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     

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.     

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     

Immunohistochemical and ultrastructural characterization of neuritic clusters around ghost tangles in the hippocampal formation in progressive supranuclear palsy brains

We performed a detailed study of swollen neurite aggregation surrounding extracellular neurofibrillary tangles (ghost tangles, GTs) in brains of patients with progressive supranuclear palsy (PSP) by immunohistochemistry and electron microscopy (EM). The complex structures, designated as tangle-associated neuritic clusters (TANCs), were found in the hippocampus and parahippocampal cortex in all five PSP brains examined. TANCs measured from 20 to 40 μm across; twice as large as nearby neurons. Each neurite was globular or fusiform in shape, measured up to 10 μm in diameter, and was found between loosened fascicles of GTs or along their outer rims. There were several subsets of neurites that were argyrophilic or immunoreactive against antibodies to either phosphorylated tau protein, phosphorylated neurofilaments, ubiquitin, or synaptophysin. On EM, TANCs consisted of numerous axon terminals of varying size, which were filled with flocculate dense bodies, vesicular profiles, and synaptic vesicles, as well as normal-looking and degenerating cell organelles. Some axons had 13- to 15-nm-thick straight tubules that showed tau immunoreactivity; however, there was little neurofilament accumulation. Most of the swollen axon terminals conformed to the ultrastructural features of either reactive or degenerating terminals. The neurites identified by immunohistochemistry only represented a minority of the swollen axons visualized by EM. Tubules of GTs were dispersed in the extracellular space, but no amyloid fibrils were found. TANCs may constitute a distinctive form of neuronal degeneration in PSP cortices. We hypothesize that axon terminal accumulation may occur in response to GT-formation. Received: 20 May 1998 / Revised, accepted: 19 November 1998     

Expression and activity of antioxidants in the brain in progressive supranuclear palsy

Recent evidence implicates oxidative stress in the pathophysiology of progressive supranuclear palsy (PSP). Thus, we undertook a study of the activity and localization of two essential antioxidant systems (superoxide dismutase [SOD] enzymes and total glutathione) in the human post-mortem PSP and control brain. Marked increases in SOD1 (Cu/ZnSOD) activity and glutathione levels were measured within most PSP brain regions examined, whereas, only the subthalamic nucleus exhibited a significant increase (+68%) in SOD2 (MnSOD) activity. Two additional cases with mild pathological abnormalities were studied. The first (case A) may represent an example of an asymptomatic PSP case, while the second (case B) had mild pathological abnormalities consistent with typical PSP. In case A, only the STN had elevated levels of SOD activity, in the absence of an increase in tissue glutathione content. In case B, SOD activities and tissue glutathione content were elevated in several regions. Immunolocalization of the SOD1 and SOD2 proteins in paraffin-embedded tissue sections revealed a marked increase in the density of SOD immunopositive profiles (particularly glia) in the typical PSP brain, particularly within the white matter. Together, our data argues strongly in favor of the involvement of oxidative stress in the etiology and progression of PSP, and suggests that deficit in SOD or glutathione metabolism are not causative.     

Distribution of cortical neurofibrillary tangles in progressive supranuclear palsy: A quantitative analysis of six cases

Summary Progressive supranuclear palsy is characterized neuropathologically by the presence of high densities of neurofibrillary tangles in several subcortical structures. In some cases, neurofibrillary tangles have also been described in the cerebral cortex. We performed a quantitative regional and laminar analysis of the distribution of these lesions in six cases of progressive supranuclear palsy. We observed that the neurofibrillary tangle distribution in the cerebral cortex was largely confined to the hippocampal formation. In particular, in all the cases neurofibrillary tangles were observed in the granule cell layer of the dentate gyrus. In the prefrontal and inferior temporal cortex, neurofibrillary tangles were predominantly distributed in layers II and III. In addition, there were moderate-to-high neurofibrillary tangle densities in the primary motor cortex. This localization pattern contrasts with the neurofibrillary tangle distribution observed in the cerebral cortex of Alzheimer's disease cases, where tangles are denser in layer V than in layer III, and where the primary motor cortex and the dentate gyrus are usually not involved. These results suggest that specific elements of the cortical circuitry might be differentially vulnerable in progressive supranuclear palsy as compared to Alzheimer's disease.Supported in part by the Brookdale Foundation and the American Health Assistance Foundation (to PRH), and ADERMA and INSERM clinical network CAR 489016 (to AD)     

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.     

Occurrence of 15-nm-wide straight tubules in neocortical neurons in progressive supranuclear palsy

Summary Ultrastructural investigations were carried out on the cerebral neocortex in two cases of progressive supranuclear palsy. In both cases, characteristic 15-nm-wide straight tubules were observed in the neurons. The numbers of cells containing the straight tubules and of tubules in individual cells were small. However, the occurrence of the tubules strongly suggests that the cerebral neocortex is also exposed to the disease process in progressive supranuclear palsy.     

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.     

Neurofibrillary tangles in Alzheimer's disease and progressive supranuclear palsy: antigenic similarities and differences

Summary The antigenic profile of neurofibrillary tangles (NFT) in Alzheimer's disease (AD), senile dementia of Alzheimer type (SDAT), progressive supranuclear palsy (PSP) and in non-demented aged humans was investigated by light and electron microscopic immunocytochemistry using antisera and monoclonal antibodies to tubulin, microtubule-associated proteins (MAP1, MAP2 and tau), neurofilament proteins and determinants unique to Alzheimer paired helical filaments (PHF). Antibodies to tau proteins labeled NFT in all cases investigated (AD, SDAT, PSP and non-demented aged humans). However, one monoclonal antibody to PHF recognized numerous tangles in AD/SDAT, but only a small minority of the PSP tangles. Antibodies to tubulin, MAP1, MAP2 and neurofilament proteins did not selectively stain NFT. Whereas pretreatment of sections with phosphatase was required for the detection of tangles with Tau-1 monoclonal antibody, digestion of sections with either phosphatase or pronase had no significant effect on the staining pattern obtained with the other antibodies. Our studies show that, as previously described for AD/SDAT, phosphorylated tau polypeptides are also a major antigenic determinant of tangles in PSP, indicating that tangle formation may follow a common pathogenetic pathway in neurofibrillary degenerations. There is, however, at least one epitope in AD/SDAT tangles which seems to be absent on, or at least inaccessible in, the 15-nm straight fibrils of PSP.Supported by a project of the Austrian Ministery of Science and Research     

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     

Preferential neurodegeneration in the cervical spinal cord of progressive supranuclear palsy

Spinal cord lesions have seldom been described in cases with progressive supranuclear palsy (PSP). We thus decided to analyze spinal cord lesions by microtubule-associated protein 2 (MAP2) immunohistochemistry in six cases of PSP, five cases of Parkinson’s disease (PD) and two cases of corticobasal degeneration (CBD), all of which cause parkinsonism, while six patients without any neurological disease served as controls. In the PSP cases, the MAP2 expression in the cervical spinal cords significantly decreased in the medial division of the anterior gray horn, intermediate gray and posterior gray horn, but showed no significant change in the substantia gelatinosa and lateral division of the anterior gray horn. The thoracic and lumbar spinal cords were well preserved for MAP2 immunoreactivity. In addition, the globose type neurofibrillary tangles and glial fibrillary tangles were more conspicuous in the cervical than in the thoracic and lumbar spinal cord in PSP cases. On the other hand, the PD and CBD cases showed no significant decrease of MAP2 immunoreactivity in the spinal cords. The small neurons, which are located rather selectively in the intermediate zone of the spinal cord, are considered to be mostly present in the interneurons, and are also thought to play a role in various types of focal dystonia, such as neck dystonia. We therefore consider the distinct decrease in the MAP2-positive neuronal processes in the cervical spinal cord may partly reflect the loss of interneurons and may, thereby, possibly cause nuchal dystonia. Received: 17 August 1998 / Revised, accepted: 9 November 1998     

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.     

Biochemical mapping of neurofibrillary degeneration in a case of progressive supranuclear palsy: evidence for general cortical involvement

A biochemical study was performed to quantify and map the neurodegenerating process in cortical and subcortical brain areas from a case of progressive supranuclear palsy (PSP). Our approach was based on a Western blot analysis of pathological Tau proteins, which are the basic components of neurofibrillary lesions. We found that: (i) the abnormal Tau proteins can be detected in all cortical areas, sometimes in larger amounts than in some subcortical areas; (ii) these abnormal Tau proteins consist of a doublet called Tau 64 and 69, except for in the entorhinal cortex where we detected, as for Alzheimer brains, the triplet of Tau proteins called Tau 55, 64 and 69; (iii) the amounts of abnormal Tau proteins were higher in some neocortical regions, especially in the frontal lobe, than in the hippocampal formation. Our results show that the neocortical pathology in PSP, as revealed by the presence of pathological proteins, is more extended than thought so far. Our biochemical approach appears to be more sensitive than the immunohistochemical one and can clearly differentiates between two types of neurofibrillary pathology, the Alzheimer type with a triplet of abnormal Tau proteins (Tau 55, 64 and 69) and the PSP type with a characteristic doublet (Tau 64 and 69).Supported by ADERMA, CH&U de Lille, and INSERM clinical network CAR 492011, Société Alzheimer du Canada and Fondation de l'Age d'Or du Québec     

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.     

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.     

Neurofibrillary pathology in progressive supranuclear palsy

Summary We describe the fine structure of the subcortical neurofibrillary tangles (NFT) in 2 cases of progressive supranuclear palsy (PSP). In case 1 (69-year-old man) about one half of the NFT in the midbrain and pons examined were composed of 13–16 nm straight filaments and the others were made up of paired helical filaments (PHF) of Alzheimer type. The NFT in case 2 consisted of straight tubules with infrequent segments of unusual twisted fibril of unknown nature. The simultaneous occurrence of straight and PHF in one of these cases suggests that the NFT in PSP may be similar to those of Alzheimer type occurring in various conditions.     

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     

Immunohistological study of grumose degeneration of the dentate nucleus in progressive supranuclear palsy

The grumose degeneration observed in the dentate nuclei of 7 cases of progressive supranuclear palsy (PSP) was studied with a panel of antibodies which included 2 neurofilaments, Tau and ubiquitin. Dentate nucleus neurons were negative with all antibodies except ubiquitin which showed a slightly positive homogeneous pattern of staining. The amorphous material surrounding swollen or normal neurons was strongly positive for neurofilament and subunits and numerous torpedoes were observed in the granular layer of the cerebellar cortex. Our results confirm that grumose degeneration consists in degeneration of terminal axons of Purkinje cells in the dentate nucleus. The positivity of dentate nucleus neurons for ubiquitin may support the concept of synaptic dysfunction between Purkinje cells and dentate nucleus neurons.