Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Cerebrospinal Fluid Biomarkers for Kii Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex

Cerebrospinal Fluid Biomarkers for Kii Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex Hindawi Publishing Corporation Journal of Neurodegenerative Diseases Volume 2013, Article ID 679089, 4 pages http://dx.doi.org/10.1155/2013/679089 Clinical Study Cerebrospinal Fluid Biomarkers for Kii Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex 1 2 3 Yui Nakayama, Satoru Morimoto, Misao Yoneda, 3 4 Shigeki Kuzuhara, and Yasumasa Kokubo Medical Department, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan Department of Neurology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakaemachi, Itabashi-ku, Tokyo 173-0015, Japan Department of Medical Welfare, Suzuka University of Medical Science, 1001-1 Kishioka-cho, Suzuka City, Mie 510-0293, Japan Department of Neurology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan Correspondence should be addressed to Yasumasa Kokubo; kokubo-y@clin.medic.mie-u.ac.jp Received 16 January 2013; Accepted 6 March 2013 Academic Editor: Peter Crouch Copyright © 2013 Yui Nakayama et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. Amyotrophic lateral sclerosis/parkinsonism-dementia complex is classified as one of the tauopathies. Methods.Thetotal tau, phosphorylated tau, and amyloid𝛽 42 levels were assayed in cerebrospinal uid fl from patients with Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex (𝑛=12 ), Alzheimer’s disease (𝑛=9 ), Parkinson’s disease (𝑛=9 ), amyotrophic lateral sclerosis (𝑛=11 ), and controls (𝑛=5 ) using specific enzyme-linked immunosorbent assay methods. Results.Total tauand phosphorylated tau did not increase and amyloid𝛽 42 was relatively reduced in Kii amyotrophic lateral sclerosis/parkinsonism- dementia complex. Relatively reduced amyloid𝛽 42 might discriminate Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex from amyotrophic lateral sclerosis and Parkinson’s disease, and the ratios of phosphorylated-tau to amyloid 𝛽 42 could discriminate Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex from Alzheimer’s disease. Conclusions. Cerebrospinal uid fl analysis may be useful to differentiate amyotrophic lateral sclerosis/parkinsonism-dementia complex from Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. 1. Introduction cerebrospinal uid fl (CSF) biomarkers for Kii ALS/PDC to discriminate it from other neurodegenerative disorders. Amyotrophic lateral sclerosis/parkinsonism-dementia com- plex (ALS/PDC) is a rare disorder endemic to Guam Island and the Kii Peninsula of Japan. It shows a unique combination 2. Material and Methods of parkinsonism, amyotrophy, and dementia [1], and the form of dementia, which shows a phenotype similar to Alzheimer’s We collected CSF samples from 12 patients with Kii ALS/PDC disease (AD), is becoming predominant in the Kii Peninsula. (6 men, 6 women, mean age67.9±3.7 years, mean illness Although Kii ALS/PDC shows several unique clinical duration 5.63 years), nine patients with AD (2 men, 7 women, features, including severe atrophy of the frontal and temporal mean age61.1±8.7 years, mean illness duration 1.92 years), lobes on magnetic resonance imaging (MRI), decreased 11 patients with ALS (8 men, 3 women, mean age60.6±12.6 cerebral blood flow in the frontal and temporal lobes on years, mean illness duration 1.1 years), nine patients with single-photon emission computed tomography (SPECT) [2], Parkinson’s disease (PD; 7 men, 2 women, mean age71.3± pigmentary retinopathy [3], and decreased cardiac I-meta- 2.2 years, mean illness duration 4.42 years), and ve fi disease iodobenzylguanidine uptake [4], a postmortem examination control patients (C; 4 men, 1 woman, mean age36.2±20.3 is required for a definitive diagnosis. Since biomarkers years). All of the patients with Kii ALS/PDC were natives of for ALS/PDC have not yet been identified, we analyzed Hohara village, which is an area of high ALS/PDC prevalence 𝐴𝛽 𝐴𝛽 2 Journal of Neurodegenerative Diseases ∗∗ ∗∗ ∗ ∗∗ ∗ ∗∗ ∗∗ 700 𝑃<0.05 𝑃<0.01 0 0 AD ALS CKii PD AD ALS C Kii PD (𝑛=9 ) (𝑛=11 ) (𝑛=4 ) (𝑛=9 ) (𝑛=9 ) (𝑛=9 ) (𝑛=11 ) (𝑛=5 ) (𝑛=12 ) (𝑛=9 ) (a) (b) ∗ ∗ ∗∗ ∗∗ ∗∗ ∗∗ 𝑃<0.05 0.3 ∗∗ 𝑃<0.01 0.25 0.2 0.15 0.1 0.05 −0.05 AD ALS C Kii PD AD ALS C Kii PD (𝑛=9 ) (𝑛=11 ) (𝑛=4 ) (𝑛=10 ) (𝑛=9 ) (𝑛=9 ) (𝑛=11 ) (𝑛=4 ) (𝑛=10 ) (𝑛=9 ) (c) (d) Figure 1: Analysis of CSF biomarkers. (a) Total tau, (b) phosphorylated tau, (c) beta-amyloid peptide (1–42), (d) the ratio of p-tau to A𝛽 42. AD: Alzheimer’s disease, ALS: amyotrophic lateral sclerosis, C: disease control, Kii: Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex, and PD: Parkinson’s disease. on the Kii Peninsula. We collected CSF samples over 10 years; randomized samples in the same manner in plural times. A therefore, the period between CSF collection and analysis factorial ANOVA was performed with CSF-t-tau, CSF-p-tau, was not standardized. eTh diagnosis of Kii ALS was made and CSF-A𝛽 42, as dependent variables, with the diagnostic according to the Airlie House criteria, since the clinical category (AD, ALS, C, Kii ALS/PDC, and PD) using JMP symptoms of Kii ALS are essentially the same as those of 9.0. All data were expressed as means± SD. A𝑃 value less classical ALS. eTh diagnosis of Kii PDC was made by a unique than 0.05 was considered statistically significant. The Ethics combination of levodopa-unresponsive parkinsonism and Committee of Mie University Graduate School of Medicine dementia, which are frequently accompanied by amyotrophy approved this study and the “Declaration of Helsinki” was of the extremities and/or pyramidal tract signs. Mini-mental followed. Informed consent was obtained from the patients state examination (MMSE) was used for the evaluation of or their families. dementia and cut-off point was 23 (data not shown). eTh frontal lobes and/or temporal lobes of ALS/PDC patients showed atrophy on MRI and/or a decrease of cerebral blood 3. Results flow on SPECT. CSF samples were immediately centrifuged at 1000×g for 15 min and stored at−80 Cwithpolypropylene CSF-A𝛽 42, CSF-t-tau, and CSF-p-tau were compared tube. eTh total tau (t-tau), phosphorylated tau (p-tau), and betweenAD, ALS, C, KiiALS/PDC,and PD.The amyloid beta (A𝛽 ) concentrations were measured with an concentrations of CSF-t-tau and CSF-p-tau were significantly enzyme-linked immunosorbent assay (ELISA) kit using a higher in AD (t-tau; 378.0± 41.76 pg/mL;𝑃 < 0.001 ,p-tau; monoclonal antibody specific for t-tau, p-tau, and A 𝛽 1–42 42.4± 6.78 pg/mL;𝑃 < 0.028 )thaninthe othergroups. (INNOTEST hTAU Ag, phosphor tau(181P), and𝛽 -amyloid However, the concentrations of CSF-t-tau and CSF-p-tau (1–42), Innogenetics, Ghent, Belgium). ELISA assays were did not differ significantly between Kii ALS/PDC, ALS, C, carried out using several samples from each group on the and PD (Figures 1(a) and 1(b)). The concentration of CSF- same plate in a randomized manner and were repeated using A𝛽 42 was significantly reduced in AD ( 402.2±56.6 pg/mL; (pg/mL) Tau (pg/mL) p-tau (pg/mL) p-tau/ Journal of Neurodegenerative Diseases 3 𝑃<0.03 ) compared to ALS and C and relatively reduced in together, CSF biomarkers of Kii ALS/PDC might have similar Kii ALS/PDC (465.4± 53.69 pg/mL;𝑃<0.018 )comparedto properties to those of 4R tauopathy, PSP, and CBD; however ALS. Most of the ALS/PDC patients had CSF concentration the relationship between tau isoform and CSF tau level values that fell below the cutoff based on C ( Figure 1(c)). remainstoberesolved. The ratios of CSF-p-tau to CSF-A 𝛽 42 were signica fi ntly Finally, the present findings, in which CSF-t-tau and increased in AD (0.125±0.02) compared with Kii ALS/PDC CSF-p-tau concentrations were not increased and CSF-A𝛽 42 (0.043±0.02;𝑃 < 0.008 ), ALS (0.035±0.019;𝑃 < 0.003 ), concentration was relatively decreased, suggest that CSF PD (0.025±0.02;𝑃<0.002 ), and C (0.027±0.09;𝑃<0.014 ) analysis may be useful to differentiate ALS/PDC from AD, (Figure 1(d)). The concentrations of CSF-t-tau, CSF-p-tau, ALS, and PD. Nevertheless there is a major limitation of the or CSF-A𝛽 42 were not related to the clinical parameters interpretation of the data. eTh size of each group is small, the (age, sex, illness duration, or dementia) in the Kii ALS/PDC age of the control group is much younger, and there were two patients. eTh number of C samples was small and the average populations in the AD group regarding the levels tau, p-tau, age of control patients was low. and A𝛽 /p-tau. Further study using groups with larger size of Generally, CSF tau level gradually increase according to subjects is needed to confirm the proposed utility of the CSF age and CSF A𝛽 is not affected by age [ 5]. CSF tau level of C biomarkers. samples was relatively low, but it was not significant. u Th s, the CSF values of C were not comparable to those Abbreviations of other groups. Nevertheless, the optimal cut-off values that discriminate C from AD were similar to those in previous ALS/PDC: Amyotrophic lateral reports [6, 7] in which a larger number of control samples sclerosis/parkinsonism-dementia complex were analyzed. CSF tau level of Kii ALS/PDC samples did not CSF: Cerebrospinal uid fl increase, although the average age of Kii ALS/PDC group was NFTs: Neurofibrillary tangles older than that of AD group. t-tau: Total tau p-tau: Phosphorylated tau AD: Alzheimer’s disease PD: Parkinson’s disease 4. Discussion MRI: Magnetic resonance imaging eTh present study showed that CSF-t-tau and CSF-p-tau SPECT: Single-photon emission computed concentrations from patients with Kii ALS/PDC were not tomography increased compared to those in the other disease groups, C: Control patients and A𝛽 42 concentration in the CSF was relatively decreased. ELISA: Enzyme-linked immunosorbent assay The ratio of CSF-p-tau to CSF-A 𝛽 42 segregates Kii ALS/PDC 3R: 3 repeat from AD. Because ALS/PDC is associated with tau pathology 4R: 4 repeat in the absence of amyloid plaques, the expectation was that PSP: Progressive supranuclear palsy ALS/PDC patients would not show the Alzheimer’s disease CBD: Corticobasal degeneration. (AD) profile of decreased A 𝛽 42 but might show increased t- tau and/or p-tau in the CSF. Disclosure In general, decreased CSF-A𝛽 42 indicates plaque pathol- ogy, and increased CSF-t-tau and CSF-p-tau indicate axonal Y. Kokubo certiefi s that allmyaffiliationsorfinancialinvolve- degeneration and tangle pathology, respectively [8]. Recently, ment, within the past year and in the foreseeable future the average age of onset of Kii ALS/PDC is increasing (e.g., employment, consultancies, honoraria, stock ownership and A𝛽 deposition is conspicuous in autopsied patients. or options, expert testimony, grants or patents received or eTh refore, decreased CSF-A 𝛽 42 may reflect A 𝛽 pathology pending, and royalties) with any organization or entity with in the most recent patients. We analyzed the precise tau a na fi ncial interest in or na fi ncial conflict with the subject isoform of over 10 patients with autopsy-proven ALS/PDC matter or materials discussed in the paper are completely recently and identified a 3R + 4R type, 4R>3Rtype, anda disclosed. All authors report no disclosures and no conflicts 4R predominant type. The glial tau pathology is particularly of interest concerning the research related to the paper. er Th e related to the 4R isoform, and we consider Kii ALS/PDC to was no ghost writing by anyone not named in the authors list. be a 4R-dominant tauopathy (unpublished data). Noguchi et al. examined the concentrations of CSF-t-tau, CSF-p-tau, and CSF-A𝛽 42 in patients with progressive supranuclear palsy Funding (PSP) and corticobasal degeneration (CBD); the concentra- tions of CSF-t-tau and CSF-p-tau did not significantly differ Thisstudy waspartlysupported by aGrant-in-Aidfromthe between PSP, CBD, and controls, and the concentration of Nagao Memorial Fund and the Mie Medical Fund; a Grant- CSF-A𝛽 42 was significantly lower in PSP and CBD than in-Aid from the Research Committee of CNS Degenerative in controls. eTh authors speculated that the absence of an Diseases; a Grant-in-Aid from the Research Committee of increase of CSF-t-tau and CSF-p-tau concentrations might Muro Disease (Kii ALS/PDC) (to Y. Kokubo: 21210301), the reflect 4R tau predominance and a reduction of CSF-A 𝛽 42 Ministry of Health, Labor, and Welfare, Japan; and a Grant- might suggest deposition or mismetabolism of A𝛽 [6]. Taken in-Aid for Scientific Research from the Ministry of Education, 4 Journal of Neurodegenerative Diseases Science, Sports, and Culture, Japan. The funding sources had no involvement in the study design or in the collection, analysis, and interpretation of data or in the writing of the paper or the decision to submit the paper for publication. Acknowledgments The authors thank Ms. Hisami Akatsuka and Ms. Jyunko Karita for their technical assistance in preparing CSF sam- ples for ELISA examination. Registration number of UMIN clinical trials registry is R000011521. References [1] S. Kuzuhara, Y. Kokubo, R. Sasaki et al., “Familial amyotrophic lateral sclerosis and parkinsonism-dementia complex of the Kii peninsula of Japan: clinical and neuropathological study and tau analysis,” Annals of Neurology,vol.49, no.4,pp. 501–511, 2001. [2] Y. Kokubo and S. Kuzuhara, “Neuroradiological study of patients with amyotrophic lateral sclerosis and parkinsonism- dementia complex on the Kii peninsula of Japan,” Archives of Neurology,vol.60, no.9,pp. 1257–1261, 2003. [3] Y.Kokubo, K. Ito, T. Fukunaga,H.Matsubara,and S. Kuzuhara, “Pigmentary retinopathy of ALS/PDC in Kii,” Ophthalmology, vol. 113, no. 11, pp. 2111.e1–2111.e2, 2006. [4] Y.Kokubo, Y. Nomura,S.Morimoto, andS.Kuzuhara, “Car- diac 123I-meta-iodobenzylguanidine scintigraphy in patients with amyotrophic lateral sclerosis and parkinsonism-dementia complex of the Kii peninsula, Japan,” Parkinsonism and Related Disorders,vol.18, pp.306–308,2012. [5] M. Sjog ¨ ren, H. Vanderstichele, H. Agren et al., “Tau and Abeta42 in cerebrospinal uid fl from healthy adults 21–93 years of age: establishment of reference values,” Clinical Chemistry, vol. 47, pp. 1776–1781, 2001. [6] M.Noguchi,M.Yoshita,Y.Matsumoto,K.Ono,K.Iwasa,and M. Yamada, “Decreased𝛽 -amyloid peptide in cerebrospinal fluid of patients with progressive supranuclear palsy and corti- cobasal degeneration,” Journal of the Neurological Sciences,vol. 237, no.1-2,pp. 61–65, 2005. [7] K. Kanemaru, N. Kameda, and H. Yamanouchi, “Decreased CSF amyloid𝛽 42 and normal tau levels in dementia with Lewy bodies,” Neurology,vol.54, no.9,pp. 1875–1876, 2000. [8] N. Mattsson, E. Rosen, O. Hansson et al., “Age and diagnostic performance of Alzheimer disease CSF biomarkers,” Neurology, vol. 78, pp. 468–476, 2012. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Neurodegenerative Diseases Hindawi Publishing Corporation

Cerebrospinal Fluid Biomarkers for Kii Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex

Download PDF
5 pages

Loading next page...
 
/lp/hindawi-publishing-corporation/cerebrospinal-fluid-biomarkers-for-kii-amyotrophic-lateral-sclerosis-0L1NzfbMs7
Publisher
Hindawi Publishing Corporation
Copyright
Copyright © 2013 Yui Nakayama et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN
2090-858X
DOI
10.1155/2013/679089
Publisher site
See Article on Publisher Site

Abstract

Hindawi Publishing Corporation Journal of Neurodegenerative Diseases Volume 2013, Article ID 679089, 4 pages http://dx.doi.org/10.1155/2013/679089 Clinical Study Cerebrospinal Fluid Biomarkers for Kii Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex 1 2 3 Yui Nakayama, Satoru Morimoto, Misao Yoneda, 3 4 Shigeki Kuzuhara, and Yasumasa Kokubo Medical Department, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan Department of Neurology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakaemachi, Itabashi-ku, Tokyo 173-0015, Japan Department of Medical Welfare, Suzuka University of Medical Science, 1001-1 Kishioka-cho, Suzuka City, Mie 510-0293, Japan Department of Neurology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan Correspondence should be addressed to Yasumasa Kokubo; kokubo-y@clin.medic.mie-u.ac.jp Received 16 January 2013; Accepted 6 March 2013 Academic Editor: Peter Crouch Copyright © 2013 Yui Nakayama et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. Amyotrophic lateral sclerosis/parkinsonism-dementia complex is classified as one of the tauopathies. Methods.Thetotal tau, phosphorylated tau, and amyloid𝛽 42 levels were assayed in cerebrospinal uid fl from patients with Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex (𝑛=12 ), Alzheimer’s disease (𝑛=9 ), Parkinson’s disease (𝑛=9 ), amyotrophic lateral sclerosis (𝑛=11 ), and controls (𝑛=5 ) using specific enzyme-linked immunosorbent assay methods. Results.Total tauand phosphorylated tau did not increase and amyloid𝛽 42 was relatively reduced in Kii amyotrophic lateral sclerosis/parkinsonism- dementia complex. Relatively reduced amyloid𝛽 42 might discriminate Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex from amyotrophic lateral sclerosis and Parkinson’s disease, and the ratios of phosphorylated-tau to amyloid 𝛽 42 could discriminate Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex from Alzheimer’s disease. Conclusions. Cerebrospinal uid fl analysis may be useful to differentiate amyotrophic lateral sclerosis/parkinsonism-dementia complex from Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. 1. Introduction cerebrospinal uid fl (CSF) biomarkers for Kii ALS/PDC to discriminate it from other neurodegenerative disorders. Amyotrophic lateral sclerosis/parkinsonism-dementia com- plex (ALS/PDC) is a rare disorder endemic to Guam Island and the Kii Peninsula of Japan. It shows a unique combination 2. Material and Methods of parkinsonism, amyotrophy, and dementia [1], and the form of dementia, which shows a phenotype similar to Alzheimer’s We collected CSF samples from 12 patients with Kii ALS/PDC disease (AD), is becoming predominant in the Kii Peninsula. (6 men, 6 women, mean age67.9±3.7 years, mean illness Although Kii ALS/PDC shows several unique clinical duration 5.63 years), nine patients with AD (2 men, 7 women, features, including severe atrophy of the frontal and temporal mean age61.1±8.7 years, mean illness duration 1.92 years), lobes on magnetic resonance imaging (MRI), decreased 11 patients with ALS (8 men, 3 women, mean age60.6±12.6 cerebral blood flow in the frontal and temporal lobes on years, mean illness duration 1.1 years), nine patients with single-photon emission computed tomography (SPECT) [2], Parkinson’s disease (PD; 7 men, 2 women, mean age71.3± pigmentary retinopathy [3], and decreased cardiac I-meta- 2.2 years, mean illness duration 4.42 years), and ve fi disease iodobenzylguanidine uptake [4], a postmortem examination control patients (C; 4 men, 1 woman, mean age36.2±20.3 is required for a definitive diagnosis. Since biomarkers years). All of the patients with Kii ALS/PDC were natives of for ALS/PDC have not yet been identified, we analyzed Hohara village, which is an area of high ALS/PDC prevalence 𝐴𝛽 𝐴𝛽 2 Journal of Neurodegenerative Diseases ∗∗ ∗∗ ∗ ∗∗ ∗ ∗∗ ∗∗ 700 𝑃<0.05 𝑃<0.01 0 0 AD ALS CKii PD AD ALS C Kii PD (𝑛=9 ) (𝑛=11 ) (𝑛=4 ) (𝑛=9 ) (𝑛=9 ) (𝑛=9 ) (𝑛=11 ) (𝑛=5 ) (𝑛=12 ) (𝑛=9 ) (a) (b) ∗ ∗ ∗∗ ∗∗ ∗∗ ∗∗ 𝑃<0.05 0.3 ∗∗ 𝑃<0.01 0.25 0.2 0.15 0.1 0.05 −0.05 AD ALS C Kii PD AD ALS C Kii PD (𝑛=9 ) (𝑛=11 ) (𝑛=4 ) (𝑛=10 ) (𝑛=9 ) (𝑛=9 ) (𝑛=11 ) (𝑛=4 ) (𝑛=10 ) (𝑛=9 ) (c) (d) Figure 1: Analysis of CSF biomarkers. (a) Total tau, (b) phosphorylated tau, (c) beta-amyloid peptide (1–42), (d) the ratio of p-tau to A𝛽 42. AD: Alzheimer’s disease, ALS: amyotrophic lateral sclerosis, C: disease control, Kii: Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex, and PD: Parkinson’s disease. on the Kii Peninsula. We collected CSF samples over 10 years; randomized samples in the same manner in plural times. A therefore, the period between CSF collection and analysis factorial ANOVA was performed with CSF-t-tau, CSF-p-tau, was not standardized. eTh diagnosis of Kii ALS was made and CSF-A𝛽 42, as dependent variables, with the diagnostic according to the Airlie House criteria, since the clinical category (AD, ALS, C, Kii ALS/PDC, and PD) using JMP symptoms of Kii ALS are essentially the same as those of 9.0. All data were expressed as means± SD. A𝑃 value less classical ALS. eTh diagnosis of Kii PDC was made by a unique than 0.05 was considered statistically significant. The Ethics combination of levodopa-unresponsive parkinsonism and Committee of Mie University Graduate School of Medicine dementia, which are frequently accompanied by amyotrophy approved this study and the “Declaration of Helsinki” was of the extremities and/or pyramidal tract signs. Mini-mental followed. Informed consent was obtained from the patients state examination (MMSE) was used for the evaluation of or their families. dementia and cut-off point was 23 (data not shown). eTh frontal lobes and/or temporal lobes of ALS/PDC patients showed atrophy on MRI and/or a decrease of cerebral blood 3. Results flow on SPECT. CSF samples were immediately centrifuged at 1000×g for 15 min and stored at−80 Cwithpolypropylene CSF-A𝛽 42, CSF-t-tau, and CSF-p-tau were compared tube. eTh total tau (t-tau), phosphorylated tau (p-tau), and betweenAD, ALS, C, KiiALS/PDC,and PD.The amyloid beta (A𝛽 ) concentrations were measured with an concentrations of CSF-t-tau and CSF-p-tau were significantly enzyme-linked immunosorbent assay (ELISA) kit using a higher in AD (t-tau; 378.0± 41.76 pg/mL;𝑃 < 0.001 ,p-tau; monoclonal antibody specific for t-tau, p-tau, and A 𝛽 1–42 42.4± 6.78 pg/mL;𝑃 < 0.028 )thaninthe othergroups. (INNOTEST hTAU Ag, phosphor tau(181P), and𝛽 -amyloid However, the concentrations of CSF-t-tau and CSF-p-tau (1–42), Innogenetics, Ghent, Belgium). ELISA assays were did not differ significantly between Kii ALS/PDC, ALS, C, carried out using several samples from each group on the and PD (Figures 1(a) and 1(b)). The concentration of CSF- same plate in a randomized manner and were repeated using A𝛽 42 was significantly reduced in AD ( 402.2±56.6 pg/mL; (pg/mL) Tau (pg/mL) p-tau (pg/mL) p-tau/ Journal of Neurodegenerative Diseases 3 𝑃<0.03 ) compared to ALS and C and relatively reduced in together, CSF biomarkers of Kii ALS/PDC might have similar Kii ALS/PDC (465.4± 53.69 pg/mL;𝑃<0.018 )comparedto properties to those of 4R tauopathy, PSP, and CBD; however ALS. Most of the ALS/PDC patients had CSF concentration the relationship between tau isoform and CSF tau level values that fell below the cutoff based on C ( Figure 1(c)). remainstoberesolved. The ratios of CSF-p-tau to CSF-A 𝛽 42 were signica fi ntly Finally, the present findings, in which CSF-t-tau and increased in AD (0.125±0.02) compared with Kii ALS/PDC CSF-p-tau concentrations were not increased and CSF-A𝛽 42 (0.043±0.02;𝑃 < 0.008 ), ALS (0.035±0.019;𝑃 < 0.003 ), concentration was relatively decreased, suggest that CSF PD (0.025±0.02;𝑃<0.002 ), and C (0.027±0.09;𝑃<0.014 ) analysis may be useful to differentiate ALS/PDC from AD, (Figure 1(d)). The concentrations of CSF-t-tau, CSF-p-tau, ALS, and PD. Nevertheless there is a major limitation of the or CSF-A𝛽 42 were not related to the clinical parameters interpretation of the data. eTh size of each group is small, the (age, sex, illness duration, or dementia) in the Kii ALS/PDC age of the control group is much younger, and there were two patients. eTh number of C samples was small and the average populations in the AD group regarding the levels tau, p-tau, age of control patients was low. and A𝛽 /p-tau. Further study using groups with larger size of Generally, CSF tau level gradually increase according to subjects is needed to confirm the proposed utility of the CSF age and CSF A𝛽 is not affected by age [ 5]. CSF tau level of C biomarkers. samples was relatively low, but it was not significant. u Th s, the CSF values of C were not comparable to those Abbreviations of other groups. Nevertheless, the optimal cut-off values that discriminate C from AD were similar to those in previous ALS/PDC: Amyotrophic lateral reports [6, 7] in which a larger number of control samples sclerosis/parkinsonism-dementia complex were analyzed. CSF tau level of Kii ALS/PDC samples did not CSF: Cerebrospinal uid fl increase, although the average age of Kii ALS/PDC group was NFTs: Neurofibrillary tangles older than that of AD group. t-tau: Total tau p-tau: Phosphorylated tau AD: Alzheimer’s disease PD: Parkinson’s disease 4. Discussion MRI: Magnetic resonance imaging eTh present study showed that CSF-t-tau and CSF-p-tau SPECT: Single-photon emission computed concentrations from patients with Kii ALS/PDC were not tomography increased compared to those in the other disease groups, C: Control patients and A𝛽 42 concentration in the CSF was relatively decreased. ELISA: Enzyme-linked immunosorbent assay The ratio of CSF-p-tau to CSF-A 𝛽 42 segregates Kii ALS/PDC 3R: 3 repeat from AD. Because ALS/PDC is associated with tau pathology 4R: 4 repeat in the absence of amyloid plaques, the expectation was that PSP: Progressive supranuclear palsy ALS/PDC patients would not show the Alzheimer’s disease CBD: Corticobasal degeneration. (AD) profile of decreased A 𝛽 42 but might show increased t- tau and/or p-tau in the CSF. Disclosure In general, decreased CSF-A𝛽 42 indicates plaque pathol- ogy, and increased CSF-t-tau and CSF-p-tau indicate axonal Y. Kokubo certiefi s that allmyaffiliationsorfinancialinvolve- degeneration and tangle pathology, respectively [8]. Recently, ment, within the past year and in the foreseeable future the average age of onset of Kii ALS/PDC is increasing (e.g., employment, consultancies, honoraria, stock ownership and A𝛽 deposition is conspicuous in autopsied patients. or options, expert testimony, grants or patents received or eTh refore, decreased CSF-A 𝛽 42 may reflect A 𝛽 pathology pending, and royalties) with any organization or entity with in the most recent patients. We analyzed the precise tau a na fi ncial interest in or na fi ncial conflict with the subject isoform of over 10 patients with autopsy-proven ALS/PDC matter or materials discussed in the paper are completely recently and identified a 3R + 4R type, 4R>3Rtype, anda disclosed. All authors report no disclosures and no conflicts 4R predominant type. The glial tau pathology is particularly of interest concerning the research related to the paper. er Th e related to the 4R isoform, and we consider Kii ALS/PDC to was no ghost writing by anyone not named in the authors list. be a 4R-dominant tauopathy (unpublished data). Noguchi et al. examined the concentrations of CSF-t-tau, CSF-p-tau, and CSF-A𝛽 42 in patients with progressive supranuclear palsy Funding (PSP) and corticobasal degeneration (CBD); the concentra- tions of CSF-t-tau and CSF-p-tau did not significantly differ Thisstudy waspartlysupported by aGrant-in-Aidfromthe between PSP, CBD, and controls, and the concentration of Nagao Memorial Fund and the Mie Medical Fund; a Grant- CSF-A𝛽 42 was significantly lower in PSP and CBD than in-Aid from the Research Committee of CNS Degenerative in controls. eTh authors speculated that the absence of an Diseases; a Grant-in-Aid from the Research Committee of increase of CSF-t-tau and CSF-p-tau concentrations might Muro Disease (Kii ALS/PDC) (to Y. Kokubo: 21210301), the reflect 4R tau predominance and a reduction of CSF-A 𝛽 42 Ministry of Health, Labor, and Welfare, Japan; and a Grant- might suggest deposition or mismetabolism of A𝛽 [6]. Taken in-Aid for Scientific Research from the Ministry of Education, 4 Journal of Neurodegenerative Diseases Science, Sports, and Culture, Japan. The funding sources had no involvement in the study design or in the collection, analysis, and interpretation of data or in the writing of the paper or the decision to submit the paper for publication. Acknowledgments The authors thank Ms. Hisami Akatsuka and Ms. Jyunko Karita for their technical assistance in preparing CSF sam- ples for ELISA examination. Registration number of UMIN clinical trials registry is R000011521. References [1] S. Kuzuhara, Y. Kokubo, R. Sasaki et al., “Familial amyotrophic lateral sclerosis and parkinsonism-dementia complex of the Kii peninsula of Japan: clinical and neuropathological study and tau analysis,” Annals of Neurology,vol.49, no.4,pp. 501–511, 2001. [2] Y. Kokubo and S. Kuzuhara, “Neuroradiological study of patients with amyotrophic lateral sclerosis and parkinsonism- dementia complex on the Kii peninsula of Japan,” Archives of Neurology,vol.60, no.9,pp. 1257–1261, 2003. [3] Y.Kokubo, K. Ito, T. Fukunaga,H.Matsubara,and S. Kuzuhara, “Pigmentary retinopathy of ALS/PDC in Kii,” Ophthalmology, vol. 113, no. 11, pp. 2111.e1–2111.e2, 2006. [4] Y.Kokubo, Y. Nomura,S.Morimoto, andS.Kuzuhara, “Car- diac 123I-meta-iodobenzylguanidine scintigraphy in patients with amyotrophic lateral sclerosis and parkinsonism-dementia complex of the Kii peninsula, Japan,” Parkinsonism and Related Disorders,vol.18, pp.306–308,2012. [5] M. Sjog ¨ ren, H. Vanderstichele, H. Agren et al., “Tau and Abeta42 in cerebrospinal uid fl from healthy adults 21–93 years of age: establishment of reference values,” Clinical Chemistry, vol. 47, pp. 1776–1781, 2001. [6] M.Noguchi,M.Yoshita,Y.Matsumoto,K.Ono,K.Iwasa,and M. Yamada, “Decreased𝛽 -amyloid peptide in cerebrospinal fluid of patients with progressive supranuclear palsy and corti- cobasal degeneration,” Journal of the Neurological Sciences,vol. 237, no.1-2,pp. 61–65, 2005. [7] K. Kanemaru, N. Kameda, and H. Yamanouchi, “Decreased CSF amyloid𝛽 42 and normal tau levels in dementia with Lewy bodies,” Neurology,vol.54, no.9,pp. 1875–1876, 2000. [8] N. Mattsson, E. Rosen, O. Hansson et al., “Age and diagnostic performance of Alzheimer disease CSF biomarkers,” Neurology, vol. 78, pp. 468–476, 2012. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal

Journal of Neurodegenerative Diseases – Hindawi Publishing Corporation

Published: Mar 27, 2013

References

  • Familial amyotrophic lateral sclerosis and parkinsonism-dementia complex of the Kii peninsula of Japan: clinical and neuropathological study and tau analysis,
    S. Kuzuhara, Y. Kokubo, R. Sasaki et al.
  • Neuroradiological study of patients with amyotrophic lateral sclerosis and parkinsonism-dementia complex on the Kii peninsula of Japan,
    Y. Kokubo and S. Kuzuhara
  • Pigmentary retinopathy of ALS/PDC in Kii,
    Y. Kokubo, K. Ito, T. Fukunaga, H. Matsubara, and S. Kuzuhara
  • Cardiac 123I-meta-iodobenzylguanidine scintigraphy in patients with amyotrophic lateral sclerosis and parkinsonism-dementia complex of the Kii peninsula, Japan,
    Y. Kokubo, Y. Nomura, S. Morimoto, and S. Kuzuhara
  • Tau and Abeta42 in cerebrospinal fluid from healthy adults 21–93 years of age: establishment of reference values,
    M. Sjögren, H. Vanderstichele, H. Agren et al.
  • Decreased β-amyloid peptide42 in cerebrospinal fluid of patients with progressive supranuclear palsy and corticobasal degeneration,
    M. Noguchi, M. Yoshita, Y. Matsumoto, K. Ono, K. Iwasa, and M. Yamada
  • Decreased CSF amyloid β42 and normal tau levels in dementia with Lewy bodies,
    K. Kanemaru, N. Kameda, and H. Yamanouchi
  • Age and diagnostic performance of Alzheimer disease CSF biomarkers,
    N. Mattsson, E. Rosen, O. Hansson et al.