and MI were recorded in patients with ACS (death: 11.4% vs. 5.4%, p = .04; MI: 11.4% vs. 3.6%, p = .02), owing to the complexity of these patients. CONCLUSIONS: This single-center study suggested that CAS is a safe and effective treatment for patients with symptomatic carotid artery stenosis, who recently underwent PTCA for ACS, requiring uninterrupted dual antiplatelet therapy.

A Novel Mutation of GFAP Causing Adult-Onset Alexander Disease.

Alexander disease (AxD) is a rare, autosomal dominant neurological disorder. Three clinical subtypes are distinguished based on age at onset: infantile (0-2 years), juvenile (2-13 years), and adult (>13 years). The three forms differ in symptoms and prognosis. Rapid neurological decline with a fatal course characterizes the early-onset forms, while symptoms are milder and survival is longer in the adult forms. Currently, the sole known cause of AxD is mutations in the GFAP gene, which encodes a type III intermediate filament protein that is predominantly expressed in astrocytes. A wide spectrum of GFAP mutations comprising point mutations, small insertions, and deletions is associated with the disease. The genotype-phenotype correlation remains unclear. The considerable heterogeneity in severity of disease among individuals carrying identical mutations suggests that other genetic or environmental factors probably modify age at onset or progression of AxD. Describing new cases is therefore important for establishing reliable genotype-phenotype correlations and revealing environmental factors able to modify age at onset or progression of AxD. We report the case of a 54-year-old Caucasian woman, previously diagnosed with ovarian cancer and treated with surgery and chemotherapy, who developed dysarthria, ataxia, and spastic tetraparesis involving mainly the left side. Cerebral and spinal magnetic resonance imaging (MRI) revealed a peculiar tadpole-like atrophy of the brainstem. Genetic analysis of the GFAP gene detected a heterozygous mutation in exon 1 (c.219G>C), resulting in an amino acid exchange from methionine to isoleucine at codon 73 (p.M73I). The expression of this mutant in vitro affected the formation of the intermediate filament network. Thus, we have identified a new GFAP mutation in a patient with an adult form of AxD.

Inter-Species Differences in Regulation of the Progranulin-Sortilin Axis in TDP-43 Cell Models of Neurodegeneration.

Cytoplasmic aggregates and nuclear depletion of the ubiquitous RNA-binding protein TDP-43 have been described in the autoptic brain tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTLD) patients and both TDP-43 loss-of-function and gain-of-function mechanisms seem to contribute to the neurodegenerative process. Among the wide array of RNA targets, TDP-43 regulates progranulin (GRN) mRNA stability and sortilin (SORT1) splicing. Progranulin is a secreted neurotrophic and neuro-immunomodulatory factor whose endocytosis and delivery to the lysosomes are regulated by the neuronal receptor sortilin. Moreover, GRN loss-of-function mutations are causative of a subset of FTLD cases showing TDP-43 pathological aggregates. Here we show that TDP-43 loss-of-function differently affects the progranulin-sortilin axis in murine and human neuronal cell models. We demonstrated that although TDP-43 binding to GRN mRNA occurs similarly in human and murine cells, upon TDP-43 depletion, a different control of sortilin splicing and protein content may determine changes in extracellular progranulin uptake that account for increased or unchanged secreted protein in murine and human cells, respectively. As targeting the progranulin-sortilin axis has been proposed as a therapeutic approach for GRN-FTLD patients, the inter-species differences in TDP-43-mediated regulation of this pathway must be considered when translating studies from animal models to patients.

TDP-43 and NOVA-1 RNA-binding proteins as competitive splicing regulators of the schizophrenia-associated TNIK gene.

The RNA-binding protein TDP-43, associated to amyotrophic lateral sclerosis and frontotemporal dementia, regulates the alternative splicing of several genes, including the skipping of TNIK exon 15. TNIK, a genetic risk factor for schizophrenia and causative for intellectual disability, encodes for a Ser/Thr kinase regulating negatively F-actin dynamics. Here we show that in the human adult nervous system TNIK exon 15 is mostly included compared to the other tissues and that, during neuronal differentiation of human induced pluripotent stem cells and of human neuroblastoma cells, TNIK exon 15 inclusion increases independently of TDP-43 protein content. By studying the possible molecular interplay of TDP-43 with brain-specific splicing factors, we found that the neuronal NOVA-1 protein competitively inhibits both TDP-43 and hnRNPA2/B1 skipping activity on TNIK by means of a RNA-dependent interaction and that this competitive mechanism is common to other TDP-43 RNA targets. We also show that the TNIK protein isoforms including/excluding exon 15 differently regulate cell spreading in non-neuronal cells and neuritogenesis in primary cortical neurons. Our data suggest a complex regulation between the ubiquitous TDP-43 and the neuron-specific NOVA-1 splicing factors in the brain that may help better understand the pathobiology of both neurodegenerative diseases and schizophrenia.

Safety and Efficacy of the New Micromesh-Covered Stent CGuard in Patients Undergoing Carotid Artery Stenting: Early Experience From a Single Centre.

OBJECTIVE/BACKGROUND: Plaque protrusion through stent struts represents one of the principal causes of cerebral embolisation during carotid artery stenting (CAS) and the stent healing period. The aim of this study was to evaluate the safety (technical success) and efficacy (clinical success) of the CGuard stent system - a new nitinol stent covered by a closed-cell polyethylene terephthalate mesh designed to prevent embolic events. METHODS: Eighty-two consecutive patients who underwent CAS with CGuard from June 2015 were included in this study. The same surgeon performed all procedures. Primary endpoints included technical and clinical success. Clinical success was considered to be absence of death, major or minor stroke. The incidence of new ischaemic brain lesions was also evaluated by diffusion weighted magnetic resonance imaging (DW-MRI) in a subgroup of patients as a secondary endpoint. RESULTS: In this study, 82 patients (73.8 ± 8.5 years, 75% male, 19% symptomatic) underwent CAS procedures. Immediate technical success was 100%, with the stenosis diameter reduced from 81.4 ± 4.9% to 11.0 ± 3.5%. There was peri-operative technical and clinical success in 100% of symptomatic patients, and in 98.5% of asymptomatic patients, because of the occurrence of one acute stent thrombosis 4 hours post-CAS followed by a minor stroke. In the post-operative period (30 days), no new events were registered. The most recent 21 patients (24%) underwent DW-MRI in the peri-operative period: new ischaemic brain lesions were recorded in 23.8% of patients and the average lesion volume per patients was 0.039 ± 0.025 cm3. CONCLUSIONS: The technical and clinical outcomes of this single centre study suggest that the CGuard may be a safe and effective device for endovascular treatment of symptomatic and asymptomatic subjects, independent of aortic arch anatomy. Further larger comparative studies are needed to confirm these benefits.

Gene-specific mitochondria dysfunctions in human TARDBP and C9ORF72 fibroblasts.

Dysregulation of RNA metabolism represents an important pathogenetic mechanism in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) due to the involvement of the DNA/RNA-binding proteins TDP-43 and FUS and, more recently, of C9ORF72. A potential link between dysregulation of RNA metabolism and mitochondrial dysfunction is recently emerged in TDP-43 disease models. To further investigate the possible relationship between these two pathogenetic mechanisms in ALS/FTD, we studied mitochondria functionality in human mutant TARDBP(p.A382T) and C9ORF72 fibroblasts grown in galactose medium to induce a switch from a glycolytic to an oxidative metabolism. In this condition we observed significant changes in mitochondria morphology and ultrastructure in both mutant cells with a fragmented mitochondria network particularly evident in TARDBP(p.A382T) fibroblasts. From analysis of the mitochondrial functionality, a decrease of mitochondria membrane potential with no alterations in oxygen consumption rate emerged in TARDBP fibroblasts. Conversely, an increased oxygen consumption and mitochondria hyperpolarization were observed in C9ORF72 fibroblasts in association to increased ROS and ATP content. We found evidence of autophagy/mitophagy in dynamic equilibrium with the biogenesis of novel mitochondria, particularly in mutant C9ORF72 fibroblasts where an increase of mitochondrial DNA content and mass, and of PGC1-α protein was observed. Our imaging and biochemical data show that wild-type and mutant TDP-43 proteins do not localize at mitochondria so that the molecular mechanisms responsible for such mitochondria impairment remain to be further elucidated. For the first time our findings assess a link between C9ORF72 and mitochondria dysfunction and indicate that mitochondria functionality is affected in TARDBP and C9ORF72 fibroblasts with gene-specific features in oxidative conditions. As in neuronal metabolism mitochondria are actively used for ATP production, we speculate that TARDBP and C9ORF72 mutations might trigger cell death by impairing not only RNA metabolism, but also mitochondria activity in ALS/FTD neurons.

CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCF(Cyclin F)). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCF(Cyclin F) substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

Non-neural phenotype of spinal and bulbar muscular atrophy: results from a large cohort of Italian patients.

OBJECTIVE: To carry out a deep characterisation of the main androgen-responsive tissues involved in spinal and bulbar muscular atrophy (SBMA). METHODS: 73 consecutive Italian patients underwent a full clinical protocol including biochemical and hormonal analyses, genitourinary examination, bone metabolism and densitometry, cardiological evaluation and muscle pathology. RESULTS: Creatine kinase levels were slightly to markedly elevated in almost all cases (68 of the 73; 94%). 30 (41%) patients had fasting glucose above the reference limit, and many patients had total cholesterol (40; 54.7%), low-density lipoproteins cholesterol (29; 39.7%) and triglyceride (35; 48%) levels above the recommended values. Although testosterone, luteinising hormone and follicle-stimulating hormone values were generally normal, in one-third of cases we calculated an increased Androgen Sensitivity Index reflecting the presence of androgen resistance in these patients. According to the International Prostate Symptom Score (IPSS), 7/70 (10%) patients reported severe lower urinal tract symptoms (IPSS score >19), and 21/73 (30%) patients were moderately symptomatic (IPSS score from 8 to 19). In addition, 3 patients were carriers of an indwelling bladder catheter. Videourodynamic evaluation indicated that 4 of the 7 patients reporting severe urinary symptoms had an overt prostate-unrelated bladder outlet obstruction. Dual-energy X-ray absorptiometry scan data were consistent with low bone mass in 25/61 (41%) patients. Low bone mass was more frequent at the femoral than at the lumbar level. Skeletal muscle biopsy was carried out in 20 patients and myogenic changes in addition to the neurogenic atrophy were mostly observed. CONCLUSIONS: Our study provides evidence of a wide non-neural clinical phenotype in SBMA, suggesting the need for comprehensive multidisciplinary protocols for these patients.

Phenotypic Modulation and Neuroprotective Effects of Olfactory Ensheathing Cells: a Promising Tool for Cell Therapy.

Olfactory Ensheathing Cells (OECs), exhibiting phenotypic characteristics of both astrocytes and Schwann Cells, show peculiar plasticity. In vitro, OECs promote axonal growth, while in vivo they promote remyelination of damaged axons. We decided to further investigate OEC potential for regeneration and functional recovery of the damaged Central Nervous System (CNS). To study OEC antigen modulation, OECs prepared from postnatal mouse olfactory bulbs were grown in different culture conditions: standard or serum-free media with/without Growth Factors (GFs) and analyzed for different neural specific markers. OEC functional characterizations were also achieved. Resistance of OECs to the neurotoxin 6-hydroxydopamine (6-OHDA) was analyzed by evaluating apoptosis and death. OEC neuroprotective properties were investigated by in vitro co-cultures or by addition of OEC conditioned medium to the neuroblastoma SH-SY5Y cells exposed to 6-OHDA. We observed: 1) modification of OEC morphology, reduced cell survival and marker expression in serum-free medium; 2) GF addition to serum-free medium condition influenced positively survival and restored basal marker expression; 3) no OEC apoptosis after a prolonged exposition to 6-OHDA; 4) a clear OEC neuroprotective tendency, albeit non statistically significant, on 6-OHDA treated SH-SY5Y cells. These peculiar properties of OECs might render them potential clinical agents able to support injured CNS.