Stride width and postural stability in frontal gait disorders and Parkinson's disease.

Older adults, as well as those with certain neurological disorders, may compensate for poor neural control of postural stability by widening their base of foot support while walking. However, the extent to which this wide-based gait improves postural stability or affects postural control strategies has not been explored. People with idiopathic Parkinson's disease (iPD, n = 72), frontal gait disorders (FGD, n = 16), and healthy older adults (n = 32) performed walking trials at their preferred speed over an 8-m-long, instrumented walkway. People with iPD were tested in their OFF medication state. Analyses of covariance were performed to determine the associations between stride width and measures of lateral stability control. People with FGD exhibited a wide-based gait compared to both healthy older adults and iPD. An increased stride width was associated with an increase in lateral margin of stability in FGD. Unlike healthy older adults or iPD, people with FGD did not externally rotate their feet (toe-out angle) or shift their center of pressure laterally to aid lateral dynamic stability during walking but slowed their gait instead to increase stability. By adopting a slow, wide-based gait, people with FGD take advantage of the passive, pendular mechanics of walking.

Predictors and Pathophysiology of Axial Postural Abnormalities in Parkinsonism: A Scoping Review.

Background: Postural abnormalities involving the trunk are referred to as axial postural abnormalities and can be observed in over 20% of patients with Parkinson's disease (PD) and in atypical parkinsonism. These symptoms are highly disabling and frequently associated with back pain and a worse quality of life in PD. Despite their frequency, little is known about the pathophysiology of these symptoms and scant data are reported about their clinical predictors, making it difficult to prompt prevention strategies. Objectives: We conducted a scoping literature review of clinical predictors and pathophysiology of axial postural abnormalities in patients with parkinsonism to identify key concepts, theories and evidence on this topic. Methods: We applied a systematic approach to identify studies, appraise quality of evidence, summarize main findings, and highlight knowledge gaps. Results: Ninety-two articles were reviewed: 25% reported on clinical predictors and 75% on pathophysiology. Most studies identified advanced disease stage and greater motor symptoms severity as independent clinical predictors in both PD and multiple system atrophy. Discrepant pathophysiology data suggested different potential central and peripheral pathogenic mechanisms. Conclusions: The recognition of clinical predictors and pathophysiology of axial postural abnormalities in parkinsonism is far from being elucidated due to literature bias, encompassing different inclusion criteria and measurement tools and heterogeneity of patient samples. Most studies identified advanced disease stage and higher burden of motor symptoms as possible clinical predictors. Pathophysiology data point toward many different (possibly non-mutually exclusive) mechanisms, including dystonia, rigidity, proprioceptive and vestibular impairment, and higher cognitive deficits.

Balance and gait in progressive supranuclear palsy: a narrative review of objective metrics and exercise interventions.

Background: The use of objective gait and balance metrics is rapidly expanding for evaluation of atypical parkinsonism, and these measures add to clinical observations. Evidence for rehabilitation interventions to improve objective measures of balance and gait in atypical parkinsonism is needed. Aim: Our aim is to review, with a narrative approach, current evidence on objective metrics for gait and balance and exercise interventions in progressive supranuclear palsy (PSP). Methods: Literature searches were conducted in four computerized databases from the earliest record up to April 2023: PubMed, ISI's Web of Knowledge, Cochrane's Library, and Embase. Data were extracted for study type (cross-sectional, longitudinal, and rehabilitation interventions), study design (e.g., experimental design and case series), sample characteristics, and gait and balance measurements. Results: Eighteen gait and balance (16 cross-sectional and 4 longitudinal) and 14 rehabilitation intervention studies were included. Cross-sectional studies showed that people with PSP have impairments in gait initiation and steady-state gait using wearable sensors, and in static and dynamic balance assessed by posturography when compared to Parkinson's disease (PD) and healthy controls. Two longitudinal studies observed that wearable sensors can serve as objective measures of PSP progression, using relevant variables of change in turn velocity, stride length variability, toe off angle, cadence, and cycle duration. Rehabilitation studies investigated the effect of different interventions (e.g., balance training, body-weight supported treadmill gait, sensorimotor training, and cerebellar transcranial magnetic stimulation) on gait, clinical balance, and static and dynamic balance assessed by posturography measurements. No rehabilitation study in PSP used wearable sensors to evaluate gait and balance impairments. Although clinical balance was assessed in 6 rehabilitation studies, 3 of these studies used a quasi-experimental design, 2 used a case series, only 1 study used an experimental design, and sample sizes were relatively small. Conclusion: Wearable sensors to quantify balance and gait impairments are emerging as a means of documenting progression of PSP. Robust evidence for improving balance and gait in PSP was not found for rehabilitation studies. Future powered, prospective and robust clinical trials are needed to investigate the effects of rehabilitation interventions on objective gait and balance outcomes in people with PSP.

Using Downgaze Palsy Progression Rate to Model Survival in Progressive Supranuclear Palsy-Richardson Syndrome.

BACKGROUND: Rapid development of downgaze palsy, the most specific symptom of progressive supranuclear palsy (PSP), has been associated with shorter survival in small studies. OBJECTIVE: We hypothesized that the progression rate of downgaze palsy and other disease features could predict survival if assessed soon after the onset of downgaze palsy in a large data set. METHODS: We used a longitudinal database of 414 patients with probable PSP-Richardson syndrome from 1994 to 2020. The data set comprised demographics and, for each visit, 28 PSP Rating Scale (PSPRS) items and PSP stage scores. We calculated the rate of progression of each PSPRS item as its item score when the downgaze item first reached 1 or more (on a 0-4 scale) divided by disease duration at that point. Multivariate Cox regression was applied to identify variables independently associated with survival. We also explored the progression pattern of total PSPRS and downgaze palsy scores with disease course. RESULTS: Independently associated with shorter survival were older onset age and faster progression of downgaze palsy, dysphagia for liquids, difficulty in returning to seat, and PSP stage. Patients with survival duration within 1 year of the median survival (6.58 years) showed approximately linear progression of the PSPRS score and downgaze palsy score during years 2 through 6 of the disease course. CONCLUSIONS: Older onset age and faster progression of downgaze palsy and several axial features are associated with shorter survival. The disease typically progresses in approximately linear fashion during years 2 through 6. These results may aid study design and patient counseling. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Modified Progressive Supranuclear Palsy Rating Scale for Virtual Assessments.

BACKGROUND: The reliability of the Progressive Supranuclear Palsy Rating Scale (PSPRS) using teleneurology has not been assessed. OBJECTIVES: To test whether removing items inadequately assessed by video would impact measurement of PSP severity and progression. METHODS: We performed secondary analyses of two data sets: the phase 2/3 trial of Davunetide in PSP and a large single-center cohort. We examined two modifications of the PSPRS: (1) removing neck rigidity, limb rigidity, and postural stability (25 items; mPSPRS-25) and (2) also removing three ocular motor items and limb dystonia (21 items; mPSPRS-21). Proportional agreement relative to the possible total scores was measured using the intraclass correlation coefficient, compared to the original PSPRS baseline values and change over 6 and 12 months. We examined the ability of both scales to predict survival in the single-center cohort using proportional hazards models. RESULTS: The mPSPRS-25 showed excellent agreement (0.99; P < 0.001) with the original PSPRS at baseline, 0.98 (P < 0.001) agreement in measuring change over 6 months, and 0.98 (P < 0.001) over 12 months. The mPSPRS-21 showed agreement of 0.94 (P < 0.001) with the original PSPRS at baseline, 0.92 (P < 0.001) at 6 months, and 0.95 (P < 0.001) at 12 months. Baseline and 6-month change in both modified scales were highly predictive of survival in the single-center cohort. CONCLUSIONS: Modified versions of the PSPRS which can be administered remotely show excellent agreement with the original scale and predict survival in PSP. The mPSPRS-21 should facilitate clinical care and research in PSP via teleneurology. © 2022 International Parkinson and Movement Disorder Society.

Perspective: Balance Assessments in Progressive Supranuclear Palsy: Lessons Learned.

Many studies have examined aspects of balance in progressive supranuclear palsy (PSP), but guidance on the feasibility of standardized objective balance assessments and balance scales in PSP is lacking. Balance tests commonly used in Parkinson's disease often cannot be easily administered or translated to PSP. Here we briefly review methodology in prior studies of balance in PSP; then we focus on feasibility by presenting our experience with objective balance assessment in PSP-Richardson syndrome and PSP-parkinsonism during a crossover rTMS intervention trial. We highlight lessons learned, safety considerations, and future approaches for objective balance assessment in PSP.

Surrogates for rigidity and PIGD MDS-UPDRS subscores using wearable sensors.

BACKGROUND: Telemedicine has the advantage of expanding access to care for patients with Parkinson's Disease (PD). However, rigidity and postural instability in PD are difficult to measure remotely, and are important measures of functional impairment and fall risk. RESEARCH QUESTION: Can measures from wearable sensors be used as future surrogates for the MDS-UPDRS rigidity and Postural Instability and Gait Difficulty (PIGD) subscores? METHODS: Thirty-one individuals with mild to moderate PD wore 3 inertial sensors at home for one week to measure quantity and quality of gait and turning in daily life. Separately, we performed a clinical assessment and balance characterization of postural sway with the same wearable sensors in the laboratory (On medication). We then first performed a traditional correlation analysis between clinical scores and objective measures of gait and balance followed by multivariable linear regression employing a best subset selection strategy. RESULTS: The number of walking bouts and turns correlated significantly with the rigidity subscore, while the number of turns, foot pitch angle, and sway area while standing correlated significantly with the PIGD subscore (p < 0.05). The multivariable linear regression showed that rigidity subscore was best predicted by the number of walking bouts while the PIGD subscore was best predicted by a combination of number of walking bouts, gait speed, and postural sway. SIGNIFICANCE: The correlation between objective sensor data and MDS-UPDRS rigidity and PIGD scores paves the way for future larger studies that evaluate use of objective sensor data to supplement remote MDS-UPDRS assessment.

Best Practices in the Clinical Management of Progressive Supranuclear Palsy and Corticobasal Syndrome: A Consensus Statement of the CurePSP Centers of Care.

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS; the most common phenotype of corticobasal degeneration) are tauopathies with a relentless course, usually starting in the mid-60s and leading to death after an average of 7 years. There is as yet no specific or disease-modifying treatment. Clinical deficits in PSP are numerous, involve the entire neuraxis, and present as several discrete phenotypes. They center on rigidity, bradykinesia, postural instability, gait freezing, supranuclear ocular motor impairment, dysarthria, dysphagia, incontinence, sleep disorders, frontal cognitive dysfunction, and a variety of behavioral changes. CBS presents with prominent and usually asymmetric dystonia, apraxia, myoclonus, pyramidal signs, and cortical sensory loss. The symptoms and deficits of PSP and CBS are amenable to a variety of treatment strategies but most physicians, including many neurologists, are reluctant to care for patients with these conditions because of unfamiliarity with their multiplicity of interacting symptoms and deficits. CurePSP, the organization devoted to support, research, and education for PSP and CBS, created its CurePSP Centers of Care network in North America in 2017 to improve patient access to clinical expertise and develop collaborations. The directors of the 25 centers have created this consensus document outlining best practices in the management of PSP and CBS. They formed a writing committee for each of 12 sub-topics. A 4-member Steering Committee collated and edited the contributions. The result was returned to the entire cohort of authors for further comments, which were considered for incorporation by the Steering Committee. The authors hope that this publication will serve as a convenient guide for all clinicians caring for patients with PSP and CBS and that it will improve care for patients with these devastating but manageable disorders.

Open-Label Phase 1 Futility Studies of Salsalate and Young Plasma in Progressive Supranuclear Palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a neurodegenerative disease without approved therapies, and therapeutics are often tried off-label in the hope of slowing disease progression. Results from these experiences are seldom shared, which limits evidence-based knowledge to guide future treatment decisions. OBJECTIVES: To describe an open-label experience, including safety/tolerability, and longitudinal changes in biomarkers of disease progression in PSP-Richardson's syndrome (PSP-RS) patients treated with either salsalate or young plasma and compare to natural history data from previous multicenter studies. METHODS: For 6 months, 10 PSP-RS patients received daily salsalate 2,250 mg, and 5 patients received monthly infusions of four units of young plasma. Every 3 months, clinical severity was assessed with the Progressive Supranuclear Palsy Rating Scale (PSPRS), and MRI was obtained for volumetric measurement of midbrain. A range of exploratory biomarkers, including cerebrospinal fluid levels of neurofilament light chain, were collected at baseline and 6 months. Interventional data were compared to historical PSP-RS patients from the davunetide clinical trial and the 4-Repeat Tauopathy Neuroimaging Initiative. RESULTS: Salsalate and young plasma were safe and well tolerated. PSPRS change from baseline (mean ± standard deviation [SD]) was similar in salsalate (+5.6 ± 9.6), young plasma (+5.0 ± 7.1), and historical controls (+5.6 ± 7.1), and change in midbrain volume (cm3 ± SD) did not differ between salsalate (-0.07 ± 0.03), young plasma (-0.06 ± 0.03), and historical controls (-0.06 ± 0.04). No differences were observed between groups on any exploratory endpoint. CONCLUSIONS: Neither salsalate nor young plasma had a detectable effect on disease progression in PSP-RS. Focused open-label clinical trials incorporating historical clinical, neuropsychological, fluid, and imaging biomarkers provide useful preliminary data about the promise of novel PSP-directed therapies.

Associations Between Amantadine Usage, Gait, and Cognition in PSP: A post-hoc Analysis of the Davunetide Trial.

Introduction: Amantadine anecdotally improves gait in progressive supranuclear palsy (PSP) but definitive data is lacking. We investigated associations between amantadine usage, gait, cognition, and activities of daily living in 310 subjects with PSP using data from the davunetide trial. Method: We compared baseline demographics, PSP Rating Scale (PSPRS), Repeat Battery for the Assessment of Neuropsychological Status (RBANS), and Schwab and England Activities of Daily Living (SEADL) scores between subjects taking vs. not taking amantadine using chi-square tests for categorical variables and independent sample t-tests for continuous variables. Using the general linear model (GLM), we tested whether group status predicted total PSPRS, PSPRS-gait and midline, total RBANS, RBANS-attention, and SEADL before and after the 52-weeks follow-up. Results: Subjects taking vs. not taking amantadine were similar at baseline, except subjects taking amantadine had a higher Clinical Global Impression (CGI) Score (p = 0.01). However, the CGI change score did not differ between groups at week 52 (p = 0.10). Using GLM models (controlling for covariates), we found that subjects taking vs. not taking amantadine did not significantly predict total PSPRS, PSPRS-gait and midline, total RBANS, RBANS-attention, or SEADL at baseline, week 52, or the change score between baseline and week 52. Discussion: This post-hoc analysis of the davunetide trial did not find an association between amantadine and gait or cognitive measures in PSP, but was not powered to find such a difference. Future studies should still examine amantadine for symptomatic benefit in multiple PSP subtypes.

"Feasibility and utility of a simple computerized test for measuring saccade latency in progressive supranuclear palsy- a proof-of-concept study".

BACKGROUND: Reliable detection of slowed vertical saccades may help discriminate progressive supranuclear palsy (PSP) from the subset of Parkinson's disease patients who lack tremor (akinetic-rigid or PD-postural instability and gait disorder PIGD subtype), and from age-related oculomotor changes. We investigated the feasibility of a camera-less computerized behavioral saccade latency paradigm previously validated in PD to discriminate probable PSP-Richardson syndrome (PSP-RS) from PD-PIGD and age-matched controls. METHODS: In this proof-of-concept case-control study, reflexive saccade latencies were measured in 5 subjects with probable PSP-RS, 5 subjects with PD-PIGD subtype, and 5 age-matched controls using the behavioral paradigm. The battery was repeated approximately one month later. All subjects were examined off levodopa by a movement disorders neurologist and by an ophthalmologist, who also performed a dilated eye exam. RESULTS: Vertical prosaccade latencies were longer in the PSP group (median = 903 ms) relative to PD (median = 268 ms) and control groups (median = 235 ms), with no overlap between groups (100% accuracy). PSP subjects also had larger vertical-horizontal discrepancies than comparison groups. Test-retest reliability for the behavioral saccade measures was good (interclass correlation coefficient = 0.948; 95% confidence interval [0.856, 0.982]), and the measures strongly correlated with clinical ratings. CONCLUSIONS: Computerized behavioral measurement of reflexive saccade latency is feasible in PSP, and potentially discriminates probable PSP-RS from the PD-PIGD subtype. Findings from this proof-of-concept study support utility of the approach for obtaining objective saccade metrics in clinical evaluations and for tracking change in future, larger trials of moderately advanced PSP. Future studies should also examine the behavioral paradigm in earlier presentations of PSP and other subtypes of PSP.

A case of Gerstmann-Straussler-Scheinker (GSS) disease with supranuclear gaze palsy.

BACKGROUND: Gerstmann-Straussler-Scheinker disease (GSS), an autosomal dominant prion disorder, usually presents as a slowly progressive cerebellar ataxia followed by later cognitive decline. We present a member of the GSS Indiana Kindred with supranuclear palsy, a less common feature in GSS. CASE PRESENTATION: A 42-year-old man presented with 12 months of progressive gait and balance difficulty. Exam was notable for ataxia and cerebellar eye movement abnormalities. Genetic testing revealed a F198S variant in the prion protein (PRNP) gene, the pathological variant of GSS associated with his family, the Indiana kindred. Eighteen months after initial presentation supranuclear palsy developed. CONCLUSIONS: GSS is a neurodegenerative prion disease with diverse clinical presentations, and exhibits greater variability in disease phenotype compared to other inherited spongiform encephalopathies. GSS should be on the differential for patients with ataxia and supranuclear palsy, and it is important to assess both horizontal and vertical saccades and optokinetic nystagmus in patients with ataxia.

Chronic meningoencephalitis with mixed pathology mimics progressive supranuclear palsy.

We report a case of a progressive supranuclear palsy-like phenotype with rapidly progressive dementia and prominent language and executive dysfunction. Pathological examination revealed no midbrain or white matter tauopathy, but rather chronic meningoencephalitis and other mixed pathology. The cerebrospinal fluid (CSF) in this case showed a novel antibody against central nervous system and renal tissue.

Apraxia of gait- or apraxia of postural transitions?

"Apraxia of gait" is not a useful concept and freezing of gait should also not be considered an apraxia. The concept of apraxia may, however, be applied to distortions of postural transitions that can accompany fronto-parietal lesions.

Impaired perception of surface tilt in progressive supranuclear palsy.

INTRODUCTION: Progressive supranuclear palsy (PSP) is characterized by early postural instability and backward falls. The mechanisms underlying backward postural instability in PSP are not understood. The aim of this study was to test the hypothesis that postural instability in PSP is a result of dysfunction in the perception of postural verticality. METHODS: We gathered posturography data on 12 subjects with PSP to compare with 12 subjects with idiopathic Parkinson's Disease (PD) and 12 healthy subjects. Objective tests of postural impairment included: dynamic sensory perception tests of gravity and of surface oscillations, postural responses to surface perturbations, the sensory organization test of postural sway under altered sensory conditions and limits of stability in stance. RESULTS: Perception of toes up (but not toes down) surface tilt was reduced in subjects with PSP compared to both control subjects (p≤0.001 standing, p≤0.007 seated) and subjects with PD (p≤0.03 standing, p≤0.04 seated). Subjects with PSP, PD and normal controls accurately perceived the direction of gravity when standing on a tilting surface. Unlike PD and control subjects, subjects with PSP exerted less postural corrective torque in response to toes up surface tilts. DISCUSSION: Difficulty perceiving backward tilt of the surface or body may account for backward falls and postural impairments in patients with PSP. These observations suggest that abnormal central integration of sensory inputs for perception of body and surface orientation contributes to the pathophysiology of postural instability in PSP.