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Table of Contents
Vol. 19, No. 5-6, 2005
Issue release date: May 2005
Section title: Original Research Article
Dement Geriatr Cogn Disord 2005;19:289–298
(DOI:10.1159/000084554)

Evaluation of Factors of Importance for Clinical Dementia Diagnosis

Nägga K.a · Garcia J.a, b · Zetterberg H.c · Blennow K.c, d · Gottfries J.e · Marcusson J.a
aDepartment of Geriatric Medicine, Linköping University Hospital and bClinical Research Centre, Linköping University, Linköping; cDepartment of Clinical Neuroscience, Section of Experimental Neuroscience, University of Göteborg, Sahlgrenska University Hospital, Mölndal; dThe Medical Research Council, and eMedicinal Chemistry, AstraZeneca R&D, Mölndal, Sweden
email Corresponding Author

Abstract

Diagnosing clinical dementia is based on an assessment of different variables, such as the patient’s medical history, known risk factors, and biochemical features. Partial least squares discriminant analysis was used to evaluate variables of importance for diagnosing dementia in a clinical dementia population. Polymorphism for genotypes of glutathione S-transferase (GST) and sulfotransferase 1A1, hypothetically of importance in dementia disorders, was also included in the analysis. The study population consisted of 73 patients with Alzheimer’s disease (AD), 14 with mixed dementia, 75 patients with vascular dementia, and 28 control cases. We found that several of the variables, such as the presence of ApoE4 allele, high cerebrospinal fluid levels of total tau protein, low levels of β-amyloid(1–42), and a low score on the Mini-Mental State Examination, facilitated a discrimination between the diagnoses compared with the controls. The different diagnoses overlapped. There were indications that genotypes of GSTs contributed to a subgrouping within AD.

© 2005 S. Karger AG, Basel


  

Key Words

  • Alzheimer’s disease
  • Apolipoprotein E
  • Homocysteine
  • Vascular dementia
  • Glutathione S-transferase
  • Sulfotransferase 1A1
  • Diagnosis
  • Partial least squares discriminant analysis

References

  1. Knopman DS, DeKosky ST, Cummings JL, et al: Practice parameter: Diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1143–1153.
  2. Ross GW, Bowen JD: The diagnosis and differential diagnosis of dementia. Med Clin N Am 2002;86:455–467.
  3. Corder E, Saunders A, Strittmatter W, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993;13:921–923.
  4. Poirier J, Davignon J, Bouthillier D, et al: Apolipoprotein E polymorphism and Alzheimer’s disease. Lancet 1993;342:697–699.
  5. Saunders A, Strittmatter W, Schmechel D, et al: Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 1993;43:1467–1472.
  6. Vandermeeren M, Mercken M, Vanmechelen E, et al: Detection of tau proteins in normal and Alzheimer’s disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. J Neurochem 1993;61:1828–1834.
  7. Arai H, Terajima M, Miura M, et al: Tau in cerebrospinal fluid: A potential diagnostic marker in Alzheimer’s disease. Ann Neurol 1995;38:649–652.
  8. Blennow K, Wallin A, Agren H, et al: Tau protein in cerebrospinal fluid: A biochemical marker for axonal degeneration in Alzheimer’s disease? Mol Chem Neuropathol 1995;26:231–245.
  9. Jensen M, Basun H, Lannfelt L: Increased cerebrospinal fluid tau in patients with Alzheimer’s disease. Neurosci Lett 1995;186:189–191.
  10. Vanderstichele H, Blennow K, Wallin A, et al: Development of a specific diagnostic test for measurement of β-amyloid(1–42) in CSF; in Fisher A, Hanin I, Yoshida M (eds): Alzheimer’s and Parkinson’s Diseases. New York, Plenum Press, 1998, pp 773–778.
  11. Galasko D, Chang L, Motter R, et al: High cerebrospinal fluid tau and low amyloid β42 levels in the clinical diagnosis of Alzheimer’s disease and relation to apolipoprotein E genotype. Arch Neurol 1998;55:937–945.
  12. Andreasen N, Hesse C, Davidsson P, et al: Cerebrospinal fluid beta-amyloid(1–42) in Alzheimer’s disease: Differences between early- and late-onset AD and stability during the course of disease. Arch Neurol 1999;56:673–680.
  13. Owen A, Schapira A, Jenner P, Marsden C: Indices of oxidative stress in Parkinson’s disease, Alzheimer’s disease and dementia with Lewy bodies. J Neural Transm Suppl 1997;51:167–173.
  14. Orth M, Schapira A: Mitochondria and degenerative disorders. Am J Med Genet 2001;106:27–36.
  15. Turner C, Schapira A: Mitochondrial dysfunction in neurodegenerative disorders and ageing. Adv Exp Med Biol 2001;487:229–251.
  16. Markesbery WR: Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med 1997;23:134–147.
  17. Schulz JB, Lindenau J, Seyfried J, Dichgans J: Glutathione, oxidative stress and neurodegeneration. Eur J Biochem 2000;267:4904–4911.
  18. Cecchi C, Latorraca S, Sorbi S, et al: Glutathione level is altered in lymphoblasts from patients with familial Alzheimer’s disease. Neurosci Lett 1999;275:152–154.
  19. Lovell M, Xie C, Markesbery W: Decreased glutathione transferase activity in brain and ventricular fluid in Alzheimer’s disease. Neurology 1998;51:1562–1566.
  20. Sheehan D, Meade G, Foley V, Dowd C: Structure, function and evolution of glutathione transferases: Implications for classification of non-mammalian members of an ancient enzyme superfamily. Biochem J 2001;360:1–16.
  21. Mannervik B, Awasthi Y, Board P, et al: Nomenclature for human glutathione transferases. Biochem J 1992;282:305–306.
  22. Juronen E, Tasa G, Veromann S, et al: Polymorphic glutathione S-transferases as genetic risk factors for senile cortical cataract in Estonians. Invest Ophthalmol Vis Sci 2000;41:2262–2267.
  23. Pemble S, Schroeder KR, Spencer SR, et al: Human glutathione S-transferase theta (GSTT1): cDNA cloning and the characterization of a genetic polymorphism. Biochem J 1994;300:271–276.
  24. Ali-Osman F, Akande O, Antoun G, et al: Molecular cloning, characterization, and expression in Escherichia coli of full-length cDNAs of three human glutathione S-transferase Pi gene variants. Evidence for differential catalytic activity of the encoded proteins. J Biol Chem 1997;272:10004–10012.
  25. Stroombergen MC, Waring RH: Determination of glutathione S-transferase mu and theta polymorphisms in neurological disease. Hum Exp Toxicol 1999;18:141–145.
  26. Nicholl D, Bennett P, Hiller L, et al: A study of five candidate genes in Parkinson’s disease and related neurodegenerative disorders. European Study Group on Atypical Parkinsonism. Neurology 1999;53:1415–1421.
  27. Falany CN: Molecular enzymology of human liver cytosolic sulfotransferases. Trends Pharmacol Sci 1991;12:255–259.
  28. Coughtrie MW, Gilissen RA, Shek B, et al: Phenol sulphotransferase SULT1A1 polymorphism: Molecular diagnosis and allele frequencies in Caucasian and African populations. Biochem J 1999;337:45–49.
  29. Rein G, Glover V, Sandler M: Multiple forms of phenolsulphotransferase in human tissues: Selective inhibition by dichloronitrophenol. Biochem Pharmacol 1982;31:1893–1897.
  30. Campbell NR, van Loon JA, Weinshilboum RM: Human liver phenol sulfotransferase: Assay conditions, biochemical properties and partial purification of isozymes of the thermostable form. Biochem Pharmacol 1987;36:1435–1446.
  31. Yamazoe Y, Nagata K, Ozawa S, Kato R: Structural similarity and diversity of sulfotransferases. Chem Biol Interact 1994;92:107–117.
  32. Bongioanni P, Donato M, Castagna M, Gemignani F: Platelet phenolsulphotransferase activity, monoamine oxidase activity and peripheral-type benzodiazepine binding in demented patients. J Neural Transm 1996;103:491–501.
  33. Seshadri S, Beiser A, Selhub J, et al: Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 2002;346:476–483.
  34. Hogervorst E, Ribeiro HM, Molyneux A, et al: Plasma homocysteine levels, cerebrovascular risk factors, and cerebral white matter changes (leukoaraiosis) in patients with Alzheimer disease. Arch Neurol 2002;59:787–793.
  35. Clarke R, Joachim C, Esiri M, et al: Leukoaraiosis at presentation and disease progression during follow-up in histologically confirmed cases of dementia. Ann NY Acad Sci 2000;903:497–500.
  36. Goyette P, Sumner JS, Milos R, et al: Human methylenetetrahydrofolate reductase: Isolation of cDNA, mapping and mutation identification. Nat Genet 1994;7:195–200.
  37. Frosst P, Blom H, Milos R, et al: A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10:111–113.
  38. Kang S-S, Zhou J, Wong PW, et al: Intermediate homocysteinemia: A thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet 1988;43:414–421.
  39. Brattström L, Wilcken DE, Öhrvik J, Brudin L: Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: The result of a meta-analysis. Circulation 1998;98:2520–2526.
  40. McIlroy SP, Dynan KB, Lawson JT, et al: Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer’s disease in Northern Ireland. Stroke 2002;33:2351–2356.
  41. Brunelli T, Bagnoli S, Giusti B, et al: The C677T methylenetetrahydrofolate reductase mutation is not associated with Alzheimer’s disease. Neurosci Lett 2001;315:103–105.
  42. 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;12:189–198.
  43. Nägga K, Gottfries J, Blennow K, Marcusson J: Cerebrospinal fluid phospho-tau, total tau and beta-amyloid(1–42) in the differentiation between Alzheimer’s disease and vascular dementia. Dement Geriatr Cogn Disord 2002;14:183–190.
  44. World Health Organization: The ICD-10 Classification of Mental and Behavioural Disorders. Geneva, World Health Organization, 1993.
  45. Andersson A, Brattström L, Isaksson A, et al: Determination of homocysteine in plasma by ion-exchange chromatography. Scand J Clin Lab Invest 1989;49:445–449.
  46. Andersson A: Studies on the determination and the metabolism of homocysteine in man; PhD thesis, Lund, 1993.
  47. Ueland PM, Refsum H, Stabler PS, et al: Total homocysteine in plasma or serum: Methods and clinical applications. Clin Chem 1993;39:1764–1779.
  48. Nägga K, Rajani R, Mårdh E, et al: Cobalamin, folate, methylmalonic acid, homocysteine, and gastritis markers in dementia. Dement Geriatr Cogn Disord 2003;16:269–275.
  49. Vanmechelen E, Vanderstichele H, Davidsson P, et al: Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: A sandwich ELISA with a synthetic phosphopeptide for standardization. Neurosci Lett 2000;285:49–52.
  50. Blennow K, Ricksten A, Prince JA, et al: No association between the α2-macroglobulin (A2M) deletion and Alzheimer’s disease, and no change in A2M mRNA, protein, or protein expression. J Neural Transm 2000;107:1065–1079.
  51. Zetterberg H, Regland B, Palmér M, et al: Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos. Eur J Hum Genet 2002;10:113–118.
  52. Garcia J, Hjälle L, Ahmadi A, et al: Study of association between dementia and polymorphism of the glutathione S-transferase M1, T1, P1 and sulfotransferase 1A1 genes, Manuscript, Sept 2004.
  53. SIMCA-P: Umeå, Umetrics AB, 2003.
  54. Linusson A, Gottfries J, Lindgren F, Wold S: Statistical molecular design of building blocks for combinatorial chemistry. J Med Chem 2000;43:1320–1328.
  55. Gottfries J, Blennow K, Wallin A, Gottfries CG: Diagnosis of dementias using partial least squares discriminant analysis. Dementia 1995;6:83–88.
  56. Wold S: Cross-validatory estimation of the number of components in factor and principal components models. Technometrics 1978;20:397–405.

    External Resources

  57. Eriksson L, Johansson E, Kettaneh-Wold N, Wold S: Multi- and megavariate data analysis. Principles and applications; in AB U (ed): Umetrics Academy. Umeå, Umetrics AB, 2001, p 533.
  58. Tiemeier H, van Tuijl HR, Hofman A, et al: Vitamin B12, folate, and homocysteine in depression: The Rotterdam Study. Am J Psychiatry 2002;159:2099–2101.
  59. Breteler MM: Vascular involvement in cognitive decline and dementia. Epidemiologic evidence from the Rotterdam Study and the Rotterdam Scan Study. Ann NY Acad Sci 2000;903:457–465.
  60. Nägga K, Rådberg C, Marcusson J: CT brain findings in clinical dementia investigation – Underestimation of mixed dementia. Dement Geriatr Cogn Disord 2004;18:59–66.
  61. Prince MJ: Vascular risk factors and atherosclerosis as risk factors for cognitive decline and dementia. J Psychosom Res 1995;39:525–530.
  62. Kalaria RN, Ballard C: Overlap between pathology of Alzheimer disease and vascular dementia. Alzheimer Dis Assoc Disord Suppl 1999;3:115–123.

    External Resources

  63. Breitner J: The role of anti-inflammatory drugs in the prevention and treatment of Alzheimer’s disease. Annu Rev Med 1996;47:401–411.
  64. in’t Veld BA, Ruitenberg A, Hofman A, et al: Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 2001;345:1515–1521.
  65. Santosh-Kumar C, Hassell K, Deutsch J, Kolhouse J: Are neuropsychiatric manifestations of folate, cobalamin and pyridoxine deficiency mediated through imbalances in excitatory sulfur amino acids? Med Hypotheses 1994;43:239–244.
  66. Robinson RG: Poststroke depression: Prevalence, diagnosis, treatment, and disease progression. Biol Psychiatry 2003;54:376–387.
  67. Berg A, Palomaki H, Lehtihalmes M, et al: Poststroke depression: An 18-month follow-up. Stroke 2003;34:138–143.
  68. Weinshilboum RM, Otterness DM, Aksoy IA, et al: Sulfation and sulfotransferases 1: Sulfotransferase molecular biology: cDNAs and genes. FASEB J 1997;11:3–14.

  

Author Contacts

Katarina Nägga, MD
Department of Geriatric Medicine
Linköping University Hospital
SE–58185 Linköping (Sweden)
Tel. +46 13 224093, Fax +46 13 227389, E-Mail Katarina.Nagga@lio.se

  

Article Information

Accepted: November 1, 2004
Published online: March 18, 2005
Number of Print Pages : 10
Number of Figures : 3, Number of Tables : 1, Number of References : 68

  

Publication Details

Dementia and Geriatric Cognitive Disorders

Vol. 19, No. 5-6, Year 2005 (Cover Date: May-June 2005)

Journal Editor: Chan-Palay, V. (New York, N.Y.)
ISSN: 1420–8008 (print), 1421–9824 (Online)

For additional information: http://www.karger.com/dem


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Diagnosing clinical dementia is based on an assessment of different variables, such as the patient’s medical history, known risk factors, and biochemical features. Partial least squares discriminant analysis was used to evaluate variables of importance for diagnosing dementia in a clinical dementia population. Polymorphism for genotypes of glutathione S-transferase (GST) and sulfotransferase 1A1, hypothetically of importance in dementia disorders, was also included in the analysis. The study population consisted of 73 patients with Alzheimer’s disease (AD), 14 with mixed dementia, 75 patients with vascular dementia, and 28 control cases. We found that several of the variables, such as the presence of ApoE4 allele, high cerebrospinal fluid levels of total tau protein, low levels of β-amyloid(1–42), and a low score on the Mini-Mental State Examination, facilitated a discrimination between the diagnoses compared with the controls. The different diagnoses overlapped. There were indications that genotypes of GSTs contributed to a subgrouping within AD.

© 2005 S. Karger AG, Basel


  

Author Contacts

Katarina Nägga, MD
Department of Geriatric Medicine
Linköping University Hospital
SE–58185 Linköping (Sweden)
Tel. +46 13 224093, Fax +46 13 227389, E-Mail Katarina.Nagga@lio.se

  

Article Information

Accepted: November 1, 2004
Published online: March 18, 2005
Number of Print Pages : 10
Number of Figures : 3, Number of Tables : 1, Number of References : 68

  

Publication Details

Dementia and Geriatric Cognitive Disorders

Vol. 19, No. 5-6, Year 2005 (Cover Date: May-June 2005)

Journal Editor: Chan-Palay, V. (New York, N.Y.)
ISSN: 1420–8008 (print), 1421–9824 (Online)

For additional information: http://www.karger.com/dem


Article / Publication Details

First-Page Preview
Abstract of Original Research Article

Received: 11/1/2004
Published online: 4/29/2005
Issue release date: May 2005

Number of Print Pages: 10
Number of Figures: 3
Number of Tables: 1

ISSN: 1420-8008 (Print)
eISSN: 1421-9824 (Online)

For additional information: http://www.karger.com/DEM


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Knopman DS, DeKosky ST, Cummings JL, et al: Practice parameter: Diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1143–1153.
  2. Ross GW, Bowen JD: The diagnosis and differential diagnosis of dementia. Med Clin N Am 2002;86:455–467.
  3. Corder E, Saunders A, Strittmatter W, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993;13:921–923.
  4. Poirier J, Davignon J, Bouthillier D, et al: Apolipoprotein E polymorphism and Alzheimer’s disease. Lancet 1993;342:697–699.
  5. Saunders A, Strittmatter W, Schmechel D, et al: Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 1993;43:1467–1472.
  6. Vandermeeren M, Mercken M, Vanmechelen E, et al: Detection of tau proteins in normal and Alzheimer’s disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. J Neurochem 1993;61:1828–1834.
  7. Arai H, Terajima M, Miura M, et al: Tau in cerebrospinal fluid: A potential diagnostic marker in Alzheimer’s disease. Ann Neurol 1995;38:649–652.
  8. Blennow K, Wallin A, Agren H, et al: Tau protein in cerebrospinal fluid: A biochemical marker for axonal degeneration in Alzheimer’s disease? Mol Chem Neuropathol 1995;26:231–245.
  9. Jensen M, Basun H, Lannfelt L: Increased cerebrospinal fluid tau in patients with Alzheimer’s disease. Neurosci Lett 1995;186:189–191.
  10. Vanderstichele H, Blennow K, Wallin A, et al: Development of a specific diagnostic test for measurement of β-amyloid(1–42) in CSF; in Fisher A, Hanin I, Yoshida M (eds): Alzheimer’s and Parkinson’s Diseases. New York, Plenum Press, 1998, pp 773–778.
  11. Galasko D, Chang L, Motter R, et al: High cerebrospinal fluid tau and low amyloid β42 levels in the clinical diagnosis of Alzheimer’s disease and relation to apolipoprotein E genotype. Arch Neurol 1998;55:937–945.
  12. Andreasen N, Hesse C, Davidsson P, et al: Cerebrospinal fluid beta-amyloid(1–42) in Alzheimer’s disease: Differences between early- and late-onset AD and stability during the course of disease. Arch Neurol 1999;56:673–680.
  13. Owen A, Schapira A, Jenner P, Marsden C: Indices of oxidative stress in Parkinson’s disease, Alzheimer’s disease and dementia with Lewy bodies. J Neural Transm Suppl 1997;51:167–173.
  14. Orth M, Schapira A: Mitochondria and degenerative disorders. Am J Med Genet 2001;106:27–36.
  15. Turner C, Schapira A: Mitochondrial dysfunction in neurodegenerative disorders and ageing. Adv Exp Med Biol 2001;487:229–251.
  16. Markesbery WR: Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med 1997;23:134–147.
  17. Schulz JB, Lindenau J, Seyfried J, Dichgans J: Glutathione, oxidative stress and neurodegeneration. Eur J Biochem 2000;267:4904–4911.
  18. Cecchi C, Latorraca S, Sorbi S, et al: Glutathione level is altered in lymphoblasts from patients with familial Alzheimer’s disease. Neurosci Lett 1999;275:152–154.
  19. Lovell M, Xie C, Markesbery W: Decreased glutathione transferase activity in brain and ventricular fluid in Alzheimer’s disease. Neurology 1998;51:1562–1566.
  20. Sheehan D, Meade G, Foley V, Dowd C: Structure, function and evolution of glutathione transferases: Implications for classification of non-mammalian members of an ancient enzyme superfamily. Biochem J 2001;360:1–16.
  21. Mannervik B, Awasthi Y, Board P, et al: Nomenclature for human glutathione transferases. Biochem J 1992;282:305–306.
  22. Juronen E, Tasa G, Veromann S, et al: Polymorphic glutathione S-transferases as genetic risk factors for senile cortical cataract in Estonians. Invest Ophthalmol Vis Sci 2000;41:2262–2267.
  23. Pemble S, Schroeder KR, Spencer SR, et al: Human glutathione S-transferase theta (GSTT1): cDNA cloning and the characterization of a genetic polymorphism. Biochem J 1994;300:271–276.
  24. Ali-Osman F, Akande O, Antoun G, et al: Molecular cloning, characterization, and expression in Escherichia coli of full-length cDNAs of three human glutathione S-transferase Pi gene variants. Evidence for differential catalytic activity of the encoded proteins. J Biol Chem 1997;272:10004–10012.
  25. Stroombergen MC, Waring RH: Determination of glutathione S-transferase mu and theta polymorphisms in neurological disease. Hum Exp Toxicol 1999;18:141–145.
  26. Nicholl D, Bennett P, Hiller L, et al: A study of five candidate genes in Parkinson’s disease and related neurodegenerative disorders. European Study Group on Atypical Parkinsonism. Neurology 1999;53:1415–1421.
  27. Falany CN: Molecular enzymology of human liver cytosolic sulfotransferases. Trends Pharmacol Sci 1991;12:255–259.
  28. Coughtrie MW, Gilissen RA, Shek B, et al: Phenol sulphotransferase SULT1A1 polymorphism: Molecular diagnosis and allele frequencies in Caucasian and African populations. Biochem J 1999;337:45–49.
  29. Rein G, Glover V, Sandler M: Multiple forms of phenolsulphotransferase in human tissues: Selective inhibition by dichloronitrophenol. Biochem Pharmacol 1982;31:1893–1897.
  30. Campbell NR, van Loon JA, Weinshilboum RM: Human liver phenol sulfotransferase: Assay conditions, biochemical properties and partial purification of isozymes of the thermostable form. Biochem Pharmacol 1987;36:1435–1446.
  31. Yamazoe Y, Nagata K, Ozawa S, Kato R: Structural similarity and diversity of sulfotransferases. Chem Biol Interact 1994;92:107–117.
  32. Bongioanni P, Donato M, Castagna M, Gemignani F: Platelet phenolsulphotransferase activity, monoamine oxidase activity and peripheral-type benzodiazepine binding in demented patients. J Neural Transm 1996;103:491–501.
  33. Seshadri S, Beiser A, Selhub J, et al: Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 2002;346:476–483.
  34. Hogervorst E, Ribeiro HM, Molyneux A, et al: Plasma homocysteine levels, cerebrovascular risk factors, and cerebral white matter changes (leukoaraiosis) in patients with Alzheimer disease. Arch Neurol 2002;59:787–793.
  35. Clarke R, Joachim C, Esiri M, et al: Leukoaraiosis at presentation and disease progression during follow-up in histologically confirmed cases of dementia. Ann NY Acad Sci 2000;903:497–500.
  36. Goyette P, Sumner JS, Milos R, et al: Human methylenetetrahydrofolate reductase: Isolation of cDNA, mapping and mutation identification. Nat Genet 1994;7:195–200.
  37. Frosst P, Blom H, Milos R, et al: A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10:111–113.
  38. Kang S-S, Zhou J, Wong PW, et al: Intermediate homocysteinemia: A thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet 1988;43:414–421.
  39. Brattström L, Wilcken DE, Öhrvik J, Brudin L: Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: The result of a meta-analysis. Circulation 1998;98:2520–2526.
  40. McIlroy SP, Dynan KB, Lawson JT, et al: Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer’s disease in Northern Ireland. Stroke 2002;33:2351–2356.
  41. Brunelli T, Bagnoli S, Giusti B, et al: The C677T methylenetetrahydrofolate reductase mutation is not associated with Alzheimer’s disease. Neurosci Lett 2001;315:103–105.
  42. 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;12:189–198.
  43. Nägga K, Gottfries J, Blennow K, Marcusson J: Cerebrospinal fluid phospho-tau, total tau and beta-amyloid(1–42) in the differentiation between Alzheimer’s disease and vascular dementia. Dement Geriatr Cogn Disord 2002;14:183–190.
  44. World Health Organization: The ICD-10 Classification of Mental and Behavioural Disorders. Geneva, World Health Organization, 1993.
  45. Andersson A, Brattström L, Isaksson A, et al: Determination of homocysteine in plasma by ion-exchange chromatography. Scand J Clin Lab Invest 1989;49:445–449.
  46. Andersson A: Studies on the determination and the metabolism of homocysteine in man; PhD thesis, Lund, 1993.
  47. Ueland PM, Refsum H, Stabler PS, et al: Total homocysteine in plasma or serum: Methods and clinical applications. Clin Chem 1993;39:1764–1779.
  48. Nägga K, Rajani R, Mårdh E, et al: Cobalamin, folate, methylmalonic acid, homocysteine, and gastritis markers in dementia. Dement Geriatr Cogn Disord 2003;16:269–275.
  49. Vanmechelen E, Vanderstichele H, Davidsson P, et al: Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: A sandwich ELISA with a synthetic phosphopeptide for standardization. Neurosci Lett 2000;285:49–52.
  50. Blennow K, Ricksten A, Prince JA, et al: No association between the α2-macroglobulin (A2M) deletion and Alzheimer’s disease, and no change in A2M mRNA, protein, or protein expression. J Neural Transm 2000;107:1065–1079.
  51. Zetterberg H, Regland B, Palmér M, et al: Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos. Eur J Hum Genet 2002;10:113–118.
  52. Garcia J, Hjälle L, Ahmadi A, et al: Study of association between dementia and polymorphism of the glutathione S-transferase M1, T1, P1 and sulfotransferase 1A1 genes, Manuscript, Sept 2004.
  53. SIMCA-P: Umeå, Umetrics AB, 2003.
  54. Linusson A, Gottfries J, Lindgren F, Wold S: Statistical molecular design of building blocks for combinatorial chemistry. J Med Chem 2000;43:1320–1328.
  55. Gottfries J, Blennow K, Wallin A, Gottfries CG: Diagnosis of dementias using partial least squares discriminant analysis. Dementia 1995;6:83–88.
  56. Wold S: Cross-validatory estimation of the number of components in factor and principal components models. Technometrics 1978;20:397–405.

    External Resources

  57. Eriksson L, Johansson E, Kettaneh-Wold N, Wold S: Multi- and megavariate data analysis. Principles and applications; in AB U (ed): Umetrics Academy. Umeå, Umetrics AB, 2001, p 533.
  58. Tiemeier H, van Tuijl HR, Hofman A, et al: Vitamin B12, folate, and homocysteine in depression: The Rotterdam Study. Am J Psychiatry 2002;159:2099–2101.
  59. Breteler MM: Vascular involvement in cognitive decline and dementia. Epidemiologic evidence from the Rotterdam Study and the Rotterdam Scan Study. Ann NY Acad Sci 2000;903:457–465.
  60. Nägga K, Rådberg C, Marcusson J: CT brain findings in clinical dementia investigation – Underestimation of mixed dementia. Dement Geriatr Cogn Disord 2004;18:59–66.
  61. Prince MJ: Vascular risk factors and atherosclerosis as risk factors for cognitive decline and dementia. J Psychosom Res 1995;39:525–530.
  62. Kalaria RN, Ballard C: Overlap between pathology of Alzheimer disease and vascular dementia. Alzheimer Dis Assoc Disord Suppl 1999;3:115–123.

    External Resources

  63. Breitner J: The role of anti-inflammatory drugs in the prevention and treatment of Alzheimer’s disease. Annu Rev Med 1996;47:401–411.
  64. in’t Veld BA, Ruitenberg A, Hofman A, et al: Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 2001;345:1515–1521.
  65. Santosh-Kumar C, Hassell K, Deutsch J, Kolhouse J: Are neuropsychiatric manifestations of folate, cobalamin and pyridoxine deficiency mediated through imbalances in excitatory sulfur amino acids? Med Hypotheses 1994;43:239–244.
  66. Robinson RG: Poststroke depression: Prevalence, diagnosis, treatment, and disease progression. Biol Psychiatry 2003;54:376–387.
  67. Berg A, Palomaki H, Lehtihalmes M, et al: Poststroke depression: An 18-month follow-up. Stroke 2003;34:138–143.
  68. Weinshilboum RM, Otterness DM, Aksoy IA, et al: Sulfation and sulfotransferases 1: Sulfotransferase molecular biology: cDNAs and genes. FASEB J 1997;11:3–14.