Abstract
TMEM106B has recently been identified as a genetic risk factor for frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). Amyotrophic lateral sclerosis (ALS), like FTLD-TDP, is characterized by pathological TDP-43 inclusions. We therefore investigated whether FTLD-TDP-associated risk genotypes at TMEM106B (1) contribute to risk of developing ALS or (2) modify the clinical presentation in ALS. Detailed clinical and pathological information from 61 postmortem ALS patients was collected by database query, retrospective chart review, and histopathological slide review. DNA from these patients, as well as 24 additional ALS patients, was genotyped for three TMEM106B single nucleotide polymorphisms known to confer increased risk of FTLD-TDP. Associations between TMEM106B genotype and ALS were investigated by comparing TMEM106B genotypes in ALS patients (n = 85) and normal controls (n = 553), and associations between TMEM106B genotype and clinical and pathologic features were explored using linear regression. Multivariate linear models were used to evaluate the contributions of TMEM106B genotype and TDP-43 pathology to cognitive performance in ALS as measured by a phonemic verbal fluency test. We found that TMEM106B genotypes did not differ between ALS patients and normal controls. However, protective alleles at TMEM106B were significantly associated with preserved cognition in ALS patients, with the strongest association seen under a major-allele-dominant genetic model. While lower TDP-43 pathology scores and protective alleles at TMEM106B both correlated with better cognitive scores, these factors were not correlated with each other and demonstrated independent effects. These findings implicate the FTLD-TDP risk gene TMEM106B in the development of cognitive impairment in ALS.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Arai T, Hasegawa M, Akiyama H et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611
Benajiba L, Le Ber I, Camuzat A et al (2009) TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann Neurol 65:470–473
Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16:271–278 discussion 278–284
Brandmeir NJ, Geser F, Kwong LK et al (2008) Severe subcortical TDP-43 pathology in sporadic frontotemporal lobar degeneration with motor neuron disease. Acta Neuropathol 115:123–131
Brooks BR, Miller RG, Swash M, Munsat TL (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1:293–299
Cedarbaum JM, Stambler N, Malta E et al (1999) The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci 169:13–21
Chen-Plotkin AS, Lee VM, Trojanowski JQ (2010) TAR DNA-binding protein 43 in neurodegenerative disease. Nat Rev Neurol 6:211–220
Chio A, Schymick JC, Restagno G et al (2009) A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis. Hum Mol Genet 18:1524–1532
Cruts M, Van Broeckhoven C (2008) Loss of progranulin function in frontotemporal lobar degeneration. Trends Genet 24:186–194
Dunckley T, Huentelman MJ, Craig DW et al (2007) Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med 357:775–788
Geser F, Brandmeir NJ, Kwong LK et al (2008) Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis. Arch Neurol 65:636–641
Geser F, Martinez-Lage M, Robinson J et al (2009) Clinical and pathological continuum of multisystem TDP-43 proteinopathies. Arch Neurol 66:180–189
Gitcho MA, Baloh RH, Chakraverty S et al (2008) TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 63:535–538
Hodges JR, Davies RR, Xuereb JH et al (2004) Clinicopathological correlates in frontotemporal dementia. Ann Neurol 56:399–406
Kabashi E, Valdmanis PN, Dion P et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574
Lezak M (1983) Neuropsychological assessment. Oxford University Press, New York
Libon DJ, Massimo L, Moore P et al (2007) Screening for frontotemporal dementias and Alzheimer’s disease with the Philadelphia Brief Assessment of Cognition: a preliminary analysis. Dement Geriatr Cogn Disord 24:441–447
Lomen-Hoerth C, Murphy J, Langmore S et al (2003) Are amyotrophic lateral sclerosis patients cognitively normal? Neurology 60:1094–1097
Mackenzie IR, Neumann M, Bigio EH et al (2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 117:15–18
Murphy JM, Henry RG, Langmore S et al (2007) Continuum of frontal lobe impairment in amyotrophic lateral sclerosis. Arch Neurol 64:530–534
Neary D, Snowden JS, Gustafson L et al (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546–1554
Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133
Pesiridis GS, Lee VM-Y, Trojanowski JQ (2009) Mutations in TDP-43 link glycine-rich domain functions to amyotrophic lateral sclerosis. Hum Mol Genet 18(R2):R156–R162
Phukan J, Pender NP, Hardiman O (2007) Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurol 6:994–1003
Sreedharan J, Blair IP, Tripathi VB et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672
Strong MJ, Grace GM, Freedman M et al (2009) Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 10:131–146
Takeda T, Uchihara T, Arai N, Mizutani T, Iwata M (2009) Progression of hippocampal degeneration in amyotrophic lateral sclerosis with or without memory impairment: distinction from Alzheimer disease. Acta Neuropathol 117:35–44
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 5:208–212
Van Deerlin VM, Sleiman PM, Martinez-Lage M et al (2010) Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet 42:234–239
Van Deerlin VM, Leverenz JB, Bekris LM et al (2008) TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol 7:409–416
Xie SX, Baek Y, Grossman M et al (2010) Building an integrated neurodegenerative disease database at an academic health center. Alzheimers Dement (in press)
Acknowledgments
We thank the patients who contributed samples to this study. We thank Robert Greene and Young Baek for technical assistance. This work was supported by the NIH (AG033101, AG17586, AG10124, AG17586, AG32953, NS44266), as well as a Burroughs Wellcome Fund Career Award for Medical Scientists and the Benaroya Fund (to ACP), and the Koller Family Foundation. VMYL is the John H. Ware, 3rd, Professor of Alzheimer’s Disease Research. JQT is the William Maul Measey-Truman G. Schnabel, Jr., Professor of Geriatric Medicine and Gerontology.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
R. Vass and E. Ashbridge contributed equally to this work.
Rights and permissions
About this article
Cite this article
Vass, R., Ashbridge, E., Geser, F. et al. Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis. Acta Neuropathol 121, 373–380 (2011). https://doi.org/10.1007/s00401-010-0782-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-010-0782-y