Pure akinesia manifested neuroleptic malignant syndrome: a clinical variant of progressive supranuclear palsy

An autopsy case of pure akinesia (PA) is reported. The patient manifested l-dopa-unresponsive akinesia without accompanying rigidity, tremor, eye movement disorder or dementia from the age of 58 years. Brain magnetic resonance T2-weighted imaging at the age of 63 showed high intensity areas in the subthalamic regions, but brain atrophy was not observed. She received amantadine-HCl and l-threo-3,4-dihydroxyphenylserine (l-DOPS) for 5 years. At the age of 66, she died of the severe illness accompanied by consciousness disturbance, hyperthermia, muscle rigidity, abnormal blood pressure and elevated serum enzymes which were derived from the muscle. We considered her condition to be neuroleptic malignant syndrome (NMS). Pathologically the brain revealed degeneration in the subthalamic nucleus, globus pallidus and substantia nigra. Neurofibrillary tangles were detected in the temporal cortex, hippocampus, amygdaloid body and spinal cord, as well as in the basal ganglia, thalamus and brain stem. These findings were consistent with that of progressive supranuclear palsy (PSP); the change in the ventral pons was insignificant, suggesting that PA may have minimum involvement in the ventral pons. The skeletal muscle showed scattered necrosis that was compatible with NMS. As far as we know, this is the first report of NMS accompanied with PA. Received: 25 March 1996 / Revised, accepted: 23 September 1996     

Mossy fiber involvement in progressive supranuclear palsy

The cerebellar cortex of progressive supranuclear palsy (PSP) cases exhibited a characteristic pathology which occurred neither in healthy aged individuals nor in cases of fully developed Alzheimer’s disease. All of the 11 PSP cases studied reveal altered mossy fiber excrescences containing abnormal and hyperphosphorylated tau protein. Moreover, this abnormal material also appeared in cerebellar oligodendrocytes. Accordingly, there is not only the destruction of the cerebellar output system, which is already known, but also the involvement of the cerebellar input system. Received: 26 November 1998 / Revised: 12 March 1999 / Accepted: 15 March 1999     

血清尿酸与进行性核上性麻痹的相关性研究

目的探讨血清尿酸与进行性核上性麻痹(PSP)的相关性。方法收集71例PSP患者,选取70例健康人群为对照组。采用两独立样本t检验比较PSP组与健康对照组血清尿酸的差异,比较不同性别、PSP各亚型之间以及各亚型与对照组之间血清尿酸差异,采用Spearman分析PSP血清尿酸与Hoehn-Yahr分期、统一帕金森病(PD)评定量表第Ⅲ部分(UPDRSⅢ)评分及病程的相关性。结果 PSP组UPDRSⅢ评分、PSPRS评分明显高于健康对照组(P0.05)。而PSP组尿酸则明显低于健康对照组(P0.05)。按不同性别比较时,男性PSP组尿酸明显低于女性(P0.01),亦低于男性健康对照组(P0.01)。PSP各亚型尿酸均明显低于健康对照组(P0.05),差异均有统计学意义。Spearman相关分析,HY分期、UPDRSⅢ评分与尿酸呈明显负相关,而病程与尿酸呈显著负相关(P0.01)。结论血清尿酸减低可能与PSP患病相关,尤其是男性患者,血清尿酸越低,PSP患病越严重;尿酸作为抗氧化剂,对PSP患者可能具有一定的保护作用。     

Predicting disease progression in progressive supranuclear palsy in multicenter clinical trials

IntroductionClinical and MRI measurements can track disease progression in PSP, but many have not been extensively evaluated in multicenter clinical trials. We identified optimal measures to capture clinical decline and predict disease progression in multicenter PSP trials.MethodsLongitudinal clinical rating scales, neuropsychological test scores, and volumetric MRI data from an international, phase 2/3 clinical trial of davunetide for PSP (intent to treat population, n = 303) were used to identify measurements with largest effect size, strongest correlation with clinical change, and best ability to predict dropout or clinical decline over one year as measured by PSP Rating Scale (PSPRS).ResultsBaseline cognition as measured by Repeatable Battery for Assessing Neuropsychological Status (RBANS) was associated with attrition, but had only a small effect. PSPRS and Clinical Global Impression (CGI) had the largest effect size for measuring change. Annual change in CGI, RBANS, color trails, and MRI midbrain and ventricular volumes were most strongly correlated with annual PSPRS and had the largest effect sizes for detecting annual change. At baseline, shorter disease duration, more severe depression, and lower performance on RBANS and executive function tests were associated with faster worsening of the PSPRS in completers. With dropouts included, SEADL, RBANS, and executive function tests had significant effect on PSPRS trajectory of change.ConclusionBaseline cognitive status and mood influence the rate of disease progression in PSP. Multiple clinical, neuropsychological, and volumetric MRI measurements are sensitive to change over one year in PSP and appropriate for use in multicenter clinical trials.     

Progressive supranuclear palsy - 20 years later

Reviewing the literature since recognition of progressive supranuclear palsy (PSP) as a clinicopathological entity 20 years ago, the present state of knowledge is delineated. The etiology of PSP is still unknown. The clinical hallmarks are supranuclear palsy of vertical gaze, axial dystonia in extension and pseudobulbar palsy with marked dysarthria and dysphagia. Accessory features include subcortical dementia, mental, extrapyramidal, pyramidal and cerebellar symptoms. PSP is a disease of the presenium (average age at onset, 59.6 years) with a male preponderance (60% men). The onset is insidious with vague complaints of dysequilibrium (60%), mental changes (46%) and disturbed vision (21%), often preceding abnormal neurological findings. The important borderland and main differential diagnosis is parkinsonism. However, in PSP, responsiveness to antiparkinsonian agents is poor and progression is rapid and fatal within few years (average survival time, 5.7 years). Promising diagnostic tools at present include CT-scanning and neuro-otologic and -ophthalmologic examination. Neuropathological findings, confined to specific diencephalic, brainstem and cerebellar nuclei, include neurofibrillary tangles (ultrastructurally different from those seen in other CNS disorders), neuron loss and gliosis. The importance of research on neurocytochemistry, brain ultrastructure and immunology in the current investigation of PSP is outlined.     

Allocortical neurofibrillary changes in progressive supranuclear palsy

Summary Silver techniques for intraneuronal cytoskeleton abnormalities (neurofibrillary tangles and neuropil threads) and extracellular A4-amyloid deposits were used to examine lesions of the cerebral cortex in six cases of progressive supranuclear palsy (three were mentally unimpaired and three showed moderate degrees of dementia). Deposits of A4-amyloid protein occurred in small numbers or were absent. Neurofibrillary tangles and neuropil threads were present in all cases and were largely confined to the allocortex. A characteristic pattern of changes was found in the entorhinal cortex. The three mentally unimpaired individuals had mild cortical changes virtually confined to the transentorhinal region while all of the demented patients showed severe destruction of the superficial cellular layer in both the transentorhinal and entorhinal region. This pattern of allocortical destruction closely resembles that seen in clinically incipient Alzheimer's disease or in mentally impaired cases of Parkinson's disease. The entorhinal region receives dense input from isocortical association areas and projects via the perforant path to the hippocampal formation. The cells of origin of major portions of the perforant path are located within the superficial entorhinal cellular layer. Destruction of this layer partially or totally disconnects the hippocampus from the isocortex. The specific pattern of entorhinal destruction is considered to contribute to cognitive impairment and personality changes, frequently seen in patients with progressive supranuclear palsy.Supported by grants from the Deutsche Forschungsgemeinschaft and the Bundesministerium für Forschung und Technologie     

Achromatic neurons in the cortex of progressive supranuclear palsy

Achromatic neurons (AN) in the cerebral cortex are a characteristic feature of several neurodegenerative conditions including Pick's disease, corticobasal degeneration and some cases of primary progressive aphasia. Although AN are occasionally seen in some other diseases, their presence in progressive supranuclear palsy (PSP) has not been previously documented. We found significant numbers of AN in the cerebral cortex of five out of seven cases which had been diagnosed pathologically as PSP. The identification of AN was greatly facilitated by the use of neurofilament immunohistochemistry. The entorhinal and transentorhinal cortices were most frequently involved, but in several cases AN were also seen throughout the neocortex. The presence and number of AN roughly correlated with a history of clinical dementia. This suggests that cortical AN may be a common and important pathological finding in PSP.     

Substantia nigra echogenicity in progressive supranuclear palsy

A normoechogenic substantia nigra (SN) is a typical finding in transcranial sonography in patients with progressive supranuclear palsy (PSP), whereas in patients with Parkinson's disease a hyperechogenic SN is characteristic. A recent classification scheme recommends the differentiation of PSP patients into those with Richardson's syndrome (RS) and those with PSP‐Parkinsonism (PSP‐P). We investigated 34 PSP patients (27 RS, 7 PSP‐P) with ultrasound of the substantia nigra in search of differentiations in the two groups. We found that most of the PSP‐P patients, according to recently published criteria, had a hyperechogenic SN (6 of 7): right (cm²) median 0.22, 25% percentile 0.21 and 75% percentile 0.36 (cm²); left (cm²) median 0.21, 25% percentile 0.20 and 75% percentile 0.30 and a normal third ventricle (mean mm) ±SD: 7.1 ± 2.43). In RS patients a normoechogenic SN (26 of 27) and an enlarged third ventricle (mean mm) ±SD: 10.3 ± 2.41) was found. These differences may elucidate the pathological differences of RS and PSP‐P. © 2010 Movement Disorder Society     

A case of spontaneous arm levitation in progressive supranuclear palsy

Progressive supranuclear palsy is one of the parkinsonial syndromes causing atypical parkinsonism. In recent reports, other than subcortical involvement, also cortical structures have been shown to be involved in progressive supranuclear palsy patients. One of the clinical presentations of this involvement is spontaneous arm levitation which is a component of alien limb syndrome. Here we report a clinically diagnosed progressive supranuclear palsy patient with spontaneous arm levitation. Clinically spontaneous levitation of one arm without denial of ownership suggests the presence of spontaneous arm levitation. Spontaneous arm levitation can occur in the setting of progressive supranuclear palsy and it possibly demonstrates the cortical involvement in this disorder. Received: 22 September 2000 / Accepted: 23 February 2001     

Individual and regional variations of phospho-tau species in progressive supranuclear palsy

The purpose of this study was to learn about possible variations in phospho-tau profiles in terms of case-to-case differences, regional modifications and diversification of tau phosphorylation sites in five PSP cases with moderate to severe frontosubcortical dysfunction. Gel electrophoresis of sarkosyl-insoluble fractions and Western blotting with five anti-tau phospho-specific antibodies directed to phosphorylation sites Thr¹⁸¹, Ser²⁰², Ser²¹⁴, Ser³⁹⁶ and Ser⁴²² were used to study four brain regions including frontal cortex, area 8, subcortical white matter of the frontal lobe, caudate/putamen: striatum, and basis pontis: pons. Although two bands of 66 and 62 kDa were observed in almost every region in each case, the intensity of the bands depends on the anti-tau phospho-specific antibody. More importantly, bands of 72, 50/55 and 37 kDa were commonly found in PSP brains, whereas other bands of about 60, 42, 33 and 29 kDa were irregularly observed. The pattern of bands differed slightly from one case to another and from one region to another. Moreover, the phospho-tau profile differed depending on the anti-tau phospho-specific antibody used. These data suggest that several species of tau are variably phosphorylated at a given time in a given region (and probably in a given cell), and that tau aggregates are composed of several phosphorylated truncated or cleaved tau molecules, in addition to phosphorylated complete tau isoforms.     

Cortical atrophy differentiates Richardson's syndrome from the parkinsonian form of progressive supranuclear palsy

To determine whether brain atrophy differs between the two subtypes of progressive supranuclear palsy (PSP), Richardson's syndrome (PSP‐RS), and PSP parkinsonism (PSP‐P), and whether such atrophy directly relates to clinical deficits and the severity of tau deposition. We compared 24 pathologically confirmed PSP cases (17 PSP‐RS and 7 PSP‐P) with 22 controls from a Sydney brain donor program. Volume loss was analyzed in 29 anatomically discrete brain regions using a validated point‐counting technique, and tau–immunoreactive neurons, astrocytes and oligodendrocytes/threads semiquantified. Correlations between the two pathological measures and the presence or absence of cardinal PSP symptoms were investigated. Cortical atrophy was more severe in PSP‐RS than PSP‐P and affected more frontal lobe regions (frontal pole, inferior frontal gyrus). The supramarginal gyrus was atrophic in both subtypes. Additionally, atrophy of the internal globus pallidus, amygdala, and thalamus was more severe in PSP‐RS. As expected, more severe frontal lobe tau pathology differentiated PSP‐RS from PSP‐P. No correlations were found between the degree of atrophy and severity of tau pathology in any region assessed, or between the severity of atrophy or tau pathology and the presence or absence of cardinal PSP symptoms. Our study shows that thalamocortical atrophy is a defining feature of PSP‐RS, but this atrophy does not correlate with the presence of any specific cardinal clinical feature. Interestingly, there is a disassociation between tau pathology and atrophy in the brain regions affected in PSP‐RS that requires further investigation. © 2010 Movement Disorder Society     

Substructure of 20 nm filaments of progressive supranuclear palsy

Summary In contrast to the ultrastructure of Alzheimer's neurofibrillary tangles (NFT), which has been well characterized as accumulations of paired helical 10-nm filaments (PHF) with 80-nm regular constrictions, the morphology of the neurofibrillary changes of PSP remains ill-defined. Until recently, the fine structure of PSP tangles was generally accepted as 15-nm straight filaments or tubules, although many reports describing different electron-microscopic findings have appeared in the literature.In this report, we present morphological data indicating a protofilamentous substructure present in straight filaments of PSP which has some points of similarity with the protofilamentous architectures which have been reported for paired helical filaments of Alzheimer's disease. The straight filaments were found to be composed of six or more helically symmetric 2–5-nm protofilaments. We conclude that despite the varied morphology of filaments in neurofibrillary tangles observed in PSP there may be some underlying identity at the molecular level with the PHF of neurofibrillary tangles of Alzheimer's disease.Supported in part by grant no. 7301400 from the Ottawa General Hospital Research Fund     

Ultrastructure of neurofibrillary tangles in progressive supranuclear palsy

Summary Ultrastructure of neurofibrillary tangles was investigated on the subcortical neurons of an autopsy case of progressive supranuclear palsy. The patient was a 64-year-old female and suffered from her illness for 9 years. Two kinds of ultrastructure were observed in the subcortical neurofibrillary tangles, i.e. the 150 A straight tubules and the 220 A twisted tubules. They appeared separately in each neuron and a transition between these two structures could not be remarked. Besides, a few particles with a paracrystalline hexagonal structure were observed in some subcortical neurons.     

Abnormal Tau proteins in progressive supranuclear palsy

Summary We have previously shown that abnormal Tau species are produced during the neurofibrillary degeneration of the Alzheimer type. These abnormal Tau proteins consist of a characteristic triplet named Tau 55, Tau 64 and Tau 69 which are constantly found in Alzheimer's disease (AD) and Downs syndrome brain regions with tangles. To determine if abnormal Tau species are also produced in other neurodegenerative conditions where intraneuronal filamentous Tau aggregates are observed, we have undertaken an immuno-blot study of brain homogenates from patients with progressive supranuclear palsy (PSP), a neurological disorder characterized by the presence of tangles in subcortical and cortical brain areas. We show here that abnormal Tau species are produced in PSP but that they are different from those in AD. Indeed, although Tau 64 and 69 were present in PSP brain homogenates, possibly as the result of an abnormal phosphorylation as in AD, they were detected in smaller amounts (three times lower) than in AD. In addition Tau 55 was undetected by the immunological tools, such as the absorbed anti-PHF antisera, which specifically label the abnormal Tau proteins. Also the two-dimensional analysis revealed different isoelectric properties. Our results suggest that the production of abnormal Tau species is a very important event during all types of neurofibrillary degeneration. The differences in the pathological Tau-variant profile that were observed between PSP and AD possibly reflect different etiopathogenetic pathways and might explain the formation of different types of filamentous Tau aggregates.Supported by grants from MRES (88c 0710), CNMATS/INSERM, C.A.R. INSERM no. 489016     

Understanding falls in progressive supranuclear palsy

IntroductionProgressive supranuclear palsy (PSP) is characterized by frequent falls which worsen with disease progression, causing substantial morbidity and mortality. Few studies have investigated which factors contribute to falls in PSP, and all have involved few participants, thus lacking necessary statistical power. The aim of this study was to identify clinical parameters most significantly associated with increasing falls in PSP, using the largest sample of patients to date.MethodsComprehensive clinical data were collected from 339 not demented PSP patients meeting the NINDS-SPSP criteria, who were divided into two groups – Infrequent Fallers (IF; n = 118) with rare falls, and Frequent Fallers (FF; n = 221) who fell occasionally to multiple times a day. Of 198 clinical parameters, we hypothesized 38 to be correlated with an increasing risk of falls. These 38 parameters were analyzed via univariate regression analysis to determine the strength of their association with fall frequency. Unit odds ratios identified the magnitude with which each parameter resulted in an increasing risk of falls.ResultsTwenty-five of 38 parameters analyzed were significantly associated with fall frequency based on univariate analysis. Symptom duration, clinical measures of disease severity, and several motoric and oculomotor clinical parameters were associated with FF. Examined cognitive parameters and slowing of vertical saccades were not.ConclusionsThe clinical parameters identified as associated with increased frequency of falls improve our understanding of why they occur and may help identify not demented PSP patients at risk for increasing falls.