Comparing the effects of augmented virtual reality treadmill training versus conventional treadmill training in patients with stage II-III Parkinson’s disease: the VIRTREAD-PD randomized controlled trial protocol

BackgroundIntensive treadmill training (TT) has been documented to improve gait parameters and functional independence in Parkinson’s Disease (PD), but the optimal intervention protocol and the criteria for tailoring the intervention to patients’ performances are lacking. TT may be integrated with augmented virtual reality (AVR), however, evidence of the effectiveness of this combined treatment is still limited. Moreover, prognostic biomarkers of rehabilitation, potentially useful to customize the treatment, are currently missing. The primary aim of this study is to compare the effects on gait performances of TT + AVR versus TT alone in II-III stage PD patients with gait disturbance. Secondary aims are to assess the effects on balance, gait parameters and other motor and non-motor symptoms, and patient’s satisfaction and adherence to the treatment. As an exploratory aim, the study attempts to identify biomarkers of neuroplasticity detecting changes in Neurofilament Light Chain concentration T0-T1 and to identify prognostic biomarkers associated to blood-derived Extracellular Vesicles.MethodsSingle-center, randomized controlled single-blind trial comparing TT + AVR vs. TT in II-III stage PD patients with gait disturbances. Assessment will be performed at baseline (T0), end of training (T1), 3 (T2) and 6 months (T3, phone interview) from T1. The primary outcome is difference in gait performance assessed with the Tinetti Performance-Oriented Mobility Assessment gait scale at T1. Secondary outcomes are differences in gait performance at T2, in balance and spatial–temporal gait parameters at T1 and T2, patients’ satisfaction and adherence. Changes in falls, functional mobility, functional autonomy, cognition, mood, and quality of life will be also assessed at different timepoints. The G*Power software was used to estimate a sample size of 20 subjects per group (power 0.95, α < 0.05), raised to 24 per group to compensate for potential drop-outs. Both interventions will be customized and progressive, based on the participant’s performance, according to a predefined protocol.ConclusionThis study will provide data on the possible superiority of AVR-associated TT over conventional TT in improving gait and other motor and non-motor symptoms in persons with PD and gait disturbances. Results of the exploratory analysis could add information in the field of biomarker research in PD rehabilitation

Sociodemographic variables, clinical features, and the role of preassessment cross-sex hormones in older trans people

Introduction: As referrals to gender identity clinics have increased dramatically over the last few years, no studies focusing on older trans people seeking treatment are available. Aims: The aim of this study was to investigate the sociodemographic and clinical characteristics of older trans people attending a national service and to investigate the influence of cross-sex hormones (CHT) on psychopathology. Methods: Individuals over the age of 50 years old referred to a national gender identity clinic during a 30-month period were invited to complete a battery of questionnaires to measure psychopathology and clinical characteristics. Individuals on cross-sex hormones prior to the assessment were compared with those not on treatment for different variables measuring psychopathology. Main Outcome Measures: Sociodemographic and clinical variables and measures of depression and anxiety (Hospital Anxiety and Depression Scale), self-esteem (Rosenberg Self-Esteem Scale), victimization (Experiences of Transphobia Scale), social support (Multidimensional Scale of Perceived Social Support), interpersonal functioning (Inventory of Interpersonal Problems), and nonsuicidal self-injury (Self-Injury Questionnaire). Results: The sex ratio of trans females aged 50 years and older compared to trans males was 23.7:1. Trans males were removed for the analysis due to their small number (n ¼ 3). Participants included 71 trans females over the age of 50, of whom the vast majority were white, employed or retired, and divorced and had children. Trans females on CHT who came out as trans and transitioned at an earlier age were significantly less anxious, reported higher levels of self-esteem, and presented with fewer socialization problems. When controlling for socialization problems, differences in levels of anxiety but not self-esteem remained. Conclusion: The use of cross-sex hormones prior to seeking treatment is widespread among older trans females and appears to be associated with psychological benefits. Existing barriers to access CHT for older trans people may need to be re-examined

The Games for Older Adults Active Life (GOAL) Project for People With Mild Cognitive Impairment and Vascular Cognitive Impairment: A Study Protocol for a Randomized Controlled Trial

Background: People living with Mild Cognitive Impairment (MCI) and Vascular Cognitive Impairment (VCI) are persons who do not fulfill a diagnosis of dementia, but who have a high risk of progressing to a dementia disorder. The most recent guidelines to counteract cognitive decline in MCI/VCI subjects suggest a multidimensional and multi-domain interventions combining cognitive, physical, and social activities. The purpose of this study is to test an innovative service that provides a multi-dimensional tele-rehabilitation program through a user-friendly web application. The latter has been developed through a participatory design involving MCI specialists, patients, and their caregivers. Particularly, the proposed tele-rehabilitation program includes cognitive, physical, and caregiver-supported social activities. The goal is to promote and preserve an active life style and counteract cognitive decline in people living with MCI/VCI.Methods:The study is a randomized controlled trial. Sixty subjects will be randomly assigned to the experimental group, who will receive the tele-rehabilitation program, or the control group, who will not receive any treatment. The trial protocol comprises three steps of assessment for the experimental group: at the baseline (T_0), after tele-rehabilitation program (T_1) and at follow-up after 12-months (T_2). Differently, the control group will be assessed twice: at the baseline and at 12-months follow-up. Both the experimental and the control group will be assessed with a multidimensional evaluation battery, including cognitive functioning, behavioral, functional, and quality of life measures. The tele-rehabilitation program lasts 8 weeks and includes cognitive exercises 3 days a week, physical activities 2 days a week, and social activities once a week. In addition, group will be given an actigraph (GENEActiv, Activisinghts Ltd., Cambridgshire, UK) to track physical and sleep activity.Discussion:Results of this study will inform on the efficacy of the proposed tele-rehabilitation to prevent or delay further cognitive decline in MCI/VCI subjects. The expected outcome is to counteract cognitive decline and improve both physical functioning and quality of life.Ethics and Dissemination:The study is approved by the Local Ethics Committee and registered in https://clinicaltrials.gov (NCT03383549). Dissemination will include submission to a peer-reviewed journal, patients, and healthcare magazines and congress presentations.Trial Registration: ClinicalTrials.gov ID: NCT03383549 (registration date: 26/dec/2017)Trial Funding: Bando FAS Salute 2014 Regione ToscanaVersion Identifier: ver 5—16/11/201

Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis.

BACKGROUND: Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. METHODS: We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. FINDINGS: Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test -0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all -0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference -0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference -0·2, SE 0·1). INTERPRETATION: Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. FUNDING: Centres of Excellence in Neurodegeneration

Borexino : geo-neutrino measurement at Gran Sasso, Italy

Geo-neutrinos, electron anti-neutrinos produced in beta-decays of naturally occurring radioactive isotopes in the Earth, are a unique direct probe of our planet's interior. After a brief introduction of the geo-neutrinos' properties and of the main aims of their study, we discuss the features of a detector which has recently provided breakthrough achievements in the field, Borexino, a massive, calorimetric liquid scintillator detector installed at the underground Gran Sasso Laboratory. With its unprecedented radiopurity levels achieved in the core of the detection medium, it is the only experiment in operation able to study in real time solar neutrino interactions in the challenging sub-MeV energy region. Its superior technical properties allowed Borexino also to provide a clean detection of terrestrial neutrinos. Therefore, the description of the characteristics of the detected geo-neutrino signal and of the corresponding geological implications are the main core of the discussion contained in this work

White matter hyperintensities are seen only in GRN mutation carriers in the GENFI cohort

© 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).Genetic frontotemporal dementia is most commonly caused by mutations in the progranulin (GRN), microtubule-associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72) genes. Previous small studies have reported the presence of cerebral white matter hyperintensities (WMH) in genetic FTD but this has not been systematically studied across the different mutations. In this study WMH were assessed in 180 participants from the Genetic FTD Initiative (GENFI) with 3D T1- and T2-weighed magnetic resonance images: 43 symptomatic (7 GRN, 13 MAPT and 23 C9orf72), 61 presymptomatic mutation carriers (25 GRN, 8 MAPT and 28 C9orf72) and 76 mutation negative non-carrier family members. An automatic detection and quantification algorithm was developed for determining load, location and appearance of WMH. Significant differences were seen only in the symptomatic GRN group compared with the other groups with no differences in the MAPT or C9orf72 groups: increased global load of WMH was seen, with WMH located in the frontal and occipital lobes more so than the parietal lobes, and nearer to the ventricles rather than juxtacortical. Although no differences were seen in the presymptomatic group as a whole, in the GRN cohort only there was an association of increased WMH volume with expected years from symptom onset. The appearance of the WMH was also different in the GRN group compared with the other groups, with the lesions in the GRN group being more similar to each other. The presence of WMH in those with progranulin deficiency may be related to the known role of progranulin in neuroinflammation, although other roles are also proposed including an effect on blood-brain barrier permeability and the cerebral vasculature. Future studies will be useful to investigate the longitudinal evolution of WMH and their potential use as a biomarker as well as post-mortem studies investigating the histopathological nature of the lesions.This work was funded by the UK Medical Research Council, the Italian Ministry of Health, and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant (CoEN015). The Dementia Research Centre is supported by Alzheimer's Research UK, Brain Research Trust, and The Wolfson Foundation. This work was supported by the NIHR Queen Square Dementia Biomedical Research Unit and the NIHR UCL/H Biomedical Research Centre. JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). KD is supported by an Alzheimer's Society PhD Studentship (AS-PhD-2015-005). JBR is supported by the Wellcome Trust (103838) and the NIHR Cambridge Biomedical Research Centre. MM is supported by the Canadian Institutes of Health Research and the Ontario Research Fund. RL is supported by Réseau de médecine génétique appliquée, Fonds de recherche du Québec—Santé (FRQS). FT is supported by the Italian Ministry of Health. DG is supported by the Fondazione Monzino and Italian Ministry of Health, Ricerca Corrente. SS is supported by Cassa di Risparmio di Firenze (CRF 2013/0199) and the Ministry of Health RF-2010-2319722. SO is supported by the Engineering and Physical Sciences Research Council (EP/H046410/1, EP/J020990/1, EP/K005278), the Medical Research Council (MR/J01107X/1), the EU-FP7 project VPH-DARE@IT (FP7-ICT-2011-9-601055), and the National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR BRC UCLH/UCL High Impact Initiative BW.mn.BRC10269). JvS is supported by The Netherlands Organisation for Health Research and Development Memorable grant (733050103) and Netherlands Alzheimer Foundation Memorable grant (733050103).info:eu-repo/semantics/publishedVersio

Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: A cross-sectional analysis

Background: Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (. GRN), microtubule-associated protein tau (. MAPT), or chromosome 9 open reading frame 72 (. C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. Methods: We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. Findings: Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test -0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all -0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference -0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference -0·2, SE 0·1). Interpretation: Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. Funding: Centres of Excellence in Neurodegenerati

Extending the phenotypic spectrum assessed by the CDR plus NACC FTLD in genetic frontotemporal dementia

INTRODUCTION: We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD). METHODS: Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD-NM scale. This was assessed in 522 mutation carriers and 310 mutation-negative controls from the Genetic Frontotemporal dementia Initiative (GENFI). RESULTS: The new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales. DISCUSSION: Adding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely. Highlights: The new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD-NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS). No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD-NM rating scale. Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains. A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales.</p

Extending the phenotypic spectrum assessed by the CDR plus NACC FTLD in genetic frontotemporal dementia

INTRODUCTION: We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD). METHODS: Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD-NM scale. This was assessed in 522 mutation carriers and 310 mutation-negative controls from the Genetic Frontotemporal dementia Initiative (GENFI). RESULTS: The new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales. DISCUSSION: Adding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely. Highlights: The new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD-NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS). No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD-NM rating scale. Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains. A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales.</p