Direct Current Stimulation of Prefrontal Cortex Is Not Effective in Progressive Supranuclear Palsy: A Randomized Trial.

BACKGROUND: Progressive supranuclear palsy (PSP) is a rare 4R-tauopathy. Transcranial direct current stimulation (tDCS) may improve specific symptoms. OBJECTIVES: This randomized, double-blinded, sham-controlled trial aimed at verifying the short-, mid-, and long-term effect of multiple sessions of anodal tDCS over the left dorsolateral prefrontal cortex (DLPFC) cortex in PSP. METHODS: Twenty-five patients were randomly assigned to active or sham stimulation (2 mA for 20 minute) for 5 days/week for 2 weeks. Participants underwent assessments at baseline, after the 2-week stimulation protocol, then after 45 days and 3 months from baseline. Primary outcomes were verbal and semantic fluency. The efficacy was verified with analysis of covariance. RESULTS: We failed to detect a significant effect of active stimulation on primary outcomes. Stimulation was associated to worsening of specific behavioral complaints. CONCLUSIONS: A 2-week protocol of anodal left DLPFC tDCS is not effective in PSP. Specific challenges in running symptomatic clinical trials with classic design are highlighted. © 2024 International Parkinson and Movement Disorder Society.

Progressive supranuclear palsy: current approach and challenges to diagnosis and treatment.

PURPOSE OF REVIEW: Since the original description of progressive supranuclear palsy (PSP) by Steele, Richardson and Olszewski, the clinical spectrum of PSP has expanded and now includes multiple phenotypic variants linked by a common disease. In this review, we discuss the evolution of the PSP syndrome and clinical criteria, with a particular focus on the 2017 Movement Disorders Society PSP criteria, its application and limitations. We also discuss our current approach to diagnosis and treatment. RECENT FINDINGS: There is a significant overlap between the different variants of PSP and multiple phenotypes that may be applied to the same patient simultaneously. Variant severity and predominance also evolve throughout the course of the disease. Each variant and level of certainty is associated with different specificity and sensitivity for underlying disease. The differential diagnosis of PSP is continuously evolving and includes other tauopathies, neurodegenerative, genetic, autoimmune and infectious disorders. MRI measurements can aid in the diagnosis. The first guidelines to help with clinical management of those patients have been recently published. SUMMARY: Although much improved, clinical PSP criteria alone remain insufficient and emphasize the need for improved biomarkers to identify patients at early stages to direct appropriate therapeutic strategies and target potential research.

[Tauopathy, motricity and cognition]. / Tauopathies, motricité et cognition.

The tauopathies are one of the families of proteinopathies causing neurodegenerative diseases. They are characterized by a combination of cognitive and motor disorders. In this article, we summarize the clinical features of progressive supranuclear palsy and cortico-basal degeneration, focusing on their cognitive-behavioral impairment profiles, which in some cases allow them to be differentiated from other neurodegenerative entities. Finally, we propose tools for therapeutic management.

Les tauopathies sont une des familles de protéinopathies engendrant des maladies neurodégénératives. Elles se caractérisent par l'association de troubles cognitifs et moteurs. Dans cet article, nous résumons les caractéristiques cliniques de la paralysie supranucléaire progressive et de la dégénérescence cortico-basale, en nous attardant sur leurs profils d'atteinte cognitivo-comportementale, qui permettent, dans certains cas, de les différencier d'autres entités neurodégénératives. Enfin, nous proposons des outils de prise en charge thérapeutique.

Cerebellar rTMS in PSP: a Double-Blind Sham-Controlled Study Using Mobile Health Technology.

There are no effective treatments in progressive supranuclear palsy (PSP). The aim of this study was to test the efficacy of theta burst repetitive transcranial magnetic stimulation (rTMS) on postural instability in PSP. Twenty PSP patients underwent a session of sham or real cerebellar rTMS in a crossover design. Before and after stimulation, static balance was evaluated with instrumented (lower back accelerometer, Rehagait®, Hasomed, Germany) 30-s trials in semitandem and tandem positions. In tandem and semitandem tasks, active stimulation was associated with increase in time without falls (both p=0.04). In the same tasks, device-extracted parameters revealed significant improvement in area (p=0.007), velocity (p=0.005), acceleration and jerkiness of sway (p=0.008) in real versus sham stimulation. Cerebellar rTMS showed a significant effect on stability in PSP patients, when assessed with mobile digital technology, in a double-blind design. These results should motivate larger and longer trials using non-invasive brain stimulation for PSP patients.

Progressive supranuclear palsy: diagnosis and management.

Treating patients with progressive supranuclear palsy (PSP) is both effective and rewarding. This review aims to share our experience in the proactive management of PSP, considering the patient, the family and the medical context in which the illness unfolds. There are many opportunities to assist your patients, ameliorate their symptoms, reduce their risks and harm, and guide them through the complex medical, social and legal minefield that characterises life with chronic neurological illness. We summarise the challenges of early diagnosis, consider PSP mimics and the role of investigations in excluding these, and discuss the available pharmacological and non-pharmacological treatment strategies to tackle the common and challenging symptoms of PSP. The best treatment will be patient centred and as part of a multidisciplinary team.

Exercise and physical activity for people with Progressive Supranuclear Palsy: a systematic review.

OBJECTIVE: To conduct a systematic review to evaluate exercise and structured physical activity for people living with Progressive Supranuclear Palsy. DATA SOURCES: AMED, CINAHL, Cochrane, EMBASE, Informit, MEDLINE, PEDro, PsycINFO, PubMed and SportDiscus were searched until 18 August 2019. Reference lists of included studies were hand-searched. METHODS: Cochrane guidelines informed review methods. English language peer-reviewed studies of any design, in any setting, were included. Method quality was appraised with the Physiotherapy Evidence Database scale and Joanna Briggs Institute instruments. Data were extracted for study design, sample characteristics and therapy content. Effectiveness was calculated where possible. RESULTS: Eleven studies were included. Method appraisal showed moderate to high risk of bias. Research designs included three randomized controlled trials, two quasi-experimental studies, one cohort study, four case studies and one case series. Sample sizes ranged from 1 to 24. Exercise interventions included supported and robot-assisted gait training, gaze training, balance re-education and auditory-cued motor training. Dosage ranged from two to five sessions per week over four to eight weeks. End-of-intervention effect sizes were small (6-minute walk test: -0.07; 95% confidence interval (CI): -0.87, 0.73) to moderate (balance: -0.61; 95% CI: -1.40, 0.23; Timed Up and Go: 0.42; 95% CI: -0.49, 1.33) and statistically non-significant. Function, quality of life and adverse events were inconsistently reported. CONCLUSIONS: For people with Progressive Supranuclear Palsy, robust evidence was not found for therapeutic exercises. Reported improvements in walking were derived from two clinical trials. The effects of structured physical activity for people with advanced Progressive Supranuclear Palsy are not known.

The Progressive Supranuclear Palsy: Past and Present Aspects.

Objectives: Recently, new criteria for sensitive and specific clinical diagnosis of progressive supranuclear palsy (PSP) have been addressed while distinct clinical phenotypes of the disorder have been increasingly described in the literature. This study aimed to describe past and present aspects of the disease as well as to highlight the cognitive and behavioral profile of PSP patients in relation to the underlying pathology, genetics and treatment procedures.Methods: A Medline and Scopus search was performed to identify articles published on this topic. Articles published solely in English were considered.Results: The most common clinical characteristics of PSP included early postural instability and falls, vertical supranuclear gaze palsy, parkinsonism with poor response to levodopa and pseudobulbar palsy. Frontal dysfunction and verbal fluency deficits were the most distinct cognitive impairments in PSP while memory, visuospatial and social cognition could also be affected. Apathy and impulsivity were also present in PSP patients and had significant impact on relatives and caregivers.Conclusions: PSP is a neurodegenerative disorder with prominent tau neuropathology. Movement, motivation and communication impairments in patients with PSP may limit participation in everyday living activities. Comprehensive neuropsychological assessments are of significant importance for PSP cognitive evaluation. Pharmacologic and non-pharmacologic approaches could be applied in order to relieve patients and improve quality of life.Clinical Implications: Executive dysfunction is the most notable cognitive impairment and dominates the neuropsychological profile of patients with PSP.

Therapeutic trial design for frontotemporal dementia and related disorders.

The frontotemporal dementia (FTD) spectrum is a heterogeneous group of neurodegenerative syndromes with overlapping clinical, molecular and pathological features, all of which challenge the design of clinical trials in these conditions. To date, no pharmacological interventions have been proven effective in significantly modifying the course of these disorders. This study critically reviews the construct and methodology of previously published randomised controlled trials (RCTs) in FTD spectrum disorders in order to identify limitations and potential reasons for negative results. Moreover, recommendations based on the identified gaps are elaborated in order to guide future clinical trial design. A systematic literature review was carried out and presented in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. A total of 23 RCTs in cohorts with diagnoses of behavioural and language variants of FTD, corticobasal syndrome and progressive supranuclear palsy syndrome were identified out of the 943 citations retrieved and were included in the qualitative review. Most studies identified were early-phase clinical trials that were small in size, short in duration and frequently underpowered. Diagnoses of populations enrolled in clinical trials were based on clinical presentation and rarely included precision-medicine tools, such as genetic and molecular testing. Uniformity and standardisation of research outcomes in the FTD spectrum are essential. Several elements should be carefully considered and planned in future clinical trials. We anticipate that precision-medicine approaches will be crucial to adequately address heterogeneity in the FTD spectrum research.

One decade ago, one decade ahead in progressive supranuclear palsy.

Fifty-five years have passed from the first description of PSP, but it is in the last decade that there has been a revolutionary change in understanding both clinical and pathophysiological aspects of this disease. Ten years ago, our knowledge about the clinical spectrum and pathophysiology of the disease was quite limited, and there was no credible clinical study on any drug treatment for this devastating disease. Today, we have discovered the wide clinical spectrum of PSP, and this led to the development of new diagnostic criteria in 2017, aiming to diagnose the disease earlier and include more phenotypes into clinical studies. Moreover, just over the past 10 years, numerous large, double-blind, clinical trials with disease-modifying agents have been conducted that provided important novel insights into disease biomarkers and progression. These studies were possible because of gained novel insights into pathophysiological processes of the disease and pave the way for the near future. In the next decade, we dare to predict the discovery of biomarkers for PSP, improvements in diagnosis using the new criteria in combination with these biomarkers, and ultimately the development of a neuroprotective therapy that could be applied to patients in a prodromal stage and spare them from this devastating disorder. © 2019 International Parkinson and Movement Disorder Society.

Exercise and Progressive Supranuclear Palsy: the need for explicit exercise reporting.

BACKGROUND: Progressive Supranuclear Palsy (PSP) is the most frequent form of atypical Parkinsonism. Although there is preliminary evidence for the benefits of gait rehabilitation, balance training and oculomotor exercises in PSP, the quality of reporting of exercise therapies appears mixed. The current investigation aims to evaluate the comprehensiveness of reporting of exercise and physical activity interventions in the PSP literature. METHODS: Two independent reviewers used the Consensus on Exercise Reporting Template (CERT) to extract all exercise intervention data from 11 studies included in a systematic review. CERT items covered: 'what' (materials), 'who' (instructor qualifications), 'how' (delivery), 'where' (location), 'when', 'how much' (dosage), 'tailoring' (what, how), and 'how well' (fidelity) exercise delivery complied with the protocol. Each exercise item was scored '1' (adequately reported) or '0' (not adequately reported or unclear). The CERT score was calculated, as well as the percentage of studies that reported each CERT item. RESULTS: The CERT scores ranged from 3 to 12 out of 19. No PSP studies adequately described exercise elements that would allow exact replication of the interventions. Well-described items included exercise equipment, exercise settings, exercise therapy scheduling, frequency and duration. Poorly described items included decision rules for exercise progression, instructor qualifications, exercise adherence, motivation strategies, safety and adverse events associated with exercise therapies. DISCUSSION: The results revealed variability in the reporting of physical therapies for people living with PSP. Future exercise trials need to more comprehensively describe equipment, instructor qualifications, exercise and physical activity type, dosage, setting, individual tailoring of exercises, supervision, adherence, motivation strategies, progression decisions, safety and adverse events. CONCLUSION: Although beneficial for people living with PSP, exercise and physical therapy interventions have been inadequately reported. It is recommended that evidence-based reporting templates be utilised to comprehensively document therapeutic exercise design, delivery and evaluation.

Progressive supranuclear palsy and multiple system atrophy: clinicopathological concepts and therapeutic challenges.

PURPOSE OF REVIEW: This update discusses novel aspects on clinicopathological concepts and therapeutic challenges in progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), arising from publications of the last 1.5 years. RECENT FINDINGS: The clinical criteria for diagnosis of PSP have been revised. Clinical variability of pathologically defined PSP and MSA makes the development of mature biomarkers for early diagnosis and biomarker-based trial design indispensable. Novel molecular techniques for biomarker supported diagnosis of PSP and MSA and for monitoring disease progression are being studied. Research in the pathophysiology of both diseases generates gradual progress in the understanding of the underlying processes. Several promising disease-modifying therapeutic approaches for PSP and MSA are now moving into clinical trials. SUMMARY: Recent research generates insights in the pathophysiological relevant processes and raises hope for earlier clinical diagnosis and disease-modifying therapies of patients with PSP and MSA.

Progressive Supranuclear Palsy: an Update.

PURPOSE OF REVIEW: Progressive supranuclear palsy (PSP) is a 4R tau neuropathologic entity. While historically defined by the presence of a vertical supranuclear gaze palsy and falls in the first symptomatic year, clinicopathologic studies identify alternate presenting phenotypes. This article reviews the new PSP diagnostic criteria, diagnostic approaches, and treatment strategies. RECENT FINDINGS: The 2017 International Parkinson and Movement Disorder Society PSP criteria outline 14 core clinical features and 4 clinical clues that combine to diagnose one of eight PSP phenotypes with probable, possible, or suggestive certainty. Evidence supports the use of select imaging approaches in the classic PSP-Richardson syndrome phenotype. Recent trials of putative disease-modifying agents showed no benefit. The new PSP diagnostic criteria incorporating the range of presenting phenotypes have important implications for diagnosis and research. More work is needed to understand how diagnostic evaluations inform phenotype assessment and identify expected progression. Current treatment is symptomatic, but tau-based therapeutics are in active clinical trials.

A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction.

Mutations in the gene encoding tau (MAPT) cause frontotemporal dementia spectrum disorders. A rare tau variant p.A152T was reported as a risk factor for frontotemporal dementia spectrum and Alzheimer's disease in an initial case-control study. Such findings need replication in an independent cohort. We analysed an independent multinational cohort comprising 3100 patients with neurodegenerative disease and 4351 healthy control subjects and found p.A152T associated with significantly higher risk for clinically defined frontotemporal dementia and progressive supranuclear palsy syndrome. To assess the functional and biochemical consequences of this variant, we generated transgenic zebrafish models expressing wild-type or A152T-tau, where A152T caused neurodegeneration and proteasome compromise. Impaired proteasome activity may also enhance accumulation of other proteins associated with this variant. We increased A152T clearance kinetics by both pharmacological and genetic upregulation of autophagy and ameliorated the disease pathology observed in A152T-tau fish. Thus, autophagy-upregulating therapies may be a strategy for the treatment for tauopathies.

Recognizing Atypical Parkinsonisms: "Red Flags" and Therapeutic Approaches.

The overlap of signs and symptoms between Parkinson's disease and the atypical parkinsonian syndromes, such as progressive supranuclear palsy, multiple system atrophy, corticobasal syndrome and dementia with Lewy bodies, can render clinical diagnoses challenging. The continued evolution of diagnostic criteria to reflect the increasingly recognized heterogeneous presentations of these diseases further complicates timely recognition and diagnosis. In this review, we provide a diagnostic approach to the classic atypical parkinsonian syndromes, with an emphasis on the key clinical and pathological features of each and the recognition of "red flags" in the setting of recent advances in diagnosis and treatment.

Progressive Supranuclear Palsy - A Case Study from the Perspective of a Primary Care Physician Son.

Progressive Supranuclear Palsy (PSP) is a rare geriatric pathology, from the abnormal deposition of the tau protein, combining the motor tremor and bradykinesia of Parkinson's disease with the cognitive defects of Alzheimer's disease. As physical and mental debilities progressively manifest in PSP, the physician, family, and patient face decisions on how to manage this terminal neurodegenerative disease. Physicians note the outcomes of decisions and often express, either to peers or internally to oneself, how they would handle a similar situation affecting their own family. In this case, we will explore PSP and examine a physician's perspective as his father navigates his journey through it.

Finding a new therapeutic approach for no-option Parkinsonisms: mesenchymal stromal cells for progressive supranuclear palsy.

BACKGROUND: The trophic, anti-apoptotic and regenerative effects of bone marrow mesenchymal stromal cells (MSC) may reduce neuronal cell loss in neurodegenerative disorders. METHODS: We used MSC as a novel candidate therapeutic tool in a pilot phase-I study for patients affected by progressive supranuclear palsy (PSP), a rare, severe and no-option form of Parkinsonism. Five patients received the cells by infusion into the cerebral arteries. Effects were assessed using the best available motor function rating scales (UPDRS, Hoehn and Yahr, PSP rating scale), as well as neuropsychological assessments, gait analysis and brain imaging before and after cell administration. RESULTS: One year after cell infusion, all treated patients were alive, except one, who died 9 months after the infusion for reasons not related to cell administration or to disease progression (accidental fall). In all treated patients motor function rating scales remained stable for at least six-months during the one-year follow-up. CONCLUSIONS: We have demonstrated for the first time that MSC administration is feasible in subjects with PSP. In these patients, in whom deterioration of motor function is invariably rapid, we recorded clinical stabilization for at least 6 months. These encouraging results pave the way to the next randomized, placebo-controlled phase-II study that will definitively provide information on the efficacy of this innovative approach. Trial registration ClinicalTrials.gov NCT01824121.

Progressive supranuclear palsy (PSP): Richardson syndrome and other PSP variants.

Phenotypic heterogeneity of progressive supranuclear palsy (PSP) has been increasingly reported in the literature and can be the source of incorrect clinical diagnosis particularly in the early stages of the disease when the classically associated symptoms of early falls and supranuclear gaze palsy may not be apparent. In addition to Richardson syndrome (RS), several atypical clinical phenotypes have been described. Advances in genetic, neuroimaging, and biochemical/molecular technologies contribute to the identification of these clinical subtypes in the context of typical PSP pathological findings. Our goal is to review the phenomenology reported in the literature that is associated with confirmed histopathological changes consistent with a PSP diagnosis and to highlight the clinical spectrum of PSP. A systematic review of the literature in PubMed through July 2015 using MeSH terms and key words related to PSP was conducted. Articles describing PSP classifications, diagnostic criteria, and case reports were reviewed and summarized. Additional PSP phenotypes not seen in recent clinicopathological studies are included. These include primary lateral sclerosis, pallido-nigro-luysian degeneration, axonal dystrophy, and multiple system atrophy in the spectrum of atypical PSP variants beyond the traditionally classified PSP subtypes. This review is intended to help with the diagnostic challenges of atypical PSP variants. We believe that large multicenter clinicopathological studies will help expand our understanding of etiology and specific mechanisms of neurodegeneration and will aid in the appropriate interpretation of outcomes when conducting clinical and basic science research.

Progressive supranuclear palsy and corticobasal degeneration: Diagnostic challenges and clinicopathological considerations.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are two atypical parkinsonian syndromes first described half a century ago. The spectrum of these conditions as well as, more generally, the concept of tauopathy have dramatically changed over the past decade and especially in recent years. In particular, clinicopathological correlations have led to the description of several subtypes of these diseases and the features they share with other neurodegenerative diseases. The present paper is a review of how the concepts of PSP and CBD have evolved over time. In particular, it focuses on the different presentations of the disease and the overlapping syndromes that can complicate the differential diagnoses. Also discussed are some of the tools that may prove useful in making a diagnosis. Indeed, differential diagnosis issues are of particular importance in light of the likely emergence of pathology-specific disease-modifying therapies in the near future.

Therapeutic advances in multiple system atrophy and progressive supranuclear palsy.

Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are relentlessly progressive neurodegenerative diseases leading to severe disability and ultimately death within less than 10 y. Despite increasing efforts in basic and clinical research, effective therapies for these atypical parkinsonian disorders are lacking. Although earlier small clinical studies in MSA and PSP mainly focused on symptomatic treatment, advances in the understanding of the molecular underpinnings of these diseases and in the search for biomarkers have paved the way for the first large and well-designed clinical trials aiming at disease modification. Targets of intervention in these trials have included α-synuclein inclusion pathology in the case of MSA and tau-related mechanisms in PSP. Since 2013, four large randomized, placebo-controlled, double-blind disease-modification trials have been completed and published, using rasagiline (MSA), rifampicin (MSA), tideglusib (PSP), or davunetide (PSP). All of these failed to demonstrate signal efficacy with regard to the primary outcome measures. In addition, two randomized, placebo-controlled, double-blind trials have studied the efficacy of droxidopa in the symptomatic treatment of neurogenic orthostatic hypotension, including patients with MSA, with positive results in one trial. This review summarizes the design and the outcomes of these and other smaller trials published since 2013 and attempts to highlight priority areas of future therapeutic research in MSA and PSP. © 2015 International Parkinson and Movement Disorder Society.

Bilateral pedunculopontine nucleus stimulation for progressive supranuclear palsy.

The pedunculopontine nucleus (PPN) is a potential target for gait disorders. We report 4 cases of bilateral PPN stimulation in progressive supranuclear palsy (PSP) patients with short-term (6 months) and long-term (18 months) follow-ups. Patients with PSP who had gait disturbances, but were able to walk with or without assistance, were selected. The patients' median age was 64 years and the disease duration 3 years. Bilateral PPN deep brain stimulation (DBS) was performed. The pacemaker was programmed using a bipolar mode and lower frequencies (20-45 Hz). The PSP rating scores (PSPRS) and their gait subscores (No. 25, 26, 27 and 28) along with PSP staging scores were used as primary end points. The total Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS III and the 39-item Parkinson's Disease Questionnaire were considered as secondary end points. Video recordings of the gaits were performed before surgery and at the 6- and 18-month follow-ups. These were retrospectively reviewed by a blinded neurologist for the primary end points. At the 6- and 18-month follow-ups, the median change in PSPRS was from 33 (baseline) to 37.5 and 47, respectively. Similarly, the PSP staging changed from 3 to 2.5 and 3.5, item 25 from 1.5 to 2 and 3.5, item 26 from 2.5 to 2 and 3.5, item 27 from 3.5 to 3 and 3.5 and item 28 from 1.5 to 1.5 and 3. Two patients in the study with the PSP-parkinsonism phenotype experienced improvement in their gait until the last follow-up. Bilateral PPN DBS can be safely performed in PSP patients despite mid-brain atrophy.