Neuropathologic basis of frontotemporal dementia in progressive supranuclear palsy.

BackgroundProgressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by neuronal loss in the extrapyramidal system with pathologic accumulation of tau in neurons and glia. The most common clinical presentation of PSP, referred to as Richardson syndrome, is that of atypical parkinsonism with vertical gaze palsy, axial rigidity, and frequent falls. Although cognitive deficits in PSP are often ascribed to subcortical dysfunction, a subset of patients has dementia with behavioral features similar to the behavioral variant of frontotemporal dementia. In this study we aimed to identify the clinical and pathological characteristics of PSP presenting with frontotemporal dementia.MethodsIn this study, we compared clinical and pathologic characteristics of 31 patients with PSP with Richardson syndrome with 15 patients with PSP with frontotemporal dementia. For pathological analysis, we used semiquantitative methods to assess neuronal and glial lesions with tau immunohistochemistry, as well image analysis of tau burden using digital microscopic methods.ResultsWe found greater frontal and temporal neocortical neuronal tau pathology in PSP with frontotemporal dementia compared with PSP with Richardson syndrome. White matter tau pathology was also greater in PSP with frontotemporal dementia than PSP with Richardson syndrome. Genetic and demographic factors were not associated with atypical distribution of tau pathology in PSP with frontotemporal dementia.ConclusionsThe results confirm the subset of cognitive-predominant PSP mimicking frontotemporal dementia in PSP. PSP with frontotemporal dementia has distinct clinical features that differ from PSP with Richardson syndrome, as well as differences in distribution and density of tau pathology. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

TRIO gene segregation in a family with cerebellar ataxia

Aim of the study: To report a family with a novel TRIO gene mutation associated withphenotype of cerebellar ataxia. Materials and methods: Seven family members of Caribbean descent were recruited through our ataxia research protocol; of the family members, the mother and all 3 children were found to be affected with severe young-onset and rapidly progressive truncal and appendicular ataxia leading to early disability. Array comparative genomic hybridization, mitochondrial DNA analysis, and whole-exome sequencing were performed on 3 of the family members (mother and 2 daughters). Results: While the maternal grandmother, great uncle and great aunt were unaffected, the mother and 3 children displayed cognitive dysfunction, severe ataxia, spasticity, and speech disturbances. Age of onset ranged between 3 and 17 years, with average current disease duration of 21 years. Whole-exome sequencing showed a variant p.A1214V in exon 22 of the TRIO gene in 3 of the family members. Array comparative genomic hybridization and mitochondrial DNA analysis were normal. The same variant was later discovered in all but one family member. Conclusions and clinical implications: The TRIO p.A1214V variant is associated with cerebellar ataxia in the studied family; it was present in all affected and unaffected family members. Phenotype is severe and broad. Anticipation seems to be present (based on 2 affected generations). It is warranted to screen additional familial early-onset and rapidly progressive ataxia cases for this genotype. TRIO gene mutations may well represent a novel spinocerebellar ataxia subtype

A Consensus Set of Outcomes for Parkinson's Disease from the International Consortium for Health Outcomes Measurement

Background: Parkinson's disease (PD) is a progressive neurodegenerative condition that is expected to double in prevalence due to demographic shifts. Value-based healthcare is a proposed strategy to improve outcomes and decrease costs. To move towards an actual value-based health care system, condition-specific outcomes that are meaningful to patients are essential. Objective: Propose a global consensus standard set of outcome measures for PD. Methods: Established methods for outcome measure development were applied, as outlined and used previously by the International Consortium for Health Outcomes Measurement (ICHOM). An international group, representing both patients and experts from the fields of neurology, psychiatry, nursing, and existing outcome measurement efforts, was convened. The group participated in six teleconferences over a six-month period, reviewed existing data and practices, and ultimately proposed a standard set of measures by which patients should be tracked, and how often data should be collected. Results: The standard set applies to all cases of idiopathic PD, and includes assessments of motor and non-motor symptoms, ability to work, PD-related health status, and hospital admissions. Baseline demographic and clinical variables are included to enable case mix adjustment. Conclusions: The Standard Set is now ready for use and pilot testing in the clinical setting. Ultimately, we believe that using the set of outcomes proposed here will allow clinicians and scientists across the world to document, report, and compare PD-related outcomes in a standardized fashion. Such international benchmarks will improve our understanding of the disease course and allow for identification of 'best practices', ultimately leading to better informed treatment decisions.This project was funded by the International Consortium for Health Outcome Measurement.S

Is it reliable to assess visual attention of drivers affected by Parkinson's disease from the backseat?—a simulator study

BACKGROUND: Current methods of determining licence retainment or cancellation is through on-road driving tests. Previous research has shown that occupational therapists frequently assess drivers' visual attention while sitting in the back seat on the opposite side of the driver. Since the eyes of the driver are not always visible, assessment by eye contact becomes problematic. Such procedural drawbacks may challenge validity and reliability of the visual attention assessments. In terms of correctly classified attention, the aim of the study was to establish the accuracy and the inter-rater reliability of driving assessments of visual attention from the back seat. Furthermore, by establishing eye contact between the assessor and the driver through an additional mirror on the wind screen, the present study aimed to establish how much such an intervention would enhance the accuracy of the visual attention assessment. METHODS: Two drivers with Parkinson's disease (PD) and six control drivers drove a fixed route in a driving simulator while wearing a head mounted eye tracker. The eye tracker data showed where the foveal visual attention actually was directed. These data were time stamped and compared with the simultaneous manual scoring of the visual attention of the drivers. In four of the drivers, one with Parkinson's disease, a mirror on the windscreen was set up to arrange for eye contact between the driver and the assessor. Inter-rater reliability was performed with one of the Parkinson drivers driving, but without the mirror. RESULTS: Without mirror, the overall accuracy was 56% when assessing the three control drivers and with mirror 83%. However, for the PD driver without mirror the accuracy was 94%, whereas for the PD driver with a mirror the accuracy was 90%. With respect to the inter-rater reliability, a 73% agreement was found. CONCLUSION: If the final outcome of a driving assessment is dependent on the subcategory of a protocol assessing visual attention, we suggest the use of an additional mirror to establish eye contact between the assessor and the driver. The clinicians' observations on-road should not be a standalone assessment in driving assessments. Instead, eye trackers should be employed for further analyses and correlation in cases where there is doubt about a driver's attention

A rare sequence variant in intron 1 of THAP1 is associated with primary dystonia

Although coding variants in THAP1 have been causally associated with primary dystonia, the contribution of noncoding variants remains uncertain. Herein, we examine a previously identified Intron 1 variant (c.71+9C>A, rs200209986). Among 1672 subjects with mainly adult-onset primary dystonia, 12 harbored the variant in contrast to 1/1574 controls (P < 0.01). Dystonia classification included cervical dystonia (N = 3), laryngeal dystonia (adductor subtype, N = 3), jaw-opening oromandibular dystonia (N = 1), blepharospasm (N = 2), and unclassified (N = 3). Age of dystonia onset ranged from 25 to 69 years (mean = 54 years). In comparison to controls with no identified THAP1 sequence variants, the c.71+9C>A variant was associated with an elevated ratio of Isoform 1 (NM_018105) to Isoform 2 (NM_199003) in leukocytes. In silico and minigene analyses indicated that c.71+9C>A alters THAP1 splicing. Lymphoblastoid cells harboring the c.71+9C>A variant showed extensive apoptosis with relatively fewer cells in the G2 phase of the cell cycle. Differentially expressed genes from lymphoblastoid cells revealed that the c.71+9C>A variant exerts effects on DNA synthesis, cell growth and proliferation, cell survival, and cytotoxicity. In aggregate, these data indicate that THAP1 c.71+9C>A is a risk factor for adult-onset primary dystonia

Asbestos-related pleural and lung fibrosis in patients with retroperitoneal fibrosis

<p>Abstract</p> <p>Background</p> <p>Retroperitoneal fibrosis (RPF) is a rare fibroinflammatory disease that leads to hydronephrosis and renal failure. In a case-control study, we have recently shown that asbestos exposure was the most important risk factor for RPF in the Finnish population. The aim of this study was to evaluate the relation of asbestos exposure to radiologically confirmed lung and pleural fibrosis among patients with RPF.</p> <p>Methods</p> <p>Chest high-resolution computed tomography (HRCT) was performed on 16 unexposed and 22 asbestos-exposed RPF patients and 18 asbestos-exposed controls. Parietal pleural plaques (PPP), diffuse pleural thickening (DPT) and parenchymal fibrosis were scored separately.</p> <p>Results</p> <p>Most of the asbestos-exposed RPF patients and half of the asbestos-exposed controls had bilateral PPP, but only a few had lung fibrosis. Minor bilateral plaques were detected in two of the unexposed RPF patients, and none had lung fibrosis. DPT was most frequent and thickest in the asbestos-exposed RPF-patients. In three asbestos-exposed patients with RPF we observed exceptionally large pleural masses that were located anteriorly in the pleural space and continued into the anterior mediastinum.</p> <p>Asbestos exposure was associated with DPT in comparisons between RPF patients and controls (case-control analysis) as well as among RPF patients (case-case analysis).</p> <p>Conclusion</p> <p>The most distinctive feature of the asbestos-exposed RPF patients was a thick DPT. An asbestos-related pleural finding was common in the asbestos-exposed RPF patients, but only a few of these patients had parenchymal lung fibrosis. RPF without asbestos exposure was not associated with pleural or lung fibrosis. The findings suggest a shared etiology for RPF and pleural fibrosis and furthermore possibly a similar pathogenetic mechanisms.</p

Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia

Loss-of-function mutations in progranulin (GRN) cause ubiquitin- and TAR DNA-binding protein 43 (TDP-43)-positive frontotemporal dementia (FTLD-U), a progressive neurodegenerative disease affecting ∼10% of early-onset dementia patients. Here we expand the role of GRN in FTLD-U and demonstrate that a common genetic variant (rs5848), located in the 3′-untranslated region (UTR) of GRN in a binding-site for miR-659, is a major susceptibility factor for FTLD-U. In a series of pathologically confirmed FTLD-U patients without GRN mutations, we show that carriers homozygous for the T-allele of rs5848 have a 3.2-fold increased risk to develop FTLD-U compared with homozygous C-allele carriers (95% CI: 1.50–6.73). We further demonstrate that miR-659 can regulate GRN expression in vitro, with miR-659 binding more efficiently to the high risk T-allele of rs5848 resulting in augmented translational inhibition of GRN. A significant reduction in GRN protein was observed in homozygous T-allele carriers in vivo, through biochemical and immunohistochemical methods, mimicking the effect of heterozygous loss-of-function GRN mutations. In support of these findings, the neuropathology of homozygous rs5848 T-allele carriers frequently resembled the pathological FTLD-U subtype of GRN mutation carriers. We suggest that the expression of GRN is regulated by miRNAs and that common genetic variability in a miRNA binding-site can significantly increase the risk for FTLD-U. Translational regulation by miRNAs may represent a common mechanism underlying complex neurodegenerative disorders

Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

CurePSP Foundation, the Peebler PSP Research Foundation, and National Institutes on Health (NIH) grants R37 AG 11762, R01 PAS-03-092, P50 NS72187, P01 AG17216 [National Institute on Aging(NIA)/NIH], MH057881 and MH077930 [National Institute of Mental Health (NIMH)]. Work was also supported in part by the NIA Intramural Research Program, the German National Genome Research Network (01GS08136-4) and the Deutsche Forschungsgemeinschaft (HO 2402/6-1), Prinses Beatrix Fonds (JCvS, 01–0128), the Reta Lila Weston Trust and the UK Medical Research Council (RdS: G0501560). The Newcastle Brain Tissue Resource provided tissue and is funded in part by a grant from the UK Medical Research Council (G0400074), by the Newcastle NIHR Biomedical Research Centre in Ageing and Age Related Diseases to the Newcastle upon Tyne Hospitals NHS Foundation Trust, and by a grant from the Alzheimer’s Society and Alzheimer’s Research Trust as part of the Brains for Dementia Resarch Project. We acknowledge the contribution of many tissue samples from the Harvard Brain Tissue Resource Center. We also acknowledge the 'Human Genetic Bank of Patients affected by Parkinson Disease and parkinsonism' (http://www.parkinson.it/dnabank.html) of the Telethon Genetic Biobank Network, supported by TELETHON Italy (project n. GTB07001) and by Fondazione Grigioni per il Morbo di Parkinson. The University of Toronto sample collection was supported by grants from Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research. Brain-Net-Germany is supported by BMBF (01GI0505). RdS, AJL and JAH are funded by the Reta Lila Weston Trust and the PSP (Europe) Association. RdS is funded by the UK Medical Research Council (Grant G0501560) and Cure PSP+. ZKW is partially supported by the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, Mayo Clinic Florida (MCF)Research Committee CR programs (MCF #90052030 and MCF #90052030), and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch (MCF #90052031/PAU #90052). The Mayo Clinic College of Medicine would like to acknowledge Matt Baker, Richard Crook, Mariely DeJesus-Hernandez and Nicola Rutherford for their preparation of samples. PP was supported by a grant from the Government of Navarra ("Ayudas para la Realización de Proyectos de Investigación" 2006–2007) and acknowledges the "Iberian Atypical Parkinsonism Study Group Researchers", i.e. Maria A. Pastor, Maria R. Luquin, Mario Riverol, Jose A. Obeso and Maria C Rodriguez-Oroz (Department of Neurology, Clínica Universitaria de Navarra, University of Navarra, Pamplona, Spain), Marta Blazquez (Neurology Department, Hospital Universitario Central de Asturias, Oviedo, Spain), Adolfo Lopez de Munain, Begoña Indakoetxea, Javier Olaskoaga, Javier Ruiz, José Félix Martí Massó (Servicio de Neurología, Hospital Donostia, San Sebastián, Spain), Victoria Alvarez (Genetics Department, Hospital Universitario Central de Asturias, Oviedo, Spain), Teresa Tuñon (Banco de Tejidos Neurologicos, CIBERNED, Hospital de Navarra, Navarra, Spain), Fermin Moreno (Servicio de Neurología, Hospital Ntra. Sra. de la Antigua, Zumarraga, Gipuzkoa, Spain), Ainhoa Alzualde (Neurogenétics Department, Hospital Donostia, San Sebastián, Spain)