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Vol. 25, No. 4, 2008
Issue release date: April 2008
Dement Geriatr Cogn Disord 2008;25:380–384

Increased Prevalence of Significant Recurrent Headache in Preclinical Familial Alzheimer’s Disease Mutation Carriers

Ringman J.M. · Romano J.D. · Medina L.D. · Rodriguez-Agudelo Y. · Schaffer B. · Varpetian A. · Ortiz F. · Fitten L.J. · Cummings J.L. · Baloh R.W.
aAlzheimer’s Disease Research Center, bUCLA Department of Neurology, cGreater Los Angeles Veterans Affairs Healthcare System, Sepulveda Campus, and dPsychiatry and Biobehavioral Science, UCLA, Los Angeles, Calif., eDepartment of Neurology, Keck School of Medicine, USC, Rancho Los Amigos National Rehabilitation Center, Downey, Calif., fNeuropsychiatry Research Memory Clinic, Olive-View UCLA Medical Center, Sylmar, Calif., and gVirginia Commonwealth University Medical School, Richmond, Va., USA; hDepartment of Neuropsychology, National Institute of Neurology and Neurosurgery, Mexico City, Mexico

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Background/Aims: A previous study found a high prevalence of headaches in persons with familial Alzheimer’s disease (FAD) due to a PSEN1 mutation. In our study we compared the prevalence of headaches between nondemented FAD mutation carriers (MCs) and non-mutation-carrying controls (NCs). Methods: A headache questionnaire that assessed the prevalence of significant headaches and diagnosis of migraine and aura by ICHD-2 criteria was administered to 27 individuals at risk for FAD. Frequency of significant headaches, migraine, and aura were compared between MCs and NCs by χ2 or Fisher’s exact tests. Results: Twenty-three subjects were at risk for PSEN1 mutations and 4 for an APP substitution. The majority of subjects were female (23/27). MCs were more likely to report significant recurrent headache than NCs (67 vs. 25%, p = 0.031). Forty percent of MCs had headaches that met criteria for migraine whereas 17% of NCs met such criteria. The tendency for a higher prevalence of headaches in MCs held for different PSEN1 and APP mutations but was not significant unless all families were combined. Conclusions: In this population, headache was more common in nondemented FAD MCs than NCs. Possible mechanisms for this include cerebral inflammation, aberrant processing of Notch3, or disrupted intracellular calcium regulation.

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  1. Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, et al: Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet 1999;65:664–670.
  2. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al: Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995;375:754–760.
  3. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al: Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 1991;349:704–706.
  4. Sherrington R, Froelich S, Sorbi S, Campion D, Chi H, Rogaeva EA, et al: Alzheimer’s disease associated with mutations in presenilin 2 is rare and variably penetrant. Hum Mol Genet 1996;5:985–988.
  5. Fox NC, Kennedy AM, Harvey RJ, Lantos PL, Roques PK, Collinge J, et al: Clinicopathological features of familial Alzheimer’s disease associated with the M139V mutation in the presenilin 1 gene: pedigree but not mutation specific age at onset provides evidence for a further genetic factor. Brain 1997;120:491–501.
  6. Ringman JM: What the study of persons at risk for familial Alzheimer’s disease can tell us about the earliest stages of the disorder: a review. J Geriatr Psychiatry Neurol 2005;18:228–233.
  7. Ringman JM, Diaz-Olavarrieta C, Rodriguez Y, Chavez M, Fairbanks L, Paz F, et al: Neuropsychological function in nondemented carriers of presenilin-1 mutations. Neurology 2005;65:552–558.
  8. Lleo A, Berezovska O, Growdon JH, Hyman BT: Clinical, pathological, and biochemical spectrum of Alzheimer disease associated with PS-1 mutations. Am J Geriatr Psychiatry 2004;12:146–156.
  9. Mann DM, Pickering-Brown SM, Takeuchi A, Iwatsubo T: Amyloid angiopathy and variability in amyloid beta deposition is determined by mutation position in presenilin-1-linked Alzheimer’s disease. Am J Pathol 2001;158:2165–2175.
  10. Lemere CA, Lopera F, Kosik KS, Lendon CL, Ossa J, Saido TC, et al: The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nat Med 1996;2:1146–1150.
  11. Houlden H, Baker M, McGowan E, Lewis P, Hutton M, Crook R, et al: Variant Alzheimer’s disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann Neurol 2000;48:806–808.
  12. Verkkoniemi A, Kalimo H, Paetau A, Somer M, Iwatsubo T, Hardy J, et al: Variant Alzheimer disease with spastic paraparesis: neuropathological phenotype. J Neuropathol Exp Neurol 2001;60:483–492.
  13. Lopera F, Ardilla A, Martinez A, Madrigal L, Arango-Viana JC, Lemere CA, et al: Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA 1997;277:793–799.
  14. Murrell J, Ghetti B, Cochran E, Macias-Islas MA, Medina L, Varpetian A, et al: The A431E mutation in PSEN1 causing familial Alzheimer’s disease originating in Jalisco State, Mexico: an additional fifteen families. Neurogenetics 2006;7:277–279.
  15. Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, et al: Early onset familial Alzheimer’s disease: mutation frequency in 31 families. Neurology 2003;60:235–239.
  16. Athan ES, Williamson J, Ciappa A, Santana V, Romas SN, Lee JH, et al: A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families. JAMA 2001;286:2257–2263.
  17. Mullan M, Tsuji S, Miki T, Katsuya T, Naruse S, Kaneko K, et al: Clinical comparison of Alzheimer’s disease in pedigrees with the codon 717 Val–>Ile mutation in the amyloid precursor protein gene. Neurobiol Aging 1993;14:407–419.
  18. Lipton RB, Bigal ME, Steiner TJ, Silberstein SD, Olesen J: Classification of primary headaches. Neurology 2004;63:427–435.
  19. Cha YH, Kane MJ, Baloh RW: Familial clustering of migraine, episodic vertigo, and Ménière’s disease. Otol Neurotol 2008;29:93–96.
  20. Lee H, Jen JC, Cha YH, Nelson SF, Baloh RW: Phenotypic and genetic analysis of a large family with migraine-associated vertigo. Headache 2007;Dec 11 (Epub ahead of print).
  21. Morris JC: Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr 1997;9(suppl 1):173–176; discussion 177–178.
  22. Russell MB, Rasmussen BK, Thorvaldsen P, Olesen J: Prevalence and sex-ratio of the subtypes of migraine. Int J Epidemiol 1995;24:612–618.
  23. Brunkan AL, Goate AM: Presenilin function and gamma-secretase activity. J Neurochem 2005;93:769–792.
  24. Dichgans M, Mayer M, Uttner I, Bruning R, Muller-Hocker J, Rungger G, et al: The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol 1998;44:731–739.
  25. Stutzmann GE, Caccamo A, LaFerla FM, Parker I: Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer’s-linked mutation in presenilin 1 results in exaggerated Ca2+ signals and altered membrane excitability. J Neurosci 2004;24:508–513.
  26. Scolding NJ, Joseph F, Kirby PA, Mazanti I, Gray F, Mikol J, et al: Abeta-related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy. Brain 2005;128:500–515.
  27. Dermaut B, Kumar-Singh S, De Jonghe C, Cruts M, Lofgren A, Lubke U, et al: Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer’s disease due to a novel presenilin 1 mutation. Brain 2001;124:2383–2392.

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