- Email: [email protected]
Diagnostic significance of tau protein in cerebrospinal fluid from patients with corticobasal degeneration or progressive supranuclear palsy
Journal of the Neurological Sciences 183 (2001) 95–98 www.elsevier.com / locate / jns
Diagnostic significance of tau protein in cerebrospinal fluid from patients with corticobasal degeneration or progressive supranuclear palsy a,
a
b
b
c
c
d
e
K. Urakami *, K. Wada , H. Arai , H. Sasaki , M. Kanai , M. Shoji , H. Ishizu , K. Kashihara , M. Yamamoto f , K. Tsuchiya-Ikemoto g , M. Morimatsu g , H. Takashima h , M. Nakagawa h , K. Kurokawa i , H. Maruyama i , Y. Kaseda i , S. Nakamura i , K. Hasegawa j , H. Oono k , C. Hikasa l , K. Ikeda a , K. Yamagata a , Y. Wakutani a , T. Takeshima a , K. Nakashima a a
Division of Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Nishimachi 36 -1, Yonago 683 -8504, Japan b Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Sendai 980 -8574, Japan c Department of Neurology, Gunma University School of Medicine, Maebashi 371 -8511, Japan d Department of Neuropsychiatry, Okayama University Medical School, 2 -5 -1 Shikata-cho, Okayama 700 -8558, Japan e Department of Neurology, Okayama University Medical School, 2 -5 -1 Shikata-cho, Okayama 700 -8558, Japan f Department of Neurology, Kagawa Prefectural Central Hospital, Kagawa, Japan g Department of Neurology, Yamaguchi University School of Medicine, Ube 755 -8505, Japan h Third Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Kagoshima 890 -8520, Japan i Third Department of Internal Medicine, Hiroshima University School of Medicine, 1 -2 -3 Kasumi, Hiroshima 734 -8551, Japan j Department of Neurology, Kitasato University School of Medicine, Sagamihara 228 -8555, Japan k Mitsubishi Chemical Corporation, Diagnostic Systems Department, Marunouchi, Tokyo 100 -0005, Japan l Department of Neurology, Tottori Red Cross Hospital, Tottori 680 -0017, Japan Received 3 November 1999; received in revised form 13 November 2000; accepted 13 November 2000
Abstract Distinguishing corticobasal degeneration (CBD) from progressive supranuclear palsy (PSP) is clinically and pathologically difficult, and a useful biological marker to discriminative these two diseases has been a subject of clinical interest. In the present study, we assessed tau protein levels in cerebrospinal fluids by sandwich ELISA to distinguish CBD from PSP. The subjects consisted of 27 cases of CBD, 30 cases of PSP, and 36 healthy controls (CTL). The tau values in CBD were significantly higher than those in PSP (P,0.001) and those in CTL (P,0.001). The assay of CSF tau provided diagnostic sensitivity of 81.5% and specificity of 80.0% between CBD and PSP according to receiver-operating characteristic (ROC) curve analysis. When values were compared separately with respect to stage of the disease, differences in the values for moderate CBD vs. moderate PSP had the greatest significance (P,0.001 sensitivity 92.3%, specificity 100.0%), followed by cases of mild CBD and PSP (P,0.005, sensitivity 100.0%, specificity 87.5%). The values in severe CBD and PSP were not significantly different (P50.07, sensitivity 100%, specificity 75.0%). Using data obtained from a larger number of disease cases, we confirmed our previous findings that tau protein levels in cerebrospinal fluids in patients with CBD are significantly higher than those in patients with PSP. Because tau protein levels in cerebrospinal fluids are significantly higher in early CBD cases than in early PSP cases, measurement of tau protein levels in cerberospinal fluids may be useful for the differential diagnosis of early CBD from early PSP. 2001 Elsevier Science B.V. All rights reserved. Keywords: CSF; Tau; CBD; PSP
1. Introduction *Corresponding author. Tel.: 181-859-34-8032; fax: 181-859-348083. E-mail address: [email protected] (K. Urakami).
The diagnostic significance of tau proteins in cerebrospinal fluids has been described in many cases of dementia of
0022-510X / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 00 )00480-9
96
K. Urakami et al. / Journal of the Neurological Sciences 183 (2001) 95 – 98
Alzheimer type (DAT) [1–3]. However, in patients with other diseases showing neurofibrillary tangles (NFT) similar to those in DAT, tau proteins in cerebrospinal fluids have not been rigorously investigated. In particular, differentiating corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) is clinically and pathologically difficult [4,5], and a useful biological marker to discriminate these two diseases has been a subject of clinical interest. We previously obtained findings on tau protein levels in cerebrospinal fluids from patients with CBD or PSP that suggested that tau protein is a potential diagnostic marker to distinguish CBD from PSP [6], but the number of cases was not adequate to distinguish CBD from PSP in various progressive stages. In the present study, we confirmed our previous findings in a small number of patients to establish the significance of tau proteins in cerebrospinal fluids in distinguishing CBD from PSP.
2. Subjects and methods
of CBD were significantly higher than in cases of PSP (P,0.001) and CTLs (P,0.001) (Fig. 1). In the CBD group, there is one patient with extremely high CSF tau. We also analysed the differences excluding that one CBD patient with an extremely high tau value and achieved the same results without that patient (P,0.001). There was no significant correlation between CSF tau and age, although CSF tau tends to increase with age (data not shown). There is also no significant difference between CSF tau and gender (data not shown). When values were separately evaluated by progressive stage of disease, the values for mild CBD and PSP were 246.8682.0 pg / ml and 90.7643.6 pg / ml, respectively; those for moderate CBD and PSP were 392.56221.6 pg / ml and 155.3654.0 pg / ml, respectively; and those for severe CBD and PSP were 191.5652.3 pg / ml and 105.3655.9 pg / ml, respectively (Fig. 2). The statistical significance was greatest for the comparison of moderate CBD and moderate PSP (P,0.001), followed by that for cases of mild CBD and PSP (P,0.005). The values in severe CBD and PSP were not significantly different (P5 0.07). There were no significant correlations between CSF
Clinical materials used for the present study were supplied by investigators in many institutions including those who were assigned as executive members of a research project on neurodegenerative diseases funded by the Ministry of Health and Welfare, Japan. Subjects consisted of 27 cases of CBD (13 males and 14 females, mean age of 63.764.9 years), 30 cases of PSP (13 males and 17 females, mean age of 65.665.1 years), and 36 healthy controls (CTL) (16 males and 20 females, mean age of 65.869.9 years). These subjects include patients (10 cases of CBD and 12 cases of PSP) from our previous study, and CTLs are the same [6]. Patients with CBD included those with probable CBD [7,8]. Patients with PSP met the standard diagnostic criteria of NINDS-SPSP [9]. Degree of symptoms (mild, moderate or severe) was rated according to criteria, respectively. After obtaining informed consent about the study from patients and their families, tau protein in cerebrospinal fluid samples was assessed by sandwich ELISA [1] using an assay kit (INNOGENETICS, Belgium). CSF tau protein concentrations in CBD, PSP and CTL groups were statistically compared using one-way ANOVA and Mann–Whitney U test. The correlations between CSF tau level and age, gender, and severity of disease were statistically evaluated by regression analysis. The ability to differentiate between CBD and PSP was evaluated by a receiver-operating characteristic (ROC) curve analysis.
3. Results Concentrations of tau protein in cerebrospinal fluids were 304.56183.8 pg / ml in CBD, 124.7659.5 pg / ml in PSP, and 128.7690.4 pg / ml in CTLs. The values in cases
Fig. 1. CSF tau protein levels in CBD and PSP. CSF, cerebrospinal fluid; CBD, corticobasal degeneration; PSP, progressive supranuclear palsy; CTL, controls. Open circles with bars indicate mean6S.D.
K. Urakami et al. / Journal of the Neurological Sciences 183 (2001) 95 – 98
97
4. Discussion
Fig. 2. Changes of CSF tau protein levels in CBD and PSP correlated with degree of symptoms. CSF, cerebrospinal fluid; CBD, corticobasal degeneration; PSP, progressive supranuclear palsy. Open circles with bars indicate mean6S.D.
tau and severity of CBD and PSP, respectively (data not shown). The cut-off values obtained by ROC analysis were 180 pg / ml in all cases, 145 pg / ml in mild cases, 230 pg / ml in moderate cases, and 140 pg / ml in severe cases. Sensitivity and specificity are shown in Table 1. Because both sensitivities and specificities were over 80% except for severe cases, ROC analysis also demonstrated that CSF tau can differentiate between CBD and PSP.
There are only a few reports describing the assessment of tau proteins in cerebrospinal fluids from patients with CBD and those with PSP [6,10,11]. Mitani et al. [10] reported that tau protein levels in cerebrospinal fluids in 9 CBD cases were significantly higher than those in 12 CTLs, but they did not assess the values in PSP patients. Arai et al. [11] reported that tau protein levels in cerebrospinal fluids in 3 CBD cases tended to be higher than those obtained in 6 PSP cases, although the difference was not statistically significant. We previously measured tau protein levels in cerebrospinal fluids from 10 patients with CBD and 12 patients with PSP to suggest for the first time that tau protein levels in cerebrospinal fluids is a potential diagnostic marker to distinguish CBD from PSP [6]. However, because this issue warranted further investigation due to an insufficient number of disease cases, we confirmed the previous findings using an increased number of cases. Although one CBD patient had an extremely high tau value, we found the same significance in results with or without that patient. Moreover, we demonstrated that CSF tau can differentiate between CBD and PSP using ROC analysis, because both sensitivities and specificities were over 80%. This result suggests that high levels of tau protein in cerebrospinal fluids are generally useful for distinguishing CBD from PSP. Because there is an overlap between CSF tau levels for the CBD, PSP and CTL groups, we also explored other parameters that might distinguish each group. There was no significant correlation between CSF tau and age, although CSF tau tends to increase with age. There was also no significant difference between CSF tau and gender. The unavailability of cognitive performance data precluded analysis of a correlation between CSF tau and cognitive performance in this multicenter study. When values were separately evaluated with respect to progressive stage of the diseases, those for CBD were always higher than those for PSP. The difference was most significant in comparison of moderate CBD and PSP (P,0.001, sensitivity 92.3%, specificity 100.0%), followed by comparison of mild CBD and PSP (P,0.005, sensitivity 100.0%, specificity 87.5%). We confirmed almost identical results excluding the one patient with an extremely high tau value in moderate cases (sensitivity 91.7%). The difference between severe CBD and PSP cases was not
Table 1 Comparison of sensitivity and specificity of CSF tau protein levels between CBD and PSP patients Cut-off value (pg / ml)
Sensitivity (%)
Total cases
180
Mild cases Moderate cases
145 230
Severe cases
140
81.5 (80.7)a 100.0 92.3 (91.7)a 100.0
a
These values exclude the one CBD patient with an extremely high tau value.
Specificity (%) 80.0 87.5 100.0 75.0
98
K. Urakami et al. / Journal of the Neurological Sciences 183 (2001) 95 – 98
significant (P50.07, sensitivity 100%, specificity 75.0%). Because discriminative diagnosis of patients with early CBD from those with early PSP has been difficult in clinical practice, the present findings that tau protein levels were significantly higher in early CBD cases than in early PSP cases mean that they might be used as a diagnostic marker that could distinguish early CBD from early PSP. Other factors may influence the overlap in values. One possible explanation is that the ELISA kit (Innogenetics) we used in this study detect not only phosphorylated but also normal tau. Selective measurement of phosphorylated tau will be necessary to decrease the overlap, and recently Ishiguro et al. developed ELISA system for phosphorylated tau in CSF [12]. The issue of differential diagnosis of patients with severe CBD from those with severe PSP warrants further investigation in a larger number of disease cases. The underlying mechanisms producing higher levels of tau protein in CBD than in PSP remain unknown. Since NFT are more abundant in lesions of PSP than in those of CBD, it was initially expected that tau protein levels in cerebrospinal fluids would be higher in patients with PSP. However, in comparison of CBD patients to PSP patients, tau-positive nerve cells were more widely spread over the cerebral cortex and neurophil threads (NT), which are largely comprised of hyperphosphorylated tau and are more abundant in the basal ganglia [4]. Thus, abundant tau protein-associated degenerative neural lesions in CBD patients may be reflected by higher levels of tau proteins in cerebrospinal fluids in patients with CBD compared to those in patients with PSP. Another reasons may be the speed of disease progression. It is already reported that patients with Creutzfeldt-Jacob disease have extremely high CSF tau values [13]. The higher CSF tau values in CBD patients might be due to a more rapid disease progression in CBD patients compared to PSP patients. As one of potentially confounding factors, it is also considered that polymorphism of the tau gene may effect concentrations of CSF tau. In the future, it will be necessary to clarify the association between CSF tau level and polymorphism of the tau gene. In conclusion, using data obtained from a larger number of disease cases, we confirmed our previous findings that tau protein levels in cerebrospinal fluids in patients with CBD were significantly higher than those in patients with PSP. Since tau protein levels in cerebrospinal fluids were significantly higher in early CBD cases than in early PSP cases, the measurement of tau protein levels in cerebrospinal fluids may be useful for the differential diagnosis of early CBD from early PSP.
Acknowledgements We thank Professor Kunio Tashiro, representative leader of the Research Project on Neurodegenerative Diseases funded by the Ministry of Health and Welfare of Japan, for valuable advice and comments throughout this study. Part of this study was supported by a grant from the Research Committee of Central Nervous System Degenerative Diseases, the Ministry of Health and Welfare of Japan.
References [1] Vandermeeren M, Mercken M, Vanmechelen E et al. Detection of tau proteins in normal and Alzheimer’s disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. J Neurochem 1993;61:1828–34. [2] Arai H, Terajima M, Miura M et al. Tau in cerebrospinal fluid: a potential diagnostic marker in Alzheimer’s disease. Ann Neurol 1995;38:649–53. [3] Kanai M, Matsubara E, Isoe K et al. Longitudinal study of cerebrospinal fluid levels of tau, Ab1–40, Ab1–42(43) in Alzheimer’s disease: A study in Japan. Ann Neurol 1998;44:17–26. [4] Mori H, Nishimura M, Namba Y et al. Corticobasal degeneration: a disease with wide-spread appearance of abnormal tau and neurofibrillary tangles, and its relation to progressive supranuclear palsy. Acta Neuropathol (Berl) 1994;88:113–21. [5] Scully RE, Mark EJ, McNeely WF et al. Case records of the Massachusetts General Hospital. New Engl J Med 1993;329:1560– 7. [6] Urakami K, Mori M, Wada K et al. A comparison of tau protein in cerebrospinal fluid between corticobasal degeneration and progressive supranuclear palsy. Neurosci Lett 1999;259:127–9. [7] Rinne JO, Lee MS, Thompson PD et al. Corticobasal degeneration a clinical study of 36 cases. Brain 1994;117:1183–96. [8] Morimatsu M, Negoro K. Corticobasal degeneration: symptomatological brain-imaging and electrophysiological studies. Rinsho-Shinkeigaku [in Japanese] 1995;35:1459–62. [9] Litvan I, Agid Y, Calne D et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): Report of the NINDS-SPSP International Workshop. Neurology 1996;47:1–9. [10] Mitani K, Furiya Y, Uchihara T et al. Increased CSF tau protein in corticobasal degeneration. J Neurol 1998;245:44–6. [11] Arai H, Morikawa Y, Higuchi M et al. Cerebrospinal fluid tau levels in neurodegenerative diseases with distinct tau-related pathology. Biochem Biophys Res Comm 1997;236:262–4. [12] Ishiguro K, Ohno H, Arai H et al. Phosphorylated tau in human cerebrospinal fluid is a diagnostic marker for Alzheimer’s disease. Neurosci Lett 1999;270:91–4. [13] Otto M, Wiltfang J, Tumani H et al. Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt-Jacob disease. Neurosci Lett 1997;225:210–2.
Diagnostic significance of tau protein in cerebrospinal fluid from patients with corticobasal degeneration or progressive supranuclear palsy a,
a
b
b
c
c
d
e
K. Urakami *, K. Wada , H. Arai , H. Sasaki , M. Kanai , M. Shoji , H. Ishizu , K. Kashihara , M. Yamamoto f , K. Tsuchiya-Ikemoto g , M. Morimatsu g , H. Takashima h , M. Nakagawa h , K. Kurokawa i , H. Maruyama i , Y. Kaseda i , S. Nakamura i , K. Hasegawa j , H. Oono k , C. Hikasa l , K. Ikeda a , K. Yamagata a , Y. Wakutani a , T. Takeshima a , K. Nakashima a a
Division of Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Nishimachi 36 -1, Yonago 683 -8504, Japan b Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Sendai 980 -8574, Japan c Department of Neurology, Gunma University School of Medicine, Maebashi 371 -8511, Japan d Department of Neuropsychiatry, Okayama University Medical School, 2 -5 -1 Shikata-cho, Okayama 700 -8558, Japan e Department of Neurology, Okayama University Medical School, 2 -5 -1 Shikata-cho, Okayama 700 -8558, Japan f Department of Neurology, Kagawa Prefectural Central Hospital, Kagawa, Japan g Department of Neurology, Yamaguchi University School of Medicine, Ube 755 -8505, Japan h Third Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Kagoshima 890 -8520, Japan i Third Department of Internal Medicine, Hiroshima University School of Medicine, 1 -2 -3 Kasumi, Hiroshima 734 -8551, Japan j Department of Neurology, Kitasato University School of Medicine, Sagamihara 228 -8555, Japan k Mitsubishi Chemical Corporation, Diagnostic Systems Department, Marunouchi, Tokyo 100 -0005, Japan l Department of Neurology, Tottori Red Cross Hospital, Tottori 680 -0017, Japan Received 3 November 1999; received in revised form 13 November 2000; accepted 13 November 2000
Abstract Distinguishing corticobasal degeneration (CBD) from progressive supranuclear palsy (PSP) is clinically and pathologically difficult, and a useful biological marker to discriminative these two diseases has been a subject of clinical interest. In the present study, we assessed tau protein levels in cerebrospinal fluids by sandwich ELISA to distinguish CBD from PSP. The subjects consisted of 27 cases of CBD, 30 cases of PSP, and 36 healthy controls (CTL). The tau values in CBD were significantly higher than those in PSP (P,0.001) and those in CTL (P,0.001). The assay of CSF tau provided diagnostic sensitivity of 81.5% and specificity of 80.0% between CBD and PSP according to receiver-operating characteristic (ROC) curve analysis. When values were compared separately with respect to stage of the disease, differences in the values for moderate CBD vs. moderate PSP had the greatest significance (P,0.001 sensitivity 92.3%, specificity 100.0%), followed by cases of mild CBD and PSP (P,0.005, sensitivity 100.0%, specificity 87.5%). The values in severe CBD and PSP were not significantly different (P50.07, sensitivity 100%, specificity 75.0%). Using data obtained from a larger number of disease cases, we confirmed our previous findings that tau protein levels in cerebrospinal fluids in patients with CBD are significantly higher than those in patients with PSP. Because tau protein levels in cerebrospinal fluids are significantly higher in early CBD cases than in early PSP cases, measurement of tau protein levels in cerberospinal fluids may be useful for the differential diagnosis of early CBD from early PSP. 2001 Elsevier Science B.V. All rights reserved. Keywords: CSF; Tau; CBD; PSP
1. Introduction *Corresponding author. Tel.: 181-859-34-8032; fax: 181-859-348083. E-mail address: [email protected] (K. Urakami).
The diagnostic significance of tau proteins in cerebrospinal fluids has been described in many cases of dementia of
0022-510X / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 00 )00480-9
96
K. Urakami et al. / Journal of the Neurological Sciences 183 (2001) 95 – 98
Alzheimer type (DAT) [1–3]. However, in patients with other diseases showing neurofibrillary tangles (NFT) similar to those in DAT, tau proteins in cerebrospinal fluids have not been rigorously investigated. In particular, differentiating corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) is clinically and pathologically difficult [4,5], and a useful biological marker to discriminate these two diseases has been a subject of clinical interest. We previously obtained findings on tau protein levels in cerebrospinal fluids from patients with CBD or PSP that suggested that tau protein is a potential diagnostic marker to distinguish CBD from PSP [6], but the number of cases was not adequate to distinguish CBD from PSP in various progressive stages. In the present study, we confirmed our previous findings in a small number of patients to establish the significance of tau proteins in cerebrospinal fluids in distinguishing CBD from PSP.
2. Subjects and methods
of CBD were significantly higher than in cases of PSP (P,0.001) and CTLs (P,0.001) (Fig. 1). In the CBD group, there is one patient with extremely high CSF tau. We also analysed the differences excluding that one CBD patient with an extremely high tau value and achieved the same results without that patient (P,0.001). There was no significant correlation between CSF tau and age, although CSF tau tends to increase with age (data not shown). There is also no significant difference between CSF tau and gender (data not shown). When values were separately evaluated by progressive stage of disease, the values for mild CBD and PSP were 246.8682.0 pg / ml and 90.7643.6 pg / ml, respectively; those for moderate CBD and PSP were 392.56221.6 pg / ml and 155.3654.0 pg / ml, respectively; and those for severe CBD and PSP were 191.5652.3 pg / ml and 105.3655.9 pg / ml, respectively (Fig. 2). The statistical significance was greatest for the comparison of moderate CBD and moderate PSP (P,0.001), followed by that for cases of mild CBD and PSP (P,0.005). The values in severe CBD and PSP were not significantly different (P5 0.07). There were no significant correlations between CSF
Clinical materials used for the present study were supplied by investigators in many institutions including those who were assigned as executive members of a research project on neurodegenerative diseases funded by the Ministry of Health and Welfare, Japan. Subjects consisted of 27 cases of CBD (13 males and 14 females, mean age of 63.764.9 years), 30 cases of PSP (13 males and 17 females, mean age of 65.665.1 years), and 36 healthy controls (CTL) (16 males and 20 females, mean age of 65.869.9 years). These subjects include patients (10 cases of CBD and 12 cases of PSP) from our previous study, and CTLs are the same [6]. Patients with CBD included those with probable CBD [7,8]. Patients with PSP met the standard diagnostic criteria of NINDS-SPSP [9]. Degree of symptoms (mild, moderate or severe) was rated according to criteria, respectively. After obtaining informed consent about the study from patients and their families, tau protein in cerebrospinal fluid samples was assessed by sandwich ELISA [1] using an assay kit (INNOGENETICS, Belgium). CSF tau protein concentrations in CBD, PSP and CTL groups were statistically compared using one-way ANOVA and Mann–Whitney U test. The correlations between CSF tau level and age, gender, and severity of disease were statistically evaluated by regression analysis. The ability to differentiate between CBD and PSP was evaluated by a receiver-operating characteristic (ROC) curve analysis.
3. Results Concentrations of tau protein in cerebrospinal fluids were 304.56183.8 pg / ml in CBD, 124.7659.5 pg / ml in PSP, and 128.7690.4 pg / ml in CTLs. The values in cases
Fig. 1. CSF tau protein levels in CBD and PSP. CSF, cerebrospinal fluid; CBD, corticobasal degeneration; PSP, progressive supranuclear palsy; CTL, controls. Open circles with bars indicate mean6S.D.
K. Urakami et al. / Journal of the Neurological Sciences 183 (2001) 95 – 98
97
4. Discussion
Fig. 2. Changes of CSF tau protein levels in CBD and PSP correlated with degree of symptoms. CSF, cerebrospinal fluid; CBD, corticobasal degeneration; PSP, progressive supranuclear palsy. Open circles with bars indicate mean6S.D.
tau and severity of CBD and PSP, respectively (data not shown). The cut-off values obtained by ROC analysis were 180 pg / ml in all cases, 145 pg / ml in mild cases, 230 pg / ml in moderate cases, and 140 pg / ml in severe cases. Sensitivity and specificity are shown in Table 1. Because both sensitivities and specificities were over 80% except for severe cases, ROC analysis also demonstrated that CSF tau can differentiate between CBD and PSP.
There are only a few reports describing the assessment of tau proteins in cerebrospinal fluids from patients with CBD and those with PSP [6,10,11]. Mitani et al. [10] reported that tau protein levels in cerebrospinal fluids in 9 CBD cases were significantly higher than those in 12 CTLs, but they did not assess the values in PSP patients. Arai et al. [11] reported that tau protein levels in cerebrospinal fluids in 3 CBD cases tended to be higher than those obtained in 6 PSP cases, although the difference was not statistically significant. We previously measured tau protein levels in cerebrospinal fluids from 10 patients with CBD and 12 patients with PSP to suggest for the first time that tau protein levels in cerebrospinal fluids is a potential diagnostic marker to distinguish CBD from PSP [6]. However, because this issue warranted further investigation due to an insufficient number of disease cases, we confirmed the previous findings using an increased number of cases. Although one CBD patient had an extremely high tau value, we found the same significance in results with or without that patient. Moreover, we demonstrated that CSF tau can differentiate between CBD and PSP using ROC analysis, because both sensitivities and specificities were over 80%. This result suggests that high levels of tau protein in cerebrospinal fluids are generally useful for distinguishing CBD from PSP. Because there is an overlap between CSF tau levels for the CBD, PSP and CTL groups, we also explored other parameters that might distinguish each group. There was no significant correlation between CSF tau and age, although CSF tau tends to increase with age. There was also no significant difference between CSF tau and gender. The unavailability of cognitive performance data precluded analysis of a correlation between CSF tau and cognitive performance in this multicenter study. When values were separately evaluated with respect to progressive stage of the diseases, those for CBD were always higher than those for PSP. The difference was most significant in comparison of moderate CBD and PSP (P,0.001, sensitivity 92.3%, specificity 100.0%), followed by comparison of mild CBD and PSP (P,0.005, sensitivity 100.0%, specificity 87.5%). We confirmed almost identical results excluding the one patient with an extremely high tau value in moderate cases (sensitivity 91.7%). The difference between severe CBD and PSP cases was not
Table 1 Comparison of sensitivity and specificity of CSF tau protein levels between CBD and PSP patients Cut-off value (pg / ml)
Sensitivity (%)
Total cases
180
Mild cases Moderate cases
145 230
Severe cases
140
81.5 (80.7)a 100.0 92.3 (91.7)a 100.0
a
These values exclude the one CBD patient with an extremely high tau value.
Specificity (%) 80.0 87.5 100.0 75.0
98
K. Urakami et al. / Journal of the Neurological Sciences 183 (2001) 95 – 98
significant (P50.07, sensitivity 100%, specificity 75.0%). Because discriminative diagnosis of patients with early CBD from those with early PSP has been difficult in clinical practice, the present findings that tau protein levels were significantly higher in early CBD cases than in early PSP cases mean that they might be used as a diagnostic marker that could distinguish early CBD from early PSP. Other factors may influence the overlap in values. One possible explanation is that the ELISA kit (Innogenetics) we used in this study detect not only phosphorylated but also normal tau. Selective measurement of phosphorylated tau will be necessary to decrease the overlap, and recently Ishiguro et al. developed ELISA system for phosphorylated tau in CSF [12]. The issue of differential diagnosis of patients with severe CBD from those with severe PSP warrants further investigation in a larger number of disease cases. The underlying mechanisms producing higher levels of tau protein in CBD than in PSP remain unknown. Since NFT are more abundant in lesions of PSP than in those of CBD, it was initially expected that tau protein levels in cerebrospinal fluids would be higher in patients with PSP. However, in comparison of CBD patients to PSP patients, tau-positive nerve cells were more widely spread over the cerebral cortex and neurophil threads (NT), which are largely comprised of hyperphosphorylated tau and are more abundant in the basal ganglia [4]. Thus, abundant tau protein-associated degenerative neural lesions in CBD patients may be reflected by higher levels of tau proteins in cerebrospinal fluids in patients with CBD compared to those in patients with PSP. Another reasons may be the speed of disease progression. It is already reported that patients with Creutzfeldt-Jacob disease have extremely high CSF tau values [13]. The higher CSF tau values in CBD patients might be due to a more rapid disease progression in CBD patients compared to PSP patients. As one of potentially confounding factors, it is also considered that polymorphism of the tau gene may effect concentrations of CSF tau. In the future, it will be necessary to clarify the association between CSF tau level and polymorphism of the tau gene. In conclusion, using data obtained from a larger number of disease cases, we confirmed our previous findings that tau protein levels in cerebrospinal fluids in patients with CBD were significantly higher than those in patients with PSP. Since tau protein levels in cerebrospinal fluids were significantly higher in early CBD cases than in early PSP cases, the measurement of tau protein levels in cerebrospinal fluids may be useful for the differential diagnosis of early CBD from early PSP.
Acknowledgements We thank Professor Kunio Tashiro, representative leader of the Research Project on Neurodegenerative Diseases funded by the Ministry of Health and Welfare of Japan, for valuable advice and comments throughout this study. Part of this study was supported by a grant from the Research Committee of Central Nervous System Degenerative Diseases, the Ministry of Health and Welfare of Japan.
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