Abstract
The clinical courses of sporadic amyotrophic lateral sclerosis (ALS) show extensive variability. Our objective was to elucidate how age of onset influences the progression of regional symptoms and functional losses in sporadic ALS. We included 648 patients with sporadic ALS from a multicenter prospective ALS cohort. We investigated the distribution of initial symptoms and analyzed the time from onset to events affecting activities of daily living (ADL) as well as the longitudinal changes in each regional functional rating score among four groups with different ages of onset. The frequencies of dysarthria and dysphagia as initial symptoms were higher in the older age groups, whereas weakness of upper limbs was the most common initial symptom in the youngest age group. The survival times and the times from onset to loss of speech and swallowing were significantly shorter in the older age group (p < 0.001), although the times from onset to loss of upper limb function were not significantly different among the age groups. According to joint modeling analysis, the bulbar score declined faster in the older age groups (<50 vs. 60–69 years: p = 0.029, <50 vs. ≥70 years: p < 0.001), whereas there was no significant correlation between the age of onset and decline in the upper limb score. Our results showed that age of onset had a significant influence on survival time and the progression of bulbar symptoms, but had no influence on upper limb function in sporadic ALS.
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Turner MR, Hardiman O, Benatar M, Brooks BR, Chio A, De Carvalho M, Ince PG, Lin C, Miller RG, Mitsumoto H, Nicholson G, Ravits J, Shaw PJ, Swash M, Talbot K, Traynor BJ, Van Den Berg LH, Veldink JH, Vucic S, Kiernan MC (2013) Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol 12(3):310–322
Nishihira Y, Tan CF, Onodera O, Toyoshima Y, Yamada M, Morita T, Nishizawa M, Kakita A, Takahashi H (2008) Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions. Acta Neuropathol 116(2):169–182
Chiò A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E, Traynor BG (2012) Prognostic factors in ALS: a critical review. Amyotroph Lateral Scler 10(5–6):310–323
Creemers H, Grupstra H, Beelen A (2015) Prognostic factors for the course of functional status of patients with ALS: a systematic review. J Neurol 262(6):1407–1423
Kelly C, Johnson BA, Lyles RH, Glass JD (2013) Prognosis and epidemiology of amyotrophic lateral sclerosis: analysis of a clinic population, 1997–2011. Neurol Clin Pract 3(4):313–320
Watanabe H, Atsuta N, Nakamura R, Hirakawa A, Watanabe H, Ito M, Senda J, Katsuno M, Izumi Y, Morita M, Tomiyama H, Taniguchi A, Aiba I, Abe K, Mizoguchi K, Oda M, Kano O, Okamoto K, Kuwabara S, Hasegawa K, Imai T, Aoki M, Tsuji S, Nakano I, Kaji R, Sobue G (2015) Factors affecting longitudinal functional decline and survival in amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Front Degener 16(3–4):230–236
Nakamura R, Atsuta N, Watanabe H, Hirakawa A, Watanabe H, Ito M, Senda J, Katsuno M, Tanaka F, Izumi Y, Morita M, Ogaki K, Taniguchi A, Aiba I, Mizoguchi K, Okamoto K, Hasegawa K, Aoki M, Kawata A, Abe K, Oda M, Konagaya M, Imai T, Nakagawa M, Tsuji S, Kaji R, Nakano I, Sobue G (2013) Neck weakness is a potent prognostic factor in sporadic amyotrophic lateral sclerosis patients. J Neurol Neurosurg Psychiatry 84(12):1365–1371
Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron Diseases (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1(5):293–299
Ohashi Y, Tashiro K, Itoyama Y, Nakano I, Sobue G, Nakamura S, Sumino S, Yanagisawa N (2001) Study of functional rating scale for amyotrophic lateral sclerosis: revised ALSFRS(ALSFRS-R) Japanese version. No To Shinkei 53(4):346–355
Atsuta N, Watanabe H, Ito M, Nakamura R, Senda J, Kato S, Sobue G (2011) Development of a telephone survey system for patients with amyotrophic lateral sclerosis using the ALSFRS-R (Japanese version) and application of this system in a longitudinal multicenter study. Brain Nerve 63(5):491–496
Kasarskis EJ, Dempsey-Hall L, Thompson MM, Luu LC, Mendiondo M, Kryscio R (2005) Rating the severity of ALS by caregivers over the telephone using the ALSFRS-R. Amyotroph Lateral Scler Other Motor Neuron Disord 6(1):50–54
Kaufmann P, Levy G, Montes J, Buchsbaum R, Barsdorf AI, Battista V, Arbing R, Gordon PH, Mitsumoto H, Levin B, Thompson JLP (2007) Excellent inter-rater, intra-rater, and telephone-administered reliability of the ALSFRS-R in a multicenter clinical trial. Amyotroph Lateral Scler 8(1):42–46
Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A (1999) The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. J Neurol Sci 169(1–2):13–21
Rizopoulos D (2011) Dynamic predictions and prospective accuracy in joint models for longitudinal and time-to-event data. Biometrics 67(3):819–829
Chi YY, Ibrahim JG (2006) Joint models for multivariate longitudinal and multivariate survival data. Biometrics 62(2):432–445
Forbes RB, Colville S, Swingler RJ (2004) The epidemiology of amyotrophic lateral sclerosis (ALS/MND) in people aged 80 or over. Age Ageing 33(2):131–134
Gordon PH, Cheng B, Salachas F, Pradat PF, Bruneteau G, Corcia P, Lacomblez L, Meininger V (2010) Progression in ALS is not linear but is curvilinear. J Neurol 257(10):1713–1717
Testa D, Lovati R, Ferrarini M, Salmoiraghi F, Filippini G (2004) Survival of 793 patients with amyotrophic lateral sclerosis diagnosed over a 28-year period. Amyotroph Lateral Scler Other Motor Neuron Disord 5(4):208–212
Tomlinson BE, Irving D (1977) The numbers of limb motor neurons in the human lumbosacral cord throughout life. J Neurol Sci 34(2):213–219
Hideyama T, Teramoto S, Hachiga K, Yamashita T, Kwak S (2012) Co-occurrence of TDP-43 mislocalization with reduced activity of an rna editing enzyme, ADAR2, in aged mouse motor neurons. PLoS One 7(8):e43469
Leslie P, Drinnan MJ, Ford GA, Wilson JA (2005) Swallow respiratory patterns and aging: presbyphagia or dysphagia? J Gerontol A Biol Sci Med Sci 60(3):391–395
Sharma G, Goodwin J (2006) Effect of aging on respiratory system physiology and immunology. Clin Interv Aging 1(3):253–260
Brooks SV, Faulkner JA (1994) Skeletal muscle weakness in old age: underlying mechanisms. Med Sci Sports Exerc 26(4):432–439
Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman OM (2000) Clinical features of amyotrophic lateral sclerosis according to the El Escorial and Airlie House diagnostic criteria: a population-based study. Arch Neurol 57(8):1171–1176
Zoccolella S, Beghi E, Palagano G, Fraddosio A, Samarelli V, Lamberti P, Lepore V, Serlenga L, Logroscino G (2006) Signs and symptoms at diagnosis of amyotrophic lateral sclerosis: a population-based study in southern Italy. Eur J Neurol 13(7):789–792
O’Toole O, Traynor BJ, Brennan P, Sheehan C, Frost E, Corr B, Hardiman O (2008) Epidemiology and clinical features of amyotrophic lateral sclerosis in Ireland between 1995 and 2004. J Neurol Neurosurg Psychiatry 79(1):30–32
Huisman MHB, de Jong SW, van Doormaal PTC, Weinreich SS, Schelhaas HJ, van der Kooi AJ, de Visser M, Veldink JH, van den Berg LH (2011) Population based epidemiology of amyotrophic lateral sclerosis using capture-recapture methodology. J Neurol Neurosurg Psychiatry 82:1165–1170
Atsuta N, Watanabe H, Ito M, Tanaka F, Tamakoshi A, Nakano I, Aoki M, Tsuji S, Yuasa T, Takano H, Hayashi H, Kuzuhara S, Sobue G (2009) Age at onset influences on wide-ranged clinical features of sporadic amyotrophic lateral sclerosis. J Neurol Sci 276(1–2):163–169
Riku Y, Atsuta N, Yoshida M, Tatsumi S, Iwasaki Y, Mimuro M, Watanabe H, Ito M, Senda J, Nakamura R, Koike H, Sobue G (2014) Differential motor neuron involvement in progressive muscular atrophy: a comparative study with amyotrophic lateral sclerosis. BMJ Open 4:e005213
Cady J, Allred P, Bali T, Pestronk A, Goate A, Miller TM, Mitra RD, Ravits J, Harms MB, Baloh RH (2015) Amyotrophic lateral sclerosis onset is influenced by the burden of rare variants in known amyotrophic lateral sclerosis genes. Ann Neurol 77(1):100–113
Kwee LC, Liu Y, Haynes C, Gibson JR, Stone A, Schichman SA, Kamel F, Nelson LM, Topol B, van Den Eeden SK, Tanner CM, Cudkowicz ME, Grasso DL, Lawson R, Muralidhar S, Oddone EZ, Schmidt S, Hauser MA (2012) A high-density genome-wide association screen of sporadic als in US veterans. PLoS One 7(3):e32768
Acknowledgments
We thank all the patients with ALS who participated in this study. We also thank all of the doctors and staff who participated in the Japanese Consortium for Amyotrophic Lateral Sclerosis research (JaCALS).
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This work was supported by a Grant (15Aek0109071 h0002) from the Japan Agency for Medical Research and Development (AMED), Health and Labour Sciences Research Grants (H26-086) and Grants-in Aid (25,461,277) for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. A section of this study is the result of the “Integrated Research on Neuropsychiatric Disorders” study, which was performed under the Strategic Research Program for Brain Sciences by the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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The ethics committees of all participating institutions approved the study. Ethical standards were consistent with the 1964 Declaration of Helsinki and its later amendments.
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Yokoi, D., Atsuta, N., Watanabe, H. et al. Age of onset differentially influences the progression of regional dysfunction in sporadic amyotrophic lateral sclerosis. J Neurol 263, 1129–1136 (2016). https://doi.org/10.1007/s00415-016-8109-0
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DOI: https://doi.org/10.1007/s00415-016-8109-0