Criteria For Progressive Supranuclear Palsy Research Articles

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.

Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis. To investigate the potential of the novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed PSP. In this cross-sectional study, participants underwent dynamic 18F-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019. Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, 18F-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex. Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP-non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [50.0%] with Parkinson disease and multiple system atrophy, 7 were men; mean [SD] age, 61 [8] years; of 10 [50.0%] with Alzheimer disease, 5 were men; mean [SD] age, 69 [10] years). Postmortem autoradiography showed blockable 18F-PI-2620 binding in patients with PSP and no binding in healthy controls. The in vivo findings from the first large-scale observational study in PSP with 18F-PI-2620 indicated significant elevation of tracer binding in PSP target regions with strongest differences in PSP vs control groups in the globus pallidus internus (mean [SD] distribution volume ratios: PSP-RS, 1.21 [0.10]; PSP-non-RS, 1.12 [0.11]; healthy controls, 1.00 [0.08]; Parkinson disease/multiple system atrophy, 1.03 [0.05]; Alzheimer disease, 1.08 [0.06]). Sensitivity and specificity for detection of PSP-RS vs any control group were 85% and 77%, respectively, when using classification by at least 1 positive target region. This multicenter evaluation indicates a value of 18F-PI-2620 to differentiate suspected patients with PSP, potentially facilitating more reliable diagnosis of PSP.

Is brain perfusion a differentiating feature in the comparison of Progressive Supranuclear Palsy Syndrome (PSPS) and Corticobasal Syndrome (CBS)?

The aim of this work is to present whether SPECT 99mTc-HMPAO can be a method of examination to possibly differentiate the syndromes. 21 patients with PSP syndrome and 14 patients with corticobasal syndrome (CBS) were examined using SPECT 99mTc-HMPAO. Perfusion single photon emission computed tomography (SPECT) as a method of examination of progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) has not been extensively analyzed in contemporary literature. Recent criteria of PSP and CBS do not describe this method of examination as primary or additional. Extended analysis was done in the context of regions of interest affected by significant average hypoperfusion (>2 standard deviations). Differences between the syndromes were subsequently evaluated using the U-Mann-Whitney test. Lack of significant differences (p < 0.05) were observed in 92 out of 94 regions of interest. However, certain asymmetries were observed in a minority of regions in both of the syndromes. Additionally, the authors of the study verified possible differences of asymmetry of perfusion of both of the syndromes. The overlapping of clinical manifestations and locations of hypoperfusion leads to a question of whether the syndromes should be interpreted as separate entities or variants of the same disease.

Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome

Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), may be difficult to distinguish in early stages and are often misdiagnosed as Parkinson disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes but have not been prospectively studied. To define the distinguishing features of PSP and CBS subtypes and to assess their usefulness in facilitating early diagnosis and separation from PD. This cohort study recruited patients with APS and PD from movement disorder clinics across the United Kingdom from September 1, 2015, through December 1, 2018. Patients with APS were stratified into the following groups: those with Richardson syndrome (PSP-RS), PSP-subcortical (including PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (including PSP-frontal and PSP-CBS overlap subtypes), MSA-parkinsonism, MSA-cerebellar, CBS-Alzheimer disease (CBS-AD), and CBS-non-AD. Data were analyzed from February 1, through May 1, 2019. Baseline group comparisons used (1) clinical trajectory; (2) cognitive screening scales; (3) serum neurofilament light chain (NF-L) levels; (4) TRIM11, ApoE, and MAPT genotypes; and (5) volumetric magnetic resonance imaging measures. A total of 222 patients with APS (101 with PSP, 55 with MSA, 40 with CBS, and 26 indeterminate) were recruited (129 [58.1%] male; mean [SD] age at recruitment, 68.3 [8.7] years). Age-matched control participants (n = 76) and patients with PD (n = 1967) were included for comparison. Concordance between the antemortem clinical and pathologic diagnoses was achieved in 12 of 13 patients with PSP and CBS (92.3%) undergoing postmortem evaluation. Applying the Movement Disorder Society PSP diagnostic criteria almost doubled the number of patients diagnosed with PSP from 58 to 101. Forty-nine of 101 patients with reclassified PSP (48.5%) did not have the classic PSP-RS subtype. Patients in the PSP-subcortical group had a longer diagnostic latency and a more benign clinical trajectory than those in PSP-RS and PSP-cortical groups. The PSP-subcortical group was distinguished from PSP-cortical and PSP-RS groups by cortical volumetric magnetic resonance imaging measures (area under the curve [AUC], 0.84-0.89), cognitive profile (AUC, 0.80-0.83), serum NF-L level (AUC, 0.75-0.83), and TRIM11 rs564309 genotype. Midbrain atrophy was a common feature of all PSP groups. Eight of 17 patients with CBS (47.1%) undergoing cerebrospinal fluid analysis were identified as having the CBS-AD subtype. Patients in the CBS-AD group had a longer diagnostic latency, relatively benign clinical trajectory, greater cognitive impairment, and higher APOE-ε4 allele frequency than those in the CBS-non-AD group (AUC, 0.80-0.87; P < .05). Serum NF-L levels distinguished PD from all PSP and CBS cases combined (AUC, 0.80; P < .05). These findings suggest that studies focusing on the PSP-RS subtype are likely to miss a large number of patients with underlying PSP tau pathology. Analysis of cerebrospinal fluid defined a distinct CBS-AD subtype. The PSP and CBS subtypes have distinct characteristics that may enhance their early diagnosis.

Falls in Progressive Supranuclear Palsy.

ABSTRACTBackgroundDespite falls being an almost universal clinical feature and central to the presentation and diagnostic criteria of progressive supranuclear palsy, our understanding of falls is surprisingly limited and there are few effective treatment options.ObjectivesTo provide an overview of the topic of the impact, assessment, mechanism, and management of falls in progressive supranuclear palsy.MethodsWe performed a literature search for “falls” and “progressive supranuclear palsy” and included additional relevant literature known to us. We synthesized this literature with experience from clinical practice.ResultsWe review current understanding of the pathophysiology of falls, highlighting the roles of the indirect pathway and the pedunculopontine nucleus. We go on to identify shortcomings in commonly used assessments to measure falls. We discuss medical and nonmedical fall prevention strategies, and finally we discuss balancing falls risk against promoting independence.ConclusionFalls are central to progressive supranuclear palsy presentation and diagnosis. Indirect locomotor and pedunculopontine nucleus dysfunction are thought to be the neural substrate of falls in this condition. Attempts to measure and prevent falls, by medical and nonmedical means, are currently limited. A personalized approach is advocated in the management of falls.

Are the International Parkinson disease and Movement Disorder Society progressive supranuclear palsy (IPMDS-PSP) diagnostic criteria accurate enough to differentiate common PSP phenotypes?

The International Parkinson Disease and Movement Disorder Society PSP study group (IPMDS-PSP) recently published new clinical diagnostic criteria for progressive supranuclear palsy (PSP). Currently, there is no data regarding the accuracy of these sets of criteria for differentiating various PSP phenotypes. We discuss the accuracy of the IPMDS-PSP criteria for differentiation of patients with the PSP- Richardson phenotype (PSP-RS) from those with the PSP-Parkinsonism (PSP-P) using data from a sample of 274 clinically diagnosed PSP patients participating in the Environmental Genetic PSP (ENGENE-PSP) case control study. Using National Institute of Neurological Disorders and Stroke and the Society for PSP (NINDS-SPSP) criteria and the Williams criteria we categorized 259 of these patients as probable PSP-RS and 15 as PSP-P. The IPD-MDS PSP-RS and PSP-P criteria were unable to distinguish the PSP-RS from the PSP-P phenotypes in this sample. Nearly all (92.6%; 240 out of 259) the PSP-RS patients and over half (60%; 9 out of 15) of the PSP-P patients fulfilled both the IPMDS criteria for PSP-RS and PSP-P. Applying the newly proposed multiple allocation extinction rules decreased the number of overlapping diagnoses among the NINDS-SPSP PSP-RS patients, however problems remained in the PSP-P group. Diagnostic accuracy might be improved by modification of timelines for development of falls and other parkinsonian features.

Clinical spectrum of higher level gait disorders (HLGD) in a tertiary care movement disorder clinic - A prospective study

Gait disorders are classified into lower, middle, and higher sensorimotor levels (Nutt 1993). HLGD are common and disabling in the elderly. To study the burden, demographic profile and etiologic profile of HLGD in a tertiary care center in India. Patients presenting with Parkinsonism and predominant lower limb involvement in the form of gait difficulty (freezing, shuffling or slowness) and/or postural instability (imbalance or falls), not completely accounted for by visual, vestibular or proprioceptive deficits, were studied. Follow up was done for 3 months. 56 consecutive patients with HLGD, forming 3.38% of new referrals, were included. 23 patients (41%) fulfilled criteria for Progressive Supranuclear Palsy (PSP) (Höglinger 2017), 11 (20%) for vascular parkinsonism (VaP) (Winikates 1999), 9 (16%) for Normal pressure hydrocephalus (NPH) (Relkin 2013), and 2 (4%) had a multisensory gait disorder. 11 cases (20%) remained unclassified. Patients with PSP (Table 1) had REM Sleep behavior disorder (RBD), extraocular abnormalities (EOM), axial rigidity, masked facies, gait freezing, inability to arise from chair unsupported, severe postural instability on pull test, and midbrain atrophy on MRI brain. Patients with VaP had ≥2 vascular risk factors, pyramidal signs, broad-based asymmetric gait, and leukoaraiosis on MRI brain. NPH was a diagnosis of exclusion (Table 1) with ventriculomegaly on MRI, and improvement at lumbar tap test (LTT) which eventually predicted VP Shunt responsiveness. PSP is the commonest HLGD. VaP and NPH are other common HLGD. Reaching a diagnosis requires assessment of all features in unison. Clinical phenotype evolves with time on follow up.

Validation of the movement disorder society criteria for the diagnosis of 4-repeat tauopathies.

The Movement Disorder Society criteria for progressive supranuclear palsy introduced the category "probable 4-repeat (4R)-tauopathy" for joint clinical diagnosis of progressive supranuclear palsy and corticobasal degeneration. To validate the accuracy of these clinical criteria for "probable 4R-tauopathy" to predict underlying 4R-tauopathy pathology. Diagnostic accuracy for 4R-tauopathies according to the established criteria was estimated retrospectively in autopsy-confirmed patients with progressive supranuclear palsy and corticobasal degeneration (grouped as 4R-tauopathies), and Parkinson's disease, multiple system atrophy, and frontotemporal lobar degeneration (grouped as non-4R-tauopathies). We identified 250 cases with progressive supranuclear palsy (N = 195) and corticobasal degeneration (N = 55) and with and non-4R-tauopathies (N = 161). Sensitivity and specificity of "probable 4R-tauopathy" was 10% and 99% in the first year and 59% and 88% at final record. The new diagnostic category "probable 4R-tauopathy" showed high specificity and may be suitable for the recruitment of patients with progressive supranuclear palsy and corticobasal degeneration into therapeutic trials targeting 4R-tauopathy. The low sensitivity underpins the need for diagnostic biomarkers. © 2019 International Parkinson and Movement Disorder Society.

Utility of the Movement Disorders Society Criteria for Progressive Supranuclear Palsy in Clinical Practice.

When the 2017 Movement Disorders Society Criteria for progressive supranuclear palsy is applied, patients may appear to have multiple phenotypes. The maximum allocation extinction rules were developed to provide a consistent method for applying the criteria and reaching a single diagnostic label. In this study, we apply both to a neuropathologic cohort of progressive supranuclear palsy and other parkinsonian conditions. An autopsy cohort of 54 patients with progressive supranuclear palsy and 56 patients with other neuropathologic diseases was selected. Clinical data were retrospectively abstracted, and the diagnostic criteria for progressive supranuclear palsy were applied. All possible phenotypes applicable were listed and maximum allocation extinction rules were applied to assess reduction in the number of phenotypes ascribed per patient. In the progressive supranuclear palsy group, 52 patients met the criteria for multiple phenotypes, with an average of 7 phenotypes per patient. In the nonprogressive supranuclear palsy group, all 56 patients had features of more than one phenotype, up to 3 per patient. After application of maximum allocation extinction rules, the majority of the patients in both groups had a single predominant phenotype. Freezing of gait, supranuclear gaze palsy, and frontal behavioral syndrome were more common in the progressive supranuclear palsy group. The diagnostic criteria for progressive supranuclear palsy identify many clinical features, thereby leading to assignment of multiple phenotypes per patient. We demonstrate that the maximum allocation extinction rules can effectively lead to a single consensus phenotype, maintaining a uniform diagnostic label for clinical and research applications.

Evaluation of mesencephalic diameter using MRI in the diagnostic differentiation of progressive supranuclear palsy (PSP) from parkinson disease (PD)

Diagnostic differentiation of progressive supranuclear palsy (PSP) from Parkinsons disease (PD) is difficult task in early stages. MR image based diagnosis plays a vital role in differentiation of parkinsonian syndromes because of its effective depiction of tissue anatomy. This study was designed to evaluate mesencephalic diameter using MRI in the differentiation of PSP from PD. A total 40 cases (20 cases clinically diagnosed with PSP and 20 cases with PD) and 20 healthy control subjects> 45 years were included. Cases were undergone with MRI (SEIMENS 1.5 Tesla) to detect antero-posterior diameter and superior profile of midbrain, tegmental hyper intensity, putamen intensity, Middle cerebellar peduncle width. AP diameter of midbrain was < 15mm in all the PSP cases, but none of the PD cases and control subjects. It has 100% sensitivity and specificity in differentiating PSP from PD and control subjects. The abnormal superior profile has 81% sensitivity, 80% specificity and 88% accuracy in identification of PSP from PD and control subjects. The measurement of mesencephalic diameter on standard routine T2 W MR images can be accurate to differentiate PSP cases from PD cases. Including this simple measure in the diagnostic criteria of PSP give effective outcome.

An Evaluation of the Progressive Supranuclear Palsy Speech/Language Variant.

The Movement Disorder Society clinical criteria for progressive supranuclear palsy (PSP) provide a framework for assessing the presence/severity of clinical symptoms and define a speech/language variant of PSP. To evaluate the clinical criteria in a cohort of speech/language patients with longitudinal follow-up. A total of 52 patients presenting with progressive apraxia of speech and/or agrammatic aphasia were followed longitudinally for up to 6 visits with clinical assessments and magnetic resonance imaging. We assessed oculomotor, postural instability, and akinesia diagnostic levels and determined whether patients met criteria for possible PSP-speech/language or probable PSP at each visit. Kaplan-Meier curves assessed time-to-event probabilities according to age. Statistical parametric mapping and midbrain volume were assessed according to disease progression. Few PSP symptoms were observed early in the disease, with oculomotor abnormalities and falls first observed 2 years after onset. Falls were more common than vertical supranuclear gaze palsy. Bradykinesia and rigidity commonly developed but axial was rarely greater than appendicular rigidity. During follow-up, 54% met criteria for possible PSP-speech/language, 38% for probable PSP-Richardson's syndrome, and 38% for probable PSP-parkinsonism, most commonly 6 to 6.9 years after onset. The probability of developing PSP was greater when onset was at an age older than 70 years. Patients who progressed to probable PSP had more parkinsonism and oculomotor impairment at baseline and greater midbrain atrophy when compared with those who did not develop probable PSP. Symptoms typical of PSP commonly develop in patients presenting with a progressive speech/language disorder. Older age appears to be an important prognostic factor in these patients.

Motor, cognitive and behavioral differences in MDS PSP phenotypes.

Movement Disorder Society (MDS) new diagnostic criteria for Progressive Supranuclear palsy (PSP) identifying different disease phenotypes were recently released. The aim of the present study is to report on the cognitive and behavioral features of the different phenotypes diagnosed according to the MDS criteria. Forty-nine PSP patients underwent an extensive battery of clinical assessments. Differences between PSP subtypes were computed with χ2 or ANOVA tests. Using the z scores, subjects were classified as having normal cognition, mild cognitive impairment, single or multiple domain, and dementia. A logistic regression model was implemented to investigate the major determinants of PSP non-Richardson's syndrome phenotype. Half of the cohort presented Richardson's syndrome (46.9%), followed by PSP with parkinsonism and corticobasal syndrome (22.4% and 14.2%, respectively). Richardson's syndrome and PSP with corticobasal syndrome presented a similar burden of disease. The only cognitive testing differentiating the phenotypes weresemantic fluency and ideomotor apraxia. The majority of our cohort was either affected by dementia or presented normal cognition. Richardson's syndrome presented the highest rate of dementia. The only marker of PSP non-Richardson's syndrome phenotype was better performance in visuo-spatial testing, implying worse visuo-spatial abilities in PSP Richardson's syndrome. Available clinical assessments hardly capture differences between PSP phenotypes. The cognitive testing differentiating the PSP phenotypes were semantic fluency and ideomotor apraxia. In PSP, mild cognitive impairment likely represents an intermediate step from normal cognition to dementia. The only marker of PSP non-Richardson's syndrome phenotype was better performance in visuo-spatial testing.

How to apply the movement disorder society criteria for diagnosis of progressive supranuclear palsy.

The Movement Disorder Society criteria for progressive supranuclear palsy define diagnostic allocations, stratified by certainty levels and clinical predominance types. We aimed to study the frequency of ambiguous multiple allocations and to develop rules to eliminate them. We retrospectively collected standardized clinical data by chart review in a multicenter cohort of autopsy-confirmed patients with progressive supranuclear palsy, to classify them by diagnostic certainty level and predominance type and to identify multiple allocations. Comprehensive data were available from 195 patients. More than one diagnostic allocation occurred in 157 patients (80.5%). On average, 5.4 allocations were possible per patient. We developed four rules for Multiple Allocations eXtinction (MAX). They reduced the number of patients with multiple allocations to 22 (11.3%), and the allocations per patient to 1.1. The proposed MAX rules help to standardize the application of the Movement Disorder Society criteria for progressive supranuclear palsy. © 2019 International Parkinson and Movement Disorder Society.

Sensitivity and Specificity of Diagnostic Criteria for Progressive Supranuclear Palsy.

In 2017, the International Parkinson and Movement Disorder Society put forward new clinical criteria for the diagnosis of PSP, recognizing diverse PSP phenotypes. In this study, we compared the sensitivity and specificity of the new criteria with the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria at different times. Patients with clinical parkinsonism, clinical and/or neuropathological diagnosis of PSP, were identified from the Society for Progressive Supranuclear Palsy brain bank. All patients had neuropathologic diagnoses and detailed clinical examination performed by a neurologist at 1 of the 3 Mayo Clinic sites, in Florida, Arizona, and Minnesota. Clinical symptoms and signs were abstracted retrospectively in a blinded fashion and used to determine whether patients met either diagnostic criterion. Patients were divided into early and late disease stage groups using a 3-year cutoff. A total of 129 patients were included, of whom 66 had PSP pathology (51%). The remainder had other neurodegenerative diseases. The overall sensitivity of the International Parkinson and Movement Disorder Society criteria was 87.9%, compared with 45.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria, whereas the specificity of the International Parkinson and Movement Disorder Society probable PSP criteria was 85.7%, compared with 90.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy. Individual patients were noted to have features of multiple PSP phenotypes. The International Parkinson and Movement Disorder Society criteria recognize several phenotypes of progressive supranuclear palsy and hence have higher sensitivity than the previous criteria. © 2019 International Parkinson and Movement Disorder Society.

The cognitive profile and executive function of progressive supranuclear palsy and multiple system atrophy patients

Introduction: Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are two relatively common forms of atypical parkinsonism seen in movement disorder clinics. This study provides an insight into the cognitive dysfunction in these two diseases. Aims: This study aims at assessing the cognitive and executive dysfunction and investigating the relationship between age, education, Montreal cognitive assessment (MOCA), and frontal assessment battery (FAB) score in a group of Indian patients with MSA and PSP. Materials and Methods: This is a hospital-based observational study with the recruitment of patients of MSA and PSP based on consensus criteria and The National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy criteria, respectively. A total of 50 patients of MSA and PSP admitted or attending outpatient department in the Department of Neurology, SMS hospital, Jaipur, were analyzed for cognitive and executive functions between December 2016 and December 2018 using MOCA and FAB. The Student's t-test was used. The level of significance was determined as itsP value withP Conclusions: Cognitive dysfunction is a major finding in PSP and MSA patients. Thus, cognitive dysfunction in a patient does not rule out MSA as considered in the previous literature and is an important diagnostic finding in PSP; yet requires future research on a larger scale.

DCTN1 F52L mutation case of Perry syndrome with progressive supranuclear palsy-like tauopathy

IntroductionPerry syndrome is a rapidly progressive, autosomal dominant parkinsonism characterized by central hypoventilation, depression and severe weight loss. To date, eight DCTN1 mutations have been identified associated with Perry syndrome. A novel F52L DCTN1 mutation case of Perry syndrome is characterized by late-onset parkinsonism and frontotemporal atrophy. MethodsA Japanese woman suffered from slowly progressing parkinsonism since age 48. At age 59, she developed central hypoventilation, and required breathing assistance. Gene analysis identified a p.F52L mutation in DCTN1 and she was diagnosed with Perry syndrome. She died of aspiration pneumonia at age 74. ResultsPostmortem examination revealed severe neuronal loss in the substantia nigra and the putamen. Immunohistochemistry for DCTN1 revealed many abnormal aggregates, mainly in neurons in the brainstem and basal ganglia. Additionally, numerous abnormal phosphorylated tau deposits including neurofibrillary tangles, tuft-shaped astrocytes and coiled bodies were observed mainly in the basal ganglia, brainstem and cerebellum. These correspond with the neuropathologic criteria for progressive supranuclear palsy. Colocalization of DCTN1 and tau were occasionally seen. Colocalization of phosphorylated α-synuclein and DCTN1 were also observed in Lewy body-like structures in oculomotor nuclei. Phosphorylated TARDBP-positive neuronal cytoplasmic inclusions were few. ConclusionIn conjunction with long disease duration and aging, our findings suggest that the F52L DCTN1 mutation may evoke severe tauopathy and moderate α-synucleinopathy.

Progressive Supranuclear Palsy: an Update.

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. 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.

18 F-flortaucipir tau positron emission tomography distinguishes established progressive supranuclear palsy from controls and Parkinson disease: A multicenter study.

18 F-flortaucipir (formerly 18 F-AV1451 or 18 F-T807) binds to neurofibrillary tangles in Alzheimer disease, but tissue studies assessing binding to tau aggregates in progressive supranuclear palsy (PSP) have yielded mixed results. We compared in vivo 18 F-flortaucipir uptake in patients meeting clinical research criteria for PSP (n = 33) to normal controls (n = 46) and patients meeting criteria for Parkinson disease (PD; n = 26). Participants underwent magnetic resonance imaging and positron emission tomography for amyloid-β (11 C-PiB or 18 F-florbetapir) and tau (18 F-flortaucipir). 18 F-flortaucipir standardized uptake value ratios were calculated (t = 80-100 minutes, cerebellum gray matter reference). Voxelwise and region-of-interest group comparisons were performed in template space, with receiver operating characteristic curve analyses to assess single-subject discrimination. Qualitative comparisons with postmortem tau are reported in 1 patient who died 9 months after 18 F-flortaucipir. Clinical PSP patients showed bilaterally elevated 18 F-flortaucipir uptake in globus pallidus, putamen, subthalamic nucleus, midbrain, and dentate nucleus relative to controls and PD patients (voxelwise p < 0.05 family wise error corrected). Globus pallidus binding best distinguished PSP patients from controls and PD (area under the curve [AUC] = 0.872 vs controls, AUC = 0.893 vs PD). PSP clinical severity did not correlate with 18 F-flortaucipir in any region. A patient with clinical PSP and pathological diagnosis of corticobasal degeneration had severe tau pathology in PSP-related brain structures with good correspondence between in vivo 18 F-flortaucipir and postmortem tau neuropathology. 18 F-flortaucipir uptake was elevated in PSP versus controls and PD patients in a pattern consistent with the expected distribution of tau pathology. Ann Neurol 2017;82:622-634.

PB 10 Identifying an imaging biomarker for progressive supranuclear palsy – a combined gray &amp; white matter meta-analysis using ALE and SDM

Background Progressive supranuclear palsy (PSP) is an atypical parkinsonian syndrome. PSP is described by clinical features of vertical gaze palsy and postural instability. Even though midbrain atrophy has been suggested as a hallmark of the disease, it has not been validated systematically so far. Methods To identify disease-specific regional atrophy in PSP, we conducted a systematic and quantitative meta-analysis on structural magnetic resonance imaging (MRI) data. Based on strict inclusion criteria 18 studies were identified in PubMed including 315 patients compared with 393 healthy controls. For analysis, the included studies were separated into studies investigating either gray or white matter atrophy. Ensuring consistent results, we used a unique approach by combining two widely used meta-analytical algorithms. The results of anatomical likelihood estimation (ALE) and Seed-basedDMapping (SDM) were superimposed in a conjunction analysis. Results The analysis of gray matter revealed that clusters in the bilateral thalamus, bilateral anterior insulae, midbrain and bilateral caudate nuclei were consistently identified as effected by both methods, SDM and ALE ( Fig. 1 ). White matter analyses revealed consistent atrophy in the bilateral superior cerebellar pedunculi, cerebral pedunculi, and midbrain. Discussion In light of previous meta-analyses investigating neurodegenerative diseases, our meta- analyses identify atrophy in the gray matter in the midbrain and in the white matter in the cerebral/cerebellar pedunculi and midbrain as disease-specific in PSP. Atrophy in these brain regions is suggested to be incorporated into new revised diagnostic criteria for PSP. The study design enabled high validity and statistical power. We combined two meta-analytic techniques, combined analyses in white and gray matter, and included the biggest cohort of PSP patients to date.

Mild Cognitive Impairment and Progression to Dementia in Progressive Supranuclear Palsy

Background: Cognitive deficits are common in progressive supranuclear palsy (PSP), but their relevance and the progression to dementia are still poorly described. The recently revised criteria for PSP consider cognitive dysfunction in the diagnostic work-up. Methods: The study retrospectively evaluated a series of 99 PSP patients with Richardson syndrome (PSP-RS), subgrouped according to cognitive and behavioural performances into PSP with normal cognition (PSP-NC), PSP with mild cognitive impairment (PSP-MCI), and PSP with dementia (PSP-D). The progression to dementia at the 3-year follow-up was assessed. Results: At baseline, 15.2% of patients were classified as PSP-NC, 43.4% as PSP-MCI, and 41.4% as PSP-D. During the 3-year follow-up, 21 out of 29 patients, previously classified as PSP-NC or PSP-MCI, converted to dementia, with an incidence rate of 241 per 1,000 patients/year. Nineteen out of 21 PSP patients (90%) developed the behavioural variant frontotemporal dementia phenotype. The only factor associated with conversion to dementia was MCI diagnosis at baseline (p = 0.023). Conclusion: Cognitive decline occurs in a great proportion of PSP-RS patients early during the disease course. In the absence of a specific phenotype, the diagnosis of MCI might identify PSP patients at greatest risk of developing dementia and should be considered further in the diagnostic assessment.