Progranulin Mutations As Risk Factors for Alzheimer Disease

Overview

Journal JAMA Neurol

Publisher American Medical Association

Date 2013 Apr 24

PMID 23609919

Citations 64

Authors

David C Perry

Manja Lehmann

Jennifer S Yokoyama

Anna Karydas

Jason Jiyong Lee

Giovanni Coppola

Lea T Grinberg

Dan Geschwind

William W Seeley

Bruce L Miller

Howard Rosen

Gil Rabinovici

Affiliations

Soon will be listed here.

Abstract

Importance: Mutations in the progranulin gene are known to cause diverse clinical syndromes, all attributed to frontotemporal lobar degeneration. We describe 2 patients with progranulin gene mutations and evidence of Alzheimer disease (AD) pathology. We also conducted a literature review.

Observations: This study focused on case reports of 2 unrelated patients with progranulin mutations at the University of California, San Francisco, Memory and Aging Center. One patient presented at age 65 years with a clinical syndrome suggestive of AD and showed evidence of amyloid aggregation on positron emission tomography. Another patient presented at age 54 years with logopenic progressive aphasia and, at autopsy, showed both frontotemporal lobar degeneration with TDP-43 inclusions and AD.

Conclusions And Relevance: In addition to autosomal-dominant frontotemporal lobar degeneration, mutations in the progranulin gene may be a risk factor for AD clinical phenotypes and neuropathology.

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References

Folstein M, Folstein S, McHugh P . "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975; 12(3):189-98. DOI: 10.1016/0022-3956(75)90026-6. View

Caccamo A, Magri A, Oddo S . Age-dependent changes in TDP-43 levels in a mouse model of Alzheimer disease are linked to Aβ oligomers accumulation. Mol Neurodegener. 2010; 5:51. PMC: 2989316. DOI: 10.1186/1750-1326-5-51. View

Morris J, Roe C, Xiong C, Fagan A, Goate A, Holtzman D . APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol. 2010; 67(1):122-31. PMC: 2830375. DOI: 10.1002/ana.21843. View

Lee J, Lee Y, Yuk D, Choi D, Ban S, Oh K . Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation. 2008; 5:37. PMC: 2556656. DOI: 10.1186/1742-2094-5-37. View

He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C . Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer's mice. J Cell Biol. 2007; 178(5):829-41. PMC: 2064547. DOI: 10.1083/jcb.200705042. View

Shi J, Shen W, Chen J, Wang B, Zhong L, Zhu Y . Anti-TNF-α reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains. Brain Res. 2010; 1368:239-47. DOI: 10.1016/j.brainres.2010.10.053. View

Ashburner J . A fast diffeomorphic image registration algorithm. Neuroimage. 2007; 38(1):95-113. DOI: 10.1016/j.neuroimage.2007.07.007. View

Yamamoto M, Kiyota T, Horiba M, Buescher J, Walsh S, Gendelman H . Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol. 2007; 170(2):680-92. PMC: 1851864. DOI: 10.2353/ajpath.2007.060378. View

Braak H, Braak E . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991; 82(4):239-59. DOI: 10.1007/BF00308809. View

10.

Ashburner J, Friston K . Voxel-based morphometry--the methods. Neuroimage. 2000; 11(6 Pt 1):805-21. DOI: 10.1006/nimg.2000.0582. View

11.

Lee M, Chen T, Cheng T, Chiu M . rs5848 variant of progranulin gene is a risk of Alzheimer's disease in the Taiwanese population. Neurodegener Dis. 2011; 8(4):216-20. DOI: 10.1159/000322538. View

12.

. Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease. Neurobiol Aging. 1997; 18(4 Suppl):S1-2. View

13.

Yin F, Banerjee R, Thomas B, Zhou P, Qian L, Jia T . Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med. 2009; 207(1):117-28. PMC: 2812536. DOI: 10.1084/jem.20091568. View

14.

Janelsins M, Mastrangelo M, Park K, Sudol K, Narrow W, Oddo S . Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice. Am J Pathol. 2008; 173(6):1768-82. PMC: 2626388. DOI: 10.2353/ajpath.2008.080528. View

15.

Uryu K, Nakashima-Yasuda H, Forman M, Kwong L, Clark C, Grossman M . Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol. 2008; 67(6):555-64. PMC: 3659339. DOI: 10.1097/NEN.0b013e31817713b5. View

16.

Brouwers N, Sleegers K, Engelborghs S, Maurer-Stroh S, Gijselinck I, van der Zee J . Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease. Neurology. 2008; 71(9):656-64. DOI: 10.1212/01.wnl.0000319688.89790.7a. View

17.

Rademakers R, Baker M, Gass J, Adamson J, Huey E, Momeni P . Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C-->T (Arg493X) mutation: an international initiative. Lancet Neurol. 2007; 6(10):857-68. DOI: 10.1016/S1474-4422(07)70221-1. View

18.

Cagnin A, Brooks D, Kennedy A, Gunn R, Myers R, Turkheimer F . In-vivo measurement of activated microglia in dementia. Lancet. 2001; 358(9280):461-7. DOI: 10.1016/S0140-6736(01)05625-2. View

19.

Josephs K, Whitwell J, Knopman D, Hu W, Stroh D, Baker M . Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. Neurology. 2008; 70(19 Pt 2):1850-7. PMC: 2779031. DOI: 10.1212/01.wnl.0000304041.09418.b1. View

20.

Hickman S, Allison E, El Khoury J . Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci. 2008; 28(33):8354-60. PMC: 2597474. DOI: 10.1523/JNEUROSCI.0616-08.2008. View