Variant Progressive Supranuclear Palsy Research Articles

Sleep disturbances in the speech-language variant of progressive supranuclear palsy

IntroductionProgressive supranuclear palsy (PSP) variants other than PSP-Richardson Syndrome (PSP-RS) have been recognized, including PSP with speech and language problems (PSP-SL). Given the reported sleep disruptions in PSP-RS, we investigated sleep abnormalities in PSP-SL. MethodsFour sleep-related screening questions were given to the caregivers of 90 patients with PSP-SL (59 suggestive of PSP-SL and 31 possible PSP-SL) and 71 probable PSP-RS (prob. PSP-RS) patients. ResultsAt least one sleep-related disturbance was observed in 35.6% of suggestive of PSP-SL, 38.7% of possible PSP-SL, and 67.6% of prob. PSP-RS, the most common being “unable to fall or stay asleep”. Prob. PSP-RS showed higher frequency of “screaming or talking in sleep”, “acting out dreams”, and “unable to fall or stay asleep” compared to both PSP-SL groups, but did not differ from possible PSP-SL in “excessive daytime sleepiness”. ConclusionSleep abnormalities are common in PSP-SL, but less frequent than prob.PSP-RS.

Update on neuroimaging for categorization of Parkinson's disease and atypical parkinsonism

Differential diagnosis of Parkinsonism may be difficult. The objective of this review is to present the work of the last three years in the field of imaging for diagnostic categorization of parkinsonian syndromes focusing on progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). Two main complementary approaches are being pursued. The first seeks to develop and validate manual qualitative or semi-quantitative imaging markers that can be easily used in clinical practice. The second is based on quantitative measurements of magnetic resonance imaging abnormalities integrated in a multimodal approach and in automatic categorization machine learning tools. These two complementary approaches obtained high diagnostic around 90% and above in the classical Richardson form of PSP and probable MSA. Future work will determine if these techniques can improve diagnosis in other PSP variants and early forms of the diseases when all clinical criteria are not fully met.

Diffusion tensor imaging analysis in three progressive supranuclear palsy variants

Clinical variants of progressive supranuclear palsy (PSP) include the classic Richardson's syndrome (PSP-RS), as well as cortical presentations such as PSP-speech/language (PSP-SL) and subcortical presentations such as PSP-parkinsonism (PSP-P). Patterns of white matter tract degeneration underlying these variants, and the degree to which white matter patterns could differentiate these variants, is unclear. Forty-nine PSP patients (28 PSP-RS, 12 PSP-P, and 9 PSP-SL) were recruited by the Neurodegenerative Research Group and underwent diffusion tensor imaging. Regional diffusion tensor imaging metrics were compared across PSP variants using Bayesian linear mixed-effects models, with inter-variant differentiation assessed using the area under the receiver operator characteristic curve (AUROC). All three variants showed degeneration of the body of the corpus callosum, posterior thalamic radiation, superior cerebellar peduncle, internal and external capsule, and superior fronto-occipital fasciculus. PSP-RS showed greater degeneration of superior cerebellar peduncle compared to PSP-P and PSP-SL, whereas PSP-SL showed greater degeneration of body and genu of the corpus callosum, internal capsule, external capsule, and superior longitudinal fasciculus compared to the other variants. Fractional anisotropy in body of the corpus callosum provided excellent differentiation of PSP-SL from both PSP-P and PSP-RS (AUROC = 0.91 and 0.92, respectively). Moderate differentiation of PSP-RS and PSP-P was achieved with fractional anisotropy in superior fronto-occipital fasciculus (AUROC = 0.68) and mean diffusivity in the superior cerebellar peduncle (AUROC = 0.65). In this pilot study, patterns of white matter tract degeneration differed across PSP-RS, PSP-SL, and PSP-P, with the body of the corpus callosum showing some utility in the differentiation of PSP-SL from the other two variants.

Quantitative evaluation of oculomotor disturbances in progressive supranuclear palsy

ObjectivesTo explore and quantify systematically the ocular abnormal movements present in progressive supranuclear palsy (PSP) from the early stages, to assess the ability of this standardized examination in the differential diagnosis of PSP from Parkinson's disease (PD), and to compare in more detail oculomotor disturbances between PSP variants. MethodsSixty-five consecutive PSP patients with <5 years of disease duration diagnosed according to MDS-PSP criteria, 25 PD patients and 25 controls comparable in age, education and disease duration were explored using a bedside battery of tests for the quantitative evaluation of oculomotor dysfunction in clinical practice. Other accepted scales were used for measurement of motor (PSPRS), cognitive (FAB) and behavioral (FBI) impairment. ResultsMeasurement of oculomotor dysfunction significantly differentiated PSP from PD and controls (p < 0.001) and showed high accuracy in the differential diagnosis of early-to-mid stage PSP from PD. PSP-Parkinsonism and PSP-Progressive Gait Freezing phenotypes showed more preserved ocular motor function compared to PSP-Richardson Syndrome, although no differences were found between PSP subtypes in the number of square wave jerks, optokinetic nystagmus defects, degree of apraxia of eyelid opening, or presence of the “Round the Houses” sign. ConclusionsUsing a bedside clinical instrument for quantifying oculomotor disturbances in PSP shows promising potential at differentiating PSP from PD, and it seems able to provide a qualitative and quantitative description of ocular motor function in parkinsonian disorders.

Motor Speech Disorders and Communication Limitations in Progressive Supranuclear Palsy.

Purpose This study describes motor speech disorders and associated communication limitations in six variants of progressive supranuclear palsy (PSP). Method The presence, nature, and severity of dysarthria and apraxia of speech (AOS) were documented, along with scores on the Apraxia of Speech Rating Scale-Version 3 (ASRS-3) for 77 (40 male and 37 female) patients with PSP. Clinician-estimated and patient-estimated communication limitations were rated using the Motor Speech Disorders Severity Rating (MSDSR) Scale and the Communicative Effectiveness Survey (CES), respectively. Descriptive statistics were calculated for each of these dependent variables. One-tailed t tests were conducted to test mean differences in ASRS-3 and CES between participants with and without AOS and between participants with and without dysarthria. Spearman rank correlations were calculated between ASRS-3 scores and clinical judgments of AOS and dysarthria severity and between MSDSR and CES ratings. Results Nine participants (12%) had normal speech. Eighty-seven percent exhibited dysarthria; hypokinetic and mixed hypokinetic-spastic dysarthria were observed most frequently. AOS was observed in 19.5% of participants across all variants, but in only 10% exclusive of the PSP speech and language variant. Nearly half presented with AOS in which neither phonetic nor prosodic features clearly predominated. The mean ASRS-3 score for participants with AOS was significantly higher than for those without and correlated strongly with clinician judgment of AOS severity. Mean ASRS-3 was higher for participants with dysarthria than for those without but correlated weakly with dysarthria severity. Mean MSDSR and CES ratings were lower in participants with AOS compared to those without and moderately correlated with each other. Conclusions Motor speech disorders that negatively impact communicative effectiveness are common in PSP and occur in many variants. This is the first description of motor speech disorders across PSP variants, setting the stage for future research characterizing neuroanatomical correlates, progression of motor speech disorders, and benefits of targeted interventions. Supplemental Material https://doi.org/10.23641/asha.14111837.

The Role of Frontal Assessment Battery and Frontal Lobe Single-Photon Emission Computed Tomography in the Differential Diagnosis of Progressive Supranuclear Palsy Variants and Corticobasal Syndrome—A Pilot Study

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are clinical syndromes classified as atypical parkinsonism. Due to their overlapping symptomatology, recent research shows the necessity of finding new methods of examination of these clinical entities. PSP is a heterogenic disease. PSP Richardson-Steele Syndrome (PSP-RS) and parkinsonism predominant (PSP-P) are the most common clinical variants of progressive supranuclear palsy syndrome. The different clinical course and life expectancy of PSP-RS and PSP-P stress the need of efficient examination in the early stages. The aim of the study was to evaluate the possible feasibility of the combined use of frontal assessment battery (FAB) and single-photon emission computed tomography (SPECT) in the differentiation of PSP-RS, PSP-P, and CBS. The findings show that FAB may be interpreted as a possible supplementary tool in the differential diagnosis of PSP-P and PSP-RS. The differences in SPECT are less pronounced. The study does not show any advantages of performing combined frontal SPECT and FAB in the differential examination of PSP and CBS. Moreover, PSP-RS and CBS, in a detailed evaluation of the frontal lobe, do not show any significant differences. This is a relatively small study which, however, highlights the relevant features of clinical examination of these rare entities.

Characterization of diagnostic certainty levels and clinical syndromes in patients with progressive supranuclear palsy in two German prospective cohorts

Background: In 2017, new diagnostic criteria for progressive supranuclear palsy (PSP) were published by the Movement Disorder Society (MDS-PSP criteria). Major novelties were the inclusion of variant PSP syndromes and the introduction of the new certainty level “suggestive of PSP”.

Multicenter Validation of Metabolic Abnormalities Related to PSP According to the MDS-PSP Criteria.

It remains unclear whether the supportive imaging features described in the diagnostic criteria for progressive supranuclear palsy (PSP) are suitable for the full clinical spectrum. The aim of the current study was to define and cross-validate the pattern of glucose metabolism in the brain associated with a diagnosis of different PSP variants. A retrospective multicenter cohort study performed on 73 PSP patients who were referred for a fluorodeoxyglucose positron emission tomography PET scan: PSP-Richardson's syndrome, n = 47; PSP-parkinsonian variant, n = 18; and progressive gait freezing, n = 8. In addition, we included 55 healthy controls and 58 Parkinson's disease (PD) patients. Scans were normalized by global mean activity. We analyzed the regional differences in metabolism between the groups. Moreover, we applied a multivariate analysis to obtain a PSP-related pattern that was cross-validated in independent populations at the individual level. Group analysis showed relative hypometabolism in the midbrain, basal ganglia, thalamus, and frontoinsular cortices and hypermetabolism in the cerebellum and sensorimotor cortices in PSP patients compared with healthy controls and PD patients, the latter with more severe involvement in the basal ganglia and occipital cortices. The PSP-related pattern obtained confirmed the regions described above. At the individual level, the PSP-related pattern showed optimal diagnostic accuracy to distinguish between PSP and healthy controls (sensitivity, 80.4%; specificity, 96.9%) and between PSP and PD (sensitivity, 80.4%; specificity, 90.7%). Moreover, PSP-Richardson's syndrome and PSP-parkinsonian variant patients showed significantly more PSP-related pattern expression than PD patients and healthy controls. The glucose metabolism assessed by fluorodeoxyglucose PET is a useful and reproducible supportive diagnostic tool for PSP-Richardson's syndrome and PSP-parkinsonian variant. © 2020 International Parkinson and Movement Disorder Society.

Diagnostic potential of automated tractography in progressive supranuclear palsy variants

BackgroundMicrostructural white matter integrity captured by diffusion-tensor imaging (DTI) is significantly more affected in progressive supranuclear palsy-Richardson's syndrome (PSP-RS) compared to PSP-parkinsonism (PSP–P). ObjectivesTo characterize the microstructural integrity of large fascicular bundles using standardized probabilistic tractography and combine it with previously established DTI- and volumetric measures of subcortical brain structures in order to evaluate its diagnostic properties for the differentiation of PSP- RS, PSP-P and Parkinson's disease (PD). MethodsDTI metrics as well as volumes of subcortical brain regions, acquired by 3T MRI of patients with PSP-RS (n = 15), PSP-P (n = 13), and a mean disease duration of 2.7 ± 1.8 years, were quantified by probabilistic tractography as well as a validated infratentorial atlas and compared to PD (n = 18) and healthy controls (n = 20). Classification accuracy of MRI measures was tested by consecutive linear discriminant analyses. ResultsDTI metrics of the anterior thalamic radiation, the corticospinal tract, the superior longitudinal fasciculus, the bundles of the corpus callosum and cingulate, the dentatorubrothalamic tract as well as volumes of the dorsal midbrain, globus pallidus and thalamus were significantly altered in PSP-RS and to a lesser extent in PSP-P compared to PD and healthy controls. Linear discriminant analysis identified DTI metrics of the dentatorubrothalamic tract and the anterior thalamic radiation as well as the volume of the dorsal midbrain to classify correctly 91.3% of PSP-RS, PSP-P and PD patients. ConclusionsObserver-independent investigations of microstructural integrity of major fiber bundles improved existing MRI processing strategies to differentiate PSP-P from PSP-RS and PD, in their early disease stages.

PSP-FTD Complex: A Possible Variant of PSP.

This study tried to find out type of lobar features found in patients with progressive supranuclear palsy (PSP) and whether they differ from those of frontotemporal dementia (FTD) as both of these are tauopathies. We studied lobar functions of 45 patients with PSP. Five (11.1%) patients had no lobar feature; 11 (24.4%) had PSP-like features like apathy, frontal release signs, impaired motor Luria written sequences, and fist-edge-palm test; and 29 (64.4%) patients had FTD-like lobar features like disinhibition, poor naming, and word finding difficulty. Among features resembling FTD, behavioural variant type occurred in 31.1%, primary progressive aphasia type occurred in 58.6%, 3.4% patients had semantic dementia type features, and 6.9% were unclassified. Hence, patients with PSP with lobar features may fall in the middle of PSP-FTD spectrum with frontal lobe features typical of PSP (PSP-frontal like) and those with frontal lobe features resembling FTD (PSP-FTD complex) in between.

Brain volume and flortaucipir analysis of progressive supranuclear palsy clinical variants.

Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy that is associated with different clinical variants, including PSP-Richardson's syndrome (PSP-RS), PSP-parkinsonism (PSP-P), PSP-corticobasal syndrome (PSP-CBS), PSP-frontal (PSP-F), PSP-progressive gait freezing (PSP-PGF) and PSP-speech/language (PSP-SL). While PSP-RS has been well-characterized on neuroimaging, the characteristics of the other atypical variants are less well defined and it is unknown how they compare to each other or relate to neuropathology. We aimed to assess and compare regional atrophy on MRI and [18F]flortaucipir uptake on PET across PSP variants. 105 PSP patients (53 PSP-RS, 23 PSP-SL, 12 PSP-P, 8 PSP-CBS, 5 PSP-F and 4 PSP-PGF) underwent volumetric MRI, with 59 of these also undergoing flortaucipir PET. Voxel-level and region-level analyses were performed comparing PSP variants to 30 controls and to each other. Semi-quantitative tau burden measurements were also performed in 21 patients with autopsy-confirmed PSP. All variants showed evidence for atrophy or increased flortaucipir uptake in striatum, globus pallidus and thalamus. Superior cerebellar peduncle volume loss was only observed in PSP-RS, PSP-CBS and PSP-F. Volume loss in the frontal lobes was observed in PSP-SL, PSP-CBS and PSP-F, with these variants also showing highest cortical tau burden at autopsy. The PSP-P and PSP-PGF variants showed more restricted patterns of neurodegeneration predominantly involving striatum, globus pallidus, subthalamic nucleus and thalamus. The PSP-SL variant showed greater volume loss and flortaucipir uptake in supplementary motor area and motor cortex compared to all other variants, but showed less involvement of subthalamic nucleus and midbrain. Compared to PSP-RS, PSP-P had larger midbrain volume and greater flortaucipir uptake in putamen. The PSP variants have different patterns of involvement of subcortical circuitry, perhaps suggesting different patterns of disease spread through the brain. These findings will be important in the development of appropriate neuroimaging biomarkers for the different PSP variants.

Alexithymia and anhedonia in early Richardson's syndrome and progressive supranuclear palsy with predominant parkinsonism.

IntroductionPhenotypic variants of progressive supranuclear palsy (PSP) are all characterized by the combination of motor symptoms of parkinsonism with a number of neuropsychiatric and cognitive disorders. Despite the strong effort in characterizing these features in PSP, alexithymia and anhedonia have not been investigated at present. Here, we aimed at investigating the qualitative and quantitative differences of alexithymia and anhedonia in the two more frequent variants of PSP, Richardson's syndrome (PSP‐RS) and PSP with predominant parkinsonism (PSP‐P) compared to Parkinson's disease (PD) patients recruited within 24 months after the onset of motor symptoms.MethodsOne hundred fifty‐five PD, 11 PSP‐P, and 14 PSP‐RS patients underwent clinical, neuropsychiatric, and neuropsychological evaluations. Alexithymia was assessed using the Toronto Alexithymia Scale‐20 item (TAS‐20), and hedonic tone was measured by the Snaith–Hamilton Pleasure Scale (SHAPS).ResultsIn PSP‐P and PSP‐RS patients, the frequency of alexithymia diagnosis was higher than in PD. On the TAS‐20 scores, PSP‐RS performed worse in the total score and in F2 sub‐scale when compared to PD. Among patients with diagnosis of depression, PSP‐RS showed higher scores in TAS‐20 total and TAS‐20 F2 than PD. No significant differences in TAS‐20 scores were found in nondepressed patients. Finally, we did not find significant differences among PD, PSP‐P, and PSP‐RS groups in the SHAPS scores.ConclusionsAlexithymia is identifiable very early in PSP‐P and PSP‐RS patients. Alexithymic symptoms differentiate PSP‐RS group from PD group but not between the two subtypes of PSP. Further, alexithymia in PSP seems to be predicted by the presence of depression. Altered emotional capability could be related to specific neurophysiological dysfunction occurring precociously in PSP; therefore, its identification could orient the diagnosis toward PSP cases.

Dysphagia in Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is the most common Parkinson-Plus syndrome and is associated with early onset of dysphagia relative to Parkinson Disease. The current study contributes to the growing understanding of swallowing dysfunction in PSP by describing oropharyngeal swallowing characteristics in a large prospective cohort of participants with PSP employing a nationally standardized videofluoroscopy protocol and a disease severity scale developed expressly for PSP. Participants were 51 adults diagnosed with PSP. Each participant underwent a clinical interview and standardized videofluorographic assessment. Swallowing function was characterized with the Modified Barium Swallow Impairment Scale (MBSImP) and Penetration-Aspiration Scale (PAS). Variables of interest were participant-reported difficulties with liquids and/or solids; overall impression score for each of the 17 individual MBSImP components, as well as Oral Total Sum and Pharyngeal Total Sum; and PAS. Data were described with median interquartile range, counts, and proportions. Spearman's rank correlations were calculated between MBSImP scores and participant-reported indices, FOIS, and PSP Rating Scale. Approximately two-thirds of participants reported difficulties with liquids, solids, or both, although fewer than 15% reported modifying consistencies. Videofluorographic findings included predominant oral phase impairments, including back and forth rocking motion of the tongue, delayed initiation of the pharyngeal swallow, and oral residue. Pharyngeal phase impairments were relatively infrequent and comparatively mild, with the exception of reduced tongue base retraction contributing to pharyngeal residue, and mildly disrupted laryngeal vestibule closure. Disease severity correlated significantly with oral (r = .0.42, p = .0.002) and pharyngeal (r = 0.41, p = .0.003) total sum scores as well as with the oral phase components of oral transport (r = .0.33, p = .0.02) and initiation of the pharyngeal swallow (r = .0.38, p = .0.007), and PAS for thin liquids (r = .0.44, p = .0.001). The PSP Rating Scale was not more strongly correlated with swallowing impairment than has been reported for other disease severity rating scales. Dysphagia is a common complaint of patients with PSP. The current findings corroborate and expand upon those reported in the literature, detailing relatively more frequent and more severe oral phase impairments and relatively spared hyolaryngeal excursion. Further research is needed to characterize the progression of dysphagia in PSP and to determine whether dysphagia varies in character or in rate of progression across variants of PSP.

Stereotypic behaviours in frontotemporal dementia and progressive supranuclear palsy

IntroductionThe behavioural variant of frontotemporal dementia (bvFTD), and the Richardson variant of progressive supranuclear palsy (PSP-RS) share several clinical signs and symptoms. Since stereotypic behaviours are fairly common in bvFTD, and are also described in other degenerative dementias including Alzheimer's disease, and parkinsonisms with dementia, we aimed to examine the extent to which stereotypies also characterise PSP-RS. MethodsWe compared 53 bvFTD patients with 40 demented PSP-RS patients, seen consecutively as outpatients at four Italian Hospitals. Patients were assessed by the Neuropsychiatric Inventory (NPI); Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) for cognitive functions; Stereotypy Rating Inventory (SRI) for stereotypies; Unified Parkinson's Disease Rating Scale (UPDRS) for motor function; and Activities of Daily Living (ADL) to assess autonomy in daily life. ResultsThe groups did not differ for age, illness duration, cognitive functions or total NPI score; PSP-RS had significantly more depressive symptoms and greater motor and autonomy compromise than bvFTD. The groups did not differ significantly on total SRI score, but bvFTD had significantly more cooking and eating stereotypies. Twenty-three (57.5%) PSP-RS and 43 (81%) bvFTD patients had at least one stereotypy; 16/23 (69.5%) PSP-RS and 9/43 (20.9%) bvFTD patients appeared aware of their stereotypies. ConclusionStereotypies were common in our demented PSP-RS patients. Further studies on earlier stage non-demented PSP patients are required to ascertain whether stereotypies are characteristic of PSP in general or are confined to PSP-RS, and whether they may be used to suggest a PSP diagnosis early in disease course.

Vestibular symptoms as the presenting feature of progressive supranuclear palsy

First described in 1964, progressive supranuclear palsy (PSP) is a chronic, sporadic, progressive neurodegenerative tauopathy. Substantial phenotypic variability inherent in PSP confers difficulty to diagnosis. Although the classic presentation, termed PSP-Richardson’s syndrome, has been well described, additional variants of PSP are increasingly emerging. Phenotypes described to date include PSP-parkinsonism, PSP-pure akinesia with gait freezing, PSP-corticobasal syndrome or PSP-progressive non-fluent aphasia. However, there has been scant description of vestibular features in PSP. Herein, we report three similar cases with ‘probable PSP’ who presented with a poorly defined vestibular syndrome and early falls, highlighting an uncommon and as yet under-recognised, vestibular presentation of PSP. Further description of the natural history of this unusual vestibular presentation of PSP may assist in earlier diagnosis and prevent mismanagement of such patients.

Neuropsychiatric and cognitive profile of early Richardson's syndrome, Progressive Supranuclear Palsy-parkinsonism and Parkinson's disease

IntroductionThe two main variants of Progressive Supranuclear Palsy (PSP), Richardson's syndrome (PSP-RS) and PSP-parkinsonism (PSP-P), share motor and non-motor features with Parkinson's disease (PD) particularly in the early stages. This makes the precocious diagnosis more challenging. We aimed at defining qualitative and quantitative differences of neuropsychiatric and neuropsychological profiles between PSP-P, PSP-RS and PD patients recruited within 24 months after the onset of symptoms, in order to clarify if the identification of peculiar cognitive and psychiatric symptoms is of help for early PSP diagnosis. MethodsPD (n = 155), PSP-P (n = 11) and PSP-RS (n = 14) patients were identified. All patients were submitted to clinical, neurological, neuropsychiatric diagnostic evaluation and to a comprehensive neuropsychiatric and neuropsychological battery. Predictors of PSP-P and PSP-RS diagnosis were identified by multivariate logistic regressions including neuropsychiatric and neuropsychological features that differed significantly among groups. ResultsThe three groups differed significantly at the Apathy Rating Scale score and at several neuropsychological domains. The multivariate logistic regressions indicated that the diagnosis of PSP-RS was predicted by phonological verbal fluency deficit whereas the presence of apathy significantly predicted the PSP-P diagnosis. ConclusionPeculiar neuropsychiatric and neuropsychological symptoms are identifiable very precociously in PSP-P, PSP-RS and PD patients. Early phonological verbal fluency deficit identifies patients with PSP-RS whereas apathy supports the diagnosis of PSP-P.

Comparison of MRI findings among pure akinesia with gait freezing, Richardson’s syndrome, and Parkinson’s disease

Background: Pure akinesia with gait freezing (PAGF) is one of the atypical variants of progressive supranuclear palsy. The diagnostic value of quantitative MRI measurements in patients with PAGF has remained to be elucidated.

Subregional Pattern of Striatal Dopamine Transporter Loss on 18F FP-CIT Positron Emission Tomography in Patients With Pure Akinesia With Gait Freezing

ImportancePure akinesia with gait freezing (PAGF) is a clinical syndrome characterized by freezing of gait, handwriting, and speech without abnormal eye movement or cognitive impairment. Several studies have suggested that PAGF may be a variant of progressive supranuclear palsy (PSP). However, the characteristics of striatal dopamine transporter loss in PAGF are unknown.ObjectiveTo investigate the subregional pattern of striatal dopamine transporter loss in patients with PAGF in comparison with patients with PSP and those with Parkinson disease (PD).Design, Setting, and ParticipantsThis retrospective case-control study included 15 patients with PAGF, 27 with PD, 20 with PSP, and 11 healthy controls who underwent F-18-fluorinated-N-3-fluoropropyl-2β-carboxymethoxy-3β-(4-iodophenyl)-nortropane (18F FP-CIT) positron emission tomography between September 1, 2008, and July 31, 2014. The positron emission tomographic images were analyzed with 12 striatal subregional and 1 occipital volume-of-interest templates. The specific to nonspecific binding ratio (SNBR) and intersubregional ratio (ISR) in patients with PAGF were compared with those in patients with PD and those with PSP.Main Outcomes and MeasuresComparisons of SNBRs of striatal subregions and ISR among patients with PAGF, PD, and PSP and healthy controls.ResultsThe mean (SD) SNBRs (1.4 [0.7]) of the whole striatum in the 15 patients with PAGF (mean [SD] age, 71.4 [6.6] years; 7 men and 8 women) were similar to those in the 20 patients (mean [SD] age, 70.6 [4.5] years; 11 men and 9 women) with PSP (1.5 [0.5]) but significantly lower than those in the 27 patients (mean [SD] age, 67.7 [5.3] years; 10 men and 17 women) with PD (3.0 [1.3]). The mean (SD) SNBRs of the caudate nuclei in patients with PAGF (1.3 [0.9]) were significantly lower than those in patients with PD (3.5 [1.5]; P < .001) but slightly higher than those in patients with PSP (1.2 [0.5]). The mean [SD] anterior caudate to ventral striatum ISRs in patients with PAGF (0.5 [0.3]) were similar to those in patients with PSP (0.4 [0.2]) but not in patients with PD (1.0 [0.2]). The mean (SD) posterior to anterior putamen ISRs in patients with PAGF (0.4 [0.2]) were similar to those in patients with PD (0.5 [0.2]) and those with PSP (0.4 [0.2]).Conclusions and RelevanceOn 18F FP-CIT positron emission tomography, patients with PAGF show a pattern of preferential dopaminergic loss similar to that seen in patients with PSP. These results suggest a similar distribution of regional neuronal loss in the substantia nigra pars compacta between PAGF and PSP. This finding may be one of the pathophysiological results suggesting that PAGF is a phenotypic variant of PSP.

AV-1451 TAU-PET IN CLINICAL VARIANTS OF PROGRESSIVE SUPRANUCLEAR PALSY

Different clinical variants of progressive supranuclear palsy (PSP) have been described, the most common of which is Richardson’s syndrome. The relationship between these clinical variants and pathology is heterogeneous, with all variants associated with tau pathology but with varying patterns of tau deposition within, and across, brain regions. Tau-PET imaging using AV-1451 demonstrates striking uptake in Alzheimer’s disease (AD), although it is unclear whether uptake is observed in the different variants of PSP. We aimed to determine whether tau deposition can be identified on AV-1451 tau-PET in different clinical variants of PSP compared to cognitively normal (CN) subjects and to compare the degree of uptake with that observed in Alzheimer’s disease (AD). Six subjects representing four clinical variants of PSP (Richardson’s syndrome n=3, pure akinesia with gait freezing (PAGF) n=1, primary progressive apraxia of speech (PPAOS) n=1, and post-surgical PSP n=1) underwent tau-PET imaging with AV-1451. These subjects were compared to 101 age-matched CN subjects and 19 subjects with AD. Regional tau-PET uptake was calculated for nine regions typically associated with tau deposition in PSP (midbrain, caudate, putamen, pallidum, supplementary motor area, superior frontal lobe, pre and post central cortex, and thalamus). The PSP subjects showed evidence for subtle elevated tau-PET uptake compared to CN subjects across all regions. Uptake was particularly evident in midbrain, pallidum, supplementary motor area and precentral cortex (Figure). The degree of tau-PET uptake in PSP was lower than AD across all regions except midbrain, pallidum and thalamus. Subtle regional differences were observed between the different clinical variants of PSP. Uptake was generally the highest in those with Richardson’s syndrome across all regions, except for precentral cortex and supplementary motor area which showed highest uptake in PPAOS. PAGF predominantly involved basal ganglia and post-surgical PSP showed subtle uptake in midbrain and thalamus.

Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci.

To determine the effects of single nucleotide polymorphisms (SNPs) identified in a genome-wide association study of progressive supranuclear palsy (PSP), we tested their association with brain gene expression, CpG methylation and neuropathology. In 175 autopsied PSP subjects, we performed associations between seven PSP risk variants and temporal cortex levels of 20 genes in-cis, within ±100kb. Methylation measures were collected using reduced representation bisulfite sequencing in 43 PSP brains. To determine whether SNP/expression associations are due to epigenetic modifications, CpG methylation levels of associated genes were tested against relevant variants. Quantitative neuropathology endophenotypes were tested for SNP associations in 422 PSP subjects. Brain levels of LRRC37A4 and ARL17B were associated with rs8070723; MOBP with rs1768208 and both ARL17A and ARL17B with rs242557. Expression associations for LRRC37A4 and MOBP were available in an additional 100 PSP subjects. Meta-analysis revealed highly significant associations for PSP risk alleles of rs8070723 and rs1768208 with higher LRRC37A4 and MOBP brain levels, respectively. Methylation levels of one CpG in the 3' region of ARL17B associated with rs242557 and rs8070723. Additionally, methylation levels of an intronic ARL17A CpG associated with rs242557 and that of an intronic MOBP CpG with rs1768208. MAPT and MOBP region risk alleles also associated with higher levels of neuropathology. Strongest associations were observed for rs242557/coiled bodies and tufted astrocytes; and for rs1768208/coiled bodies and tau threads. These findings suggest that PSP variants at MAPT and MOBP loci may confer PSP risk via influencing gene expression and tau neuropathology. MOBP, LRRC37A4, ARL17A and ARL17B warrant further assessment as candidate PSP risk genes. Our findings have implications for the mechanism of action of variants at some of the top PSP risk loci.