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.     

Ultrastructure of neurofibrillary tangles in progressive supranuclear palsy

Summary The fine structure of neurofibrillary tangles in the hippocampal gyrus, substantia nigra, pontine nuclei and locus coeruleus of the brain was postmortem studied in a case of progressive supranuclear palsy. Straight tubules and twisted tubules were observed in both the cortical and subcortical neurofibrillary tangles. Most tubules appeared separately in each neuron but a few straight tubules were mixed with the twisted tubules in the cortical tangles. The implication and possible significance of this findings are discussed.     

The fine structure of subcortical neurofibrillary tangles in progressive supranuclear palsy

Summary The fine structure of subcortical neurofibrillary tangles was investigated in pallidum, substantia nigra, periaqueductal gray, pontine reticular gray, and dentate nucleus of 5 autopsy cases of Progressive Supranuclear Palsy. Only tangles due to straight 150 Å wide filaments have been detected. These findings, obtained from a large series of cases and areas examined, confirm previous observations on the fine structure of neurofibrillary tangles in Progressive Supranuclear Palsy and suggest that the association between tangles due to straight filaments and tangles due to twisted tubules, so far described in one case, is probably exceptional.This investigation was financially supported by the Ministero per la Pubblica Istruzione and Regione Liguria     

Widespread spinal cord involvement in progressive supranuclear palsy

We describe the histopathologic features of spinal cord lesions in 10 cases of progressive supranuclear palsy (PSP) and review the literature. Histologic examination revealed atrophy with myelin pallor in the anterior funiculus and anterolateral funiculus in the cervical and thoracic segments in eight of the 10 cases, whereas the posterior funiculus was well preserved. The degrees of atrophy of the anterior funiculus and the anterolateral funiculus correlated with that of the tegmentum of the medulla oblongata. Myelin pallor of the lateral corticospinal tract was observed in two of the 10 cases. Microscopic observation of the spinal white matter, particularly the cervical segment, revealed a few to several neuropil threads, particularly in the white matter surrounding the anterior horn after Gallyas‐Braak (GB) staining or AT‐8 tau immunostaining. However, the posterior funiculus was completely preserved from the presence of argyrophilic or tau‐positive structures. In the spinal gray matter, widespread distribution of neurons with cytoplasmic inclusions and neuropil threads was observed, particularly in the medial division of the anterior horn and intermediate gray matter, especially in the cervical segment. Globose‐type neurofibrillary tangles and pretangles were found. The distribution of GB‐ or AT‐8 tau‐positive small neurons and neuropil threads resembled that of the spinal interneurons. In conclusion, the spinal cord, especially the cervical segment, is constantly involved in the pathologic process of PSP. We speculate that spinal interneurons and their neuronal processes, particularly in the medial division of the anterior horn and intermediate gray matter of the cervical segment, are most severely damaged in the PSP spinal cord.     

Distribution of tangles and threads in the cerebral cortex in progressive supranuclear palsy

Recent studies have described silver- and tau-positive glia and threads in the degenerating lesions of progressive supranuclear palsy. In this study, Gallyas-Braak silver impregnation and several immunohistochemical techniques were employed to examine the distribution of tangles, abnormal glia and threads in the cerebral cortex of nine cases of progressive supranuclear palsy. In addition to neurofibrillary tangles, argentophilic glia and threads were impregnated exclusively by GaIIyas-Braak technique. This technique demonstrated two types of glia profiles: tightly coiled intra-cytoplasmic profiles surrounding nuclei (coiled profiles) and thorn-like profiles with radial ramifications (thorn-like profiles). Thorn-like profiles are possibly in astrocytes and were detected in the cerebral cortex, while coiled profiles are possibly in oligodendroglia and were detected both in the cerebral cortex and subcortical white matter. Topographically, many neurofibrillary tangles were constantly seen in the frontal cortex and in the pre-central gyrus. Numerous neurofibrillary tangles were detected in the entorhinal cortex of the two brains. Argentophilic glia and threads were also frequent both in the frontal cortex and the precentral gyrus: however, they were more frequent in the pre-central gyrus that in the frontal cortex in four of the eight cases examined. In two brains, argentophilic threads were distributed widely in the cerebral cortex and white matter except for the temporal cortex. In immunohistochemical studies, argentophilic glia and threads were mostly positive for Tau 2, and a small number of them were weakly positive for ubiquitin and paired helical filament protein. The immunoproperties of these abnormal glia and threads seemed to be virtually identical to those of neurofibrillary tangles. These findings indicate that cytoskeletal abnormalities related with abnormal tau proteins may occur concordantly both in neuronal and glial cells, especially in the pre-central gyrus. Cytoskeletal abnormalities occurring in the sub-cortical nuclei may be involved in the primary motor cortex.     

Neuropathology of progressive supranuclear palsy

The fundamental neuropathological findings of progressive supranuclear palsy (PSP) are presented, based on 14 autopsied cases of PSP. The blunt pathologies of PSP are degeneration in the substantia nigra, globus pallidus, subthalamic nuclei, dentate nucleus of the cerebellum and red nucleus, where there are neuronal loss, gliosis and neurofibrillary changes, to varying degree. In addition, the atrophy of the midbrain, especially the characteristic pattern of tegmental atrophy of the pons exhibiting a hand-bag profile, is an important finding. Hypertrophy of inferior olivary nucleus is frequently observed, suggesting the existence of lesions in the dentato-olivary system. Hypoxemic affects at the agonal stage should be noted because death of Purkinje cells of the cerebellum leads to degeneration of their axons and subsequently to the decrease of grumose degeneration in the dentate nucleus. Familial PSP have been reported by several authors but all case in the present study were sporadic.     

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     

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)     

Corticobasal degeneration: a disease with widespread appearance of abnormal tau and neurofibrillary tangles,and its relation to progressive supranuclear palsy

The neuropathological findings, including immunohistochemistry and electron microscopy, of two patients with clinical findings consistent with corticobasal degeneration (CBD) are reported. Both patients showed degeneration of the precentral cortex, the substantia nigra, the pallidum, and the thalamus. Many ballooned neurons were seen in the cerebral cortex, and argentophilic, skein-like inclusions suggesting neurofibrillary tangles (NFTs) were found in the brain stem and precentral cortex in patient 1. In contrast, patient 2 clearly showed NFTs in the brain stem and dentate nucleus which were indistinguishable from those seen in progressive supranuclear palsy (PSP), while only a few ballooned neurons were found in the cerebral cortex. Gallyas silver stain showed many argentophilic inclusions suggesting NFTs in the brain stem, subcortical nuclei, and cerebral cortex in both patients. Immunohistochemistry for tau showed tau-positive neurons in the cerebral cortex, brain stem, subcortical nuclei and spinal cord, and tau-positive glial cells were seen in the cerebral cortex, white matter and subcortical nuclei, and thread-like structures were seen in the cerebral cortex and white matter. Electron microscopy of the brain stem showed NFTs consisting of paired helical filaments in patient 1, and paired helical filaments and straight tubules in patient 2. Immunoelectron microscopy revealed parallel tau-positive filaments in the cerebral cortex in patent 1. From the two patients, the widespread appearance of abnormal tau and NFTs is one of the essential pathological features in CBD, and it also appears that CBD and PSP have some common underlying pathological processes. Patient 2 is closer to PSP than patient 1 and suggests CBD would link to PSP.     

Spinal cord lesions in progressive supranuclear palsy: some new observations

Summary The spinal cord was examined in two cases of progressive supranuclear palsy. In both cases, cells with neurofibrillary tangles were seen in the anterior horn, posterior horn, lateral horn, Clark's column, and intermediate gray. The tangles were most frequently observed in the posterior horn. The results suggest that the spinal cord is involved in the pathological process of progressive supranuclear palsy.Supported by NIH Grant No. 2P50 NS 11605-10     

Progressive supranuclear palsy: extensive neuropil threads in addition to neurofibrillary tangles

Summary Light microscopic immunohistochemical investigations were performed on neurofibrillary tangles (NFT) in four histologically confirmed cases of Alzheimer's disease (AD) and in five patients with a progressive supranuclear palsy (PSP). The antibody panel included antisera to the neuronal microtubule-associated protein, tau, and to isolated paired helical filaments (PHF), as well as mouse monoclonal antibodies (MAbs) to phosphorylated epitopes on high and medium molecular weight neurofilament subunits (RT97 and BF10, respectively). Paraffin sections were also impregnated with the Gallyas silver method, which specifically stains tangles and cortical neuropil threads in AD, but does not stain normal neurofilaments. All tangles in PSP and AD showed consistent immunostaining with antibodies to tau protein and isolated PHF, regardless of their localization. MAbs RT97 and BF10, however, did not stain or only weakly stained, subcortical tangles in PSP and AD, whereas most cortical NFT in AD were intensely immunostained. All tangles in PSP were as heavily impregnated with Gallyas as they were in AD. Furthermore there were extensive networks of Gallyaspositive, tau- and PHF-immunoreactive neurites in subcortical gray areas containing NFT, and bundles of positive axons in white matter tracts interconnecting subcortical nuclei of PSP. Our studies indicate a much more extensive disruption of fibrillar proteins in PSP subcortical neurons than previously reported. They furthermore indicate a very similar antigenic profile of NFT in PSP and AD, as far as subcortical neurons are concerned.     

Autobiographical memory in progressive supranuclear palsy

Background: We aimed to investigate recall of autobiographical memories across lifetime periods in patients with progressive supranuclear palsy (PSP). Method: Patients with PSP (n = 10) were given a test of autobiographical and personal semantic information and the Addenbrooke’s Cognitive Examination (ACE). The result was compared to 30 matched neurologically intact participants. Result: A mild autobiographical memory impairment was observed in PSP without a temporal gradient for the recall of autobiographical or personal semantic information. Performance correlated with verbal fluency in ACE. Conclusion: Patients with PSP show mild deficits in autobiographical memory, which is likely to reflect a frontal retrieval deficit.     

Astrocytic tau pathology positively correlates with neurofibrillary tangle density in progressive supranuclear palsy

Tufted astrocytes (TAs) are considered reliable, specific markers for the neuropathologic diagnosis of progressive supranuclear palsy (PSP). It is known that neurofibrillary tangles (NFTs) may relate directly to neurodegeneration, but the role of glial tau pathology is not well determined. To examine the hypothesis that TAs are as pathogenic as NFTs and that both might have a common accumulation, we evaluated the topographic relationship between TAs and NFTs in 12 cases of PSP. The sections of 13 different parts of the brain were stained using the Gallyas-Braak method, and TAs and NFTs were counted and compared statistically. The number of TAs significantly correlated with that of NFTs in the central gray matter, pontine nuclei, and tegmentum, which are responsible for the main symptoms in PSP. In the examined allocortex, however, NFTs were abundant without accompanying TAs. Staining with the specific antibody for 4-repeat tau (RD4) and 3-repeat tau (RD3) was performed to clarify this discrepancy from the standpoint of tau isoforms. NFTs in the entorhinal cortex were stained with both RD3 and RD4, but NFTs in the premotor cortex were stained with only RD4. The nature of NFTs in the allocortical area was different from that of the isocortex in PSP. TAs in the isocortex may share the same pathologic cascade with NFTs stained only by RD4. These results suggest that TAs are part of the same pathologic process as NFTs in PSP.     

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     

Prevalence of progressive supranuclear palsy in Yonago, Japan.

There have been few reports of the prevalence of progressive supranuclear palsy (PSP): the present study examines its prevalence in Japan and compares the findings with those in Europe and the United States. The prevalence per 100,000 was 5.82 (men, 9.14; women, 2.75), and the 95% confidence interval was 1.78 to 9.86 (men, 1.82-16.47; women, -1.08-6.65). Our data were comparable to those of studies in Europe and the United States.     

Donepezil in the treatment of progressive supranuclear palsy

OBJECTIVES: To evaluate the effect of 3 month therapy with donepezil, a centrally acting cholinesterase inhibitor, on cognitive performances, motor function and daily living activities in progressive supranuclear palsy (PSP). MATERIALS AND METHODS: Six patients with a diagnosis of PSP were evaluated at baseline and after 3 months of treatment with donepezil, 10 mg given at bedtime. Cognitive functions, motor symptoms and daily activities were evaluated by means of appropriate rating scales. RESULTS: Donepezil was not effective on cognitive dysfunction and did not change ratings of daily living. Parkinsonian symptoms were unaffected by donepezil treatment. CONCLUSIONS: Cholinergic replacement therapy alone is not likely to improve symptoms in a disorder characterized by a more widespread impairment of monoaminergic systems. Larger studies may be necessary to confirm the lack of effect of donepezil in this disorder.     

Immunohistochemical study of a case with progressive supranuclear palsy without ophthalmoplegia

Summary A case of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome; PSP) with parkinsonism and absence of gaze palsy or mental changes is reported. Neuropathological examination, apart from typical changes, showed, lack of midbrain tegmentum demyelination, marked loss of Purkinje cells and presence of hyalin-line bodies in individual neurons of the substantia nigra. Immunostaining against tau-1 protein revealed the prevalence of a diffuse reaction in locus coeruleus neurons; reflecting either different ability of these cells to accumulate straight filaments, or a various time sequence of neurofibrillary tanglesformation. Ferritin immunohistochemistry demonstrated widespread microglial cell proliferation, confirming further the generalized character of CNS pathology in PSP.     

Enlargements of somatosensory-evoked potentials in progressive supranuclear palsy

OBJECTIVE: To evaluate the usefulness of the somatosensory-evoked potential (SEP) in differentiating progressive supranuclear palsy (PSP) from other movement disorders. MATERIALS AND METHODS: The median nerve SEPs were studied in patients with PSP, Parkinson's disease and essential tremor, and in healthy controls. RESULTS: The amplitudes of the median nerve SEPs were enlarged only in patients with PSP. In four of the 10 patients with PSP, giant SEPs were elicited either unilaterally or bilaterally. CONCLUSIONS: The enlargement of the SEP in PSP may be useful for early differentiation of PSP, and this enlargement suggest a disease-specific dysfunction in the sensory processing mechanism of PSP which distinguishes it from other movement disorders.     

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