Acta Neuropathologica
Acta Neuropathol. (Berl.) 48, 27-30 (1979)
('? Springer-Verlag 1979
Ultrastructure of Neurofibrillary Tangles in Progressive Supranuclear Palsy S. Yagishita 1, Y. Itoh 1, N. A m a n o 1, T. N a k a n o 2, and A. Saitoh 3 Division of Pathology 1 and Division of Neurology2, Kanagawa Rehabilitation Center, Nanasawa 516, Kanagawa-Ken, Japan Kanagawa Kinkoh-in Hospital3, Kanagawa-Ken, Japan
Summary. The fine structure of neurofibrillary tangles in the hippocampal gyrus, substantia nigra, pontine nuclei and locus coeruleus of the brain was postm o r t e m 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.
neuroleptic drugs. He began to have tremor of the hands, dysarthria, and difficulty of swallowing at the age of 64 years. By 64 years of age he had developedbradykinesia, ante- and retropulsion, and absence of voluntary movements of the eyes. He was not demented. Besides the conventional examination of the central nervous system, specimens weretaken from formalin-fixedmaterial of the substantia nigra, locus coeruleus, pontine nuclei, and hippocampal gyrus for electron microscopy.The tissueswereplaced in 2.5 % glutaraldehydesolution, postfixed in t % osmic acid, dehydrated in alcohol and embedded in Epon 812. Ultrathin sections were stained with uranyl acetate and lead citrate and observed in the Hitachi HU-12 electron microscope at 75 kv.
Key words: Progressive supranuclear palsy Neurofibrillary tangles - Ultrastructure - Straight tubule - Twisted tubule
Results
Gross Appearance and Light Microscopy
Ultrastructural observations of neurofibrillary tangles in progressive supranuclear palsy (PSP) were reported by Tellez-Nagel et al. (1973), Roy et al. (1974), Powell et al. (1974) and Bugiani et al. (1979). They reported 15nm straight tubules in the tangles which were different from the tangles found in any other diseases (Lampert, 1971). Only T o m o n a g a (1977) described straight and twisted tubules in the tangles in PSP. This communication also reports both straight and twisted tubules in the neurofibrillary tangles in PSP. Usually, the tubules occurred separately in each neuron; only occasionally did both tubules coexist in the same neuron; a transition between the two could not be demonstrated.
Materials and Methods The specimenwas from a man of 69 who was diagnosedto suffer from schizophrenia with anthrophobia, delusions and hallucination, etc. From the age of 45 until his death he bad been treated with
Offprint requests to: S. Yagishita, M. D. (address see above)
The brain weighed 1,280 g and appeared slightly atrophic. Microscopic examination revealed neuronal loss, gliosis, and many neurofibrillary tangles of variable degree, in the nucleus subthalamicus, substantia nigra, superior colliculi, red nucleus, locus coeruleus, and dentate nucleus. The tangles were flame-shaped and globose in type. The cortex of hippocampus showed occasional neurofibrillary tangles. No significant alteration was noted in the cerebral cortex and upper spinal cord.
Electron Microscopy The majority of the tangles in the locus coeruleus, substantia nigra and pontine nuclei corresponded to central aggregates of interlacing bundles of tubules (Fig. 1). The tubules were of indeterminate length and measured about 1 2 - 1 7 n m in width (Fig.2). A few of the tangles were composed of circling bundles of twisted tubules in which the interval of periodic constrictions was 8 0 - 1 2 0 n m (Fig. 3). The frequency of these tubules in the cerebral cortex was reversed, most of the tangles being composed of circling bundles of twisted tubules (Figs. 4 and 5) and
0001-6322/79/0048/0027/$1.00
28
Acta Neuropathol. (Berl.) 48 (1979)
Fig.1. Part of a tangle, consisting of straight tubules running in a random fashion. Substantia nigra, x 120,000 Fig.2. Cross-section of straight tubules. They appear to have a tubular structure, x 210,000
Fig.3. Interlacing bundles of twisted tubules in locus coeruleus, x 36,000
the minority of straight tubules (Fig.7). Only occasionally did straight tubules appear to be mixed with the twisted tubules (Fig. 6). A transition between the straight and twisted tubules could not be demonstrated. Discussion
The case reported here showed clinical and pathological findings that were consistent with PSP (Ishino et al.,
1974; Steele et al., 1964). The ultrastructure of the neurofibrillary tangles of PSP has been reported only occasionally. The tangles were composed of straight tubules or filaments 15 nm in diameter in the reports of Tellez-Nagel et al. (1973), Powell et al. (1974), Roy et al. (1974), and Bugiani et al. (1979) and only of twisted tubules in that of Ishii et al. (1979). The occurrence of both straight and twisted tubules is described only by T o m o n a g a (1977) who considered the straight tubules
S. Yagishita et al. : Neurofibrillary Tangles in Progressive Supranuclear Palsy
29
Fig.4. Many twisted tubules in part of a neuron. Hippocampal gyrus. • 64,000
Fig.5. Cross-section of twisted tubules. They seem to be arciform and not tubular, x 110,000 Fig.6. A straight tubule admixed in twisted tubules. Hippocampal gyrus. x 90,000
to be a stage in the formation of the twisted tubules. Probst (1977) reported a case with widespread subcortical neurofibrillary tangles, cell loss and gliosis (atypical case of PSP) in a man of 81. The tangles consisted of two kinds of neurofibrillary material; straight fine filaments of 1 0 n m and twisted tubules with average diameter of 20nm. There were no 15-nm straight tubules. He supposed that the twisted tubules may be formed by the helicoid torsion of neurofilaments although he could not demonstrate a transition of neurofilaments to twisted tubules. In an atypical case of senile dementia, Oyanagi (1974) observed a close relationship of these two structures and demonstrated a transition of neurofilaments to twisted tubules. In the
present case both twisted tubules and straight tubules were observed separately in the neurons but only occasionaly did both twisted tubules and straight tubules occur in the same neuron. We did not observe a transition of these two structures but their concurrence suggests that in their origin they may be related to each other. N o r m a l human neurons present 24-nm tubules and 10-nm filaments; the filaments are resistant to postmortem autolysis and formalin fixation. The pathological, twisted tubules are also well preserved in formalin-fixed specimens. The 24nm-tubules are unstable and in autopsy formalin-fixed tissue, their structure easily disappear. However the straight tubules described here
30
Acta Neuropathol. (Berl.) 48 (1979)
Fig.7. Parallel straight tubules in hippocampal gyrus, x 108,000
were stable to formalin fixation and autolysis. Recently, we have had the opportunity to study an atypical case ofpresenile dementia with many neurofibrillary tangles, granulovacuolar degeneration, and Lewy bodies (in prep.), where the tangles were composed of both straight 20-nm tubules and twisted tubules. These straight tubules were also very stable to formalin fixation and postmortem autolysis. Kuroda et al. (1979) described 12-nm formalin-resistant tubules. They were straight or wavy tubules and were different from any other fibrous proteins hitherto described. For the present the exact nature of these fibrous proteins is not elucidated.
References Bugiani, L., Mancardi, G. L., Brusa, A., Ederli, E. : The fine structure of subcortical neurofibrillary tangles in progressive supranuclear palsy. Acta Neuropathol. (Berl.) 45, 147-152 (1979) Ishii, Y., Itoh, T. : An autopsy case of progressive supranuclear palsy. Clin. Neurol. (Tokyo) 19, 187 (1979) Ishino, H., Ikeda, H., Otsuki, S.: Progressive supranuclear palsy. Review of the literature with presentation of a case. Folia Psychiat. Neurol. Jpn. 28, 187--196 (1974) Kuroda, S., Hirano, A., Otsuki, S.: A case of quadriplegia and myoclonic movement with massive neurofibrillary changes. II. Further neuropathological study. Neurol. Med. Chir. (Tokyo) 10, 44-49 (1979)
Lampert, P.: Fine structural changes of neurites in Alzheimer's disease. Acta Neuropathol. (Ber[.) [Suppl. VI 49-53 (1971) Oyanagi, S. : An electron microscopic observation on senile dementia, with special references to transformation of neurofilaments to twisted tubules and a structural connection of Pick bodies to Alzheimer's neurofibrillary changes. Adv. Neurol. (Jpn.) 18, 77-88 (1974) Powell, H., London, G., Lampert, P. : Neurofibrillary tangles in progressive supranuclear palsy. Electron microscopic observations. J. NeuropathoI. Exp. Neurol. 26, 637-653 (1974) Probst, A. : D6g~n6rescence de neurofibrillaire sous-corticale senile avec presence de tubule contournes et de filaments droits. Forme atypique de la paralysie supranucleaire progressive. Rev. Neurol. (Paris) 133, 417-428 (1977) Roy, S., Hirano, A., Ghatak, N. R., Zimmermann, H. M. : Electron microscopic study of neurofibrillary tangles in SteeleRichardson-Olszewski syndrome, Acta Neuropathol. (Bed.) 29, 175 - 179 (1974) Steele/J. C., Richardson, J:-C., Otszewski, J. : Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchaI dystonia, and dementia. Arch. Neurol. 10, 333-359 (1964) Tellez-Nagel, I., Wisniewski, H, M. : Ultrastructure of neurofibrillary tangles in Steele-Richardson-Olszewski syndrome. Arch. Neurol. 29, 324-327 (1973) Terry, R. D.: Neuronal fibrous protein in human pathology. J. Neuropathol. Exp. Neurol. 30, 8 - 1 9 (1971) Tomonaga, M.: Ultrastructure of neurofibrillary tangles in progressive supranuclear palsy. Acta Neuropathol. (Berl.) 37, 177181 (1977) Received May 14, 1979/Accepted July 5, 1979
Acta Neuropathol. (Berl.) 48, 27-30 (1979)
('? Springer-Verlag 1979
Ultrastructure of Neurofibrillary Tangles in Progressive Supranuclear Palsy S. Yagishita 1, Y. Itoh 1, N. A m a n o 1, T. N a k a n o 2, and A. Saitoh 3 Division of Pathology 1 and Division of Neurology2, Kanagawa Rehabilitation Center, Nanasawa 516, Kanagawa-Ken, Japan Kanagawa Kinkoh-in Hospital3, Kanagawa-Ken, Japan
Summary. The fine structure of neurofibrillary tangles in the hippocampal gyrus, substantia nigra, pontine nuclei and locus coeruleus of the brain was postm o r t e m 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.
neuroleptic drugs. He began to have tremor of the hands, dysarthria, and difficulty of swallowing at the age of 64 years. By 64 years of age he had developedbradykinesia, ante- and retropulsion, and absence of voluntary movements of the eyes. He was not demented. Besides the conventional examination of the central nervous system, specimens weretaken from formalin-fixedmaterial of the substantia nigra, locus coeruleus, pontine nuclei, and hippocampal gyrus for electron microscopy.The tissueswereplaced in 2.5 % glutaraldehydesolution, postfixed in t % osmic acid, dehydrated in alcohol and embedded in Epon 812. Ultrathin sections were stained with uranyl acetate and lead citrate and observed in the Hitachi HU-12 electron microscope at 75 kv.
Key words: Progressive supranuclear palsy Neurofibrillary tangles - Ultrastructure - Straight tubule - Twisted tubule
Results
Gross Appearance and Light Microscopy
Ultrastructural observations of neurofibrillary tangles in progressive supranuclear palsy (PSP) were reported by Tellez-Nagel et al. (1973), Roy et al. (1974), Powell et al. (1974) and Bugiani et al. (1979). They reported 15nm straight tubules in the tangles which were different from the tangles found in any other diseases (Lampert, 1971). Only T o m o n a g a (1977) described straight and twisted tubules in the tangles in PSP. This communication also reports both straight and twisted tubules in the neurofibrillary tangles in PSP. Usually, the tubules occurred separately in each neuron; only occasionally did both tubules coexist in the same neuron; a transition between the two could not be demonstrated.
Materials and Methods The specimenwas from a man of 69 who was diagnosedto suffer from schizophrenia with anthrophobia, delusions and hallucination, etc. From the age of 45 until his death he bad been treated with
Offprint requests to: S. Yagishita, M. D. (address see above)
The brain weighed 1,280 g and appeared slightly atrophic. Microscopic examination revealed neuronal loss, gliosis, and many neurofibrillary tangles of variable degree, in the nucleus subthalamicus, substantia nigra, superior colliculi, red nucleus, locus coeruleus, and dentate nucleus. The tangles were flame-shaped and globose in type. The cortex of hippocampus showed occasional neurofibrillary tangles. No significant alteration was noted in the cerebral cortex and upper spinal cord.
Electron Microscopy The majority of the tangles in the locus coeruleus, substantia nigra and pontine nuclei corresponded to central aggregates of interlacing bundles of tubules (Fig. 1). The tubules were of indeterminate length and measured about 1 2 - 1 7 n m in width (Fig.2). A few of the tangles were composed of circling bundles of twisted tubules in which the interval of periodic constrictions was 8 0 - 1 2 0 n m (Fig. 3). The frequency of these tubules in the cerebral cortex was reversed, most of the tangles being composed of circling bundles of twisted tubules (Figs. 4 and 5) and
0001-6322/79/0048/0027/$1.00
28
Acta Neuropathol. (Berl.) 48 (1979)
Fig.1. Part of a tangle, consisting of straight tubules running in a random fashion. Substantia nigra, x 120,000 Fig.2. Cross-section of straight tubules. They appear to have a tubular structure, x 210,000
Fig.3. Interlacing bundles of twisted tubules in locus coeruleus, x 36,000
the minority of straight tubules (Fig.7). Only occasionally did straight tubules appear to be mixed with the twisted tubules (Fig. 6). A transition between the straight and twisted tubules could not be demonstrated. Discussion
The case reported here showed clinical and pathological findings that were consistent with PSP (Ishino et al.,
1974; Steele et al., 1964). The ultrastructure of the neurofibrillary tangles of PSP has been reported only occasionally. The tangles were composed of straight tubules or filaments 15 nm in diameter in the reports of Tellez-Nagel et al. (1973), Powell et al. (1974), Roy et al. (1974), and Bugiani et al. (1979) and only of twisted tubules in that of Ishii et al. (1979). The occurrence of both straight and twisted tubules is described only by T o m o n a g a (1977) who considered the straight tubules
S. Yagishita et al. : Neurofibrillary Tangles in Progressive Supranuclear Palsy
29
Fig.4. Many twisted tubules in part of a neuron. Hippocampal gyrus. • 64,000
Fig.5. Cross-section of twisted tubules. They seem to be arciform and not tubular, x 110,000 Fig.6. A straight tubule admixed in twisted tubules. Hippocampal gyrus. x 90,000
to be a stage in the formation of the twisted tubules. Probst (1977) reported a case with widespread subcortical neurofibrillary tangles, cell loss and gliosis (atypical case of PSP) in a man of 81. The tangles consisted of two kinds of neurofibrillary material; straight fine filaments of 1 0 n m and twisted tubules with average diameter of 20nm. There were no 15-nm straight tubules. He supposed that the twisted tubules may be formed by the helicoid torsion of neurofilaments although he could not demonstrate a transition of neurofilaments to twisted tubules. In an atypical case of senile dementia, Oyanagi (1974) observed a close relationship of these two structures and demonstrated a transition of neurofilaments to twisted tubules. In the
present case both twisted tubules and straight tubules were observed separately in the neurons but only occasionaly did both twisted tubules and straight tubules occur in the same neuron. We did not observe a transition of these two structures but their concurrence suggests that in their origin they may be related to each other. N o r m a l human neurons present 24-nm tubules and 10-nm filaments; the filaments are resistant to postmortem autolysis and formalin fixation. The pathological, twisted tubules are also well preserved in formalin-fixed specimens. The 24nm-tubules are unstable and in autopsy formalin-fixed tissue, their structure easily disappear. However the straight tubules described here
30
Acta Neuropathol. (Berl.) 48 (1979)
Fig.7. Parallel straight tubules in hippocampal gyrus, x 108,000
were stable to formalin fixation and autolysis. Recently, we have had the opportunity to study an atypical case ofpresenile dementia with many neurofibrillary tangles, granulovacuolar degeneration, and Lewy bodies (in prep.), where the tangles were composed of both straight 20-nm tubules and twisted tubules. These straight tubules were also very stable to formalin fixation and postmortem autolysis. Kuroda et al. (1979) described 12-nm formalin-resistant tubules. They were straight or wavy tubules and were different from any other fibrous proteins hitherto described. For the present the exact nature of these fibrous proteins is not elucidated.
References Bugiani, L., Mancardi, G. L., Brusa, A., Ederli, E. : The fine structure of subcortical neurofibrillary tangles in progressive supranuclear palsy. Acta Neuropathol. (Berl.) 45, 147-152 (1979) Ishii, Y., Itoh, T. : An autopsy case of progressive supranuclear palsy. Clin. Neurol. (Tokyo) 19, 187 (1979) Ishino, H., Ikeda, H., Otsuki, S.: Progressive supranuclear palsy. Review of the literature with presentation of a case. Folia Psychiat. Neurol. Jpn. 28, 187--196 (1974) Kuroda, S., Hirano, A., Otsuki, S.: A case of quadriplegia and myoclonic movement with massive neurofibrillary changes. II. Further neuropathological study. Neurol. Med. Chir. (Tokyo) 10, 44-49 (1979)
Lampert, P.: Fine structural changes of neurites in Alzheimer's disease. Acta Neuropathol. (Ber[.) [Suppl. VI 49-53 (1971) Oyanagi, S. : An electron microscopic observation on senile dementia, with special references to transformation of neurofilaments to twisted tubules and a structural connection of Pick bodies to Alzheimer's neurofibrillary changes. Adv. Neurol. (Jpn.) 18, 77-88 (1974) Powell, H., London, G., Lampert, P. : Neurofibrillary tangles in progressive supranuclear palsy. Electron microscopic observations. J. NeuropathoI. Exp. Neurol. 26, 637-653 (1974) Probst, A. : D6g~n6rescence de neurofibrillaire sous-corticale senile avec presence de tubule contournes et de filaments droits. Forme atypique de la paralysie supranucleaire progressive. Rev. Neurol. (Paris) 133, 417-428 (1977) Roy, S., Hirano, A., Ghatak, N. R., Zimmermann, H. M. : Electron microscopic study of neurofibrillary tangles in SteeleRichardson-Olszewski syndrome, Acta Neuropathol. (Bed.) 29, 175 - 179 (1974) Steele/J. C., Richardson, J:-C., Otszewski, J. : Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchaI dystonia, and dementia. Arch. Neurol. 10, 333-359 (1964) Tellez-Nagel, I., Wisniewski, H, M. : Ultrastructure of neurofibrillary tangles in Steele-Richardson-Olszewski syndrome. Arch. Neurol. 29, 324-327 (1973) Terry, R. D.: Neuronal fibrous protein in human pathology. J. Neuropathol. Exp. Neurol. 30, 8 - 1 9 (1971) Tomonaga, M.: Ultrastructure of neurofibrillary tangles in progressive supranuclear palsy. Acta Neuropathol. (Berl.) 37, 177181 (1977) Received May 14, 1979/Accepted July 5, 1979
