Background: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are two common forms of primary neurodegenerative dementia. Mutations in 3 genes (PSEN1, PSEN2, and APP) have been identified in patients with early-onset AD. Methods: We performed gene sequencing in PSEN1, PSEN2, and APP in 61 AD and 35 FTD Chinese patients. Amyloid load using 11C-labeled Pittsburgh compound B (11C-PIB) positron emission tomography (PET) and cerebral glucose metabolism using 18F-fludeoxyglucose PET were evaluated in patients carrying mutations. Results: We identified 1 known pathogenic PSEN1 (p.His163Arg, c.488A>G) mutation and 3 novel PSEN2 mutations in 6 patients. The novel mutation PSEN2 (p.His169Asn, c.505C>A) was identified in 1 patient with familial late-onset AD and in 1 sporadic FTD patient. The PSEN2 (p.Val214Leu, c.640G>T; p.Lys82Arg, c.245A>G) mutations were identified in 2 early-onset AD patients and 1 early-onset AD patient, respectively. Three patients with PSEN2 mutations were observed to have PIB retention on the cortex and striatum. One patient with the FTD phenotype was not observed to have PIB retention. Conclusion: PSEN2 mutations are common in the Chinese Han population with a history of AD and FTD. Pathogenic mutations or risk variants in the PSEN2 gene can influence both FTD and AD phenotypic traits and show variations in neuroimaging characterization. © 2014 S. Karger AG, Basel

1.
Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA: Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 2003;60:1119-1122. 2 2009 Alzheimer's disease facts and figures. Alzheimers Dement 2009;5:234-270.
2.
2009 Alzheimer's disease facts and figures. Alzheimers Dement 2009;5:234-270.
3.
Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002;297:353-356.
4.
Goate A, Chartier-Harlin M-C, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor M, Owen M, Hardy J: Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 1991;349:704-706.
5.
Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH: Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 1995;375:754-760.
6.
Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, Mar L, Sorbi S, Nacmias B, Piacentini S, Amaducci L, Chumakov I, Cohen D, Lannfelt L, Fraser PE, Rommens JM, St George-Hyslop PH: Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 1995;376:775-778.
7.
Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K: Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 1995;269:973-977.
8.
Cruchaga C, Chakraverty S, Mayo K, Vallania FL, Mitra RD, Faber K, Williamson J, Bird T, Diaz-Arrastia R, Foroud TM, Boeve BF, Graff-Radford NR, St Jean P, Lawson M, Ehm MG, Mayeux R, Goate AM: Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One 2010;7:e31039.
9.
Samaranch L, Cervantes S, Barabash A, Alonso A, Cabranes JA, Lamet I, Ancin I, Lorenzo E, Martinez-Lage P, Marcos A, Clarimon J, Alcolea D, Lleo A, Blesa R, Gomez-Isla T, Pastor P: The effect of MAPT H1 and APOE epsilon4 on transition from mild cognitive impairment to dementia. J Alzheimers Dis 2010;22:1065-1071.
10.
Ji Y, Liu M, Huo YR, Liu S, Shi Z, Liu S, Wisniewski T, Wang J: Apolipoprotein Ε ε4 frequency is increased among Chinese patients with frontotemporal dementia and Alzheimer's disease. Dement Geriatr Cogn Disord 2013;36:163-170.
11.
Mendez MF, McMurtray A: Frontotemporal dementia-like phenotypes associated with presenilin-1 mutations. Am J Alzheimers Dis Other Demen 2006:21:281-286.
12.
Rabinovici GD, Miller BL: Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management. CNS Drugs 2010;24:375-98.
13.
Neary D, Snowden J, Mann D: Frontotemporal dementia. Lancet Neurol 2005;4:771-780.
14.
Seelaar H, Rohrer JD, Pijnenburg YA, Fox NC, Swieten JC: Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. J Neurol Neurosurg Psychiatry 2011;82:476-486.
15.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:939-944.
16.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 4, Text Revision. Washington, American Psychiatric Association, 2000, pp 157-158.
17.
Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998;51:1546-1554.
18.
Giovagnoli AR, Marcon G, Giaccone G, Confaloni AM, Tagliavini F: Cognitive deficits in familial Alzheimer's disease associated with M239V mutation of presenilin 2. Dement Geriatr Cogn Disord 2006;22:238-243.
19.
Urakami K, Adachi Y, Wakutani Y, Isoe K, Ji Y, Takahashi K, Nakashima K: Epidemiologic and genetic studies of dementia of the Alzheimer type in Japan. Dement Geriatr Cogn Disord 1998;9:294-298.
20.
Ikeuchi T, Kaneko H, Miyashita A, Nozaki H, Kasuga K, Tsukie T, Tsuchiya M, Imamura T, Ishizu H, Aoki K, Ishikawa A, Onodera O, Kuwano R, Nishizawa M: Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406W mutations. Dement Geriatr Cogn Disord 2008;26:43-49.
21.
Jayadev S, Leverenz JB, Steinbart E, Stahl J, Klunk W, Yu CE, Bird TD: Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2. Brain 2010;133:1143-1154.
22.
Binetti G, Signorini S, Squitti R, Alberici A, Benussi L, Cassetta E, Frisoni GB, Barbiero L, Feudatari E, Nicosia F, Testa C, Zanetti O, Gennarelli M, Perani D, Anchisi D, Ghidoni R, Rossini PM: Atypical dementia associated with a novel presenilin-2 mutation. Ann Neurol 2003;54:832-836.
23.
Marcon G, Di Fede G, Giaccone G, Rossi G, Giovagnoli AR, Maccagnano E, Tagliavini F: A novel Italian presenilin 2 gene mutation with prevalent behavioral phenotype. J Alzheimers Dis 2009;16:509-511.
24.
Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergström M, Savitcheva I, Huang GF, Estrada S, Ausén B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Långström B: Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol 2004;55:306-319.
25.
Klunk WE, Price JC, Mathis CA, Tsopelas ND, Lopresti BJ, Ziolko SK, Bi W, Hoge JA, Cohen AD, Ikonomovic MD, Saxton JA, Snitz BE, Pollen DA, Moonis M, Lippa CF, Swearer JM, Johnson KA, Rentz DM, Fischman AJ, Aizenstein HJ, DeKosky ST: Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci 2007;27:6174-6184.
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