Course Syllabus
Table of Contents
Course Description and Disclaimer...... Page 2 Venue and Accreditation Information..……………………………………………………………Page 3 Faculty Listing and Industry Disclosures.…………………………………………………………Page 4 Agenda Friday, October 10 ………………………………………………………………...……..Page 7 Agenda Saturday, October 11……………………………………………………………………..Page 8 Lecture Material…………………………………………………………………….……..…….. Page 9 The Milestones of PSP Research (9) Richardson’s syndrome (12) Other Clinical Presentations (15) How to Test Ocular Movements in PSP (17) Neuroradiological Pearls to Identify PSP (25) Symptomatic Approach (26) Palliative care in PSP (34) The Physiology of Tau in Humans (36) Pathophysiology of Tau Accumulation (37) Animal Models of PSP (48) CSF Biomarkers (59) Update on Neuropathology (62) Review on Clinical Trials (63) Future Therapeutic Options (64) Cognitive Changes in PSP – How to best identify them? (65) Early and Late Behavioral Changes in PSP (66) PSP and CBD: One Disease or Two? (67) PSP-look-alikes (68) Is Neurogenetics a Useful Research and Diagnostic Tool? (71) Neurophysiology and PSP: Recent Advances (84) Health Related Quality of Life in Patients with PSP (97) NINDS-SPSP criteria: Why do we need to update them? (99)
50 Years of Progressive Supranuclear Palsy Munich, Germany | October 10-11, 2014
Course Description Despite that research on PSP and related disorders has recently improved at all levels - molecular, brain circuitry, epidemiological and clinical - there has not been a single MDS-sponsored meeting about this devastating disorder. This course is intended to fill this gap, combining an update of the current understanding of PSP and a basic teaching course for those entering into this field. The most active researchers in the field of PSP from Europe will be invited to share their current knowledge and to discuss future research with the audience.
Learning Objectives
At the conclusion of this activity, you should be able to: Identify features of classical and atypical PSP Describe the pros and cons of available diagnostic criteria for PSP Understand and discuss current research on novel pharmacological and non-pharmacological disease-modifying therapies for PSP Discuss recent advances in neuroimaging and CSF biomarkers to aid in differential diagnosis of PSP and other similar disorders Recognize and discuss potential ways to improve multidisciplinary care of PSP
Recommended Audience This course is intended for general medical practitioners, neurology residents, specialist nurse practitioners and other paramedical equivalents in related fields with a working knowledge of diagnosis and general management of this condition.
Evaluations Please take time to complete the evaluation form provided at this course. Your input and comments are essential in planning future educational programs for MDS. When completed, evaluations may be returned to the registration desk or the MDS International Secretariat.
Educational Disclaimer The primary purpose of MDS programming is to provide educational opportunities that enhance patient care. Information presented, as well as publications, technologies, products and/or services discussed are intended to inform attendees about the knowledge, techniques and experiences of physicians who are willing to share such information with colleagues. A diversity of opinions exists in the medical field, and the views of the course’s faculty are offered solely for educational purposes. Faculty members’ views do not represent those of MDS and do not constitute endorsement by MDS. MDS disclaims any and all liability for all claims which may result from the use of information, publications, products and/or services discussed at this program.
Recordings Prohibited Audio and videotaping are not allowed during the course. Photography is also not allowed during the activity.
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50 Years of Progressive Supranuclear Palsy Munich, Germany | October 10-11, 2014
Course Venue
Johannissaal Hall in the Nymphenburg Palace in Munich Schloss Nymphenburg 1 80638 München, Germany
EACCME Accreditation
The course 50 Years of Progressive Supranuclear Palsy is accredited by the European Accreditation Council for Continuing Medical Education (EACCME) to provide the following CME activity for medical specialists. The EACCME is an institution of the European Union of Medical Specialists (UEMS), www.uems.net.
The course 50 Years of Progressive Supranuclear Palsy is designated for a maximum of 9 hours of European external CME credits. Each medical specialist should claim only those hours of credit that he/she actually spent in the educational activity.
Through an agreement between the European Union of Medical Specialists and the American Medical Association, physicians may convert EACCME credits to an equivalent number of AMA PRA Category 1 Credits™. Information on the process to convert EACCME credit to AMA credit can be found at www.ama-assn.org/go/internationalcme.
Live educational activities, occurring outside of Canada, recognized by the UEMS-EACCME for ECMEC credits are deemed to be Accredited Group Learning Activities (Section 1) as defined by the Maintenance of Certification Program of The Royal College of Physicians and Surgeons of Canada.
EACCME credits Each medical specialist should claim only those hours of credit that he/she actually spent in the educational activity. The EACCME credit system is based on 1 ECMEC per hour with a maximum of 3 ECMECs for half a day and 6 ECMECs for a full- day event.
Visit the 50 Years of Progressive Supranuclear Palsy webpage following the course in order to print your course certificate and your EACCME certificate.
International Parkinson and Movement Disorder Society – European Section MDS International Secretariat 555 East Wells Street, Suite 1100 ● Milwaukee, WI 53202 USA Email: [email protected] Phone: +1 (414) 276-2145 ● Fax : +1 (414) 276-3349
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50 Years of Progressive Supranuclear Palsy Munich, Germany | October 10-11, 2014
Course Directors
Carlo Colosimo, MD Sapienza University of Rome, Italy Carlo Colosimo has served as a consultant and advisory board member for Allergan, Ipsen, Merz and UCB; has received grant/research support from Ipsen; and receives royalties from CIC Edizioni Internazionali Publishers and Cambridge University Press.
Günter Höglinger, MD Technical University Munich (TUM) German Center for Neurodegenerative Diseases e.V. (DZ NE) Munich, Germany Günter Höglinger has served as a consultant for UCB, BMS and Sellas; has received grant/research support from UCB; and has received honoraria from UCB and Teva.
Course Faculty
Angelo Antonini, MD, PhD Institute of Neurology, IRCCS San Camillo, Venice, Italy Angelo Antonini has served as a consultant for UCB and AbbVie; has received grant/research support from Italian Research Health Ministry, Neureca Foundation and Gossweiler Foundation; and received honoraria from UCB, AbbVie, Novartis and GSK.
Thomas Arzberger, MD Centre for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich Department of Psychiatry, Ludwig-Maximilians-University Munich German Centre for Neurodegenerative Diseases (DZ NE) Munich Thomas Arzberger has no financial relationships to disclose.
Thomas H Bak, MD University of Edinburgh, UK Thomas H Bak has received grant/research support from ESRC, WFN, MND Association (UK) and MND Scotland.
Kailash Bhatia, MD Institute of Neurology, London Kailash Bhatia has served as a consultant for GSK, Orion, Ipsen, Merz and LLC; has received grant/research support from Ipsen, Halley Steward Trust, the wellcome trust MRC,Dystonia coalition and PD UK; has received honoraria from MDS, EFN, ENS, Ipsen, Mertz, GSK, Orion, LLC and Boehringer Ingelheim; has intellectual property rights with Oxford Press; and receives royalties from Oxford Press.
Matteo Bologna, MD PhD Sapienza University of Rome, Italy Matteo Bologna has received grant/research support from Dystonia Coalition (NS065701).
Luc Buée, PhD Inserm UMR837, Univ. Lille, CHR, Lille, France Luc Buée has intellectual property rights with Inventor Patents.
4 David J Burn, MD, FRCP Institute of Neuroscience Newcastle University, UK David J Burn has received grant/research support from GlaxoSmithKline; and has received royalties from Henry Stewart Associates (publishing).
Richard Dodel, MD Klinik für Neurologie Philipps-Universität Universitätsklinikum Gießen und Marburg GmbH, Germany Richard Dodel has received grant support from Baxter, Bayer Schering, Behring-Rontgen-Stiftung, BMBF, CSL Behring, Deutsche Gesellschaft fur Neurologie, Deutsche Parkinson Vereinigung, DGSM Deutsche Gesellschaft für Schlafmedizin, Faber-Stiftung, Hector-Stiftung, Internationale Parkinson Fonds, Lundbeck, Medtronic, M.J.Fox Foundation, Movement Disorder Society, Novartis, Rentschler, UKGM, ZLB Behring, Deutsche Forschungsgemeinschaft; has received personal fees from Astra Zeneca, Baxter, Boehringer Ingelheim, Canadian Blood Services, Contingo Consulting, CSL Behring, Deutsche Fortbildungsgesellschaft HNO-Ärzte, Deutsche Ophthalmologische Gesellschaft, DZNE Deutsches Zentrum für neurodegenerative Erkrankungen, Eisai, Elsevier, GlaxoSmithKline, Helios Klinik Wuppertal, Hessisches Ministerium für Arbeit, Familie und Gesundheit, Klinikum Ludwigsburg, Klinikum Münster, Lilly, Lundbeck, Med Panel, Medizinische Hochschule Hannover, Medizinisch-Naturwissenschaftliche Gesellschaft Wuppertal, Merz Pharmaceuticals, Neurologie Regensburg, Novartis, Octapharma, Orion Pharma, Österr. Gesellschaft für Schlafmedizin und -Forschung, Patienteninitiative MS und MP, Paul-Martini-Stiftung, Pfizer, Semantics, Solvay, Springer Verlag, TEVA Pharma, Thieme Verlag, UCB, Westermayer Verlag, Vitos Klinik Bad Emstal, Med Update, Consult Complete and GroupH; has received non-financial support from Abbott / Abbvie, Academy of Finland, ARVO / Pfizer Ophthalmics Research Institute, Baxter, Betreuungsverein Biedenkopf, BioLago eV Konstanz, British Society of Immunology, Chinesisch-Deutsches Zentrum Wissenschaftsförderung, Desitin, Deutsche Parkinson Gesellschaft, Deutsche Parkinson Vereinigung, Deutsche PSP-Gesellschaft, DGSM Deutsche Gesellschaft für Schlafmedizin, DZNE Deutsches Zentrum für neurodegenerative Erkrankungen, EBC European Brain Council, EFNA European Federation of Neurological Associations, Eisai, Fraunhofer Institut für System- und Innovationsforschung Karlsruhe, Helmholtz Kohorte, nstitut für Fort- und Weiterbildung, Kenes International, KKS Netzwerke, Klinik Bad Aibling, Klinikum Düsseldorf, Klinisches Demenzzentrum Göttingen, KNDD Kompetenznetz Degenerative Demenzen, Kompetenznetze in der Medizin, Krankenhaus Dierdorf-Selters, Lundbeck, Novartis, Octapharma, Orion Pharma, Quanup, Universität Duisburg-Essen, Universität Köln, Universität München, Vitos Klinik Herborn and Vitos Klinik Weilmünster; and has other interactions with Affiris, Baxter, GE Healthcare, Lilly, Novartis, Octapharma, Parexel, Solvay and Transmit GmbH.
Jan Kassubek, MD Dept. of Neurology, University of Ulm, Germany Jan Kassubek has served as a consultant for UCB Pharma, GlaxoSmithKline, Teva, Medtronic, Boehringer Ingelheim and Abbott; and has received honoraria from UCB Pharma, GlaxoSmithKline, Teva, Medtronic, Boehringer Ingelheim , Abbott, Merz and Bayer.
Stefan Lorenzl, MD Clinic for Neurology Agatharied Research Associate University of Munich, Germany Stefan Lorenzl has served as a consultant for UCB; has received grant/research support from TEVA; and has received honoraria from UCB, Teva and Boehringer.
Eva- Maria Mandelkow, MD German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany Eva Maria Mandelkow has no financial relationships to disclose.
Brit Mollenhauer, MD Paracelsus-Elena Klinik, Kassel
5 Universitätsmedizin Göttingen Brit Mollenhauer has served as a consultant for Roche; has received support for grants/research from Teva Pharma and GE Healthcare; and has received honoraria from Teva Pharma and Glaxo Smith Kline.
Huw Morris, MD UCL Institute of Neurology Huw Morris has received grant/research support from Medical Research Council, PSP Association, Parkinson's UK, and Medtronic; has received honoraria from UCB and Teva-Lundbeck; and has intellectual property rights on METHOD FOR DIAGNOSING A NEURODEGENERATIVE DISEASE (C9orf72) Patent 2013030588.
Ulrich Müller, MD Institut für Humangenetik Justus-Liebig-Universität-Giessen Ulrich Müller has no financial relationships to disclose.
Wolfgang H. Oertel, MD Hertie-Senior Research Professor Past-Chairman, Dep. Neurology, Philipps University Marburg, Germany Wolfgang Oertel has served as a consultant for Mundipharma, Novartis and UCB; and has received honoraria from Abbvie, Desitin, Novartis and UCB.
Olivier Rascol, MD, PhD Departments of Clinical Pharmacology and Neurosciences Faculty of Medicine Purpan University UPS of Toulouse III Olivier Rascol has no financial relationships to disclose.
Maria Stamelou, MD, PhD University of Athens, Greece Maria Stamelou has received honoraria from Actelion.
John C. Steele MD, FRACP(C), FACP Micronesian Health Study II, Guam John C. Steele has no financial relationships to disclose.
John C. Van Swieten, MD, PhD Erasmus Medical Centre Rotterdam, Netherlands John C. Van Swieten has no financial relationships to disclose.
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50 Years of Progressive Supranuclear Palsy Munich, Germany | October 10-11, 2014
Friday October 10, 2014 SESSION 1 – TEACHING COURSE: THE BASICS OF PSP 8:00‐9:00 Registration 9:00 Welcome to the Workshop Günter Höglinger and Carlo Colosimo 9:10‐9:40 The milestones of PSP research John Steele 9:40‐10:10 Richardson’s syndrome Carlo Colosimo 10:10‐10:40 Other clinical presentations Günter Höglinger 10:40‐11:00 How to test ocular movements in PSP Jan Kassubek 11:00‐11:30 Coffee‐Break 11:30‐12:00 Neuroradiological pearls to identify PSP Angelo Antonini 12:00‐12:30 Symptomatic approach David Burn 12:30‐13:00 Palliative care in PSP Stefan Lorenzl 13:00‐14:00 Lunch
SESSION 2 – UPDATE ON THE NEUROBIOLOGY OF PSP 14:00‐14:30 The physiology of tau in humans Eva Mandelkow 14:30‐15:00 Pathophysiology of tau accumulation Huw Morris 15:00‐15:30 Animal models of PSP Luc Buee 15:30‐16:00 CSF biomarkers Brit Mollenhauer 16:00‐16:30 Coffee break 16:30‐17:00 Update on neuropathology Thomas Arzberger 17:00‐17:30 Review on clinical trials Olivier Rascol 17:30‐18:00 Future therapeutic options Wolfgang Oertel
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50 Years of Progressive Supranuclear Palsy Munich, Germany | October 10-11, 2014
Saturday October 11, 2014 SESSION 3 – UPDATE ON THE CLINICAL ISSUES P8:30‐9:00 Cognitive changes in PSP – how to best identify them? John C van Swieten 9:00‐9:30 Early and late behavioral changes in PSP Thomas Bak 9:30‐10:00 PSP and CBD: one disease or two? Kailash Bhatia 10:00‐10:30 PSP‐look‐alikes Maria Stamelou 10:30‐11:00 Coffee break 11:00‐11:30 Is Neurogenetics a useful research and diagnostic tool? Ulrich Müller 11:30‐12:00 Neurophysiology and PSP: recent advances Matteo Bologna 12:00‐12:30 Health related quality of life Richard Dodel 12:30‐13:00 NINDS‐SPSP criteria: why do we need to update them Günter Höglinger 13:00‐13:15 Workshop in review
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50 Years of Progressive Supranuclear Palsy
The Milestones of PSP Research John Steele
Milestones in PSP research during 50 years
I am delighted by being with you all and particularly with many friends I have known for many years as we sought to understand the disease we know as progressive supranuclear palsy.
The organizers have asked me to begin this international Movement Disorder symposium by discussing the milestones that now lead us to conclude it is a proteinopathy, and a universal and sporadic 4R taupathy with multiple phenotypes which is transmissible to mice and perhaps between humans.
We agree, I think, that PSP was probably first described by Charles Dickens, a literary master of medical illnesses, in 1857, while on a walking tour in southern England with his friend Wilke Collins, where he observed; “a chilled, slow, earthy, fixed man. A cadaverous man of measured speech. A man who seemed as unable to wink, as if his eyelids had been nailed to his forehead. A man whose eyes—two spots of fire—had no more motion than if they had been connected with the back of his skull by screws driven through them, and riveted and bolted outside among his gray hair. He had come in and shut the door, and he now sat down. He did not bend himself to sit as other people do, but seemed to sink bolt upright, as if in water, until the chair stopped him.”
100 years later, in 1955, in Toronto Canada, neurologist Clifford Richardson began our present journey of research and understanding of PSP when he recognized a similar illness in a successful business executive who was his good friend. As Richardson puzzled about is features of progressive supranuclear palsy of gaze and bulbar muscles, axial dystonia, gait impairment and dementia he identified 3 other patients with similar symptoms and he realized then their illnesses must be an unrecognized neurodegenerative syndrome.
He resisted opinions by neuropathologist colleagues that it was a variant of post encephalitic parkinsonism, and in 1962 he asked Jerzy Olszewski, the new professor of neuropathology at the Banting Institute and me as his resident to examine seven cases which he had identified.
We found the histopathology of neurofibrillary degeneration and gliosis in brain stem and subcortical nuclei was quite as distinctive as the clinical syndrome, but we could not be certain if it was a primary neurodegenerative disease like Alzheimer’s disease was assumed to be, or a noninflammatory infection akin to scrapie and kuru which were just then beginning to be described.
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Interest in progressive supranuclear palsy has expanded since our description in 1964, and during the past 45 years its features have been vigorously investigated by an increasing number of neuroscientists using new biological techniques and studies that are facilitated by internet communication and international meetings.
By 2014 we have learned PSP is a 4R tauopathy. Richardson’s syndrome, as he originally described in 1963 is its principal manifestation but PSP disease also includes diverse phenotypes of parkinsonism, corticobasal degeneration, pure akinesia with gait freezing, frontotemporal dementia and progressive nonfluent aphasia. Furthermore we have learned Richardson’s syndrome is not unique to PSP disease, and it occurs also in the ALS/Parkinsonism-dementia of Guam and in Guadeloupean parkinsonism.
As multiple system atrophy and corticobasal degeneration have been defined and studied in similar fashion to PSP, and as they are compared with the classical neurodegenerations of Parkinson’s disease, Alzheimer’s disease and ALS remarkable similarities are now recognized between them. All are featured by an abnormal and spreading protein that is specific to the neurodegeneration and accumulates in nerve cells and glia. Although some neurodegenerations are due to identified gene mutations, the majority are sporadic without obvious inheritance or family predisposition. Except for the 3 and 4R tauopathy of post encephalitic parkinsonism that followed epidemic lethargica, and subacute sclerosing panencephalitis that is sometimes a sequel of measles, and the spongiform encephalopathy of kuru which came after single feasts during mortuary cannibalism, there is no obvious preceding cause of these sporadic proteinopathies. Their onset is silent and asymptomatic, and it is not known if environmental exposure is single and isolated, or repeated and cumulative. It is not certain to what extent the pathogenesis may relate to genetic predisposition or protection,
On Guam, a tropical island in the Western Pacific, the ALS/Parkinsonism-dementia complex has held my interest for 32 years. It is a geographic isolate of a familial and long latency polyproteinopathy which includes all the immunohistochemical proteins of all the major universal neurodegenerations. Its phenotypes are as diverse as its abnormal proteins, and include classical ALS, PD, atypical parkinsonism with PSP and CBD, and Alzheimer-type dementia. During the past 50 years, this single disease has slowly declined by its principal phenotypes of ALS and PDC, and its age in onset has steadily increased. In 2010, classical ALS which was 100 times more common than elsewhere in 1953, no longer occurs on the island. Parkinsonism with dementia is uncommon and only 29 cases older than 70 were recently identified in a 2003 community survey of elderly Guamanians.
The remarkable decline and disappearance of ALS/PDC in this distant place gives me hope that related and universal proteinopathies could end in the same way. But we must first identify its environmental cause and that remains our intention.
10 The challenge to Neurology in years ahead is to understand why abnormal proteins form, how they are acquired, and how each adversely affects the nervous system. We need to learn about their spread, and why the same protein can give rise to different phenotypes, and different proteins can cause the same phenotype. These will be new milestones as we will learn about protein metabolism and understand how we can influence and modify their abnormalities to prevent neurodegeneration.
In 1964, we were not certain if PSP was a classical neurodegeneration and akin to Alzheimer’s disease, or an infection due to a slow latent and temperate virus akin to scrapie. And we were aware of its similarities to post encephalitic parkinsonism. 45 years later we are still not certain. But we have learned that PSP and other neurodegenerations are due to the accumulation of abnormal proteins in the nervous system, and we are optimistic that future advances in understanding protein metabolism will give knowledge of pathogenesis and methods of cure.
I thank the Movement Disorders Society for making this meeting possible. And I congratulate the Dr. Hoglinger and his organizers for bringing together foremost authorities of PSP from all countries to know just where we are and how to move forward with others organizations like the Tau Consortium and CurePSP which have similar interests.
During 50 years we have made great progress in understanding PSP and other neurodegenerative diseases . We are not at an end or even the beginning of an end, but we are now at the end of a beginning to find their cause and their cure. I’m confident we will.
Thank you.
John Steele MD, FRCP©, FACP Neurologist
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50 Years of Progressive Supranuclear Palsy
Richardson’s syndrome Carlo Colosimo Department of Neurology and Psychiatry, Sapienza University, Rome, Italy
Fifty years ago, Richardson, Steele and Olszewski presented at the American Neurological Association meeting the clinical and neuropathological features of eight patients, representing the first description of progressive supranuclear palsy (PSP). Their classical paper, remarkably accurate, insightful and complete, still forms the basis for recognizing this disease [1,2]. The post‐ mortem examination of their cases showed prominent nerve cell loss and gliosis in the pallidum, red nucleus and subthalamic nuclei, and in the reticular formation [2]. Similar changes were noted in substantia nigra, locus coeruleus, superior colliculi, vestibular and dentate nuclei. Neurofibrillary tangles and granuovacuolar changes were also noted with the same distribution. No cortical pathology was described in the original report. The biochemical underpinnings of PSP became clearer in 1986, when it was first reported that the filamentous aggregates found brain autopsies from patients with PSP shared antigenic determinants with microtubule‐associated protein tau [3]. The advances in neurosciences of PSP during the last decades have led to the discovery that abnormal 4‐repeat tau deposition in brainstem, basal ganglia and neocortical areas is the main event in the pathogenesis of the disorder. The most frequently reported symptoms at onset in the classic form of this disease are impaired balance, movement slowness, subtle personality changes (apathy, disinhibition), bulbar symptoms and impaired oculomotion [4]. In the early stage of the classic PSP phenotype, the motor symptoms already respond poorly to dopaminergic drugs [5]. In the more advanced stages, patients manifesting classic PSP generally have a motor disorder characterized by bilateral bradykinesia, axial rigidity, and imbalance with severe gait unsteadiness. The prominent axial rigidity influences the posture, which may be characteristically erect like the cases reported by Richardson and collaborators (who depicted it as ‘nuchal dystonia’), or more closely resemble the stooped posture seen in Parkinson’s disease (PD). Progressive imbalance leads to repeated and frequent falls (usually backward). Some patients may have postural tremor and less commonly tremor at rest resembling PD. Patients with PSP often develop dysphagia and a characteristic growling high‐ pitched severe dysarthria, with mixed spastic and parkinsonian features. The diagnostic feature that best distinguishes PSP is a vertical gaze limitation with preserved oculocephalic reflexes: however, vertical gaze problems may be absent in up to 50% of the cases, and are rarely the presenting symptom of PSP. Because upgaze limitations can be present also in healthy persons (owing to anatomical changes within the orbit during aging), downgaze limitations are a far more specific finding suggesting PSP. An important point in the differential diagnosis is that several neurological conditions other than PSP can manifest with apparently similar oculomotor dysfunction (Table 1). Already Steele and Richardson noted that the disease they described extended beyond the motor system to include “mental symptoms”, “personality changes”, and “dementia” [2]. The prominent bradykinesia characterizing PSP is paralleled by cognitive slowing, difficulty in
12 generating words, and severe apathy [6]. In contrast, other cognitive functions such as language comprehension, recognition memory and visuospatial functions remain relatively well preserved. The clinical spectrum of PSP has been recently expanded in several clinical syndromes with distinctive features from the classical description of Richardson and co‐workers. All these clinical PSP variants reflect varying anatomical tau pathology distributions, but they share histopathologic, biochemical and genetic features with classic PSP. In 2005 Williams and colleagues renamed the classic PSP form as Richardson’s syndrome (RS), also proposing other terms for the different phenotypes of this disease [7]. RS probably represents only a minority of all cases of definite PSP. The estimated prevalence of PSP (per 100.000 in the population) in the various studies ranges from 1.3 to 4.9, but is possibly underestimated, whereas the analytical epidemiology of PSP is even more uncertain. [8]. The clinical symptoms of PSP commonly begin in the seventh decade, although occasionally as early as the fifth decade. The median onset age is of 63 years, and the disease affects both sexes despite a slight male predominance [4]. PSP is a disease characterized by a progressive worsening of neurological symptoms and increasing motor disability. Cognitive and behavioural symptoms also progress, but tend to remain selective until the late stages of the disease; in particular, the behavioural picture remains dominated by the pronounced apathy. The prognosis of PSP remains poor, and the disease leads to death within a few years after symptom onset. Mean survival ranges from 5.9 to 9.7 years according to the different series. These data come from series including mainly patients with the RS phenotype: other clinical variants differ in disease progression rates and disease duration, usually having a longer disease course than RS.
References
1. Richardson JC, Steele JC, Olszewski J. Supranuclear ophthalmoplegia, pseudobulbar palsy, nuchal dystonia and dementia. Transactions of the American Neurological Association 8, 25‐29 (1963). 2. Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch Neurol 10, 333‐359 (1964). 3. Pollock NJ, Mirra SS, Binder LI, Hansen LA, Wood JG. Filamentous aggregates in Pick's disease, progressive supranuclear palsy, and Alzheimer's disease share antigenic determinants with microtubule‐associated protein, tau. Lancet Nov 22;2[8517],1211 (1986) 4. Colosimo C, Bak TH, Bologna M, Berardelli A. Fifty years of progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 85:938‐944 (2014) 5. Colosimo C, Albanese A, Hughes AJ, de Bruin VM, Lees AJ. Some specific clinical features differentiate multiple system atrophy (striatonigral variety) from Parkinson’s disease. Arch Neurol 52, 294‐298 (1995). 6. Bak T.H., Crawford L.M., Berrios G., Hodges J.R. Behavioural symptoms in progressive supranuclear palsy and frontotemporal dementia. J Neurol Neurosurg Psychiatry 81, 1057‐1059 (2010). 7. Williams DR, et al. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSP‐parkinsonism. Brain 128, 1247– 1258 (2005) 8. Schrag A, Ben‐Shlomo Y, Quinn NP. Prevalence of progressive supranuclear palsy and multiple system atrophy: a cross‐sectional study. Lancet 354, 1771‐1775 (1999)
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Table 1. Other causes of vertical ophthalmoplegia ______Parkinson’s disease Multiple system atrophy parkinsonian variant Corticobasal degeneration Dementia with Lewy bodies Motor neuron disease Frontotemporal dementia and parkinsonism linked to chromosome 17 Huntington’s disease AD cerebellar ataxias (SCA 1, 2, 3, 7, 17) Kufor‐Rakeb disease (PARK 9) Hereditary spastic paraplegia Postencephalitic parkinsonism Prion diseases Progressive external ophthalmoplegia Multi‐infarct state Tumors compressing the brainstem (pinealoma, glioma) CNS lymphoma Myasthenia gravis Niemann‐Pick type C disease Drug‐induced disorder Wernicke’s encephalopathy Whipple’s disease ______
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50 Years of Progressive Supranuclear Palsy
Other clinical presentations Günter U. Höglinger
Prof. Dr. Günter U. Höglinger, Dept. of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), München, Max Lebsche Platz 30, D-81677 Munich, Germany. Phone: +49-89-7095-8406, Fax: +49-89-2180-75432-8406, [email protected].
In 1963 J.C. Steele, J.C. Richardson and J. Olszewski described eight cases of progressive supranuclear palsy (PSP) with a clinical syndrome,1 which is now termed Richardson’s syndrome (RS).2 Several atypical phenotypes have been described since then.3-6 - In 2005, a single-center systematic analysis of 103 definite PSP cases highlighted a second distinct PSP phenotype, namely PSP with parkinsonism (PSP-P).2 - In 2007, the same group described six definite PSP cases manifesting as pure akinesia with gait freezing (PSP-PAGF).7 - Further single-centre clinico-pathological studies with smaller numbers of patients have identified additional PSP phenotypes, e.g. PSP with corticobasal syndrome (PSP-CBS),8-10 frontotemporal dementia (PSP-FTD),9, 11, 12 progressive non-fluent aphasia (PSP-PNFA)13-16 and cerebellar ataxia (PSP-C).17, 18 In a multi-centric, multi-national cohort of 100 autopsy-confirmed patients, we studied the phenotypic spectrum of PSP by retrospective chart review. Only 24% of cases presented as RS and more than half of the cases either showed overlapping features of several pre-described phenotypes, or features not fitting proposed classification criteria for PSP phenotypes. Classification of patients according to predominant clinical features in the first 2 years of the disease course allowed a more comprehensive description of the phenotypic spectrum. When analysing the predominant clinical features in the first 2 years of the disease, the most common predominance types were PSP-RS, -PI (predominant postural instability), -OM (predominant oculomotor dysfunction), -P, -FTD and -CBS, capturing almost the entire population, while many of these patients developed other features later in the disease course. Thirteen cases remained unclassified. In terms of prognosis, the mildest clinical course was observed in PSP-P. After 10 years, PSP-P patients had the lowest frequency of supranuclear gaze palsy, frontal dysfunction, cognitive decline and dysphagia, and they survived significantly longer than patients of any other predominance type did. Cumulative mortality after 5 years was about 30% in PSP-RS, PSP-CBS and PSP-FTD, but only in 5.3% PSP-P and 0% in PSP-OM. In summary, the phenotypic spectrum of PSP may be broader and more variable than previously described in single-centre studies. Thus, too strict clinical criteria defining distinct phenotypes may not reflect this variability. A more pragmatic clinical approach using predominance types could potentially be more helpful in the early recognition and for making prognostic predictions for these patients.
15 References 1. Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch Neurol 1964;10:333–59 2. Williams DR, de Silva R, Paviour DC, et al. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSP-parkinsonism. Brain 2005;128:1247–58. 3. Dubas F, Gray F, Escourolle R., Steele-Richardson-Olszewski disease without ophthalmoplegia. 6 clinico-anatomic cases. [Review]. Rev Neurol (Paris) 1983;139:407-16. 4. Davis PH, Bergeron C, McLachlan DR. Atypical presentation of progressive supranuclear palsy. Ann Neurol 1985;17:337–43. 5. Morris HR, Gibb G, Katzenschlager R, et al. Pathological, clinical and genetic heterogeneity in progressive supranuclear palsy. Brain 2002;125:969-75. 6. Daniel SE, de Bruin VM, Lees AJ. The clinical and pathological spectrum of Steele-Richardson- Olszewski syndrome (progressive supranuclear palsy): a reappraisal. Brain 1995;118:759-70. 7. Williams DR, Holton JL, Strand K, Revesz T, Lees AJ. Pure akinesia with gait freezing: a third clinical phenotype of progressive supranuclear palsy. Mov Disord 2007;22:2235–41. 8. Tsuboi Y, Josephs KA, Boeve BF, et al. Increased tau burden in the cortices of progressive supranuclear palsy presenting with corticobasal syndrome. Mov Disord 2005;20:982–8. 9. Josephs KA, Petersen RC, Knopman DS, et al. Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP. Neurology 2006;66:41–8. 10. Ling H, de Silva R, Massey LA, et al. Characteristics of progressive supranuclear palsy presenting with corticobasal syndrome: a cortical variant. Neuropathol Appl Neurobiol. 2014; 40:149-63. 11. Han HJ, Kim H, Park JH, et al. Behavioral changes as the earliest clinical manifestation of progressive supranuclear palsy. J Clin Neurol 2010;6:148–51. 12. Hassan A, Parisi JE, Josephs KA. Autopsy-proven progressive supranuclear palsy presenting as behavioral variant frontotemporal dementia. Neurocase 2012;18:478-88. 13. Boeve B, Dickson D, Duffy J, Bartleson J, Trenerry M, Petersen R. Progressive nonfluent aphasia and subsequent aphasic dementia associated with atypical progressive supranuclear palsy pathology. Eur Neurol 2003;49:72–8. 14. Mochizuki A, Ueda Y, Komatsuzaki Y, Tsuchiya K, Arai T, Shoji S. Progressive supranuclear palsy presenting with primary progressive aphasia—clinicopathological report of an autopsy case. Acta Neuropathologica 2003;105:610–4. 15. Donker Kaat L, Boon AJ, Kamphorst W, Ravid R, Duivenvoorden HJ, van Swieten JC. Frontal presentation in progressive supranuclear palsy. Neurology 2007;69:723–9. 16. Josephs KA, Duffy JR. Apraxia of speech and nonfluent aphasia: a new clinical marker for corticobasal degeneration and progressive supranuclear palsy. Curr Opin Neurol 2008;21:688–92. 17. Kanazawa M, Shimohata T, Toyoshima Y, et al. Cerebellar involvement in progressive supranuclear palsy: a clinicopathological study. Mov Disord 2009;24:1312–8. 18. Iwasaki Y, Mori K, Ito M, Tatsumi S, Mimuro M, Yoshida M. An autopsied case of progressive supranuclear palsy presenting with cerebellar ataxia and severe cerebellar involvement. Neuropathology 2013;33:561–7.
16
50 Years of Progressive Supranuclear Palsy
How to test ocular movements in PSP Jan Kassubek
PSP is associated with a wide spectrum of oculomotor deficits including but beyond the eponymous supranuclear gaze palsy. By clinical examination, many of these symptoms and signs can be discovered; a more detailed investigation e.g. for differential diagnostic reasons in early stages of the disease can be performed by video-oculography (VOG). By hands of VOG, nearly similar oculomotor deficits have been shown in both RS and PSP-P even in the early course when motor symptoms of PSP-P are very similar to PD. VOG is useful in clinical diagnostics, also with respect to other entities, although overlapping findings exist. Prospective longitudinal data should be acquired in order to assess the biomarker potential of oculomotor alterations in PSP (and other Parkinsonian syndromes), in correlation to other technical parameters such as neuroimaging.
17 Howtotest ocularmovementsinPSP
JanKassubek
UniversitätsklinikfürNeurologie,Ulm
Bedside Screening: PSP
• initially slowing ofvertical saccades • slowingofdownwardsaccadesisconsideredthehallmarkofPSP andisincludedinthediagnosticcriteria • PSPpatients’ eyesmighttonically driftinresponsetothevisualcue inthedirectionoftheslowphaseofthenystagmus (lossof reflexivesaccades) • advanceddisease:possiblycompleteophthalmoplegia • markedlyhypometric verticalandhorizontalsaccades • smoothpursuitatleastmoderatelyimpaired • prominentfixationinstabilitywithsmallͲamplitudehorizontal squarewavejerks • markedlydiminishedblinkrate • eyeͲopeningandeyeͲclosingapraxia • `lazy lid phenomenon` (S. Lorenzl) Anderson & McAskill, Nat Rev Neurol 2013
18 nonͲinvasive:VideoͲOculography EyeLink® I EyeSeeCam®
Oculomotor LabinUlm
stimulus presentation
Reactive (vertical) saccades
pathologically reduced peak eye velocity (<200°/s) stimulus PSPpatient
° 400
/ 15 ° /s 0 Eye Velocity 100
Position Eye Ͳ15
peak eye velocity (>400°/s) 400 healthycontrol °
/ 15 ° /s 0 Eye Velocity 100
Position Eye Ͳ15 0 0.5 1.0 1.5 2.0 2.5 3.0
time /s Gorges et al., J Ophthalmol 2014
19 PSP: subtypes RS und PSP-P
Williams et al., Brain 2005
Saccadic Eye Movements z Functional networks: saccades z selection of saccades based on Hikosaka & Wurtz 1983
parietal cortex frontal cortex
phasic
basal ganglia planned
unplanned tonic inhibition Colliculus superior
brainstem
ocular muscles
Pathophysiology of vertical gaze palsy in PSP
NOR lesions of burst neurons in riMLF PSP (rostral interstitial nucleus of the medial longitudinal fascicle) for vertical saccades -> decreased firing rate -> decreased saccade velocity.
20 VOG: velocities of reactive saccades in PSP
600 PD and controls did not differ horizontal 400 PSP-P and RS significantly slower than PD and controls 200 PSP-P and RS with no significant differences 0 velocity -40 -20 0 20 40 individual level: in 10 out of 12 RS and 4 out of 5 -200 PSP-P patients peak velocity below 5%-Percentile of
PSP-P the controls -400 RS 600 CNT IPD vertical -600 400 amplitude
200
0
velocity -40 -20 0 20 40
-200
PSP-P -400 RS CNT IPD -600 amplitude Pinkhardt etal.,JNeurol (2008)
Individual variability of SNGP in PSP
PSP-RS PSP-P 500 500 1 4.1 400 10 400 4.2 300 13 300 16 4.3 200 200 17 100 11.1 18 100
0 24 0 25.1 -30 -20 -10 0 10 20 30 26 -30 -20 -10 0 10 20 30 -100 -100 25.2 31 -200 -200 121.1 125.1
-300 121.2 -300 131.1 124 -400 -400 CTL CTL vertikale Maximalgeschwindigkeit vertikale [°/s] vertikale Maximalgeschwindigkeit vertikale [°/s] -500 -500 Amplitude [°] Amplitude [°]
CTL CTL
NB: Slow vertical saccades not in all PSP patients
21 Executive control:antiͲsaccade
stimulus antiͲsaccade °
/ 20 0
Position Eye Ͳ20 erroneous response °
/ 20 0
Position Eye Ͳ20
Ͳ0.02 0 0.2 0.4 0.6 0.8 1.0 time /s
VOG: PSP-P vs. RS
VOG helps to differentiate PD and PSP-P already in early stages and clinically similar presentation (saccade velocity).
Williams et al. described SNGP in PSP-P (if any) to occur late in the disease course – based upon clinical examination.
PSP-P and RS could not be differentiated by VOG in this retrospective study.
Oculomotor functions in Parkinsonian syndromes
Apraxia CBS Literature GP PSP In `atypical` Parkinsonism, oculomotor pathology occurs with large overlap. SPEM Saccades PD patients also show pathological pursuit and pathological reactive saccades. „cerebellar“
PD MSA
22 VOG: SPEM in MSA
MSA vs. PD vs. CTL SPEM horizontal: significant difference between MSA, PD and CTL [0.375 Hz > 0.125 Hz]
MSA-C vs. MSA-P No significant difference for Gain and Phase angle between MSA-C and MSA-P (49% of MSA with OPCD and SND (Ozawa et al., Brain 2004)
Parkinsonism and oculomotor deficits: differential diagnostics
Pinkhardt & Kassubek, Parkinsonism Rel Disord (2011)
Utility of eye movement recordings in PSP
Anderson & McAskill, Nat Rev Neurol (2013)
23 Conclusion I: Present knowledge
• With respect to the subdivision of the clinical PSP syndrome to RS and PSP-P, a clinically assessable vertical gaze palsy is not described as a leading symptom in early PSP-P.
´ By hands of VOG, nearly similar oculomotor deficits have been shown in both RS and PSP-P with a prominent decreased saccadic velocity (vertical > horizontal), decreased gain of saccades, and smooth pursuit eye movements even in the early course of the disease when motor symptoms of PSP-P are very similar to PD.
´ VOG is useful in clinical diagnostics, also with respect to other entities, although overlapping findings exist.
Anderson & McAskill, Nat Rev Neurol (2013)
Conclusion II: Present knowledge deficits
• Prospective longitudinal data in early stages of PSP-P and RS are lacking and should be acquired in order to assess the biomarker potential of oculomotor alterations in PSP and other Parkinsonian syndromes.
´ correlation to other technical parameters (e.g. MRI) ABV DTI ifc MRI
Prof. H.-J- Huppertz, Knake et al., Mov Whitwell et al., Parkinsonism Rel Disord (2011) Zürich Disord (2010) • For that purpose, more experience in multi-center data acquisition and postprocessing needs to be gained
´ first studies exist (AL-108 PSP Study, Allon Therapeutics)
24
50 Years of Progressive Supranuclear Palsy
Neuroradiological Pearls to Identify PSP Angelo Antonini
NOTES: ______
25
50 Years of Progressive Supranuclear Palsy
Symptomatic Approach David Burn
Despite an increased knowledge of the pathophysiological processes involved in Progressive Supranuclear Palsy, and the role of tau in particular, advances in the symptomatic treatment of this aggressive neurodegenerative disease have been frustratingly slow. Indeed, no drug therapy has major symptomatic benefit in PSP and treatment remains both anecdotal and responses often idiosyncratic. Very few high quality studies have been performed, with the majority of reports being case studies and small series. Unlike Parkinson’s disease, which could be hailed as a paradigm of success in identifying a neurochemical deficit and administering a replacement, “simple” neurotransmitter replacement strategies have been ineffective for PSP. Similarly, deep brain stimulation and other neurosurgical approaches cannot be recommended at the present time. A multidisciplinary approach is of key importance in the best management of people with PSP, whilst providing much needed support for carers is essential. Future improvements in longevity and quality of care for people with PSP are likely to come from a combination of earlier and more accurate diagnosis coupled with advances in developing novel agents aimed at retarding progression of the underlying pathophysiological mechanisms.
26 50 Years of Progressive Supranuclear Palsy 9/29/2014 Symptomatic Approach David Burn
PSP Treatment: Symptomatic Approach
David Burn October 2014
Know Your Enemy?
• Diffuse neuronal loss & neurotransmitter involvement • Basic pathophysiology of PSP still not known • Animal models do not fully recapitulate disease features • Difficulty identifying tractable targets
Symptomatic Treatment Aims
• Improve mobility/bradykinesia/reduce falls – dopaminergic drugs • Improve memory/behaviour? – cholinergic drugs • Other symptoms – dysphagia & dysarthria – mood – gritty/dry eyes
27 50 Years of Progressive Supranuclear Palsy 9/29/2014 Symptomatic Approach David Burn
A Few Home Truths
• No drug therapy has major symptomatic benefit in PSP – treatment is anecdotal & idiosyncratic • Very few high quality studies have been performed – majority case studies & small series • “Simple” neurotransmitter replacement strategies ineffective to date
Trial Considerations in PSP
Observation Qualification Implication for Trial
Uncommon disorder Prevalence 5 per 100,000 Large geographical area or multicentre study required
Delayed diagnosis & May be up to 50% disease Early disease modification misdiagnosis common duration may be difficult Signal: noise consideration Emerging animal FTDP-17 & related Ability to assess drugs at models transgenics mechanistic level
Lack of biomarker Imaging? Dependence upon clinical Blood / CSF marker? observations / new validation required Short disease course Median disease duration May use functional / death 6-7 years as robust end-points
PSP: Overview of RCTs
van Balken & Litvan 2008
28 50 Years of Progressive Supranuclear Palsy 9/29/2014 Symptomatic Approach David Burn
Dopaminergic Drugs I
• Review of L-dopa based on 56 reports (n=548) – small open-label trials, retrospective series / case reports • Mild to moderate benefit reported in ~ 35% (rigidity & gait) – effects ill-sustained – side effects • nausea, low blood pressure, confusion • hallucinations, jaw spasm, dyskinesias (uncommon) Van Balken & Litvan 2008
Dopaminergic Drugs II
• Oral dopamine agonists – bromocriptine, lisuride, pramipexole – range of receptor affinity profiles – small studies – negative results & visual hallucinations common • Apomorphine – 5/6 failed to respond to s/c injection
Burn & Warren 2005; Van Balken & Litvan 2008
Cholinergic Treatments
ACh: Acetylcholine AChE: Acetylcholinesterase
Scopolamine blockade of cholinergic system worsens gait & cognition in PSP
Cholinesterase inhibitors improve symptoms in AD & PDD
29 50 Years of Progressive Supranuclear Palsy 9/29/2014 Symptomatic Approach David Burn
Basal Ganglia Cholinergic cholinergic neurons transmission Frontal cortex + Striatum ++ Cholinergic transmission Thalamus MD nucleus +++
Basal forebrain Brain stem cholinergic nuclei cholinergic nuclei nbM +++ Warren 2005 PPN ++
Cholinergic Drugs
• Cholinesterase inhibitors – early physostigmine trials inconclusive • some benefits on cognition noted • CSF studies suggested poor CNS penetration – 2 donepezil trials (6 & 19 patients, latter in cross-over RCT design) • no overall benefit • some motor symptoms worse • Muscarinic receptor agonists – RS-86 (M1/M2 receptor agonist) no benefit • M1 predicted to have positive effects & M2 negative effects • more selective receptor strategies helpful?
Foster 1989; Fabbrini 2001; Litvan 2001
Serotonergic Therapies
• Amitriptline (25-75mg) – response rate of 42% in aggregate of 60 patients • Nortriptyline & imipramine – less evidence & anecdotally less benefit • Fluoxetine – inconsistent benefits (impulsivity?) • Methysergide – initial reports of benefit in 9/12 not replicated
30 50 Years of Progressive Supranuclear Palsy 9/29/2014 Symptomatic Approach David Burn
Other Drugs
• Amantadine – “minor benefit” in ~ 20% • Noradrenergic agents α – idazoxan ( 2 antagonist: minor benefit in mobility, balance & dexterity)1 α 2 – efaroxan ( 2 antagonist: no benefit) – L-DOPS • Zolpidem3,4 α – 1GABAA agonist may produce minor improvements – not confirmed in clinical practice • Gabapentin5 – reduced anti-saccadic error rate but no UPDRS III benefit
1 Ghika 1991; 2 Rascol 1998; 3 Daniele 1999; 4 Mayr 2002; 5 Poujois 2007
Botulinum Toxin
• Dystonia – present in ~33% PSP – variable benefit • Blepharospasm & eyelid apraxia – success rate up to 95% – pretarsal site preferred? • Drooling – care not to increase dysphagia • Freezing of gait (?)
Van Balken & Litvan; Barsottini 2010
Electroconvulsive Therapy
• ECT – n=5 patients (9 treatments) – transient AEs included • confusion (all) • worsening of speech & swallowing – “dramatic response” (from completely wheelchair-bound state to independent ambulation) in 1, mildly improved (2), & unchanged (2) • rTMS – some improvement in dysarthria after 2 weeks of cerebellar intermittent theta burst stimulation
Barclay 1996; Brusa 2014
31 50 Years of Progressive Supranuclear Palsy 9/29/2014 Symptomatic Approach David Burn
Deep Brain Stimulation
• DBS-STN or GPi not indicated – case reports failed to improve • DBS-PPN evaluated in small series – 2 cases (died 3 & 6 months post- ⌧⌧⌧ ⌧⌧⌧ surgery) – “slight” & “transient” improvements noted in gait, mood & eye movements
Okun 2005; Hazrati 2012
Further Management I
• Depression / apathy – tricyclic vs. SSRI vs. SNRI • Impulsivity – SSRI (valproate?) • Constipation – push fluids / high fibre diet / aperients • Eating & swallowing – OT devices – SLT advice – PEG
Further Management II
• Vision – dry / sore eyes: eye sprays or eye drops – inability to look down: prism glasses – photophobia: wrap-around dark glasses – eyelid apraxia / blepharospasm: botox • PSP Association / Support Groups – Specialist Care Advisers – carer support
32 50 Years of Progressive Supranuclear Palsy 9/29/2014 Symptomatic Approach David Burn
Personal Practice
Accurate diagnosis
Motor= NMS, esp. L-dopa mood
Amantadine Amitriptyline Venlafaxine
Conclusion
• What has been achieved in symptomatic management of PSP over 50 years? • Drug treatments of limited benefit for most symptoms • Multi-disciplinary input vital as aids may be of considerable help • Emphasis switched to disease- modification for paradigm-shift
33 50 Years of Progressive Supranuclear Palsy
Palliative Care in Progressive Supranuclear Palsy Prof. Dr. Stefan Lorenzl, Dipl. Pall. Med. (Univ. Cardiff)
Paracelsus Medical University Salzburg, Austria Interdisciplinary Center of Palliative Medicine, Ludwig Maximilians University, Munich Hospital Agatharied, Germany
Patients with chronic neurologic disorders suffer from the burden of disease progression without the hope for a cure. Therefore, symptom management and palliative care approaches should be included early on. Palliative care aims at improving a patient’s quality of life and meaning in life by alleviating suffering due to physical, psychosocial and spiritual illness. Since no curative and only limited life- prolonging treatment options are available for patients with Progressive Supranuclear Palsy (PSP), a palliative care approach can help to create a treatment plan that considers all aspects of the disease. A palliative approach to PSP does not mean to limit treatment and focus on pain. Instead, the whole “unit of care”, consisting of the patient and his relatives and caregivers, should be perceived with all their needs.
It has become clear in recent years that the “total symptom” concept, the multiprofessional approach, early palliative care integration and academic models, all are very relevant to many patients suffering from movement disorders. However, still only a few patients find their way to palliative care units or into hospices. Patients with PSP are not traditionally managed by palliative care teams. However, as there are no disease-modifying agents available, and the wide spectrum of symptoms have a significant impact on the quality of life of the patients and families, palliative intervention has a lot to offer in the management of these conditions.
Disease trajectory in PSP is frequently divided into the supportive phase, the phase of transition and the terminal phase. In contrast to the normal life expectancy of patients suffering from PD, the median survival of PSP is estimated at 6 – 9 years.
Distressing motor symptoms include bradykinesia, muscle rigidity, dystonia and instability of gait. Physiotherapy is the mainstay of non-pharmacologic therapy to improve balance and self-confidence. Painful dyskinesias and dystonias are distressing for patients and carers and require aggressive management. Increased sweating, delayed gastric emptying, constipation, sialorrhea and urinary urge incontinence are part of the dysautonomic spectrum of PSP.
34
Progressive dysphagia is due to rigidity and hypokinesia as well as the gradual involvement of the dorsal motor nucleus of the vagus nerve in the disease process. So far, there is no evidence to suggest a survival or quality of life benefit by feeding tube placement in advanced PSP. This remains an individual decision following discussion with patient and caregivers.
Despite PSP is rapidly progressive, there is now evidence that quality of life can be preserved with high quality palliative care. However, in the first years of the disease almost one third of patients has suicidal ideation and might seek assisted suicide.
As the patient becomes more and more disabled and persistent neuropsychiatric problems develop, the priority of care shifts to preservation of quality of life through effective symptom control.
In their last days of life, patients with PSP often suffer from pneumonia. Bradykinesia increases dramatically, and often even spasticity is seen. Communication might not been possible due to severe generalized dystonia (including larynx and pharynx muscles as well as mouth opening dystonia). Eyes are often wide open, but apparently there is an inability to control eye movements. Seizures as well as myoclonic jerks occur frequently. It is not rare for patients to exhibit profound cachexia, even if tube feeding has been placed earlier on. However, patients are often able to understand and want to participate in decisions. Therefore, decisions regarding life limiting procedures should be discussed not only with the relatives but also with the patient. In our experience, most patients with PSP refuse life- prolonging therapies.
35
50 Years of Progressive Supranuclear Palsy
The physiology of Tau in Humans Eva Mandelkow NOTES: ______
36 Pathophysiology of tau accumulation in PSP
Huw Morris UCL Institute of Neurology
!0&,0(&1' OM#,6.@#7?#@62#2D712;02#@6.@#@.C#7?#@62#02;@>.9#=9.G2>#7;# (*(I# PM#,6.@#17?2.?2?#.;1#>29.@21#17?2.?2#:<129?#.>2# >292D.;@I# QM#,6.@#:206.;7?:?#:756@#/2#7:=<>@.;@J.;1#E62>2#.>2# @62#@62>.=2CA0#@.>52@?# RM#,6.@#.>2#@62#;2F@#?@2=?I## #
37 The microtubule associated protein tau
MAPT: Alternative splicing of
Exon 1 2 3 4 4A 5 6 7 8 9 10 11 12 13 exons 2, 3 and 10
1 441 2N,4R Tau protein: 1 412 1N,4R Six isoforms in CNS 1 383 0N,4R 1 410 2N,3R 1 381 1N,3R 1 352 0N,3R
Courtesy of John Hardy
PD is negatively associated with the MAPT H2 haplotype
NSF NSF (1-21) (1-13) MAPT CRHR1 H1
NSF NSF (1-21) (1-13) MAPT CRHR1 H1H2
45.5 44.5 43.5 TEL CEN Courtesy of John Hardy
There are two association signals at the MAPT locus
H1/H2 H1c –rs242557
38 &C(+#L#C9@2>;.AD2#?=9707;5#<3#@.C# 2$"PC%QK(!)%#L#!)#C;3<9121#=><@27;#>2?=<;?2# *+-S#L#" #$!##<957#L#!;1<=9.?:70#@>.4087;5# &' (#L#&G297;#C??<07.@21#'975<12;1><0G@2# .?70# (><@27;#67569G#2F=>2??21#7;#/>.7;?@2:#
39 "'#.'(-'.'&'&0(%&*$&'.'#.'.#/'(-'.'&'$&*.,#)'+)#2&,'(*' ! 3'
Courtesy of Dr Ling
40 Is the Mendelian disease FTDP-17 a good model for the sporadic disease PSP and will this help us develop new therapies?
41 VIDEO
DK280 I260V P301L/S -2 +3 +12 G389R G272V N279K +13 +14 +16 V337M R406W K257T
9 10 11 12 13
Missense mutations outside exon 10
Missense mutations in exon 10
Intronic and exonic mutations which affect exon 10 splicing
DK280 I260V P301L/S -2 +3 +12 G389R G272V N279K +13 +14 +16 V337M R406W K257T
9 10 11 12 13
Destabilization of microtubules
? Enhanced filament/aggregate formation Alteration in the 4R/3R ratio
Alteration in Ser/Thr phosphorylation sites
42 PSP FTDP17T
Exon 10 splicing Exon 10 Non-Exon 10 coding coding
Genetics H1/H1c +3, +16, N279K, P301L, P301S R406W R5L
Clinical Parkinsonism, Gait, Parkinsonism, Gait bvFTD bvFTD, Dementia SNGP SNGP
EM Straight filaments Slender twisted Irregular SFs, PHFs filaments twisted ribbon, SF
Protein 4R>3R 4R>3R 4R>3R 4R=3R
RNA 4R>3R 4R>3R 4R=3R 4R=3R
Glial Tufted astrocytes TA ++, Variable Variable Pathology Oligodendroglial coiled bodies
Noble W et al. PNAS 2005;102:6990-6995
©2005 by National Academy of Sciences
43 Can we link the Mendelian and non-Mendelian diseases?
Do the genetic risk factors for PSP recapitulate Mendelian disorders?
Do the genetic risk factors for PSP recapitulate Mendelian disorders?
44 Do the genetic risk factors for PSP recapitulate Mendelian disorders?
H1c vs other H1 - 10% increase in total tau 25% increase in 4R tau
PSP FTDP-17
MAPT Age MAPT splicing, Age expression Coding mutation and splicing SpreadSpr PERK MOBP STX6 Neuronal and gliglial tau MAPT accumulationacc Activation of aggregation UPS
Mitochondrial MicrotubuleMic failure destabilization
MAPT clearance
45 What are the therapeutic targets?
Reduction in tau levels
Anti-tau aggregation therapy
Kinase inhibitors; Phosphatase enhancers
Autophagy stimulation
Microtubule stabilizing agents
Anti-tau propagation therapies
Alteration in 4R:3R tau ratio
What are the therapeutic targets?
Reduction in tau levels
Alteration in 4R:3R tau ratio
Anti-tau aggregation therapy: Grape seed extract, Methylene blue
Kinase inhibitors; Phosphatase enhancer: SVP, Lithium, Tideglusib –ve
Autophagy stimulation: Trehalose
Microtubule stabilizing agents: Davuentide –ve; EpothiloneD
Anti-tau propagation therapies: Immunization
!0&,0(&1' OM#,6.@#7?#@62#2D712;02#@6.@#@.C#7?#@62#02;@>.9#=9.G2>#7;# (*(I# PM#,6.@#17?2.?2?#.;1#>29.@21#17?2.?2#:<129?#.>2# >292D.;@I# QM#,6.@#:206.;7?:?#:756@#/2#7:=<>@.;@J.;1#E62>2#.>2# @62#@62>.=2CA0#@.>52@?# RM#,6.@#.>2#@62#;2F@#?@2=?I## #
46 Pathophysiology of tau accumulation in PSP
Huw Morris UCL Institute of Neurology
47 28/09/14
Animal models of PSP
Luc BUEE Inserm, CHR-University of Lille France
Today’s talk
• Tau transgenic models (FTDP-17 muta ons, tau overexpression) • Neuroinflamma on • Other models (KO dicer à miRNA124) • Tau spreading with len viral vectors encoding tau in rats: differen al spreading of 3R and 4R isoforms • Open up on therapeu cs
Environmental toxins
48 28/09/14
P P τ 74 τ 74 PSP in τ 69 τ 69 τ 64 τ 64 French τ 60 τ 60 Caribbean AD Guadeloupe PSP Guam
Gene cs and epigenomics
49 28/09/14
Gene c / 4R Tau
Tau transgenic mice
Tau transgenic mice
• Theory versus experimental – Choice of the muta on – Choice of the promoter – Choice of the isoform • Which phenotypes? – Neuronal versus glial – Cor cal, subcor cal, brainstem…
50 28/09/14
THY-Tau mice (1N4R G272V/P301S)
Tau transgenic mice overexpress pro-inflammatory markers
Microarray experiments (FC>2) Biological Sample Background Genes 12 month old THY-Tau22 vs. WT mice processes frequency frequency Ccl3, C3, H2-Ab1, Immune 479/33218 8/29 (27,6%) Ccl4, Cd74, Ccl5, response (1,4%) Clec7a, Cxcl5 Inflammatory 241/33218 Ccl3, C3, Ccl4, Ccl5, response 6/29 (20,7%) (0,7%) Clec7a, Cxcl5
Defense 474/33218 Ccl3, C3, Ccl4, Cd74, 7/29 (24,1%) response (1,4%) Ccl5, Clec7a, Cxcl5 Ccl3, C3, H2-Ab1, Immune system 820/33218 Ccl4, Cd74, Ccl5, 8/29 (27,6%) process (2,5%) Clec7a, Cxcl5
Response to 357/33218 Ccl3, C3, Ccl4, Ccl5, 6/29 (20,7%) wounding (1,1%) Clec7a, Cxcl5
111/33218 Chemotaxis 4/29 (13,8%) Ccl3, Ccl4, Ccl5, Cxcl5 (0,3%) Ccl3, C3, Creb313, Response to 1154/33218 8/29 (27,6%) Ccl4, Cd74, Ccl5, stress (3,5%) Clec7, Cxcl5 Response to Ccl3, C3, Ccl4, Ccl5, 587/33218 external 6/28 (20,7%) Clec7a, Cxcl5 (1,8%) stimulus Ccl3, Zic-1, C3, Response to 2279/33218 Creb313, H2-Ab1, 10/29 (34,5%) THY-Tau22 WT stimulus (6,9%) Ccl4, Cd74, Ccl5, Martin Figeac Clec7a, Cxcl5
Microglia
pathogen CD11b CD68
CD45 Microglia
Innate immune response
CD68 CD45 CD11b 200 250 150 1500 ** ** *** 200 150 *** * 100 1000 150 100 100 ** 50 50050 50 expression
Relative mRNA Relative *** 0 0 0 0 3 7 12 3 7 12 3 7 12 3 7 12 months
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Microglia
pathogen CD11b CD68
phagocytosis
CD45 Microglia
Innate immune response
3 months CD11b 12 months
Chemokines/cytokines Chemokines
CCL3 CCL4 CCL5 CXCL5 500 500 500 250 *** *** *** ** 400 400 400 *** 200 ** 300 300 300 150 *** 200 * 200 200 100 * expression 100 100 100 50 Relative mRNA 0 0 0 0 3 7 12 3 7 12 3 7 12 3 7 12
Chemokines Receptors
CCR1 CCR5 1500400 200 *** *** 300 150 1000 200 100 ** 500 expression 100 50 Relative mRNA *** 0 0 0 3 7 12 3 7 12 3 7 12 months Months months Months
Adaptative markers
Slamf9 ITGAX CD3 1500 300 1500 300 ** *** ** * 1000 ** ** 200 ** 1000 200 ** ** 500
expression 100 500 * 100 expression Relative mRNA *** 0 Relative mRNA 0 3 7 12 0 0 3 7 12 3 7 12 3 7 12 months
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Adaptative markers : Lymphocytes
CD8 3 months 12 months
10 ** 2 8 6 * Diapedesis 4
cells / mm cells 2 Number of CD8+ 0 3 7 12 months
Epigenomics & miRNAs
miRNAs regulate gene expression
• Small (19–22 nt), endogenous non-coding RNAs
• Encoded in the genome
• Wide range of expression: Few to 100,000 copies per cell
• Es mated that ~25-50 % of all genes are regulated by miRNAs
• Each miRNA can regulate up to 100+ different genes
• Each gene can be regulated by mul ple miRNAs
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Proof of principle – Dicer cKO mice • Progressive neurodegeneration • Reduced brain size • Enlarged ventricles • Inflammation • Neuritic and synaptic changes • Apoptosis (in some cases)
X~21nt
Hum Mol Genet 2010
miRNAs and Tau exon 10 splicing (The analysis of Dicer cKO mice)
Smith P, Delay C et al. Hum Mol Genet 2012
Tau splicing in progressive supranuclear palsy
E2 E3 E10 E2 E3 E10 τ 74 τ 74 τ 69 τ 69 τ 64 τ 64 τ 60
Ex : Alzheimer’s disease Ex : Progressive Supranuclear palsy
*
* Tau E2 Tau E2 * * p-Tau TauTau E10E10 p-Tau Tau E10
Smith P, Delay C et al. Hum Mol Genet 2012
54 28/09/14
Searching for miRNA/gene candidates
9 10 11
9 11 miR-132 (decrease in PSP) PTBP2 Tau miRNA may explain some changes in Tauopathies such as Tau phosphorylation and Tau splicing
Viral vectors & Tau spreading
55 28/09/14
To determine how Tou pathology spreads: Tou protein transfer in vitro
S umato I'll rmc Axonal compunmt>nl Colttpannunt M icrogr
To determine how Tou pathology spreads: Tou protein transfer in vitro
S11ntato I'll rmc Axonal compurtmt>nl Compunnunt Micmgr ..... Exogenous WT VS-Tau is actively transferred from donor cells to recipient cells. To determine how Tau pathology spreads: Tau protein transfer in vivo hTau46WT(2+3-10+) E2 EIO N< [!]BI=i lc::::====:::::JIEji~IJ:I=]Ict OKPIPNPLLGLDST -- (T~~g V~) 56 28/09/14 TAU PATHOLOGY SPREADING Subiculum CA1 IL 30 µm 30 µm 30 µm Caudal DP Rostral Dujardin S. et al. Acta Neuropathol Commun 2014 IS 30 µm hTau46WT! +2.7 +1.7 +0.7 -0.3 -1.3 -2.3 -3.3 -4.3 -5.3 -6.3 -7.3 -8.3 IS +2.20 mm IS -7.60 mm Hyper Pi Tau AT8! 8 months! Aggregated Tau Misfolded Tau MC1! 4 months! Aggregated Tau Aggregated AT100! Tau 2 months! Pathology progression The trans-synap c transfer of wt tau protein mediates progressive tau pathology ISOFORMS, MUTATIONS AND PROPAGATION …? Caudal secondary regions Injec on Site Rostral secondary regions +5.7 +4.7 +3.7 +2.7 +1.7 +0,5 -0.3 -1.3 -2.3 -3.3 -4.3 -5.3 -6.3 -7.3 -8.3 +5.4 ± 0.2 -8.4 ± 0.2 h1N4R WT * +0.8 ± 1.2 -7.5 ± 0.2 h1N4R P332S *** -3.3 ± 0.5 -7.5 ± 0.2 h1N4R P301L * +1.0 ± 1.5 -7.8 ± 0.3 h1N3R WT *** -3.1 ± 1.0 -7.6± 0.4 h1N3R P332S 57 28/09/14 Open up new therapeu cs Conclusions • Numerous animal models are available • Lowering Tau levels may be an interes ng approach but Tau has different physiological roles • Tau immunotherapy works in experimental models showing Tau overexpression – What about endogeneous Tau?? • Is Tau alterna ve splicingthe real target? 58 50 Years of Progressive Supranuclear Palsy CSF Biomarkers Brit Mollenhauer Georg August University Goettingen and Paracelsus-Elena Klinik, Kassel, Germany At the present time, progressive Supranuclear Palsy (PSP) is diagnosed clinically based on the presence of cardinal motor and oculomotor features 1, but the diagnostic accuracy of PSP is only 70-75% 2. No simple objective indicator or biomarker exists to support the clinical diagnosis and determine the progression of the disease. Therefore, their clinical diagnosis relies on expert opinion. Based on genetic 3 and neuropathologic implications 4, the characterisation of tau-protein in human body fluids represents a logical, disease-linked marker candidate to possibly separate between primary tau-related disorders from other [e.g. á- synuclein (aSyn)-related] neurological diseases. Due to the progression of tau pathology in tau-related disorders 5 it may also serve as a marker of the progression of the disease. These genetic and pathological links make tau a key target for therapeutic development. However, for effective translation into the clinic, there is a need to determine the exact species of tau protein in human samples and identifying which species are more prevalent in pathological disease. Many fundamental decisions in medical practice outside the field of neurodegeneration are based on objective laboratory biomarkers. Since cerebrospinal fluid (CSF) is in direct contact with the central nervous system, it is obvious that any changes in biochemical composition of brain parenchyma should be predominantly reflected in the CSF. In fact, the permeation of brain-derived proteins is prioritized to the diffusion of blood proteins into CSF. Total tau protein in cerebrospinal fluid (CSF) is a biomarker for Alzheimer’s disease 6 but is not a reliable diagnostic test for other tauopathies. The concentration of CSF total and phosphorylated tau protein has been explored in PSP by commercially available enzyme-linked immunosorbent assay (ELISA). There no alteration of the levels between PSP and other neurodegenerative diseases was seen (Arai et al., 1997: Urakami et al., 2001 and 2002). After the detection of tau protein fragments in brain species, the quantification of tau forms in CSF by Western/Immunoblot (after immunprecipitation) has been established by Borroni et al. 2008 und 2009). There the ratio of 33kDa/55kDa tau forms revealed decreased levels in CSF of PSP patients compared to other neurodegenerative 59 diseases (Borroni et al., 2009). The different tau isoforms (i.e. 3 and 4 repeat-tau) occur thru alternative splicing. The imbalance of these tau isoform homeostasis characterise disease- specific pathogenesis 7. In fact we showed a significant decrease of 4R-tau in PSP by sensitive immune-PCR 8-10. Tau isoforms were identified and characterized within neurodegenerative disorders showing different pattern in PSP confirming a disease specific pathological progression 9-11. Especially truncated (33 kDa) and extended (55 kDa) forms of tau were detected in CSF and in cerebral cortex with a reduced ratio between the 33 kDa and 55 kDa form in CSF of PSP patients. Hence, partially proteolyzed tau is a promising marker for PSP diagnosis. Besides these known tau isoforms, other so called “surrogate” marker candidates in CSF have already been proposed for PSP like decreased â-amyloid 1-42 12, neurofilament light chains 13 and increased aSyn 14, 15 etc. 1. Litvan I, Agid Y, Calne D, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996; 47(1): 1-9. 2. Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 2002; 125(Pt 4): 861-70. 3. Hoglinger GU, Melhem NM, Dickson DW, et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 2011; 43(7): 699-705. 4. Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 1989; 3(4): 519-26. 5. Brettschneider J, Del Tredici K, Irwin DJ, et al. Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD). Acta Neuropathol 2014; 127(3): 423-39. 6. Blennow K, Wallin A, Agren H, Spenger C, Siegfried J, Vanmechelen E. Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? Mol Chem Neuropathol 1995; 26(3): 231-45. 7. de Silva R, Lashley T, Gibb G, et al. Pathological inclusion bodies in tauopathies contain distinct complements of tau with three or four microtubule-binding repeat domains as demonstrated by new specific monoclonal antibodies. Neuropathol Appl Neurobiol 2003; 29(3): 288-302. 8. Luk C, Compta Y, Magdalinou N, et al. Development and assessment of sensitive immuno-PCR assays for the quantification of cerebrospinal fluid three- and four-repeat tau isoforms in tauopathies. J Neurochem 2012; 123(3): 396-405. 9. Borroni B, Gardoni F, Parnetti L, et al. Pattern of Tau forms in CSF is altered in progressive supranuclear palsy. Neurobiol Aging 2009; 30(1): 34-40. 10. Borroni B, Malinverno M, Gardoni F, et al. Tau forms in CSF as a reliable biomarker for progressive supranuclear palsy. Neurology 2008; 71(22): 1796-803. 11. Arai T, Ikeda K, Akiyama H, et al. Identification of amino-terminally cleaved tau fragments that distinguish progressive supranuclear palsy from corticobasal degeneration. Ann Neurol 2004; 55(1): 72- 9. 12. Noguchi M, Yoshita M, Matsumoto Y, Ono K, Iwasa K, Yamada M. Decreased [beta]-amyloid peptide42 in cerebrospinal fluid of patients with progressive supranuclear palsy and corticobasal degeneration. Journal of the Neurological Sciences 2005; 237(1-2): 61-5. 60 13. Hall S, Ohrfelt A, Constantinescu R, et al. Accuracy of a Panel of 5 Cerebrospinal Fluid Biomarkers in the Differential Diagnosis of Patients With Dementia and/or Parkinsonian Disorders. Arch Neurol 2012: 1-8. 14. Mollenhauer B, Locascio JJ, Schulz-Schaeffer W, Sixel-Doring F, Trenkwalder C, Schlossmacher MG. alpha-Synuclein and tau concentrations in cerebrospinal fluid of patients presenting with parkinsonism: a cohort study. Lancet Neurol 2011; 10(3): 230-40. 15. Hong Z, Shi M, Chung KA, et al. DJ-1 and alpha-synuclein in human cerebrospinal fluid as biomarkers of Parkinson's disease. Brain 2010; 133(Pt 3): 713-26. 61 50 Years of Progressive Supranuclear Palsy Update on the neuropathology of PSP Thomas Arzberger, Carolin Kurz, Günter Höglinger PSP is a neurodegenerative multiple system disease characterized by intracytoplasmic aggregates of hyperphosphorylated 4-repeat isoforms of microtubuli-associated-protein tau (hp4R-MAPT) in neurons and glial cells of cortex, subcortical nuclei, brain stem and cerebellum. The neuropathogical hallmark is the occurrence of hp4R-MAPT in processes of astrocytes (“tufted astrocytes”) in the striatum and/or frontal neocortex (Brodman areas 6 and 8). Areas with most severe neurodegeneration (i.e. loss of neurons and gliosis) are both segments of globus pallidus, subthalamic nucleus, substantia nigra and cerebellar dentate nucleus in most cases. However, the degree of neurodegeneration and the abundance of hp4R-MAPT inclusion pathology vary between cases. The investigation of additional protein aggregates associated with other neurodegenerative diseases (like Alzheimer disease, Lewy body disease, argyrophilic grain disease etc.) in 100 neuropathologically confirmed PSP autopsy cases revealed the co-existence of argyrophilic hp4R-MAPT containing grains in 55% of the cases mainly located in amygdala, entorhinal cortex and the cornu ammonis 1/subiculum region. Furthermore 71% of the cases showed Alzheimer associated neurofibrillary tangle pathology up to Braak & Braak stage III, 54% beta-amyloid plaques up to Thal phase 5, 7% additional Lewy- body/Lewy neurite pathology, 4% TDP43 aggregates. Only 14% of all PSP cases were pure PSP cases without any co-aggregating proteins. The co-existence of co-aggregating proteins subdivides PSP cases into several neuropathological groups. Whether these groups correlate with clinical symptoms, disease severity or disease duration is still under investigation. 62 50 Years of Progressive Supranuclear Palsy Review on Clinical Trials Olivier Rascol NOTES: ______ 63 50 Years of Progressive Supranuclear Palsy Future Therapeutic Options (Available Online) Wolfgang Oertel NOTES: ______ 64 50 Years of Progressive Supranuclear Palsy Cognitive Changes in PSP John C van Swieten NOTES: ______ 65 50 Years of Progressive Supranuclear Palsy Early and Late Behavioral Changes in PSP Thomas Bak NOTES: ______ 66 50 Years of Progressive Supranuclear Palsy PSP and CBD: One disease or two? Kailash Bhatia NOTES: ______ 67 50 Years of Progressive Supranuclear Palsy PSP Look-alikes Maria Stamelou Summary A variety of diverse disorders may cause a PSP-like phenotype, e.g. a clinical picture that resembles Richardson’s syndrome.1 A correct diagnosis has important clinical and research implications; some of the PSP-look alikes may be treatable, or have a different prognosis from PSP; some others may be inherited, and their identification will allow genetic councelling or offer important pathophysiological clues for sporadic PSP. The diagnosis of these PSP-look alikes is often simple, by identifying features unusual for sporadic PSP, such as earlier age of onset, unusual associated features or positive family history. Genetic conditions that may present with a PSP phenotype include MAPT, PGRN, C9ORF72 and DCTN1 mutations carriers. 2When the age of onset (too early), the tempo of evolution (too rapid) and the associated features (other signs such as prominent ataxia) are atypical for PSP, one should also consider disorders that may be (partially) treatable such as Whipple’s, Niemann-Pick C and paraneoplastic syndromes. However, the major diagnostic problems are caused by other sporadic neurodegenerative conditions and mainly other tauopathies, such as CBD and FTD. For the differential diagnosis of these conditions, there are still no clinical signs or biomarkers to accurately predict pathology. Neurodegenerative disorders The typical phenotype of patients with mutations in genes causing frontotemporal lobar degeneration (FTLD) is the behavioural variant (bvFTD), but mutations in a number of other genes have been identified to cause FTD-parkinsonism phenotypes. PSP phenotypes have been mainly associated with microtubule-associated protein tau (MAPT) and progranulin gene (PGRN) mutations [tau and TDP-43 pathology, respectively], both inherited in a dominant pattern. The age at onset in MAPT mutation carriers is between the 3rd to 5th decade (range: 25-65 years), thus earlier than the mean age of onset in PSP (63 years). A positive family history of parkinsonism or dementia is almost always present in MAPT mutation carriers, as their penetrance is almost 100 %, and they are rare in sporadic disease, although the first de novo mutation has been recently described. Early episodic memory impairment, prominent behavioural problems and semantic dementia are prevalent in patients with MAPT mutations, and may precede the onset of motor symptoms. 3 The mean age at onset in PGRN mutations carriers is 60 years (range: 35-83 years). PGRN mutations reach a penetrance of 90% at age 70, so a positive family history is not always present. PGRN mutations carriers usually show signs of parietal lobe involvement (e.g. dyscalculia, limb apraxia etc.) and progressive non-fluent aphasia (PNFA), which are unusual for sporadic PSP. Hallucinations may occur in up to 25% of patients with PGRN mutations and may be another helpful clue, as they rarely occur in sporadic PSP or in MAPT mutation carriers. 4 68 Hexanucleotide expansions in chromosome 9 open reading frame 72 (C9ORF72) (TDP-43 pathology) cause FTD-amyotrophic lateral sclerosis (ALS) overlap syndromes. 35% of these patients may also have atypical parkinsonism, and cases with slowness of vertical saccades, parkinsonism, frontal dementia and abnormal DaTSCANs, mimicking PSP have been reported. 5 Perry syndrome is a rare autosomal dominant disorder due to mutations in the dynactin (DCTN1) gene underpinned pathologically by TDP-43 inclusions. The age of onset ranges from 30-61 years. The penetrance is close to 50%. The typical phenotype includes parkinsonism with varying combinations of central hypoventilation, weight loss, and psychiatric symptoms (e.g. apathy, hallucinations). Response to levodopa varies from no response to significant improvement and development of motor fluctuations and dyskinesias. Recently, dynactin mutations have been described in families with a PSP-phenotype. 6 Other disorders that may present typically with supranuclear gaze palsy comprise Kufor-Rakeb syndrome due to ATP13A2 mutations, a rare autosomal recessive disorder, characterized by juvenile- onset (12–29 years), levodopa-responsive parkinsonism (with fluctuations and dyskinesias), vertical SGP, cognitive dysfunction (dementia and visual hallucinations) and pyramidal signs. Further characteristic features include oculogyric dystonic spasms and facial-faucial-finger mini-myoclonus. T2*-weighted MRI imaging may show evidence of brain iron accumulation in some patients, which can be a helpful clue to suspect this disorder. Westphal variant Huntington’s disease ay present with parkinsonism and slowness of saccades, however, the age of onset in these disorders, is too young for PSP, and do not really pose diagnostic dilemmas. Neuro-metabolic disorders Niemann-Pick C is an autosomal recessive lysosomal lipid storage disorder characterized by accumulation of unesterified cholesterol and glycolipids in the endosomal/lysosomal system. Biochemical diagnosis of Niemann-Pick C is made by filipin staining of cultured skin fibroblasts, with subsequent confirmation of the diagnosis made by mutation analysis of the NPC1 (the majority) and NPC2 genes. Miglustat is the only approved treatment for the neurologic manifestations of the disease, and patients who begin treatment early respond better, highlighting the need for early diagnosis. The adult-onset neurological form is infrequent and can present within the 2nd or 3rd decades in most patients (up to 54 years). The most common neurological features include vertical supranuclear gaze palsy, cerebellar ataxia, dysarthria, dysphagia, cognitive dysfunction and psychiatric symptoms. Gaucher’s disease is an autosomal recessive lysosomal storage disorder caused by mutations in the glucocerebrosidase (GBA) gene, leading to deficiency of the enzyme b-glucosidase. It is more prevalent in Ashkenazi Jews. Diagnosis can be made by measuring GBA activity in leukocytes (low) and plasma chitotriosidase (high), and subsequent testing of the GBA gene. Enzymatic replacement therapy (alglucerase, imiglucerase), and substrate reduction therapy with miglustat are available treatments, without which the outcome of Gaucher’s disease is extremely unfavourable. Adult-onset parkinsonism from the 3rd to the 7th decade has been documented in Gaucher’s disease 1 and 3. Patients usually have slow horizontal saccades and increased latency launching horizontal saccades. However, some Gaucher’s disease patients with prominent slowness of vertical saccades and cognitive dysfunction, mimicking PSP, have been reported. Systemic associated features such as splenomegaly, hepatomegaly, bone crisis, bone pain, anaemia and thrombocytopenia are helpful diagnostic clues. 69 Prion disorders Genetic Creutzfeldt–Jakob Disease (gCJD) has been linked to a variety of mutations within the prion protein gene (PRNP). Patients with disease onset between their 5th and 7th decade, vertical SGP, ‘worried facial appearance’, postural instability, axial rigidity and frontal dementia mimicking PSP, have been described in gCJD, mostly with the E200K but rarely also with further mutations and in sporadic CJD. References: 1. Stamelou M, Quinn NP, Bhatia KP. "Atypical" atypical parkinsonism: new genetic conditions presenting with features of progressive supranuclear palsy, corticobasal degeneration, or multiple system atrophy-a diagnostic guide. Mov Disord 2013;28(9):1184-1199. 2. Fogel BL, Clark MC, Geschwind DH. The neurogenetics of atypical parkinsonian disorders. Semin Neurol 2014;34(2):217-224. 3. Choumert A, Poisson A, Honnorat J, et al. G303V tau mutation presenting with progressive supranuclear palsy-like features. Mov Disord 2012;27(4):581-583. 4. Tremolizzo L, Bertola F, Casati G, Piperno A, Ferrarese C, Appollonio I. Progressive supranuclear palsy-like phenotype caused by progranulin p.Thr272fs mutation. Mov Disord 2011;26(10):1964-1966. 5. Le Ber I, Camuzat A, Guillot-Noel L, et al. C9ORF72 Repeat Expansions in the Frontotemporal Dementias Spectrum of Diseases: A Flow-chart for Genetic Testing. J Alzheimers Dis 2013;34(2):485- 499. 6. Caroppo P, Le Ber I, Clot F, et al. DCTN1 mutation analysis in families with progressive supranuclear palsy-like phenotypes. JAMA Neurol 2014;71(2):208-215. 70 50 Years of Progressive Supranuclear Palsy Is neurogenetics a useful research and diagnostic tool in PSP? Ulrich Müller Institute of Human Genetics Justus-Liebig-University Schlangenzahl 14 35392 Gießen Progressive supranuclear palsy (PSP) is mainly a sporadic movement disorder. Both genetic variants and environmental factors contribute to disease in the great majority of cases. In only a few families a monogenic etiology of PSP was observed; mode of inheritance was autosomal dominant. A positional cloning approach identified MAPT as “disease gene” in these rare families and several muations (R5L, ∆N296, G303V) have been described. MAPT also plays an important role in the common sporadic cases. Here a variant of MAPT functions as a predisposing genetic risk factor and not as the causative gene as in the few monogenic cases. It is the H1 haplotype of MAPT that increases risk for PSP. This haplotype is common in the general population and necessary but not sufficient for disease development. The H1 haplotype which is only found in Europeans originated from a ~900kb inversion of the MAPT region. The other (non-inverted) major haplotype is referred to as H2. Both the H1 and the H2 haplotype are further divided in several sub-haplotypes. Only sub-haplotype H1c with a frequency of less than 10% is associated with PSP. Conversely, the H2 haplotype is negatively associated with PSP and has a protective function. The predisposing role of the H1c haplotype appears to be mediated by one single nucleotide polymorphism (SNP) which is located in the 5´promoter region of MAPT. It is referred to as rs242557 (A/G). The risk allele (A) is associated with significantly increased transcription of MAPT and increased incorporation of the alternatively spliced exon 10 in the transcript. Exon 10 codes for one of the four microtubule- binding repeat domains and exclusion or inclusion result in the 3R-tau or 4R-tau isoform, respectively. It is likely that the H1c allele triggers the neurodegenerative process via a combined effect of increased MAPT transcription and alternative splicing favoring exon 10. This results in increased levels of the more fibrillogenic 4R-tau isoform and might be the molecular basis of the 4R-tau-dominant pathology characteristic of PSP. 71 A comprehensive genome-wide association study (GWAS) has identified additional gene variants that increase risk of PSP. This GWAS studied more than 1,100 pathology confirmed cases (exploratory cohort) in addition to a comparable number of clinically diagnosed cases (confirmatory cohort) and a total of more than 6,500 controls. This extensive international project was supported by the CurePSP+ Charles D. Peebler Jr. PSP and CBD Genetics Program. Significant previously unidentified signals (P < 5 × 10−8) were associated with PSP risk at STX6, EIF2AK3 and MOBP. These genes encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component. Although the nature of variation of these genes is currently not known, alterations in their expression are likely. These alterations render the brain more susceptible to yet ill-defined adverse environmental factors. In the case of aberrant expression of EIF2AK3 neurons of PSP patients might become more susceptible to cellular stress and damage. The GWAS also confirmed the predisposing role of the H1 haplotype of MAPT in PSP and identified an independent variant that influences MAPT brain expression. Epigenetic modifications constitute an additional layer of complexity of PSP pathogenesis. In a first attempt at identifying epigenetic changes we performed whole genome methylation analysis of DNA from forebrain of PSP patients and controls. Several genes were found to be hyper - or hypo- methylated in PSP as compared to controls. Both genetic and epigenetic analyses are likely to improve diagnosis of PSP and facilitate development of causative therapies. 72 50 Years of Progressive Supranuclear Palsy Is neurogenetics a useful research and diagnostic tool in PSP? Ulrich Müller 50 Years of Progressive Supranuclear Palsy Munich, October 10-11, 2014 Genetics of PSP (Scientific, diagnostic, and therapeutic relevance) Ulrich Müller Institute of Human Genetics Justus-Liebig University Giessen, Germany Progressive Supranuclear Palsy • Prevalence 4‐6/100,000 • Most cases sporadic • Complex etiology: Both genetic and environmental factors contribute to disease • <1% of cases monogenic Monogenic forms • Both autosomal dominant and recessive modes of inheritance • Linkage to chromosome 17 • Delineation of region harboring MAPT 73 50 Years of Progressive Supranuclear Palsy Is neurogenetics a useful research and diagnostic tool in PSP? Ulrich Müller MAPT mutations in monogenic forms of PSP Identification of 3 mutations in MAPT (R5L (AR) in exon1, ∆N296 (AR), and G303V (AD) in exon 10) in patients with characteristic phenotype Monogenic segregation of PSP AR AD del N296 G303V Silent MAPT S305S mutation • Pathogenic in several tauopathies (Frontotemporal dementia, PSP) • AD mode of inheritance • AGT > AGC transition in exon 10 • Increases splicing in of exon 10, results in overproduction of tau isoforms containing four repeats (4R) Stanford PM et al. (200): Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene: Expansion of the disease phenotype caused by tau gene mutations. Brain. 2000 May;123: 880‐93 Skoglund L et al. (2008) The tau S305S mutation causes frontotemporal dementia with parkinsonism. Eur J Neurol. 2008 Feb;15(2):156‐61. 74 50 Years of Progressive Supranuclear Palsy Is neurogenetics a useful research and diagnostic tool in PSP? Ulrich Müller MAPT plays major predisposing role in sporadic PSP • Structure of MAPT gene • Structure of tau protein • Predisposing variant H1 haplotype of MAPT is the major genetic risk factor in PSP and contributes up to 68% of the genetic risk Melquist et al., 2007 75 50 Years of Progressive Supranuclear Palsy Is neurogenetics a useful research and diagnostic tool in PSP? Ulrich Müller Subjects N H1 H2 H1/H1 H1/H2 H2/H2 OR 95%C.I. P‐value Controls 424 80.2 19.8 65.3 29.7 5.0 PSP 274 93.6 6.4 88.0 11.3 0.7 3.9 2.6‐5.9 <0.001 <0.001 H1 haplotype more common in PSP than in Controls (from Rademakers et al. (2005) Hum. Mol. Genet. 14: 3281 – 3291) GWAS to detect additional gene loci predisposing to PSP since H1c haplotype confers less than 2/3 of the genetic risk GWAS 76 50 Years of Progressive Supranuclear Palsy Is neurogenetics a useful research and diagnostic tool in PSP? Ulrich Müller Quality Control (QC) 1,163 3,658 autopsy-confirmed Controls PSP n=9 n=2 n=6 duplicate cases gender matching mismatch outliers n=23 n=1 related <98% genotype n=1 completion rate gender mismatch n=10 n=368 <98% genotype matching outliers completion rate 1,114 3,287 autopsy-confirmed Controls PSP GWAS identified three additional risk genes in PSP and confirmed importance of MAPT: Vesicle membrane fusion, Golgi- endosomes (p=2.3x10-10) Inhibits translation initiation upon accumulation of misfolded proteins in ER (ER-stress) (p=3.2x10-13) Abundant myelin constituent expressed exclusively in oligodendrocytes (p=1.0x10-16) 77 50 Years of Progressive Supranuclear Palsy Is neurogenetics a useful research and diagnostic tool in PSP? Ulrich Müller MAPT MAPT controlling for H1/H2 Association results for the relationship between SNP genotypes and mRNA transcripts MOBP MAPT MAPT controlling for H1/H2 EIF2AK3 Eukaryotic translation initiation factor 2‐alpha kinase 3 (PERK) UPR induces dimerization and transautophosphorylation of PERK phosphorylates translation‐initiation factor2 (eIF2α) inhibits global translation 78 50 Years of Progressive Supranuclear Palsy Is neurogenetics a useful research and diagnostic tool in PSP? Ulrich Müller PERK EIF2AK3 PERK eukaryotic translation initiation factor 2 alpha kinase Unfolded protein response From Imaizumi, 2006 STX6 Syntaxin 6 Involved in intracellular vesicle fusion and trafficking Part of SNARE (SNAP (Soluble NSF Attachment Protein) REceptor 79 50 Years of Progressive Supranuclear Palsy Is neurogenetics a useful research and diagnostic tool in PSP? Ulrich Müller Putative effect of gene variants discovered in GWAS • EIF2AK3: altered gene expression? • STX6: altered gene expression? • MAPT: H1/H2 inversion polymorphism: altered expression plus preferential use of exon 3 • MOBP: evidence of small effect on gene expression Epigenetic modification adds an additional layer of complexity to the pathogenesis of PSP Frontal cortex PSP 80 50 Years of Progressive Supranuclear Palsy Is neurogenetics a useful research and diagnostic tool in PSP? Ulrich Müller Epigenetic analysis at DNA level, investigation of cytosine methylation Bisulfite conversion of cytosine to uracil (thymine) 81 50 Years of Progressive Supranuclear Palsy Is neurogenetics a useful research and diagnostic tool in PSP? Ulrich Müller Differential methylation pattern in frontal lobe tissue of PSP patients PSP control n=94 vs. n=88 frontal lobe frontal lobe Infinium HumanMethylation450 BeadChip (Illumina) 485.577 potential methylation sites (CpG islands) in the promoter region of 99% of the RefSeq-genes Differential methylation pattern in frontal lobe tissue of PSP patients PSP control n=94 vs. n=88 frontal lobe frontal lobe after QC: 1.118 CpG-sites hypermethylated data of 366.030 methylation sites 530 CpG-sites hypomethylated t-Test Differential methylation pattern in frontal lobe tissue of PSP patients 1.118 CpG-sites hypermethylated 2 x SA 530 CpG-sites hypomethylated 82 50 Years of Progressive Supranuclear Palsy Is neurogenetics a useful research and diagnostic tool in PSP? Ulrich Müller Illumina‐450k‐Methylation Array (456.838 genomic markers on autosomes) 94 PSP Patients vs. 72 Controls (age & gender matched) methylation difference number of markers hypomethylated number of makers hypermethylated all 1.724 1.050 >0,5% 1.586 879 >1,0% 1.414 672 >2,0% 893 422 p<0.05 >5,0% 50 42 all 518 175 >0,5% 509 161 >1,0% 486 135 >2,0% 365 98 p<0.01 >5,0% 20 28 Conclusions: Relevance of genetic approaches to analysis of PSP Scientific: Unraveling of pathological mechanisms in PSP, improvement of understanding of tauopathies, explanation of aspects of neurodegeneration Diagnostic: Presently limited application. Epigenetic studies might help identify PSP- specific biomarkers Therapeutic: Discovery of predisposing genetic variants and of abnormally methylated genes supports development of causative therapies Thank you! Gießen: Axel Weber, Pia Winter München: Günter Höglinger, Hans Kretschmar Jacksonville: Dennis Dickson PSP Genetics Consortium Funding: CurePSP Foundation Peebler PSP Research Foundation 83 50 Years of Progressive Supranuclear Palsy Neurophysiology and PSP: recent advances Matteo Bologna Over the last decades neurophysiological studies allowed to investigate central nervous system dysfunction at multiple levels in progressive supranuclear palsy (PSP). Brainstem degeneration in PSP is reflected by the absent or reduced startle responses to acoustic and somesthesic stimulation and abnormalities of trigeminal reflexes. Transcranial magnetic stimulation highlighted an enhanced corticospinal excitability and reduced intracortical inhibition, probably related to cortical GABA-ergic interneuron degeneration. By contrast, short-latency afferent inhibition, a neurophysiological marker that reflects the excitability in intracortical cholinergic circuits is normal. More advanced transcranial magnetic stimulation techniques have also highlighted abnormally enhanced cortical synaptic plasticity in PSP, possibly due to a mechanism involving cortical GABA-ergic interneurons in primary motor cortex. Kinematic techniques allowed to investigate several oculomotor abnormalities reflecting the widespread degeneration in cortical, subcortical and brainstem areas. Finally kinematic analysis of finger movements demonstrated that bradykinesia in PSP differs from bradykinesia in PD. The relationships between these neurophysiological abnormalities and the major PSP symptoms is still unclear. Future studies should investigate patients in the early stages of disease, and follow-up abnormalities over the disease course. Given that most of the neurophysiological abnormalities present in PSP are also shared by patients with other atypical parkinsonian disorders, further effort is needed to define the specific neurophysiological changes in PSP. 84 “Neurophysiology and PSP: recent advances” Matteo Bologna 50 Years of Progressive Supranuclear Palsy Munich, Germany - October 11th, 2014 OVERVIEW • Neurophysiological techniques – Electrophysiology – Kinematic analysis / Movement studies • Neurophysiological abnormalities in PSP • Possible pathophysiological and clinical implications BRAINSTEM REFLEXES Startle reflex Trigeminal blink reflex Auditory tone, 124 dB, 1000 Hz, 50 ms, Cruccu & Deuschl 2000 Brown et al. 1991 Berardelli et al., 1998 85 Kinematic Analysis / Movement studies Infrarded cameras Reflective markers Finger tapping Experimental setting Blinking NEUROPHYSIOLOGICAL MEASURES: SUMMARY • Electrophysiological studies – BRAINSTEM REFLEXES • Startle reflex • Trigeminal blink reflex: R1, R2 latencies, R2 recovery cycle – EEG recordings/ Somatosensory Evoked Potentials (SEP) – Transcranial Magnetic Stimulation (TMS) • Corticospinal/intracortical excitability, connectivity measures • Plasticity mechanisms • Kinematic Analysis / Movement studies – Eye and eyelid movements – Finger tapping 86 OVERVIEW • Neurophysiological techniques – Electrophysiology – Kinematic analysis / Movement studies • Neurophysiological abnormalities in PSP • Possible pathophysiological and clinical implications STARTLE REFLEX IN PSP Healthy subjects PSP patients Brown et al. 1991 Vidailhet et al., 1991; Kofler 2000 TRIGEMINAL BLINK REFLEX IN PSP Supraorbital nerve stimulation R2 R1 NORMAL R1, R2 AND LATENCY Vidahilet et al. 1992 Valls-Solé et al. 1997 PROLONGED R2 LATENCY Sommer et al. 2001 ENHANCED R2 RECOVERY Valls-Solé et al. 1997 Sommer et al., 2001 Bologna et al. 2009 87 BASAL GANGLIA MODULATION OF TRIGEMINAL BLINK REFLEX CIRCUITS Basso & Evinger 1996 CORTICOSPINAL/INTRACORTICAL EXCITABILITY IN PSP • Measurements: central motor conduction time (CMCT), motor thresholds (MT), input-output recruitment curve (I/O MEP), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inibithion (SAI) • Major results: – CMCT is prolonged – I/O MEP curve are increased – SICI is reduced – ICF and SAI are normal Khun et al., 2004; Nardone et al. 2005; Morita et al. 2008 BASAL GANGLIA MODULATION OF CORTICAL CIRCUITS Wichmann et al, 2011 88 INTERHEMISPHERIC INHIBITION IN PSP • More severe reduction of intrehemispheric inhibition in RS patients as compared to PSP-P and PD • Significant correlation between reduction of intrehemispheric inhibition and Addenbrooke's cognitive examination Wittstock et al., 2013 PLASTICITY • Activity-dependent changes in the strength of the synaptic connection. • In animal experiments plasticity is quantified by measuring short- or long-term changes in post-synaptic responses after repetitive stimulation of pre-synaptic terminals (Cooke & Bliss, 2006), through the activation of the N-methyl-d-aspartate (NMDA) glutamatergic receptors (Collingridge et al., 1983; Cooke and Bliss, 2006). • In human TMS studies the term plasticity commonly refers to long-term changes in the amplitude of MEPs after applying protocols of repetitive TMS (rTMS) (Berardelli et al., 2008, Zieman et al., 2008). 89 CORTICAL PLASTICITY IN PARKINSONS’ DISEASE (Studies using Theta-Burst Stimulation - TBS) iTBS cTBS Abnormally increased NA NA Normal Huang et al., 2011 Kishore et al., 2012a* Kishore et al., 2012a* Huang et al., 2011 Zamir et al., 2012a Abnormally reduced Suppa et al. 2011 Eggers et al., 2010 Kishore et al., 2012a Kishore et al., 2012a Kishore et al., 2012b Kishore et al., 2012b *stable responders to L-dopa STUDIES ON CORTICAL PLASTICITY IN PARKINSONIAN SYNDROME • In PSP the facilitatory effect of iTBS is enhanced (Conte et al., 2012) • In contrast, in patients with PD and Multiple System Atrophy (MSA) TBS- induced after-effects are anromally reduced (Eggers et al., 2010; Suppa et al., 2011, 2013; Huang et al., 2011; Kishore et al., 2012) • PSP is pathologically characterized by neurofibrillary tangles emerging from tau protein deposition and prominent cortical and subcortical atrophy. Thus in PSP, exaggerated TBS responses might reflect a more prominent cortical degeneration, including loss of M1 inhibitory interneurons (Halliday et al., 2005; Hoover et al., 2010; Conte et al., 2012) • PD and MSA are pathologically characterized by deposition of alpha- synuclein (a-SYN) in cortical and subcortical brain regions, including M1 (Su et al., 2001; Ahmed et al., 2012). Given that a-SYN plays a crucial role in regulating neurotransmission and synaptic plasticity, its deposition might contribute to impaired synaptic plasticity in both PD and MSA (Cabin et al., 2002) 90 THE ROLE OF THE CEREBELLUM IN THE PATHOPHYSIOLOGY OF PSP • Clinico-pathological studies • Neurophysiology - reduced eyeblink classical conditioning - reduced cerebellar-brain inhibition CEREBELLAR INVOLVEMENT IN PSP: A CLINICOPATHOLOGICAL STUDY • Cerebellar ataxia as the initial and principal symptom • Neuronal loss with gliosis (A) and higher densities of coiled bodies (B) in the cerebellar dentate nucleus and cortex Kanazawa et al. 2009 EYE-BLINK CONDITIONING Supraorbital nerve Supraorbital nerve electrical stimulation electrical stimulation Auditory tone Auditory tone 400 ms 400 ms α blink α blink Conditioned response 91 EYE-BLINK CONDITIONING IN PSP Sommer e coll., 2001 CEREBELLAR DYSFUNCTION IN PROGRESSIVE SUPRANUCLEAR PALSY: A TRANSCRANIAL MAGNETIC STIMULATION STUDY • Cerebellar function was evaluated using suppressive effects of TMS over the cerebellum on MEPs elicited by TMS over the contralateral motor cortex, i.e. cerebellar inhibition (CBI) • The CBI was reduced in PSP patients suggesting that Purkinje cells or the dentato-thalamo-cortical pathway assessed by CBI is involved in PSP • The results are compatible with the pathological findings showing severe dentate nucleus degeneration in PSP patients Shirota et al., 2010 OCULOMOTOR ABNORMALITIES IN PSP Early stages • Slow vertical saccadic movements • Hypometric saccades • Reduced blinking • Square-wave jerks Middle stages • Supranuclear vertical gaze palsy • Lid retraction with very rare blinking (<3) • Impaired convergence • Apraxia of eyelid opening or closing Late stages • Supranuclear horizontal gaze palsy • Loss of oculocephalic reflexes • Blepharospasm Bhidayasiri et al. 2001; Garbutt et al., 2009 • Disconjugate gaze Modified from Golbe LI. Progressive supranuclear palsy. In: Neurodegenerative diseases. Edited by M. Flint Beal, A.E. Lang and A. Ludolph. Cambridge University Press, 663-681 (2005) 92 SPONTANEOUS BLINK RATE Healthy subjects (~ 20 blinks/min) PSP (1-5 blinks/min) Karson et al., 1984; Bologna et al. 2009 Healthy controls PSP patients • Voluntary, spontaneous and reflex blinking all show abnormal kinematic parameters in patients with PSP • Abnormal voluntary, spontaneous and reflex blinking in patients with PSP reflects the widespread cortical, subcortical and brainstem degeneration related to this disease Healthy controls PSP patients Abnormal switching between the closing and opening phase during voluntary blinking: -altered basal ganglia function? -altered cortical motor areas activity? 93 Healthy controls Opening phase abnormalities during PSP patients reflex blinking: midbrain degeneration? Periacqueductal Grey Nucleus Centralis Caudalis Levator Palpebrae Superioris Graber and Straudinger 1997 Schmidtke Bϋttner-Ennever 1992 PD patients PSP patients • Repetitive finger tapping is commonly used to assess bradykinesia, i.e. 'slowness of initiation with progressive reduction in speed and amplitude of repetitive action‘ in Parkinson's disease. • Patients with progressive supranuclear palsy have a specific finger tap pattern of 'hypokinesia without decrement'. 94 OVERVIEW • Neurophysiological techniques – Electrophysiology – Kinematic analysis / Movement studies • Neurophysiological abnormalities in PSP • Possible pathophysiological and clinical implications PATHOPYSIOLOGICAL & CLINICAL IMPLICATIONS • Comprehension of the pathophysiological basis od sign and symptoms • Improve diagnostic accuracy • Enable differential diagnosis • Individuate biomarkers of disease progression • Objective assessment of novel therapeutic strategies DRAWBACKS • Limited sample size /clinical hetereogeneity of PSP • Limited number of longitudinal studies • Lack of pathological follow up • Selection bias / low diagnostic accuracy of clinical criteria 95 CONCLUSIONS • The relationships between these neurophysiological abnormalities and the PSP symptoms is still unclear • Future studies should investigate patients in the early stages of disease, and follow-up abnormalities over the disease course • Given that most of the neurophysiological abnormalities present in PSP are also shared by patients with other atypical parkinsonian disorders, further effort is needed to define the specific neurophysiological changes in PSP ACKNOWLEDGEMENTS Antonella Conte Daniele Belvisi Giovanni Fabbrini Carlo Colosimo & Alfredo Berardelli 96 50 Years of Progressive Supranuclear Palsy Health-Related Quality of Life in Patients with PSP Richard Dodel Department of Neurology, Philipps-University Marburg, Germany Starting in the 1980s there has been an increasing apprehension that traditional clinical end‐ points such as morbidity and mortality alone do not sufficiently reflect the complexitiy of outcomes of medical interventions (1). Additional concepts, called patient‐reported outcomes (PRO), have been introduced to allow insight into patients’ experiences in different areas of function. A large variety of areas, which may be differently affected, have been identified such as mobility, life satisfaction, sexuality, cognition, mood and the ability to fulfil occupational, social, and family roles in daily life. Among PROs, the concept of Quality of life (QoL) has emerged as a broad term to describe those domains of evaluation. This approach is a paradigm shift since it changes the focus of attention from physicians’ (objective) evaluation of symptoms to functioning and establishes the patients’ (subjective) perspective. A large number of QoL life scales and health status measurements are available, generic scales but also disease‐specific scales, which can be used over a range of diseases or can individually evaluate the major domains affected by a certain disease, respectively. The Movement Disorder Society has recently evaluated the available health status measurements and scales for patients with Parkinson’s disease (2, 3). For patients with progressive supranuclear palsy only a few studies have been performed to evaluate health‐related quality of life (4‐9). Nevertheless, Schrag and coworkers have developed a disease‐specific scale for its use in patients with PSP. Unfortunately, not many clinical trials have included this scale, yet(10). The following scales have been used in patients with PSP to evaluate health status of those patients: the EQ‐5D including the EQ‐VAS, the QOLAS (a generic, patient‐driven approach to QoL assessment), the Medical Outcomes Study Short Form Health Survey (SF‐36), the disease‐specific QoL instrument for patients with Parkinson’s disease (PD; PDQ‐39), the Parkinson’s Disease Questionnaire (PDQ)‐8. Independently of the scales used, all studies showed a decreased quality of life in patients with PSP. Quality of life was also more affected compared to idiopathic Parkinson’s disease and age‐adjusted normal population, but similar to other atypical Parkinsonian syndromes. The most impaired domains were mobility, activities of daily living and anxiety; determinants of HrQoL were disease severity, depression, dementia. 97 No data of large longitudinal studies on health‐related quality of life in patients with PSP are currently available. Thus, our understanding of domains affected from a patients’ perspective is limited. In addition, further aspects of quality of life beyond the disease‐related domains such as social functioning, religion, etc. have not been evaluated in this group of patients. References: 1. Felce D, Perry J. Quality of life: its definition and measurement. Res Dev Disabil 1995; 16:51‐74. 2. Dodel R, Jonsson B, Reese JP, Winter Y, Martinez‐Martin P, Holloway R, Sampaio C, Ruzicka E, Hawthorne G, Oertel W, Poewe W, Stebbins G, Rascol O, Goetz CG, Schrag A. Measurement of costs and scales for outcome evaluation in health economic studies of Parkinson's disease. Mov Disord 2014; 29:169‐176. 3. Martinez‐Martin P, Jeukens‐Visser M, Lyons KE, Rodriguez‐Blazquez C, Selai C, Siderowf A, Welsh M, Poewe W, Rascol O, Sampaio C, Stebbins GT, Goetz CG, Schrag A. Health‐related quality‐of‐life scales in Parkinson's disease: critique and recommendations. Mov Disord 2011; 26:2371‐2380. 4. Schrag A, Selai C, Davis J, Lees AJ, Jahanshahi M, Quinn N. Health‐related quality of life in patients with progressive supranuclear palsy. Mov Disord 2003; 18:1464‐1469. 5. Schrag A, Selai C, Quinn N, Hobart J. Measuring health‐related quality of life in patients with progressive supranuclear palsy. Neurocase 2005; 11:246‐249. 6. Schrag A, Sheikh S, Quinn NP, Lees AJ, Selai C, Mathias C, Litvan I, Lang AE, Bower JH, Burn DJ, Low P, Jahanshahi M. A comparison of depression, anxiety, and health status in patients with progressive supranuclear palsy and multiple system atrophy. Mov Disord 2010; 25:1077‐1081. 7. Winter Y, Spottke AE, Stamelou M, Cabanel N, Eggert K, Hoglinger GU, Sixel‐Doering F, Herting B, Klockgether T, Reichmann H, Oertel WH, Dodel R. Health‐related quality of life in multiple system atrophy and progressive supranuclear palsy. Neurodegener Dis 2011; 8:438‐446. 8. Winter Y, Stamelou M, Cabanel N, Sixel‐Doring F, Eggert K, Hoglinger GU, Herting B, Klockgether T, Reichmann H, Oertel WH, Dodel R, Spottke AE. Cost‐of‐illness in multiple system atrophy and progressive supranuclear palsy. J Neurol 2011; 258:1827‐1834. 9. Higginson IJ, Gao W, Saleem TZ, Chaudhuri KR, Burman R, McCrone P, Leigh PN. Symptoms and quality of life in late stage Parkinson syndromes: a longitudinal community study of predictive factors. PLoS One 2012; 7:e46327. 10. Schrag A, Selai C, Quinn N, Lees A, Litvan I, Lang A, Poon Y, Bower J, Burn D, Hobart J. Measuring quality of life in PSP: the PSP‐QoL. Neurology 2006; 67:39‐44. 98 50 Years of Progressive Supranuclear Palsy NINDS-SPSP Criteria: Why do we need to update them? Günter U. Höglinger Prof. Dr. Günter U. Höglinger, Dept. of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), München, Max Lebsche Platz 30, D-81677 Munich, Germany. Phone: +49-89-7095-8406, [email protected]. In 1996, the National Institute of Neurological Disorders and Stroke and the Society for PSP (NINDS- SPSP) criteria have been proposed for the clinical diagnosis of PSP, based on the analysis of clinical features of a case mix of patients with pathologically confirmed forms of parkinsonism1. Briefly, the NINDS-SPSP criteria rely on the identification of a progressive disorder with onset after the 40th yr. of life combining the two cardinal features, i.e. postural instability with falls during the first year of the disease and slow vertical saccades or supranuclear gaze palsy. A list of exclusion criteria aims to sort out look-alike disorders. Two sets of the NINDS-SPSP criteria have been proposed to achieve different levels of diagnostic certainty: 'clinically probable PSP' criteria aimed at high specificity, accepting compromised sensitivity, to identify patients for research purposes; 'clinically possible PSP' criteria aimed at high sensitivity, accepting compromised specificity, to identify patients for medical care1. Diagnostic gold standard for 'definite PSP' is the post mortem neuropathological diagnosis2. Validation of these criteria in an independent set of patients demonstrated a high positive predictive value (PPV) for both NINDS-SPSP ‘possible’ and ‘probable’ criteria, albeit low sensitivity, particularly during the early course of the disease3. We analyzed 98 Progressive Supranuclear Palsy patients and 46 disease controls. The NINDS-SPSP ‘probable’ criteria yielded shorter time to diagnosis, slightly higher specificity and positive predictive value, and similar sensitivity compared to the NNIPPS criteria. Unexpectedly, the NINDS-SPSP ‘possible’ criteria yielded the lowest sensitivity, specificity and positive predictive value. A combination of NINDS-SPSP ‘possible’ and ‘probable’ criteria yielded the highest sensitivity. Patients with clinical manifestations other than Richardson`s syndrome fulfilled the NINDS or NNIPPS diagnostic criteria at significantly lower frequency and were diagnosed as PSP after longer disease duration. 3 These data demonstrate that the NINDS-SPSP criteria are highly specific for PSP. Their sensitivity for Richardson`s syndrome is low in the first three years and acceptable during the later course. Sensitivity for other clinical manifestations (e.g. PSP-P, PSP-FTD, PSP-PAGF) are very low throughout the course of the disease. Therefore, the MDS-endorsed PSP study group aims to revise these criteria, aiming to 99 improve sensitivity in the early clinical course for typical and atypical manifestations, without compromising specificity. References 1. Litvan I, Jankovic J, et al. Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). Neurology 1996;46:922-930. 2. Hauw JJ, Daniel SE, Dickson D et al. Preliminary NINDS neuropathologic criteria for Steele- Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology 1994;44:2015. 3. Osaki Y, Ben-Shlomo Y, Lees AJ et al. Accuracy of clinical diagnosis of progressive supranuclear palsy. Movement Disorders 2004;19 :181–189. 4. Respondek G, Roeber S, Kretzschmar H, et al. Accuracy of the National Institute for Neurological Disorders and Stroke/Society for Progressive Supranuclear Palsy and neuroprotection and natural history in Parkinson plus syndromes criteria for the diagnosis of progressive supranuclear palsy. Mov Disord 2013;28:504-9. 100