Neuropsychiatric manifestations are common in Alzheimer's disease (AD) and their phenotypic expression might be related to physiopathological and genetic causes. Multiple studies have implicated oxidative stress to the pathogenesis and possible etiology of AD. One of the mechanisms to protect cells from oxidative stress is the expression of heat-shock proteins (HSP). HSPA1B (alternatively known as HSP70-2) has been related to AD pathophysiology. In the present analysis, 77 AD patients were classified according to their cognitive status with the Neuropsychiatric Inventory and were genotyped for an insertion/deletion (A1/A2) polymorphism. The A2 allele conferred a significant increase of psychiatric morbidity in an allele-dose manner (P < .05). This pattern can be attributed to all AD stages and the severity of the behavioral disturbances was higher for those patients carrying one or two A2 alleles. These results indicate a possible association between the A2 allele and an overexpression of noncognitive symptoms in AD. (J Geriatr Psychiatry Neurol 2003: 16-146-150).
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References
1.
1. Ballard C, Lowery K, Powell I, et al. Impact of behavioral and psychological symptoms of dementia on caregivers. Int Psychogeriatr2000; 12:93-105.
2.
2. Balesteri L, Grossberg A, Grossberg GT. Behavioral and psychological symptoms of dementia as a risk factor for nursing home placement. Int Psychogeriatr2000; 12:59-63.
3.
3. Beeri MS, Werner P, Adar Z, et al. Economic cost of Alzheimer disease in Israel. Alzheimer Dis Assoc Disord2002; 16:73-80.
4.
4. Petry S, Cummings JL, Hill MA, Shapira J. Personality alterations in dementia of the Alzheimer type. Arch Neurol1988; 45:1187-1190.
5.
5. Rubin EH, Kinscherf DA. Psychopathology of very mild dementia of the Alzheimer type. Am J Psychiatry1989; 146:1017-1021.
6.
6. Mega MS, Cummings JL, Fiorello T, Gornbein J. The spectrum of behavioral changes in Alzheimer's disease. Neurology1996; 46:130-135.
7.
7. Murphy GM, Taylor J, Tinklenberg JR, Yesavage JA. The apolipoprotein E epsilon 4 is associated with increased behavioral disturbance in Alzheimer's disease. Am J Geriatr Psychiatry1997; 5:88-89.
8.
8. Ramachandran G, Marder K, Tang M, et al. A preliminary study of apolipoprotein E genotype and psychiatric manifestations of Alzheimer's disease. Neurology1996; 47:256-259.
9.
9. Weiner MF, Vega G, Risser RC, et al. Apolipoprotein E epsilon 4, other risk factors, and course of Alzheimer's disease. Biol Psychiatry1999; 45:633-638.
10.
10. Forsell Y, Basun H, Corder EH, et al. Psychotic symptoms and apolipoprotein E genotypes in an elderly population. Biol Psychiatry1998; 44:139-140.
11.
11. Harwood DG, Barker WW, Ownby RL, et al. Apolipoprotein-E (APO-E) genotype and symptoms of psychosis in Alzheimer's disease. Am J Geriatr Psychiatry1999; 7:119-123.
12.
12. Hirono N, Mori E, Yasuda M, et al. Lack of effect of apolipoprotein E E4 allele on neuropsychiatric manifestations in Alzheimer's disease. J Neuropsychiatry Clin Neurosci1999; 11:66-70.
13.
13. Holmes C, Levy R, McLoughin DM, et al. Apolipoprotein E: noncognitive decline in late onset Alzheimer's disease. J Neurol Neurosurg Psychiatry1996; 61:580-583.
14.
14. Levy ML, Cummings JL, Fairbanks LA, et al. Apolipoprotein E genotype and noncognitive symptoms in Alzheimer's disease. Biol Psychiatry1999; 45:422-425.
15.
15. Lopez OL, Kamboh MI, Becker JT, et al. The apolipoprotein E ε4 allele is not associated with psychiatric symptoms or extrapyramidal signs in probable Alzheimer's disease. Neurology1997; 49:794-797.
16.
16. Lyketsos CG, Baker L, Warren A, et al. Depression, delusions, and hallucinations in Alzheimer's disease: no relationship to apolipoprotein E genotype. J Neuropsychiatry Clin Neurosci1997; 9:64-67.
17.
17. Holmes C, Arranz MJ, Powell JF, et al. 5-HT2A and 5-HT2C receptor polymorphisms and psychopathology in late onset Alzheimer's disease. Hum Mol Genet1998; 7:1507-1509.
18.
18. Sweet RA, Nimgaonkar VL, Kamboh MI, et al. Dopamine receptor genetic variation, psychosis, and aggression in Alzheimer disease. Arch Neurol1998; 55:1335-1340.
19.
19. Sweet RA, Nimgaonkar VL, Devlin B, et al. Increased familial risk of the psychotic phenotype of Alzheimer disease. Neurology2002; 58:907-911.
20.
20. Papolla MA, Sos M, Omar RA, Sambamurti K. The heat shock/oxidative stress connection: relevance to Alzheimer disease. Mol Chem Neuropathol1996; 28:21-34.
21.
21. Rottkamp CA, Nunomura A, Raina AK, et al. Oxidative stress, antioxidants, and Alzheimer disease. Alzheimer Dis Assoc Disord2000; 14:S62-S66.
22.
22. Butterfield DA, Drake J, Pocernich C, Castegna A. Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid β-peptide. Trends Mol Med2001; 7:548-553.
23.
23. Beckmann RP, Mizzen LE, Welch WJ. Interaction of Hsp 70 with newly synthesized proteins: implication for protein folding and assembly. Science1990; 248:850-854.
24.
24. Gething MJ, Sambrook J. Protein folding in the cell. Nature1992; 355:33-45.
25.
25. Hartl FU. Molecular chaperones in cellular protein folding. Nature1996; 381:571-579.
26.
26. Salvotinek AM, Biesecker LG. Unfolding the role of chaperones and chaperonins in human disease. Trends Genet2001; 17:528-535.
27.
27. McGeer PL, Klegeris A, Walker DG, et al. Pathological proteins in senile plaques. Tohoku J Exp Med1994; 174:269-277.
28.
28. Kirby BA, Merril CR, Ghanbari H, Wallace WC. Heat shock proteins protect against stress-related phosphorylation of tau in neuronal PC12 cells that have acquired thermotolerance. J Neurosci1994; 14:5687-5693.
29.
29. Harrison PJ, Procter AW, Exworthy T, et al. Heat shock protein (hsx70) mRNA expression in human brain: effects of neurodegenerative disease and agonal state. Neuropathol Appl Neurobiol1993; 19:10-21.
30.
30. Hamos JE, Oblas B, Pulaski-Salo D, et al. Expression of heat shock proteins in Alzheimer's disease. Neurology1991; 41:345-650.
31.
31. Yoo BC, Seidl R, Cairns N, Lubec G. Heat-shock protein 70 levels in brain of patients with Down syndrome and Alzheimer's disease. J Neural Transm1999; 57:315-322.
32.
32. Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry1995; 52:998-1007.
33.
33. Kim JJ, Lee SJ, Toh KY, et al. Identification of antibodies to heat shock proteins 90 kDa and 70 kDa in patients with schizophrenia. Schizophr Res2001; 52:127-135.
34.
34. Schwarz MJ, Riedel M, Gruber R, et al. Antibodies to heat shock proteins in schizophrenic patients: implications for the mechanism of the disease. Am J Psychiatry1999; 156:1103-1104.
35.
35. McKhann G, Drachman D, Folstein M, et al. 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. Neurology1984; 34:939-944.
36.
36. Cummings JL, Mega M, Gray K, et al. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology1994; 44:2308-2314.
37.
37. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for clinician. J Psychiatr Res1975; 12:189-198.
38.
38. Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: a laboratory manual. 2nd ed. Woodbury, NY: Cold Spring Harbor Laboratory Press, 1989.
39.
39. Dressel R, Gunther E. A pentanucleotide tandem duplication polymorphism in the 3' untranslated region of the HLA-linked heat-shock protein 70-2 (HSP70-2) gene. Hum Genet1994; 94:585-586.
40.
40. Petersen RB, Lindquist S. Regulation of HSP70 synthesis by messenger RNA degradation. Cell Regul1989; 1:135-149.
41.
41. Moseley PL, Wallen ES, McCafferty JD, et al. Heat stress regulates the human 70-kDa heat-shock gene through the 3'-untranslated region. Am J Physiol1993; 264:L533-L537.
42.
42. Schwerin M, Maak S, Hagendorf A, et al. A 3'-UTR variant of the inducible porcine hsp70.2 gene affects mRNA stability. Biochim Biophys Acta2002; 1578:90-94.
43.
43. Johnson G, Refolo LM, Merril CR, Wallace W. Altered expression and phosphorylation of amyloid precursor protein in heat shocked neuronal PC12 cells. Brain Res Mol Brain Res1993; 19:140-148.
