Diagnosis Of Progressive Supranuclear Palsy Research Articles

Locus coeruleus pathology in progressive supranuclear palsy, and its relation to disease severity

The locus coeruleus is the major source of noradrenaline to the brain and contributes to a wide range of physiological and cognitive functions including arousal, attention, autonomic control, and adaptive behaviour. Neurodegeneration and pathological aggregation of tau protein in the locus coeruleus are early features of progressive supranuclear palsy (PSP). This pathology is proposed to contribute to the clinical expression of disease, including the PSP Richardson’s syndrome. We test the hypothesis that tau pathology and neuronal loss are associated with clinical heterogeneity and severity in PSP.We used immunohistochemistry in post mortem tissues from 31 patients with a clinical diagnosis of PSP (22 with Richardson’s syndrome) and 6 control cases. We quantified the presence of hyperphosphorylated tau, the number of pigmented cells indicative of noradrenergic neurons, and the percentage of pigmented neurons with tau-positive inclusions. Ante mortem assessment of clinical severity using the PSP rating scale was available within 1.8 (±0.9) years for 23 patients.We found an average 49% reduction of pigmented neurons in PSP patients relative to controls. The loss of pigmented neurons correlated with disease severity, even after adjusting for disease duration and the interval between clinical assessment and death. The degree of neuronal loss was negatively associated with tau-positive inclusions, with an average of 44% of pigmented neurons displaying tau-inclusions.Degeneration and tau pathology in the locus coeruleus are related to clinical heterogeneity of PSP. The noradrenergic deficit in the locus coeruleus is a candidate target for pharmacological treatment. Recent developments in ultra-high field magnetic resonance imaging to quantify in vivo structural integrity of the locus coeruleus may provide biomarkers for noradrenergic experimental medicines studies in PSP.

Midbrain morphology in idiopathic normal pressure hydrocephalus: A progressive supranuclear palsy mimic.

Various MRI markers have been applied to support the diagnosis of progressive supranuclear palsy (PSP), such as midbrain diameter and surface, superior cerebellar peduncle (SCP) width, midbrain to pons (m/p) diameter and surface ratio and the Magnetic Resonance Parkinsonism Index (MRPI). These markers provide excellent diagnostic accuracy in discriminating Richardson's syndrome from other causes of Parkinsonism. Idiopathic normal pressure hydrocephalus (iNPH) may mimic Richardson's syndrome, particularly in cases of subtle opthalmokinetic abnormalities. The aim of this study was to compare these MRI markers in PSP and iNPH and examine their diagnostic accuracy. Forty-three patients with probable PSP, 17 patients with iNPH, and 29 controls were included. Midbrain diameter and surface, SCP width, m/p diameter and surface ratio and the MRPI were recorded. The "hummingbird sign," "morning glory sign" and "mickey mouse sign" were also evaluated. Analysis of covariance, chi-squared test, and ROC curve analysis were used as appropriate. All MRI measurements differed significantly among the three study groups. Comparison of PSP and iNPH patients produced the following significant differences: midbrain diameter (P<.0001), m/p diameter ratio (P<.0001), SCP width (P=.050), and MRPI (P=.049). None of these markers produced combined high (>80%) specificity and sensitivity. Qualitative MRI signs were specific, but lacked sensitivity. Midbrain morphology in iNPH may resemble that of PSP. Established MRI markers of midbrain and SCP atrophy cannot confidently differentiate PSP from iNPH. MRI markers do not provide combined high sensitivity and specificity for the differential diagnosis of PSP from iNPH.

Methods and utility of quantitative brainstem measurements in progressive supranuclear palsy versus Parkinson's disease in a routine clinical setting

Background and PurposeThe clinical diagnosis of progressive supranuclear palsy can be challenging, as the clinical presentation overlaps with that of Parkinson's disease and multiple system atrophy. We sought to examine the practical utility of radiologic markers of progressive supranuclear palsy by investigating whether these markers could distinguish between patients with progressive supranuclear palsy-Richardson syndrome (PSP-RS) and those with Parkinson's disease based on imaging obtained in a typical clinical setting, not in a prospective research environment. Materials and methodsThis retrospective study included 13 patients with PSP-RS and 13 patients with Parkinson's disease who were followed for either condition at our institution at the time of the study and who had MRI records available. Patients were selected without regard to type of imaging obtained. All diagnoses were confirmed by a trained movement disorders specialist using validated diagnostic criteria. Groups were matched for age and disease duration at the time of scanning. MRI records were retrospectively obtained, and image analysis was performed by investigators blinded to disease classification. Midbrain area, midbrain to pons area ratio, midbrain anterior-posterior diameter, and MR parkinsonism index were calculated for each patient. ResultsAll established measures of identifying progressive supranuclear palsy (midbrain area, midbrain to pons area ratio, midbrain anterior-posterior diameter, and MR parkinsonism index) were significantly different between patients with PSP-RS and those with Parkinson's disease. ConclusionPreviously established radiographic markers distinguishing between PSP-RS and Parkinson's disease have practical utility in the clinical setting and not just in well-designed prospective analyses.

Frontrunner in Translation: Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a four-repeat tau proteinopathy. Abnormal tau deposition is not unique for PSP and is the basic pathologic finding in some other neurodegenerative disorders such as Alzheimer's disease (AD), age-related tauopathy, frontotemporal degeneration, corticobasal degeneration, and chronic traumatic encephalopathy. While AD research has mostly been focused on amyloid beta pathology until recently, PSP as a prototype of a primary tauopathy with high clinical-pathologic correlation and a rapid course is a crucial candidate for tau therapeutic research. Several novel approaches to slow disease progression are being developed. It is expected that the benefits of translational research in this disease will extend beyond the PSP population. This article reviews advances in the diagnosis, epidemiology, pathology, hypothesized etiopathogenesis, and biomarkers and disease-modifying therapeutic approaches of PSP that is leading it to become a frontrunner in translation.

Diffusion Tensor MRI to Distinguish Progressive Supranuclear Palsy from α-Synucleinopathies.

Background The differential diagnosis of progressive supranuclear palsy (PSP) and Lewy body disorders, which include Parkinson disease and dementia with Lewy bodies, is often challenging due to the overlapping symptoms. Purpose To develop a diagnostic tool based on diffusion tensor imaging (DTI) to distinguish between PSP and Lewy body disorders at the individual-subject level. Materials and Methods In this retrospective study, skeletonized DTI metrics were extracted from two independent data sets: the discovery cohort from the Swedish BioFINDER study and the validation cohort from the Penn Frontotemporal Degeneration Center (data collected between 2010 and 2018). Based on previous neuroimaging studies and neuropathologic evidence, a combination of regions hypothesized to be sensitive to pathologic features of PSP were identified (ie, the superior cerebellar peduncle and frontal white matter) and fractional anisotropy (FA) was used to compute an FA score for each individual. Classification performances were assessed by using logistic regression and receiver operating characteristic analysis. Results In the discovery cohort, 16 patients with PSP (mean age ± standard deviation, 73 years ± 5; eight women, eight men), 34 patients with Lewy body disorders (mean age, 71 years ± 6; 14 women, 20 men), and 44 healthy control participants (mean age, 66 years ± 8; 26 women, 18 men) were evaluated. The FA score distinguished between clinical PSP and Lewy body disorders with an area under the curve of 0.97 ± 0.04, a specificity of 91% (31 of 34), and a sensitivity of 94% (15 of 16). In the validation cohort, 34 patients with PSP (69 years ± 7; 22 women, 12 men), 25 patients with Lewy body disorders (70 years ± 7; nine women, 16 men), and 32 healthy control participants (64 years ± 7; 22 women, 10 men) were evaluated. The accuracy of the FA score was confirmed (area under the curve, 0.96 ± 0.04; specificity, 96% [24 of 25]; and sensitivity, 85% [29 of 34]). Conclusion These cross-validated findings lay the foundation for a clinical test to distinguish progressive supranuclear palsy from Lewy body disorders. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Shah in this issue.

Clinicopathological co-morbidity of progressive supranuclear palsy and amyotrophic lateral sclerosis

Coexistence of distinct neurodegenerative diseases in single cases recently gathers greater attention. In this line, phenotypic co-occurrence of progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) has been documented in several cases. That said, clinicopathological co-mobidity of the two diseases has remained unproven. We investigated neuropathological characteristics of two patients who clinically presented both PSP and ALS. The patients, without family history of neurological disorders, first presented with atypical parkinsonism consistent with PSP with Richardson’s syndrome or progressive gait freezing. In a few years, they developed muscle weakness with or without pseudobulbar symptoms, which was compatible with ALS. Disease duration was 5-8 years after the onset of PSP and 1-2 years after the onset of ALS. Neuropathological findings demonstrated coexistence of PSP and ALS in both cases. Immunohistochemical examination in a recent case confirmed 4-repeat tauopathy including globose type neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies, as well as TAR DNA-binding protein 43 kDa pathology in association with upper and lower motor neuron degeneration. In this case, immunoblotting showed hyperphosphorylated full-length 4-repeat tau bands with 64 and 68 kDa and C-terminal fragments with 33 kDa, supporting the diagnosis of PSP and excluding other parkinsonian disorders such as corticobasal degeneration. Our cases highlight clinicopathological comorbidity of PSP and ALS in sporadic cases. The possibility of multiple proteinopathies should be considered when distinct symptoms developed in the disease course.

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.

Diagnostic validity of magnetic resonance parkinsonism index in differentiating patients with progressive supranuclear palsy from patients with Parkinson's disease

BackgroundProgressive supranuclear palsy is a neuropathologically defined disease, and many studies worked on detecting the diagnostic use of Magnetic resonance imaging. This article purposed to detect the diagnostic performance of Magnetic resonance parkinsonism index (MRPI). MethodsWe systematically searched electronic database PubMed for articles published since 1996 using the National Institute of Neurological Disorders and Stroke and Society for PSP (NINDS-SPSP) criteria as the diagnostic standard. Methodological quality was assessed by Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) and software Review Manager 5.3, software STATA 14.0 and meta-disc were applied in statistics analysis. ResultsTotally 14 articles were included in this article. MRPI is proved to have pooled sensitivity of 0.98, pooled specificity of 0.99 in differentiating patients with Progressive supranuclear palsy (PSP) from patients with Parkinson's disease (PD) and the area under the Receiver operating characteristic curve value was 1.00. ConclusionMRPI shows excellent performance in differentiating patients with PSP from patients with PD, the clinical usage of MRPI in auxiliary diagnosis of PSP is recommended.

Increased Signal in the Superior Cerebellar Peduncle of Patients with Progressive Supranuclear Palsy.

ObjectiveThe provisional diagnosis of progressive supranuclear palsy (PSP) depends on a combination of typical clinical features and specific MRI findings, such as atrophy of the tegmentum in the midbrain. Atrophy of the superior cerebellar peduncle (SCP) distinguishes PSP from other types of parkinsonism. Histological factors affect the conventional fluid-attenuated inversion recovery (FLAIR) signals, such as the extent of neuronal loss and gliosis.MethodsWe investigated patients with PSP to verify the percentage of patients with various PSP phenotypes presenting a high signal intensity in the SCP. Three interviewers, who were not informed about the clinical data, visually inspected the presence or absence of a high signal intensity in the SCP on the FLAIR images. We measured the pixel value in the SCP of each patient. Clinical characteristics were evaluated using the Mann-Whitney test, followed by the χ2 test.ResultsTen of the 51 patients with PSP showed a high signal intensity in the SCP on FLAIR MRI. Higher pixel values were observed within the SCP of patients with a high signal intensity in the SCP than in patients without a high signal intensity (p < 0.001). The sensitivity and specificity of the high signal intensity in the SCP of patients with PSP was 19.6% and 100%, respectively. This finding was more frequently observed in patients with PSP with Richardson’s syndrome (PSP-RS) (25.7%) than other phenotypes (6.2%).ConclusionThe high signal intensity in the SCP on FLAIR MRI might be an effective diagnostic tool for PSP-RS.

Efficient RT-QuIC seeding activity for \u03b1-synuclein in olfactory mucosa samples of patients with Parkinson\u2019s disease and multiple system atrophy

BackgroundParkinson’s disease (PD) is a neurodegenerative disorder whose diagnosis is often challenging because symptoms may overlap with neurodegenerative parkinsonisms. PD is characterized by intraneuronal accumulation of abnormal α-synuclein in brainstem while neurodegenerative parkinsonisms might be associated with accumulation of either α-synuclein, as in the case of Multiple System Atrophy (MSA) or tau, as in the case of Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP), in other disease-specific brain regions. Definite diagnosis of all these diseases can be formulated only neuropathologically by detection and localization of α-synuclein or tau aggregates in the brain. Compelling evidence suggests that trace-amount of these proteins can appear in peripheral tissues, including receptor neurons of the olfactory mucosa (OM).MethodsWe have set and standardized the experimental conditions to extend the ultrasensitive Real Time Quaking Induced Conversion (RT-QuIC) assay for OM analysis. In particular, by using human recombinant α-synuclein as substrate of reaction, we have assessed the ability of OM collected from patients with clinical diagnoses of PD and MSA to induce α-synuclein aggregation, and compared their seeding ability to that of OM samples collected from patients with clinical diagnoses of CBD and PSP.ResultsOur results showed that a significant percentage of MSA and PD samples induced α-synuclein aggregation with high efficiency, but also few samples of patients with the clinical diagnosis of CBD and PSP caused the same effect. Notably, the final RT-QuIC aggregates obtained from MSA and PD samples owned peculiar biochemical and morphological features potentially enabling their discrimination.ConclusionsOur study provide the proof-of-concept that olfactory mucosa samples collected from patients with PD and MSA possess important seeding activities for α-synuclein. Additional studies are required for (i) estimating sensitivity and specificity of the technique and for (ii) evaluating its application for the diagnosis of PD and neurodegenerative parkinsonisms. RT-QuIC analyses of OM and cerebrospinal fluid (CSF) can be combined with the aim of increasing the overall diagnostic accuracy of these diseases, especially in the early stages.

Co-morbidity of progressive supranuclear palsy and amyotrophic lateral sclerosis: a clinical-pathological case report

BackgroundThe coexistence of distinct neurodegenerative diseases in single cases has recently attracted greater attention. The phenotypic co-occurrence of progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) has been documented in several cases. That said, the clinicopathological comorbidity of these two diseases has not been demonstrated.Case presentationA 77-year-old man presented with gait disturbance for 2 years, consistent with PSP with progressive gait freezing. At 79 years old, he developed muscle weakness compatible with ALS. The disease duration was 5 years after the onset of PSP and 5 months after the onset of ALS. Neuropathological findings demonstrated the coexistence of PSP and ALS. Immunohistochemical examination confirmed 4-repeat tauopathy, including globose-type neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies as well as TAR DNA-binding protein 43 kDa pathology in association with upper and lower motor neuron degeneration. Immunoblotting showed hyperphosphorylated full-length 4-repeat tau bands (64 and 68 kDa) and C-terminal fragments (33 kDa), supporting the diagnosis of PSP and excluding other parkinsonian disorders, such as corticobasal degeneration. Genetic studies showed no abnormalities in genes currently known to be related to ALS or PSP.ConclusionsOur case demonstrates the clinicopathological comorbidity of PSP and ALS in a sporadic patient. The possibility of multiple proteinopathies should be considered when distinct symptoms develop during the disease course.

The genetic and clinico-pathological profile of early-onset progressive supranuclear palsy.

BackgroundStudies on early‐onset presentations of progressive supranuclear palsy (PSP) have been limited to those where a rare monogenic cause has been identified. Here, we have defined early‐onset PSP (EOPSP) and investigated its genetic and clinico‐pathological profile in comparison with late‐onset PSP (LOPSP) and Parkinson's disease (PD).MethodsWe included subjects from the Queen Square Brain Bank, PROSPECT‐UK study, and Tracking Parkinson's study. Group comparisons of data were made using Welch's t‐test and Kruskal‐Wallis analysis of variance. EOPSP was defined as the youngest decile of motor age at onset (≤55 years) in the Queen Square Brain Bank PSP case series.ResultsWe identified 33 EOPSP, 328 LOPSP, and 2000 PD subjects. The early clinical features of EOPSP usually involve limb parkinsonism and gait freezing, with 50% of cases initially misdiagnosed as having PD. We found that an initial clinical diagnosis of EOPSP had lower diagnostic sensitivity (33%) and positive predictive value (38%) in comparison with LOPSP (80% and 76%) using a postmortem diagnosis of PSP as the gold standard. 3/33 (9%) of the EOPSP group had an underlying monogenic cause. Using a PSP genetic risk score (GRS), we showed that the genetic risk burden in the EOPSP (mean z‐score, 0.59) and LOPSP (mean z‐score, 0.48) groups was significantly higher (P < 0.05) when compared with the PD group (mean z‐score, −0.08).ConclusionsThe initial clinical profile of EOPSP is often PD‐like. At the group level, a PSP GRS was able to differentiate EOPSP from PD, and this may be helpful in future diagnostic algorithms. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

"One line": A method for differential diagnosis of parkinsonian syndromes.

Neurological findings are important for the differential diagnosis of Parkinson's disease (PD), multiple system atrophy with predominant parkinsonian features (MSA-P), and progressive supranuclear palsy (PSP). There is currently no fast and reliable method to distinguish these patients. To address this, we propose a novel approach to measure midbrain and pons size using a longitudinal "one line" method from the mid-sagittal view. Structural images were acquired from 101 subjects who underwent 3.0T MRI (20 controls, 44 PD, 20 MSA, 12 PSP, and 5 corticobasal syndrome). We measured the middle cerebellar peduncle (MCP), superior cerebellar peduncle (SCP), midbrain, and pons. Brainstem size was measured by area or length of the longitudinal axis, which we named the "one line" method. We conducted intraclass correlation coefficients to assess the extent of agreement and consistency among raters, and receiver operating characteristic curves were used to determine diagnostic accuracy. Intraclass correlation coefficients (ICC) of MCP width were excellent in sagittal and axial sections while those of SCP width were moderate. There were also excellent ICCs between raters for "one line" method of the midbrain and pons, while areas showed good ICCs. "One line" method and area of the midbrain were better than SCP width for the differential diagnosis of PSP from MSA-P and PD. In contrast, there was no clearly superior measurement for differentially diagnosing MSA-P. The "one line" method was comparable with area for inter-rater agreement and diagnostic accuracy even though this was a simple and fast way.

Midbrain area for differentiating Parkinson’s disease from progressive supranuclear palsy

ObjectivesWe aimed to investigate the values of midbrain area in diagnosing Parkinson’s Disease (PD) and progressive supranuclear palsy (PSP) by using transcranial sonography (TCS). Disease duration effect on brain sonographic findings could decrease the accuracy of TCS in PD and PSP patients. We reduced the disease duration effect on sonographic differences found between PD and PSP patients by using multivariate analysis. Patients and MethodsPatients with clinical diagnosis of PSP and PD were recruited. We used SonoSite Edge II Ultrasound system to measure midbrain area, diameter of third ventricle and substantia nigra echogenicity. Diagnostic value of each measured area in sonography was estimated regarding its power for diagnosing PD or PSP. Independent sample t-test, Regression analysis and receiver operating characteristic (ROC) curve were performed using SPSS software. ResultsOf 35 patients, 18 were PD and 17 PSP cases. The mean midbrain area was 4.86 ± 0.71cm2 in PD patients and 3.61 ± 0.85cm2 in those with PSP (P < 0.005). Regression for reducing the effect of disease duration on midbrain area variances between patients with PD and PSP revealed a significant P value (P < 0.005, Adjusted R2 = 0.36). The sensitivity and specificity of midbrain area in diagnosing PD were 83.3% and 70.6% respectively. The sensitivity of the third ventricle size in diagnosing PSP was 82% although its specificity was 62%. ConclusionMidbrain area in patients with PD was wider than those with PSP that was not affected by disease duration. Midbrain area was the most accurate index for diagnosing PD by TCS although third ventricle size was the most sensitive one for diagnosing PSP.

Pyramidal system involvement in progressive supranuclear palsy \u2013 a clinicopathological correlation

BackgroundWe aimed to produce a detailed neuropathological analysis of pyramidal motor system pathology and provide its clinical pathological correlation in cases with definite progressive supranuclear palsy (PSP).MethodsPyramidal motor system pathologies were analyzed in 18 cases with neuropathologically confirmed PSP. Based on a retrospective clinical analysis, cases were subtyped according to Movement Disorder Society criteria for clinical diagnosis of PSP as probable, possible or suggestive of PSP with Richardson’s syndrome (n = 10), PSP with predominant corticobasal syndrome (n = 3), PSP with predominant parkinsonism (n = 3), PSP with predominant speech/language disorder (n = 1), and PSP with progressive gait freezing (n = 1). Clinical manifestations of motor neuron involvement (pseudobulbar or bulbar signs and spasticity) were retrospectively assessed semiquantitatively. Neuropathologically, hyperphosphorylated tau-related pyramidal motor system neuronal, neuritic, and glial pathology using anti-tau AT8 clone immunohistochemistry, was also evaluated.ResultsClinical manifestations of pyramidal motor system involvement were found in patients with different PSP subtypes. A statistically significant higher load of tau pathology was found in the pyramidal system in PSP-Richardson’s syndrome compared to other PSP subtypes (p = 0.016); however, there was no significant correlation between pyramidal system tau pathology and related motor clinical symptoms.ConclusionsTau pathology in the spinal cord and pyramidal motor system structures is very common in progressive supranuclear palsy and may neuropathologically supplement the distinction between classic Richardson’s syndrome from other progressive supranuclear palsy subtypes.

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.

Is the Latency from Progressive Supranuclear Palsy Onset to Diagnosis Improving?

Progressive supranuclear palsy (PSP) is a neuropathologically defined disease with a broad clinical spectrum. It can initially be mistaken for other neurodegenerative diseases. Diagnosis of PSP earlier in the course may reduce its psychological and financial burden, permit earlier access to neuroprotective interventions, and avoid unnecessary diagnostic and therapeutic measures. Our impression is that physicians are more aware of PSP in the 2010s than in the 1990s. This study tests that hypothesis using the latency from symptom onset to PSP diagnosis as a surrogate outcome. We reviewed records of 385 patients with "possible" or "probable" PSP from 1990 to 2016 at the Movement Disorders Center, Rutgers Robert Wood Johnson Medical School. The time from symptom onset to diagnosis was calculated for each patient and labeled as latency. We used the Pearson correlation coefficient, Student's t-test, and ANOVA as appropriate. Our data show that the mean latency (SD) from symptom onset to diagnosis PSP, in months, was 43.76 (25.60) in the 1990s, 40.76 (28.73) in the 2000s, and 29.15 (16.80) in the 2010s (P < .001). There was also an inverse relationship between age at onset and latency (Pearson's r = -0.23, P < .001). This relationship did not affect the statistical significance of our main observation. Our finding suggests that there is a progressive reduction in the latency over the past three decades. It may reflect increased awareness of PSP by physicians in our referral area.

Energization and spoken language production: Evidence from progressive supranuclear palsy

Energization is the process of initiating and sustaining a response over time. It has been described as one of three key “supervisory” attentional control processes associated with the frontal lobes. Attentional mechanisms, such as energization, are critical for a range of cognitive functions, such as spontaneous speech and other higher-order tasks. We aimed to investigate the process of energization in a case series of patients with progressive supranuclear palsy (PSP). Patients with a diagnosis of PSP (N = 5), patient controls with a neurodegenerative condition (Alzheimer's disease N = 3, frontotemporal dementia N = 2) and healthy older adult controls (N = 30) were assessed on a standard neuropsychological battery, including executive tasks and standard attention and language tests. Energization was investigated using word fluency tasks, samples of spontaneous speech and an experimental button-pressing concentration task. Response rates for the word fluency, spontaneous speech and concentration tasks were separated into time periods, in order to compare response rates at different points across the tasks (e.g., first 15 s vs. last 45 s in a 60 s task). Four PSP patients showed a clear response pattern indicative of a decrease in energization. Healthy and patient controls remained consistent in their responding over time. Understanding how these underlying processes are impaired in PSP can ultimately inform intervention and management strategies, and has theoretical implications for models of spoken language production.

Progressive supranuclear palsy and multiple system atrophy: clinicopathological concepts and therapeutic challenges.

This update discusses novel aspects on clinicopathological concepts and therapeutic challenges in progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), arising from publications of the last 1.5 years. The clinical criteria for diagnosis of PSP have been revised. Clinical variability of pathologically defined PSP and MSA makes the development of mature biomarkers for early diagnosis and biomarker-based trial design indispensable. Novel molecular techniques for biomarker supported diagnosis of PSP and MSA and for monitoring disease progression are being studied. Research in the pathophysiology of both diseases generates gradual progress in the understanding of the underlying processes. Several promising disease-modifying therapeutic approaches for PSP and MSA are now moving into clinical trials. Recent research generates insights in the pathophysiological relevant processes and raises hope for earlier clinical diagnosis and disease-modifying therapies of patients with PSP and MSA.

Corticobasal degeneration with TDP-43 pathology presenting with progressive supranuclear palsy syndrome: a distinct clinicopathologic subtype.

Corticobasal degeneration (CBD) is a clinically heterogeneous tauopathy, which has overlapping clinicopathologic and genetic characteristics with progressive supranuclear palsy (PSP). This study aimed to elucidate whether transactive response DNA-binding protein of 43kDa (TDP-43) pathology contributes to clinicopathologic heterogeneity of CBD. Paraffin-embedded sections of the midbrain, pons, subthalamic nucleus, and basal forebrain from 187 autopsy-confirmed CBD cases were screened with immunohistochemistry for phospho-TDP-43. In cases with TDP-43 pathology, additional brain regions (i.e., precentral, cingulate, and superior frontal gyri, hippocampus, medulla, and cerebellum) were immunostained. Hierarchical clustering analysis was performed based on the topographical distribution and severity of TDP-43 pathology, and clinicopathologic and genetic features were compared between the clusters. TDP-43 pathology was observed in 45% of CBD cases, most frequently in midbrain tegmentum (80% of TDP-43-positive cases), followed by subthalamic nucleus (69%). TDP-43-positive CBD was divided into TDP-limited (52%) and TDP-severe (48%) by hierarchical clustering analysis. TDP-severe patients were more likely to have been diagnosed clinically as PSP compared to TDP-limited and TDP-negative patients (80 vs 32 vs 30%, P < 0.001). The presence of downward gaze palsy was the strongest factor for the antemortem diagnosis of PSP, and severe TDP-43 pathology in the midbrain tectum was strongly associated with downward gaze palsy. In addition, tau burden in the olivopontocerebellar system was significantly greater in TDP-positive than TDP-negative CBD. Genetic analyses revealed that MAPT H1/H1 genotype frequency was significantly lower in TDP-severe than in TDP-negative and TDP-limited CBD (65 vs 89 vs 91%, P < 0.001). The homozygous minor allele frequencies in GRN rs5848 and TMEM106B rs3173615 were not significantly different between the three groups. In conclusion, the present study indicates that CBD with severe TDP-43 pathology is a distinct clinicopathologic subtype of CBD, characterized by PSP-like clinical presentations, severe tau pathology in the olivopontocerebellar system, and low frequency of MAPT H1 haplotype.