Stierwalt, Julie A. G.

Abstract Background Dysphagia can lead to fatal aspiration pneumonia in progressive supranuclear palsy (PSP). Little is known about the longitudinal progression of dysphagia or whether it differs across PSP clinical variants. Objectives To characterize longitudinal changes in dysphagia across PSP variants and determine relationships with disease severity and rate of atrophy in PSP‐related regions. Methods Sixty‐one PSP patients were recruited and underwent at least two serial evaluations, comprising neurological and videofluorographic exams, and MRI. Variables‐of‐interest were the oral and pharyngeal total sum scores (OTSS/PTSS) from the Modified Barium Swallow Impairment Profile, the Penetration Aspiration Scale (PAS), Functional Oral Intake Scale (FOIS), and lingual pressure assessments. Rates of change were compared across PSP variants and related to baseline scores, PSP Rating Scale and regional brain atrophy rates. Results Dysphagia progressed longitudinally, particularly with worsening in OTSS and anterior and posterior lingual pressures. Rate of change in OTSS was fastest in PSP with predominant speech‐language disorder. Negative correlations were observed between rates of change and baseline scores for OTSS, PTSS and PAS. Rates of change in lingual pressure measures correlated with rates of change in the PSP Rating Scale. Rate of change in the FOIS correlated with rates of change in OTSS and lingual pressure. Rates of brain atrophy were associated with baseline OTSS, PTSS, and PAS. Conclusions Dysphagia and lingual pressure worsen over time in PSP, with variability in rates of change in the OTSS across PSP variants and evidence that dysphagia is related to rates of atrophy.

Abstract Objective: We investigated differences in cognition between variants of progressive supranuclear palsy (PSP) including PSP-Richardson (PSP-RS) and subcortical and cortical variants using updated diagnostic criteria and comprehensive neuropsychological assessment. Method: We recruited 140 participants with PSP (age = 71.3 ± 6.9 years; education = 15.0 ± 2.8 years; 49.3% female) who completed neurological and neuropsychological assessment. Participants received diagnoses of PSP clinical variants at their evaluation (or retrospectively if evaluated before 2017) according to the Movement Disorder Society PSP criteria. We grouped variants as PSP-RS (62 participants), PSP-Cortical (25 with PSP-speech/language and 9 with PSP-corticobasal syndrome), and PSP-Subcortical (27 with PSP-parkinsonism, 11 with PSP-progressive gait freezing, and 6 with PSP-postural instability). Analysis of covariance adjusted for age assessed for differences in neuropsychological performance between variants across cognitive domains. Results: PSP-Cortical participants performed worst on measures of visual attention/working memory (Spatial Span Forward/Backward/Total), executive function (Frontal Assessment Battery), and language (Letter Fluency). PSP-RS participants performed worst on verbal memory (Camden Words). There were no significant group differences for the MoCA or indices of visuospatial function. There were no sex or education differences between PSP groups; however, there were differences in age at visit and disease duration. Conclusions: In a large sample of participants with PSP, there were differences in cognition across PSP-RS, PSP-Subcortical, and PSP-Cortical variants, with PSP-Cortical and, to a lesser extent, PSP-RS, performing worse on tests of attention and executive function. These findings suggest cognitive distinctions among PSP clinical variants and highlight the value of neuropsychological assessment in differential diagnosis of PSP subtypes for more accurate and timely clinical classification.

ABSTRACT Background and Purpose Diffusion tensor imaging (DTI) is commonly used to assess the integrity of gray and white matter (WM) structures in progressive supranuclear palsy (PSP). Beyond DTI, nontraditional diffusion techniques such as diffusion kurtosis imaging (DKI) have been shown to characterize brain tissue further. In this work, we aim to determine the utility of DKI in the differential diagnosis of PSP—Richardson syndrome (PSP‐RS) and PSP with predominant parkinsonism (PSP‐P) from Parkinson's disease (PD) and controls. Methods A multishell diffusion‐weighted sequence was acquired at 3 Tesla on a Siemens system in 22 patients with PSP‐RS, 23 with PSP‐P, 19 with PD, and 19 controls. Fractional anisotropy, mean diffusivity, kurtosis fractional anisotropy (KFA), and mean kurtosis (Kmean) were calculated for nine deep gray matter regions and six different WM tracts. Results DKI identified differences (not found by DTI) between control and PSP groups in the globus pallidum externus, subthalamic region, and putamen, with Kmean in the putamen able to differentiate PSP‐RS and PD. DKI WM measurements in the body of the corpus callosum and dentatorubrothalamic tract differentiated PSP‐RS from PD, and the corticostriatal tract differentiated PSP‐P from PD. KFA in the body of the corpus callosum identified worse microstructural anomalies in PSP‐RS compared to PSP‐P. DKI metrics correlated with the severity of ocular motor impairment and parkinsonism scores. Conclusions DKI measurements could differentiate PSP‐RS, PSP‐P, and PD and, hence, may be a promising imaging tool for studying structural neuropathological changes in PSP.

Abstract Normal pressure hydrocephalus is typically defined by the triad of gait disturbance, cognitive impairment, and urinary incontinence, and is characterized on MRI by disproportionately enlarged subarachnoid-space. Gait disturbance is also a commonly reported symptom in Parkinsonian disorders, especially progressive supranuclear palsy, although the frequency, clinical significance and mechanisms of hydrocephalus in these disorders are unclear. We aimed to assess the prevalence of hydrocephalic MRI parameters in a large cohort of Parkinsonian disorders and evaluate associations with clinical features and abnormalities on MRI and PET. Two hundred and thirty-eight participants with a Parkinsonian disorder, including 181 progressive supranuclear palsy, 36 corticobasal syndrome and 21 Parkinson’s disease, were enrolled from Mayo Clinic by the Neurodegenerative Research Group between September 2009 to October 2023. Automated detection of disproportionately enlarged subarachnoid-space hydrocephalus (D) was applied and using Evans’ index (E) cut-off point >0.3, participants were classified based on both measures as imaging-suggestive of hydrocephalus (D+E+), enlarged subarachnoid-space only (D+E−), large Evans’ index only (D−E+) and no imaging evidence of hydrocephalus (D−E−). Demographic, clinical and imaging features, including magnetic resonance parkinsonism index, cortical and subcortical volumes, white matter hyperintensities, diffusion tractography metrics, and metabolism on PET, were compared across groups. Among the 238 participants, 24 had borderline subarachnoid space scores and were excluded. The remaining 214 participants were classified as: D+E+ (n = 20, 9%); D+E− (n = 8, 4%); D−E+ (n = 71, 33%) and D−E− (n = 115, 54%). Among the progressive supranuclear palsy participants, 11% were D+E+, 4% D+E−, 34% D−E+ and 51% D−E−. Most cases (n = 18) in the imaging-suggestive of hydrocephalus D+E+ group had progressive supranuclear palsy. The D+E+ participants were older, had more disorientation, more downgaze palsy, greater midbrain and cortical atrophy, lower striatal metabolism, greater degeneration of long-range white matter tracts, larger cistern areas and more periventricular and deep white matter hyperintensities compared to the D−E− participants without imaging evidence of hydrocephalus. The D+E− participants had the highest metabolism in the paracentral lobule and superior parietal gyrus. The D−E+ participants showed worse disease severity and greater midbrain and cortical atrophy compared to the D−E− participants. These findings demonstrate that disproportionately enlarged subarachnoid-space hydrocephalus occurs in ∼15% of progressive supranuclear palsy participants, and is associated with worse clinical and imaging outcomes, as well as white matter hyperintensities. We hypothesize that disproportionately enlarged subarachnoid-space may be a mechanistic byproduct of degeneration and subsequent cerebrospinal fluid flow re-distribution in progressive supranuclear palsy.

Abstract Background Classic progressive supranuclear palsy RS syndrome (PSP‐RS) is characterized by early postural instability/falls and vertical supranuclear gaze palsy, although other signs/symptoms can occur, for example, axial rigidity, bradykinesia, and cognitive dysfunction. The Movement Disorders Society‐PSP (MDS‐PSP) criteria consider probable PSP‐RS a homogenous syndrome, but this has not been tested. Objectives We aim to investigate relationships between signs/symptoms of PSP‐RS beyond its core features and determine whether PSP‐RS is a homogeneous syndrome. Methods 118 participants who met MDS‐PSP criteria for probable PSP‐RS were analyzed. All participants received an independent clinical diagnosis based on clinical judgment. We first performed a Network Analysis using qgraph with Spearman's correlation to quantify relationships between 16 signs/symptoms followed by a k‐means clustering analysis using the same signs/symptoms to identify possible heterogeneity of the PSP‐RS designation. Results Five network clusters were identified, reflecting: (1) tremor, (2) sensitivity to bright light, (3) oculomotor function, (4) cognition, and (5) akinetic‐rigidity‐praxis. Worse akinetic‐rigidity was associated with better oculomotor function, but worse cognition. Cluster analysis revealed two clusters. Cluster I ( n = 89) had more severe clinical features than Cluster II ( n = 29). Cluster II had a higher frequency of participants (37.9%) clinically judged as not PSP‐RS: these participants were less likely to have PSP pathology on autopsy ( P = 0.03). Conclusions Some signs/symptoms of PSP‐RS strongly associate and are more likely to co‐occur. PSP‐RS, as defined by the MDS‐PSP criteria includes a subset of participants not clinically judged as PSP‐RS who are less likely to have PSP pathology.

AbstractBackgroundProgressive supranuclear palsy (PSP) can present with different clinical variants which show distinct, but partially overlapping, patterns of neurodegeneration and tau deposition in a PSP network of regions, including cerebellar dentate, superior cerebellar peduncle, midbrain, thalamus, basal ganglia, and frontal lobe. We sought to determine whether disruptions in functional connectivity within this PSP network measured using resting‐state functional MRI (rs‐fMRI) differed between PSP‐Richardson’s syndrome and the cortical and subcortical variants of PSP.MethodStructural MRI and rs‐fMRI scans were collected for 40 PSP‐RS, 24 PSP‐cortical (12 speech and language; 10 corticobasal syndrome; 2 frontal) and 36 PSP‐subcortical (18 parkinsonism; 11 progressive gait freezing; 6 postural instability; 1 oculomotor) participants who met the Movement Disorder Society PSP clinical criteria (Table 1). Ninety‐six participants underwent flortaucipir‐PET scans. MRIs were processed using CONN Toolbox. Functional connectivity between seeds placed throughout the PSP network was compared between each PSP group and 83 healthy controls, and between the PSP groups, covarying for age and sex.ResultsConnectivity was reduced throughout the network in PSP‐RS compared to controls (Figure 1A), involving cerebellar dentate, midbrain nuclei, subthalamic nuclei, basal ganglia, thalamus, and frontal regions. Frontal regions showed reduced connectivity to other regions in the network in PSP‐cortical, including substantia nigra and superior cerebellar peduncle. Disruptions in connectivity in PSP‐subcortical were less pronounced, with the strongest disruption between the pallidum and putamen. When PSP groups were compared to each other (Figure 1B), PSP‐RS had lower connectivity from the thalamus and cerebellar dentate to the cortex compared to PSP‐subcortical and from the thalamus to substantia nigra than PSP‐cortical. PSP‐subcortical had lower connectivity from the subthalamic nucleus to caudate than PSP‐RS and from the subthalamic nucleus to substantia nigra than PSP‐cortical and higher connectivity from the thalamus to the prefrontal cortex than both the other variants. Voxel‐based analyses replicated these patterns. There was moderate evidence that tau uptake in the PSP network regions influenced connectivity between these regions in PSP.ConclusionsPatterns of disrupted functional connectivity revealed both variant‐specific and shared disease pathways among PSP variants, providing insight into the disease heterogeneity beyond patterns of atrophy.

AbstractBackgroundSelf‐administered cognitive assessments demonstrate usability and ability to detect cognitive decline in Alzheimer’s disease, but usability in other neurodegenerative diseases is understudied. We investigated whether Mayo Test Drive (MTD), a self‐administered multi‐device compatible cognitive assessment platform, demonstrates usability and correlation with traditional neuropsychological tests in a pilot study of individuals with progressive supranuclear palsy (PSP).MethodEleven individuals with PSP (mean age = 69.6±7.2 years; mean education = 15.3±2.7 years; 72.7% male; 90.9% white; PSP Rating Scale [PSPRS] = 32.4±15.5) enrolled in a Neurodegenerative Research Group study at Mayo Clinic participated. Participants completed neurological evaluation, traditional neuropsychological assessment, in‐person self‐administered MTD comprised of the Stricker Learning Span and Symbols Test, and a MTD usability questionnaire with quantitative and qualitative questions. Participants received diagnoses of PSP clinical variants per Movement Disorders Society‐PSP criteria. Seven participants had PSP‐Richardson, two had PSP‐postural instability, and two had PSP‐parkinsonism. We used descriptive analyses to examine usability questions, qualitative analyses for free text responses, and Spearman correlations to analyze associations between MTD and traditional tests of global cognition and five cognitive domains.ResultTen of eleven patients completed MTD (average completion time [minutes] = 22.2±6.5). Study staff terminated one participant’s session early due to an appointment conflict; we excluded this participant from analyses. Six participants completed MTD with tablets and four used smartphones. Participants reported high ease completing MTD (9.00±1.76 on 0‐10 scale) and comfortability using their devices (9.40±1.58). All participants reported they could complete MTD independently, with one participant indicating need for assistance with hyperlinks and three reporting need for assistance with QR codes. Qualitative data suggested three participants had motoric difficulty using the tablets; these individuals had the greatest PSPRS symptom severity, although MTD performance was not correlated with the PSPRS (rho = ‐.122; p>.05). MTD performance significantly correlated with the MoCA (rho = 0.88) and tests of attention, executive, and visuospatial function (Table).ConclusionIn a MTD usability pilot for participants with PSP, participants reported high ease and comfort completing MTD independently; those with greater motor symptoms had more difficulty navigating technology. Additionally, performances on MTD were correlated with the MoCA and other in‐person assessments, demonstrating convergent validity.

AbstractBackgroundSelf‐administered cognitive assessments demonstrate usability and ability to detect cognitive decline in Alzheimer’s disease, but usability in other neurodegenerative diseases is understudied. We investigated whether Mayo Test Drive (MTD), a self‐administered multi‐device compatible cognitive assessment platform, demonstrates usability and correlation with traditional neuropsychological tests in a pilot study of individuals with progressive supranuclear palsy (PSP).MethodEleven individuals with PSP (mean age = 69.6±7.2 years; mean education = 15.3±2.7 years; 72.7% male; 90.9% white; PSP Rating Scale [PSPRS] = 32.4±15.5) enrolled in a Neurodegenerative Research Group study at Mayo Clinic participated. Participants completed neurological evaluation, traditional neuropsychological assessment, in‐person self‐administered MTD comprised of the Stricker Learning Span and Symbols Test, and a MTD usability questionnaire with quantitative and qualitative questions. Participants received diagnoses of PSP clinical variants per Movement Disorders Society‐PSP criteria. Seven participants had PSP‐Richardson, two had PSP‐postural instability, and two had PSP‐parkinsonism. We used descriptive analyses to examine usability questions, qualitative analyses for free text responses, and Spearman correlations to analyze associations between MTD and traditional tests of global cognition and five cognitive domains.ResultTen of eleven patients completed MTD (average completion time [minutes] = 22.2±6.5). Study staff terminated one participant’s session early due to an appointment conflict; we excluded this participant from analyses. Six participants completed MTD with tablets and four used smartphones. Participants reported high ease completing MTD (9.00±1.76 on 0‐10 scale) and comfortability using their devices (9.40±1.58). All participants reported they could complete MTD independently, with one participant indicating need for assistance with hyperlinks and three reporting need for assistance with QR codes. Qualitative data suggested three participants had motoric difficulty using the tablets; these individuals had the greatest PSPRS symptom severity, although MTD performance was not correlated with the PSPRS (rho = ‐.122; p>.05). MTD performance significantly correlated with the MoCA (rho = 0.88) and tests of attention, executive, and visuospatial function (Table).ConclusionIn a MTD usability pilot for participants with PSP, participants reported high ease and comfort completing MTD independently; those with greater motor symptoms had more difficulty navigating technology. Additionally, performances on MTD were correlated with the MoCA and other in‐person assessments, demonstrating convergent validity.