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The efficacy of corruption perception indices to truly capture and accurately measure corruption behaviours has been often criticised. In fact, perceptions about corruption may not match actual experience and could represent distorted beliefs. Motivated by this criticism, we investigate the difference between perceived and experienced corruption (i.e., bribery) in public services in Europe by means of a theoretical model and an empirical analysis. Firstly, we model perceived corruption as a function of experienced corruption and a perception bias. Then, we employ a generalised setting of structural equation models to derive two distinct measures of perceived and experienced corruption from microdata on the public administration sector in Europe. The indices we obtain allow us to compare countries according to both measures of public corruption. Finally, our results suggest that perceptions of corruption may be affected by sources of media bias.

Cognitive impairment is an essential feature of Huntington’s disease (HD) and dementia is a predictable outcome in all patients. However, validated instruments to assess global cognitive performance in the field of HD are lacking. We aimed to explore the utility of the Parkinson’s disease-Cognitive Rating Scale (PD-CRS) for the screening of global cognition in HD. A multicenter cohort of 132 HD patients at different disease stages and 33 matched healthy controls were classified as having preserved cognition, mild cognitive impairment (HD-MCI) or dementia (HD-Dem) according to the Clinical Dementia Rating and Functional Independence Score. The PD-CRS and the Mini-Mental State Examination were administered. Receiver operating characteristic curve analysis was used to determine optimal cutoffs to differentiate patients according to their cognitive status. A PD-CRS cutoff score ≤ 81/82 was optimal to detect HD-MCI (sensitivity = 93%; specificity = 80%; area under the curve (AUC) = 0.940), and ≤ 63/64 was optimal to detect HD-Dem (sensitivity = 90%; specificity = 87%; AUC = 0.933). MMSE scores failed to show robust psychometric properties in this context. The PD-CRS is a valid and reliable instrument to assess global cognition in HD in routine clinical care and clinical trials.

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic small-vessel disease that is characterized by a wide range of neurologic and neuropsychological impairments. Constructional impairments have been reported in some cases but have never been assessed systematically.To evaluate constructional abilities and their cognitive and neural correlates in nondemented individuals with CADASIL.Thirty individuals with CADASIL who were not affected by clinically relevant cognitive deterioration and 30 healthy controls (HC) underwent an extensive cognitive assessment and paper-and-pencil visuoconstructional tasks in order to detect constructional impairments. Performance on the visuoconstructional tasks was correlated with the cognitive assessment scores and with quantitative indices of regional gray matter atrophy (obtained via FreeSurfer image analysis) and white matter involvement.The individuals with CADASIL achieved significantly lower scores on the cognitive assessment compared with the HC. Poor visuoconstructional abilities were observed in seven (23.3%) of the individuals with CADASIL when performing the copy drawing task and in nine (30%) when performing the Rey Complex Figure Test. Logistic regression revealed that visuoconstructional impairments were significantly associated with scores on the Frontal Assessment Battery and the Attentional Matrices Test. Morphometric results revealed that scores on the visuoconstructional tasks were related to gray matter atrophy of the left frontal lobe and right parietal lobe.Impairments on visuoconstructional tasks are quite common in individuals with CADASIL, even in the lack of clinically relevant cognitive deterioration, and are critically related to frontal and parietal atrophy.

We screened 62 late-onset ataxia patients for the AAGGG pathological expansion in the RFC-1 gene that, when biallelic, causes Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS). Nine patients tested positive. Six had a previous diagnosis of sporadic adult-onset ataxia (SAOA) and three of multisystem atrophy type C (MSA-C). Further six patients were heterozygous for the pathological RFC-1 expansion, four with an initial diagnosis of MSA-C and two of SAOA. In comparison with CANVAS, MSA-C patients had faster progression and shorter disease duration to walking with aids. An abnormal DaTscan does not seem to contribute to differential diagnosis between CANVAS and MSA-C.

Introduction Spinocerebellar ataxia type 14 (SCA14) is a dominantly inherited neurological disorder characterized by slowly progressive cerebellar ataxia. SCA14 is caused by mutations in PRKCG, a gene encoding protein kinase C gamma (PKCγ), a master regulator of Purkinje cells development. Methods We performed next-generation sequencing targeted resequencing panel encompassing 273 ataxia genes in 358 patients with genetically undiagnosed ataxia. Results We identified fourteen patients in ten families harboring nine pathogenic heterozygous variants in PRKCG, seven of which were novel. We encountered four patients with not previously described phenotypes: one with episodic ataxia, one with a spastic paraparesis dominating her clinical manifestations, and two children with an unusually severe phenotype. Conclusions Our study broadens the genetic and clinical spectrum of SCA14.

Wilson's Disease (WD) is an autosomal recessive disorder caused by excessive copper deposition in liver, brain and other organs. The clinical picture is characterized by hepatic, psychiatric and neurological dysfunction. Movement disorders are the core neurological features, although non-motor symptoms (NMS), as cognitive/affective, autonomic and sleep disorders, may occur over time. We aimed to assess the frequency of NMS in WD patients compared with healthy subjects.Twenty-seven patients affected with genetically proven WD (12 F, 15 M) and 35 healthy controls (Ctrl; 17 F, 18 M), comparable for age and education, were enrolled. Eighteen patients presented with the neurological form of the disease (NV) and nine with the non-neurological variant (NNV). NMS were assessed in all subjects by the following clinical scales: Mini-Mental State Examination (MMSE), Non-Motor Symptoms Scale (NMSS), SCOPA-AUT Questionnaire, Apathy Evaluation Scale (AES), Beck Depression Inventory (BDI), Epworth Sleepiness Scale (ESS), Restless Legs Syndrome Rating Scale (RLSRS), REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP-RS).We found that the patients showed more severe and frequent NMS and daytime sleepiness, and lower MMSE than Ctrl. In comparison to healthy subjects, NV subjects showed statistically significant higher ESS, NMSS, and RLSRS scores, and a lower MMSE score. Subtle and subclinical extrapyramidal/pyramidal signs and brain MRI signal abnormalities were detected in patients considered as asymptomatic for neurological disturbances.NMS are common among WD patient, in particular those with NV, likely due to the widespread pathological changes throughout the central nervous system.

The pattern and permeability characteristics that compose three-dimensional (3D) textiles are important as a textile shading component to the architecture, engineering and construction (AEC) industry. Moreover, due to their complex geometry, 3D fabrics require a detailed modeling for correct evaluation of performance. This paper aims to present and investigate the optical properties of six 3D fabrics proposed as an alternative to traditional roller blind shading systems, which could guarantee high daylight availability and visual comfort. The light transmission distribution for the different samples has been characterized by carrying out angular visual transmittance measurements, using integrating sphere optical benches, and virtual modeling using Radiance's genBSDF tool. The Bidirectional Scattering Distribution Function (BSDF) calculated with Radiance shows a good fit with the optical angular measurements, which were used as a benchmark and to calibrate models. The performance of the 3D textiles, in terms of illuminance, daylight availability, and glare, was assessed considering two of the set of 3D textiles as alternative materials for a movable internal roller shade system in an open office. The innovative system was compared with a traditional single layer fabric roller blind under different shading control strategies, 3D fabrics demonstrate the potential of increasing Daylight Autonomy while providing better uniformity and better connection with the outdoors due to a higher openness factor. The shading effect created by the 3D geometry of the textile can increase the openness factor while restricting glare.

Primary familial brain calcification (PFBC) is a rare disorder mostly characterized by calcium deposits in the basal ganglia and a wide spectrum of neurologic and psychiatric symptoms, typically inherited as an autosomal dominant trait. Recently, MYORG was reported as the first autosomal recessive causal gene in PFBC patients of Chinese and Middle Eastern origin. Herein, we describe the first PFBC patient of European descent found to carry a novel homozygous MYORG mutation (p.N511Tfs*243). Interestingly, the patient's father, a heterozygous carrier of the same mutation, showed diffuse bilateral cerebral calcifications with no symptoms other than very mild postural tremor.

Gustatory perception has been poorly explored in Parkinson's disease (PD). Aim of this study was to assess the flavor ability in PD patients, using the "flavor test" (FT), a new standardized and validated tool to examine the flavor perception. Thirty-eight patients (17 F and 21 M) and 36 control subjects (15 F and 21 M) comparable for age and gender were enrolled. All the subjects underwent the flavor test (FT), the Sniffin' Sticks test (SST), and the gustometry test (GT), based on the basic four tastants ("salty," "sour," "sweet," and "bitter"). PD patients presented a FT score significantly lower than controls (p

Aim: Our aim was to describe the rearrangements of the brain activity related to genetic mutations in the SPAST gene. Methods: Ten SPG4 patients and ten controls underwent a 5 min resting state magnetoencephalography recording and neurological examination. A beamformer algorithm reconstructed the activity of 90 brain areas. The phase lag index was used to estimate synchrony between brain areas. The minimum spanning tree was used to estimate topological metrics such as the leaf fraction (a measure of network integration) and the degree divergence (a measure of the resilience of the network against pathological events). The betweenness centrality (a measure to estimate the centrality of the brain areas) was used to estimate the centrality of each brain area. Results: Our results showed topological rearrangements in the beta band. Specifically, the degree divergence was lower in patients as compared to controls and this parameter related to clinical disability. No differences appeared in leaf fraction nor in betweenness centrality. Conclusion: Mutations in the SPAST gene are related to a reorganization of the brain topology.

Introduction Psychosis in Parkinson’s disease (PD) is common and consists of hallucinations, illusions, and delusions. Among the latter, delusional jealousy, also named Othello syndrome (OS), might impair the quality of life of both patients and their partners. We aimed to perform a systematic review and report a series of PD patients presenting with OS. Methods A systematic review research was performed in PubMed database, excluding non-English articles, single case reports, reviews and neuropathology articles, comments, and articles concerning OS associated with deep brain stimulation (DBS) and levodopa-carbidopa intestinal gel infusion. We also described eleven PD patients (9 M and 2 F) with OS, identified in a cohort of consecutive 153 patients, comparing them with eleven matched no OS (nOS) PD subjects taken from the same cohort. Results We included eight articles (four case series and four cross-sectional studies). OS resulted more common among males than females. We did not find higher levodopa dose and levodopa equivalent dose for dopamine agonists and for all anti-parkinsonian drugs in our OS group. In our case series, OS patients showed visual hallucinations (p=0.001) and a trend to have depression (p=0.080) more frequently than nOS ones. Conclusions OS is not a rare disorder in PD, probably due not only to abnormal dopaminergic stimulation but also to serotonergic dysfunction in biologically predisposed subjects. Visual hallucinations and other concomitant psychiatric diseases, in particular depression, might represent a risk factor for the OS development.

Objectives: To evaluate the retinal and choriocapillaris vascular networks in macular region and the central choroidal thickness (CCT) in patients affected by Huntington disease (HD), using optical coherence tomography angiography (OCTA) and enhanced depth imaging spectral-domain OCT (EDI SD-OCT). Methods: We assessed the vessel density (VD) in superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris (CC) using OCTA, while CCT was measured by EDI SD-OCT. Results: Sixteen HD patients (32 eyes) and thirteen healthy controls (26 eyes) were enrolled in this prospective study. No significant difference in retinal and choriocapillaris VD was found between HD patients and controls while CCT turned to be thinner in patients respect to controls. There were no significant relationships between OCTA findings and neurological parameters. Conclusion: The changes in choroidal structure provide useful information regarding the possible neurovascular involvement in the physiopathology of HD. Choroidal vascular network could be a useful parameter to evaluate the vascular impairment that occurs in this neurodegenerative disease.

The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.

AIM Progressive Supranuclear Palsy (PSP) is a progressive neurodegenerative tauopathy characterised by motor, behavioural and cognitive dysfunction. While in the last decade, sensory and autonomic disturbances as well as peripheral nerve involvement are well-recognised in Parkinson's Disease (PD), little is known in this regard for PSP. Herein, we aim to assess peripheral sensory and autonomic nerve involvement in PSP and to characterise possible differences in morpho-functional pattern compared to PD patients. METHODS We studied 27 PSP and 33 PD patients without electrophysiological signs of neuropathy, and 33 healthy controls (HC). In addition to motor impairment, evaluated by means of UPDRS-III and the PSP rating scale, all patients underwent clinical, functional and morphological assessment of sensory-autonomic nerves through dedicated questionnaires, sympathetic skin response, dynamic sweat test and skin biopsies. The analysis of cutaneous sensory and autonomic innervation was performed using indirect immunofluorescence and confocal microscopy. RESULTS PSP patients displayed a length-dependent loss of sensory and autonomic nerve fibres associated with functional impairment compared to HC and, overall, a more severe picture than in PD patients. The disease severity correlated with the loss of intraepidermal nerve fibre density in the leg of PSP patients (p

Background: Arithmetic word-problem solving depends on the interaction of several cognitive processes that may be affected early in the disease in gene-mutation carriers for Huntington’s disease (HD). Objective: Our goal was to examine the pattern of performance of arithmetic tasks in premanifest and manifest HD, and to examine correlations between arithmetic task performance and other neuropsychological tasks. Methods: We collected data from a multicenter cohort of 165 HD gene-mutation carriers. The sample consisted of 31 premanifest participants: 16 far-from (>12 years estimated time to diagnosis; preHD-A) and 15 close-to (≤12 years estimated time to diagnosis; preHD-B), 134 symptomatic patients (early-mild HD), and 37 healthy controls (HC). We compared performance between groups and explored the associations between arithmetic word-problem solving and neuropsychological and clinical variables. Results: Total arithmetic word-problem solving scores were lower in preHD-B patients than in preHD-A (p

Background and aim In the scientific literature, there is unanimous consensus that hospitalization in stroke unit (SU) is the most important treatment for stroke patients. In this regard, the Act number 70/2015 by the Italian government identified specific skills that contribute to a classification of SU and outlined a “hub and spoke” stroke network. The aim of our study was to check the coverage of requirements of first and second level SU in the national territory and to shed light on any deficit or misdistribution of resources. Material and methods In 2019, a survey on the current situation related to stroke care in Italy was carried out by the Italian Society of Neurology (SIN), The Italian Stroke Organization (ISO), and the Association for the Fight against Stroke (A.L.I.Ce). Results First level SU was found to be 58 against a requirement, according to the Act 70/2015, of 240. Second level SU was found to be 52 compared with an expected requirement of 60. Neurointerventionists were 280 nationally, with a requirement of 240. A misdistribution of resources within individual regions was often seen. Conclusions The survey demonstrated a severe shortage of beds dedicated to cerebrovascular diseases, mainly because of lack of first level SU, especially in central and southern Italy. It also suggests that the current hub and spoke system is not yet fully implemented across the country and that resources should be better distributed in order to ensure uniform and fair care for all stroke patients on the whole territory.

Neuroacanthocytosis (NA) syndromes are a group of genetically defined diseases characterized by the association of red blood cell acanthocytosis, progressive degeneration of the basal ganglia and neuromuscular features with characteristic persistent hyperCKemia. The main NA syndromes include autosomal recessive chorea-acanthocytosis (ChAc) and X-linked McLeod syndrome (MLS). A series of Italian patients selected through a multicenter study for these specific neurological phenotypes underwent DNA sequencing of the VPS13A and XK genes to search for causative mutations. Where it has been possible, muscle biopsies were obtained and thoroughly investigated with histochemical assays. A total of nine patients from five different families were diagnosed with ChAC and had mostly biallelic changes in the VPS13A gene (three nonsense, two frameshift, three splicing), while three patients from a single X-linked family were diagnosed with McLeod syndrome and had a deletion in the XK gene. Despite a very low incidence (only one thousand cases of ChAc and a few hundred MLS cases reported worldwide), none of the 8 VPS13A variants identified in our patients is shared by two families, suggesting the high genetic variability of ChAc in the Italian population. In our series, in line with epidemiological data, McLeod syndrome occurs less frequently than ChAc, although it can be easily suspected because of its X-linked mode of inheritance. Finally, histochemical studies strongly suggest that muscle pathology is not simply secondary to the axonal neuropathy, frequently seen in these patients, but primary myopathic alterations can be detected in both NA syndromes.

Biallelic mutations in STUB1, which encodes the E3 ubiquitin ligase CHIP, were originally described in association with SCAR16, a rare autosomal recessive spinocerebellar ataxia, so far reported in 16 kindreds. In the last 2 years, a new form of spinocerebellar ataxia (SCA48), associated with heterozygous mutations in the same gene, has been described in 12 kindreds with autosomal dominant inheritance. Methods We reviewed molecular and clinical findings of both SCAR16 and SCA48 described patients. Results and conclusion SCAR16 is characterized by early onset spastic ataxia and a wide disease spectrum, including cognitive dysfunction, hyperkinetic disorders, epilepsy, peripheral neuropathy, and hypogonadism. SCA48 is an adult-onset syndrome characterized by ataxia and cognitive-psychiatric features, variably associated with chorea, parkinsonism, dystonia, and urinary symptoms. SCA48, the last dominant ataxia to be described, could emerge as the most frequent among the SCAs due to conventional mutations. The overlap of several clinical signs between SCAR16 and SCA48 indicates the presence of a continuous clinical spectrum among recessively and dominantly inherited mutations of STUB1. Different kinds of mutations, scattered over the three gene domains, have been found in both disorders. Their pathogenesis and the relationship between SCA48 and SCAR16 remain to be clarified.

Background Huntington’s disease (HD) patients often present with abnormal modulation of blood pressure and heart rate. We investigated whether cardiac autonomic innervation assessed by 123I-metaiodobenzylguanidine (MIBG) imaging is impaired in HD patients, in comparison with controls (Ctrl). Methods Fifteen patients (6 F and 9 M) were assessed by the motor section of the Unified HD Rating Scale, the Total Function Capacity, and the scale for outcomes in Parkinson’s disease-autonomic (SCOPA-AUT) questionnaire. All patients and 10 Ctrl (5 F and 5 M) underwent 123I-MIBG imaging. From planar images, the early and late heart-to-mediastinum (H/M) ratios and myocardial washout rates (WR) were calculated. Results We did not find significant differences in early and late H/M ratios and WR between the two groups. At individual level, three patients showed reduced early and/or late H/M ratios. The most common autonomic complaints were gastrointestinal and genitourinary disorders. SCOPA-AUT questionnaire score results positively correlated with the disease duration and WR. Conclusions Our study indicates that myocardial postganglionic sympathetic innervation is essentially preserved or only minimally involved in HD. These findings suggest that the cardiovascular dysfunction might be mainly due to the impairment of brain areas associated with the regulation and modulation of the heart function.

Timed neuropsychological tests do not take into account physical impairment during scoring procedures. Dysarthria and upper limb impairment can be easily measured with the PATA rate test (PRT) and the nine-hole pegboard test (9HPT). We recently validated a normalization method for timed neuropsychological tests using the PRT and 9HPT (p9NORM). We now validate the p9NORM in Parkinson’s disease (Yarnall et al. Neurology 82(4):308–316; 2014) and multiple system atrophy (MSA). We enrolled twenty-six patients with PD, eighteen patients with MSA, and fifteen healthy controls (HC). p9NORM was applied to patients with abnormal PRT and/or 9HPT. All subjects were tested with a comprehensive neuropsychological battery. No differences emerged in demographics across groups: (PD: mean age ± SD 66 ± 8; education 9 ± 4 years; MSA: age 60 ± 8; education 10 ± 4 years; HC: age 61 ± 12; education 9 ± 4 years). In MSA patients, the scores on the trail making test (TMT-A p = 0.003; TMT-B p = 0.018), attentional matrices (AM; p = 0.042), and symbol digit modalities test (SDMT p = 0.027) significantly differed following application of p9NORM. In PD patients, the TMT-A (p < 0.001), TMT-B (p = 0.001), and AM (p = 0.001) differed after correction. PD and MSA showed cognitive impairment relative to HC performance. When comparing MSA with PD, the SDMT, AM, and fluencies were similar. TMT-A and -B raw scores were different between groups (p = 0.006; p = 0.034), but these differences lost significance after p9NORM corrections (p = 0.100; p = 0.186). We confirm that the p9NORM can be successfully used in both PD and MSA patients, as it mitigates the impact of disability on timed tests, resulting in a more accurate analysis of cognitive domains.

The present study aims to benchmark the models utilized for estimating the solar irradiance on vertical planes that can facilitate the determination of critical conditions, which are utilized in the glazed facade design. Accordingly, in the first part of the study, the performance of PVGIS databases for Europe for estimating the solar irradiance components on the horizontal surfaces is compared with the on-site measurements at Bolzano airport (Italy). It is demonstrated that PVGIS-SARAH estimates both the global and diffuse solar irradiance components, compared to on-site measurements, with an acceptable error range ( ± 2–5%). The accuracy of isotropic and anisotropic transposition models is then compared for the same location, which demonstrates that the isotropic model tends to underestimate the global vertical incident irradiance by 6–12% of the daily peak value, while an agreement between the estimations of the anisotropic Perez model and the measurements is observed. Next, the performance of Ineichen, Solis and SPECMAGIC clear sky models, transposed with anisotropic Perez model, have been assessed utilizing field measurements on vertical facades at four different locations in Europe. The broadband version of Solis clear sky model, transposed with anisotropic Perez model, demonstrates R 2 scores between 0.85 to 0.95 for the considered locations, indicating that this approach can be utilized as an alternative to open-source/commercially available data sources to estimate the solar irradiance on vertical facades. Finally, for the case study of a triple glazing system, comparing the surface temperatures obtained employing the latter approach with those determined using other commonly utilized irradiance data sources shows a discrepancy of up to 7 °C.

Epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST syndrome) is a rare channelopathy due to KCNJ10 mutations. So far, only mild cerebellar hypoplasia and/or dentate nuclei abnormalities have been reported as major neuroimaging findings in these patients. We analyzed the clinical and brain MRI features of two unrelated patients (aged 27 and 23 years) with EAST syndrome carrying novel homozygous frameshift mutations (p.Asn232Glnfs*14and p.Gly275Valfs*7) in KCNJ10, detected by whole exome sequencing. Brain MRI examinations at 8 years in Patient 1 and at 13 years in Patient 2 revealed a peculiar brain and spinal cord involvement characterized by restricted diffusion of globi pallidi, thalami, brainstem, dentate nuclei, and cervical spinal cord in keeping with intramyelinic edema. The follow-up studies, performed, respectively, after 19 and 10 years, showed mild cerebellar atrophy and slight progression of the brain and spinal cord T2 signal abnormalities with increase of the restricted diffusion in the affected regions. The present cases harboring novel homozygous frameshift mutations in KCNJ10 expand the spectrum of brain abnormalities in EAST syndrome, including mild cerebellar atrophy and intramyelinic edema, resulting from abnormal function of the Kir4.1 inwardly rectifying potassium channel at the astrocyte endfeet, with disruption of water-ion homeostasis.

Recently, a new form of autosomal recessive early-onset parkinsonism (PARK20), due to mutations in the gene encoding the phosphoinositide phosphatase, Synaptojanin 1 (Synj1), has been reported. Several genes responsible for hereditary forms of Parkinson’s disease are implicated in distinct steps of the endolysosomal pathway. However, the nature and the degree of endocytic membrane trafficking impairment in early-onset parkinsonism remains elusive. Here, we show that depletion of Synj1 causes drastic alterations of early endosomes, which become enlarged and more numerous, while it does not affect the morphology of late endosomes both in non-neuronal and neuronal cells. Moreover, Synj1 loss impairs the recycling of transferrin, while it does not alter the trafficking of the epidermal growth factor receptor. The ectopic expression of Synj1 restores the functions of early endosomes, and rescues these trafficking defects in depleted cells. Importantly, the same alterations of early endosomal compartments and trafficking defects occur in fibroblasts of PARK20 patients. Our data indicate that Synj1 plays a crucial role in regulating the homeostasis and functions of early endosomal compartments in different cell types, and highlight defective cellular pathways in PARK20. In addition, they strengthen the link between endosomal trafficking and Parkinson’s disease.

Summary Background Most patients with Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies do not carry mutations in known disease-causing genes. The aim of this study was to identify a novel gene implicated in the development of these disorders. Methods Our study was done in three stages. First, we did genome-wide linkage analysis of an Italian family with dominantly inherited Parkinson's disease to identify the disease locus. Second, we sequenced the candidate gene in an international multicentre series of unrelated probands who were diagnosed either clinically or pathologically with Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies. As a control, we used gene sequencing data from individuals with abdominal aortic aneurysms (who were not examined neurologically). Third, we enrolled an independent series of patients diagnosed clinically with Parkinson's disease and controls with no signs or family history of Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies from centres in Portugal, Sardinia, and Taiwan, and screened them for specific variants. We also did mRNA and brain pathology studies in three patients from the international multicentre series carrying disease-associated variants, and we did functional protein studies in in-vitro models, including neurons from induced pluripotent stem-like cells. Findings Molecular studies were done between Jan 1, 2008, and Dec 31, 2017. In the initial kindred of ten affected Italian individuals (mean age of disease onset 59·8 years [SD 8·7]), we detected significant linkage of Parkinson's disease to chromosome 14 and nominated LRP10 as the disease-causing gene. Among the international series of 660 probands, we identified eight individuals (four with Parkinson's disease, two with Parkinson's disease dementia, and two with dementia with Lewy bodies) who carried different, rare, potentially pathogenic LRP10 variants; one carrier was found among 645 controls with abdominal aortic aneurysms. In the independent series, two of these eight variants were detected in three additional Parkinson's disease probands (two from Sardinia and one from Taiwan) but in none of the controls. Of the 11 probands from the international and independent cohorts with LRP10 variants, ten had a positive family history of disease and DNA was available from ten affected relatives (in seven of these families). The LRP10 variants were present in nine of these ten relatives, providing independent—albeit limited—evidence of co-segregation with disease. Post-mortem studies in three patients carrying distinct LRP10 variants showed severe Lewy body pathology. Of nine variants identified in total (one in the initial family and eight in stage 2), three severely affected LRP10 expression and mRNA stability (1424+5delG, 1424+5G→A, and Ala212Serfs*17, shown by cDNA analysis), four affected protein stability (Tyr307Asn, Gly603Arg, Arg235Cys, and Pro699Ser, shown by cycloheximide-chase experiments), and two affected protein localisation (Asn517del and Arg533Leu; shown by immunocytochemistry), pointing to loss of LRP10 function as a common pathogenic mechanism. Interpretation Our findings implicate LRP10 gene defects in the development of inherited forms of α-synucleinopathies. Future elucidation of the function of the LRP10 protein and pathways could offer novel insights into mechanisms, biomarkers, and therapeutic targets. Funding Stichting ParkinsonFonds, Dorpmans-Wigmans Stichting, Erasmus Medical Center, ZonMw—Memorabel programme, EU Joint Programme Neurodegenerative Disease Research (JPND), Parkinson's UK, Avtal om Lakarutbildning och Forskning (ALF) and Parkinsonfonden (Sweden), Lijf and Leven foundation, and cross-border grant of Alzheimer Netherlands–Ligue Europeene Contre la Maladie d'Alzheimer (LECMA).

This study evaluates the calculation approach of the energy requirements for artificial lighting inside buildings of different use according to EN15193-1:2017, defining the main scope of the standard, highlighting its limitations, and proposing improvements. The evaluation was carried out through a parametric analysis to determine the influence of window-to-wall ratio, distribution of windows, presence of side opening, glazing visible transmittance, and overhang length on the calculation of the Lighting Energy Numeric Indicator (LENI) for a living room and an office at four representative locations (Bratislava, Stockholm, London, Athens). The standard was tested against DAYSIM, a Radiance-based simulation tool for calculating daylight availability, whose results were post-processed to obtain the energy requirements for artificial lighting. For many windows close to each other, the standard's approach to superimpose the daylight factors (DF) for overlapping daylit areas led to an overestimated total DF and therefore an underestimated LENI. For rooms with low window-to-facade and window-to-wall ratio, the standard's calculation was inaccurate. The daylight supply factor tabulated in the standard was too low for latitudes below 45°, leading to an overestimation of the LENI. For latitudes above 60°, the opposite effect was observed. Summarising, the standard underestimated the LENI by about 10% on average.

Spinocerebellar ataxia type 2 (SCA2) is among the most common forms of autosomal dominant ataxias, accounting for 15% of the total families. Occurrence is higher in specific populations such as the Cuban and Southern Italian. The disease is caused by a CAG expansion in ATXN2 gene, leading to abnormal accumulation of the mutant protein, ataxin‐2, in intracellular inclusions. The clinical picture is mainly dominated by cerebellar ataxia, although a number of other neurological signs have been described, ranging from parkinsonism to motor neuron involvement, making the diagnosis frequently challenging for neurologists, particularly when information about the family history is not available. Although the functions of ataxin‐2 have not been completely elucidated, the protein is involved in mRNA processing and control of translation. Recently, it has also been shown that the size of the CAG repeat in normal alleles represents a risk factor for ALS, suggesting that ataxin‐2 plays a fundamental role in maintenance of neuronal homeostasis.

Early diagnosis of neural changes causing cerebral impairment is critical for proposing preventive therapies for Parkinson&rsquo, s disease (PD). Biomarkers currently available cannot be informative of PD onset since they are characterized by analysing post-mortem tissues from patients with severe degeneration of the substantia nigra. Skin fibroblasts (SF) are now recognized as a useful model of primary human cells, capable of reflecting the chronological and biological aging of the subjects. Here a lipidomic study of easily accessible primary SF is presented, based on hydrophilic interaction liquid chromatography coupled to electrospray ionization and mass spectrometry (HILIC/ESI-MS). Phospholipids (PL) from dermal fibroblasts of five PD patients with different parkin mutations and healthy control SF were characterized by single and tandem MS measurements using a hybrid quadrupole-Orbitrap and a linear ion trap mass analysers. The proposed approach enabled the identification of more than 360 PL. Univariate statistical analyses highlight abnormality of PL metabolism in the PD group, suggesting down- or up-regulation of certain species according to the extent of disease progression. These findings, although preliminary, suggest that the phospholipidome of human SF represents a source of potential biomarkers for the early diagnosis of PD. The dysregulation of ethanolamine plasmalogens in the circulatory system, especially those containing polyunsaturated fatty acids (PUFA), might be likely associated with neurodegeneration.

PARK20, an early onset autosomal recessive parkinsonism is due to mutations in the phosphatidylinositol-phosphatase Synaptojanin 1 (Synj1). We have recently shown that the early endosomal compartments are profoundly altered in PARK20 fibroblasts as well as the endosomal trafficking. Here, we report that PARK20 fibroblasts also display a drastic alteration of the architecture and function of the early secretory compartments. Our results show that the exit machinery from the Endoplasmic Reticulum (ER) and the ER-to-Golgi trafficking are markedly compromised in patient cells. As a consequence, PARK20 fibroblasts accumulate large amounts of cargo proteins within the ER, leading to the induction of ER stress. Interestingly, this stressful state is coupled to the activation of the PERK/eIF2a/ATF4/CHOP pathway of the Unfolded Protein Response (UPR). In addition, PARK20 fibroblasts reveal upregulation of oxidative stress markers and total ROS production with concomitant alteration of the morphology of the mitochondrial network. Interestingly, treatment of PARK20 cells with GSK2606414 (GSK), a specific inhibitor of PERK activity, restores the level of ROS, signaling a direct correlation between ER stress and the induction of oxidative stress in the PARK20 cells. All together, these findings suggest that dysfunction of early secretory pathway might contribute to the pathogenesis of the disease.