Stephens, Yehkyoung C.

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.

Background: Progressive apraxia of speech (PAOS) is a neurodegenerative disorder most commonly arising from a 4-repeat tauopathy that affects the programming or planning of speech, although many patients develop a Parkinson-plus syndrome. The role of neuroinflammation as a disease mechanism is unknown. We investigated the spatial pattern of neuroinflammation in PAOS using PET and evaluated whether it is associated with disease severity, presence of Parkinson-plus features, and tau PET uptake. Patients and Methods: Twenty-five PAOS patients (13 with Parkinson-plus features) and 30 controls underwent inflammatory 11C-ER176 and tau 18F-flortaucipir PET scans as well as detailed clinical assessments. Multiple linear regression analyses compared the inflammatory standardized uptake value ratio (SUVR) between PAOS and controls and assessed the relationship with clinical test scores. Pearson correlation analysis examined the relationship between inflammatory and tau SUVRs. Results: PAOS had greater neuroinflammatory SUVR than controls in the precentral, supplementary motor area, frontal gyri, putamen, pallidum, subthalamic nucleus, and red nucleus (adjusted P < 0.05). Greater neuroinflammation was associated with worse parkinsonism, and patients who had developed Parkinson-plus features showed a broader pattern of neuroinflammation, extending to prefrontal, temporal and parietal cortices. Neuroinflammation correlated with tau uptake in most (96%) PAOS patients (r > 0.3, P < 0.05). The higher correlation was associated with worse parkinsonism (r = 0.61, P < 0.05) and disease severity (r = 0.54, P < 0.05). Conclusions: 11C-ER176 PET analysis demonstrates neuroinflammation in frontal and subcortical regions in PAOS which is particularly severe and widespread with the development of Parkinson-plus clinical features. The colocalization of neuroinflammation and tau may support a relationship between these disease mechanisms.

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 &gt;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.

AbstractINTRODUCTIONAlzheimer's disease (AD) pathology causes corticobasal syndrome (CBS) in 21%–50% of patients. Studies have assessed hypometabolism in CBS according to β‐amyloid (A) positron emission tomography (PET), but the understanding of the association of both AD‐tau (T) and A with hypometabolism is incomplete.METHODSThirty‐three CBS patients and 45 controls underwent fluorodeoxyglucose (FDG), flortaucipir, and Pittsburgh compound‐B PET and were classified as A± and T±. FDG‐PET uptake was extracted for 12 regions‐of‐interest in dominant (most affected) and non‐dominant hemispheres and compared across A/T groups.RESULTSA+T+ patients had greater hypometabolism in temporo‐parieto‐occipital cortices than A+T‐ and A‐T‐ groups, with no differences observed between the A+T‐ and A‐T‐ groups. FDG asymmetry was more accentuated in A+T+ patients. Medial temporal and basal ganglia metabolism were similar across AT groups.DISCUSSIONAmyloid and tau positivity contribute synergistically to hypometabolism and asymmetry in temporo‐parieto‐occipital cortices in CBS, with AD‐like patterns of hypometabolism observed only in A+T+ patients.Highlights Amyloid (A) and tau PET (T) status can be used to stratify CBS patients. A+T+ CBS patients show more hypometabolism in temporo‐parieto‐occipital cortices. Medial temporal metabolism (typical AD pattern) is similar across AT groups. Parieto‐occipital cortices should be assessed when investigating AT pathology in CBS. Amyloid and tau positivity contribute synergistically to hypometabolism and asymmetry in CBS.