Quecksilber und Alzheimer-Erkrankung

Zusammenfassung

Bei Personen, welche von der Alzheimer-Demenz (AD) betroffen waren, fanden sich z. T. erhöhte Quecksilberkonzentrationen in Gehirnproben und Blut. Experimentell konnte in Tierexperimenten und in vitro gezeigt werden, dass schon geringste Mengen von Quecksilber in der Lage sind, AD-typische Nervenzellveränderungen auszulösen. Andere Metalle wie Zink, Aluminium, Kupfer, Blei, Cadmium, Mangan, Eisen, Chrom konnten dabei in niedrigen Konzentrationen diese Veränderungen nicht verursachen, steigerten aber die toxischen Wirkungen von Quecksilber (Hg).

Die Hauptquellen der menschlichen Quecksilberbelastung sind Fisch (Methyl-Hg) und Amalgam (Hg-Dampf). Regelmäßiger Fischkonsum scheint das Risiko, an der Alzheimer-Demenz zu erkranken, zu reduzieren. Amalgam besteht aus etwa 50 % Quecksilber, welches aus den Füllungen kontinuierlich freigesetzt und z. T. vom Organismus aufgenommen wird. Amalgamfüllungen führen dabei zu 2 - 10-fach höheren Quecksilberkonzentrationen im Gehirngewebe.

Personen, welche erblich bedingt eine bestimmte Untergruppe eines Transportproteins für Fette aufweisen (Apolipoprotein E4), haben ein erhöhtes AD-Risiko. Dies könnte dadurch bedingt sein, dass APO E4 Schwermetalle nicht gut binden kann. Neuere Therapieansätze zur Behandlung der Alzheimer-Erkrankung beinhalten u. a. die Gabe von Medikamenten, welche Metalle aus dem Gehirn entfernen. Erste Erfolge wurden mit der Gabe von Chelatbildnern, welche synergistisch toxisch wirkende Metalle (Fe, Al, Zn, Cu) und auch Hg entfernen oder binden können, erzielt. Aufgrund der zurzeit bestehenden Datenlage lässt sich die Frage, ob Hg ein maßgeblicher pathogener Faktor für AD ist, nicht eindeutig beantworten. Die zusammenfassende Berücksichtigung der Erkenntnisse aus epidemiologischen und demografischen Studien und der wichtigsten Quecksilberexpositionsquellen in Industrieländern sowie klinischen und experimentellen Studien und schließlich dem Zahnzustand von Alzheimer-Patienten im Vergleich zu Kontrollen lassen eine Rolle von Quecksilber bei der Entstehung der Alzheimererkrankung als möglich erscheinen. Andere Faktoren, welche als (Teil)Ursachen diskutiert werden (z. B. andere Metalle, chronische Entzündungsprozesse, Ernährungsfaktoren, Vitaminmangel, oxidativer Stress, metabolische Beeinträchtigungen usw.), könnten dabei als Kofaktoren angesehen werden.

Abstract

Higher mercury concentrations were found in brain regions and blood of some patients with Alzheimer's disease (AD). Low levels of inorganic mercury were able to cause AD- typical nerve cell deteriorations in vitro and in animal experiments. Other metals like zinc, aluminum, copper, cadmium, manganese, iron, and chrome are not able to elicit all of these deteriorations in low levels, yet they aggravate the toxic effects of mercury (Hg). Main human sources for mercury are fish consumption (Methyl-Hg) and dental amalgam (Hg vapour). Regular fish consumption reduces the risk of development of AD. Amalgam consists of approx. 50 % of elementary mercury which is constantly being vaporized and absorbed by the organism. Mercury levels in brain tissues are 2 - 10 fold higher in individuals with dental amalgam.

Persons showing a genetically determined subgroup of transportation protein for fats (apolipoprotein E4) have an increased AD risk. Apoliprotein E (APO E) is found in high concentrations in the central nervous system. The increased AD risk through APO E4 might be caused by its reduced ability to bind heavy metals. Latest therapeutic approaches to the treatment of Alzheimer disease embrace pharmaceuticals which remove or bind metals from the brain. Preliminary success has been documented with chelation of synergistic toxic metals (Fe, Al, Zn, Cu) and therefore also Hg. The available data does not answer the question, whether mercury is a relevant risk factor in AD distinctively. In sum, the findings from epidemiological and demographical studies, the frequency of amalgam application in industrialized countries, clinical studies, experimental studies and the dental state of Alzheimer patients in comparison to controls suggest a decisive role for inorganic mercury in the etiology of Alzheimer’s disease. Other factors currently discussed as causes (e. g. other metals, inflammations, dietetic factors, vitamin deficiency, oxidative distress, and metabolic impairments) may act as co-factors.

Schlüsselwörter

Alzheimer - Demenz - Quecksilber - Amalgam - Metalle - Neurotoxizität

Key words

Alzheimer' disease - dementia - mercury - dental amalgam - metals - neurotoxicity

Literatur

• 1 Beyreuther K, Einhäupl K M, Förstl H, Kurz A. Demenzen - Grundlagen und Klinik. Stuttgart 2002
• 2 Ernst R L, Hay J W. Economic research on Alzheimer disease: a review of the Alzheimer.  Alzheimer Disease & Associated Disorders. 1997;  11 135-145
• 3 Haidinger G, Binder H KM. Epidemiologic progression of dementia diseases in Austria until the year 2050.  Gesundheitswesen. 1992;  54 162-166
• 4 Brookmeyer R, Gray S. Methods for projecting the incidence and prevalence of chronic diseases in aging populations: application to Alzheimer's.  Statistics in Medicine. 2000;  19 1481-1493
• 5 Breteler M M, Claus J J, Duijn C M van, Launer L J, Hofman A. Epidemiology of Alzheimer's.  Epidemiologic Reviews. 1992;  14 59-82
• 6 Bickel H. Dementia syndrome and Alzheimer disease: an assessment of morbidity and annual incidence in Germany.  Gesundheitswesen. 2000;  62 211-218
• 7 Kornhuber H. Prevention of dementia (including Alzheimer’s disease).  Gesundheitswesen. 2004;  66 346-351
• 8 Miech R A, Breitner J C, Zandi P, Khachaturian A S, Anthony J C, Mayer L. Incidence of AD may decline in the early 90 s for men, later for women: The Cache County study.  Neurology. 2002;  58 209-218
• 9 Hendrie H C, Osuntokun B O, Hall K S. et al . Prevalence of Alzheimers's disease and dementia in two communities: Nigerian Africans and African Americans.  American Journal of Psychiatry. 1995;  152 1485-1492
• 10 Grant W B. Dietary Links to Alzheimer's Disease.  Journal of Alzheimers disease. 1999;  1 197-201
• 11 Osuntokun B O, Hendrie H C, Ogunniyi A O. et al . Cross-cultural studies in Alzheimer's disease.  Ethnicity & Disease. 1992;  2 352-427
• 12 Haley B. The relationship of toxic effects of mercury to exacerbation of the medical condition classified as alzheimer's disease. (http://www.fda.gov/ohrms/dockets/dailys/02/Sep02/091602/80027dd5.pdf.) 2003
• 13 Arendt T. Neuronale Pathologie. In: Beyreuther K, Einhäupl KM, Förstl H, Kurz A, eds. Demenzen - Grundlagen und Klinik. Stuttgart: Thieme 2002: 106-117
• 14 Braak E, Griffing K, Arai K. et al . Neuropathology of Alzheimer's disease: what is new since A. Alzheimer?.  European Archives of Psychiatry & Clinical Neuroscience. 1999;  249 14-22
• 15 Braak H. Neuroanatomy of Alzheimer's disease.  Alzheimer's Disease Review. 1997;  3 235-247
• 16 Dickson D W, Crystal H A, Mattiace L A. et al . Identification of normal and pathological aging in prospectively studied nondemented elderly humans.  Neurobiology of Aging. 1999;  13 179-189
• 17 Braak H, Braak E, Yilmazer D, Bohl J. Age-related changes of the human cerebral cortex. In: Cruz-Sanchez FF, Ravid R, Cuzner ML, eds. Neuropathological diagnostic criteria for brain banking. Amsterdam 1995: 14-19
• 18 Frölich L, Sandbrink R, Hoyer S. Molekulare Pathologie. In: Beyreuther K, Einhäupl KM, Förstl H, Kurz A, eds. Demenzen - Grundlagen und Kllinik. Stuttgart: Thieme 2002: 72-98
• 19 Hartmann T, Beyreuther K. Molekulare Pathologie Teil 2. In: Beyreuther K, Einhäupl KM, Förstl H, Kurz A, eds. Demenzen - Grundlagen und Klinik. Stuttgart: Thieme 2002: 99-105
• 20 Cherny R A, Atwood C S, Xilinas M E. et al . Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice.  Neuron. 2001;  30 665-676
• 21 Strittmatter W J, Roses A D. Apolipoprotein E and Alzheimer's disease.  Annual Review of Neuroscience. 1996;  19 53-77
• 22 Farrer L A, Cupples L A, Haines J L. et al . Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis.  JAMA. 1997;  278 1349-1356
• 23 Pendergrass J C, Haley B E, Vimy M J, Winfield S A, Lorscheider F L. Mercury vapor inhalation inhibits binding of GTP to tubulin in rat brain: similarity to a molecular lesion in Alzheimer diseased brain.  Neurotoxicology. 1997;  18 315-324
• 24 Stewart W F, Schwartz B S, Simon D, Kelsey K, Todd A C. ApoE genotype, past adult lead exposure, and neurobehavioral function.  Environmental Health Perspectives. 2002;  110 501-505
• 25 Godfrey M E, Wojcik D P, Krone C A. Apolipoprotein E genotyping as a potential biomarker for mercury neurotoxicity.  Journal of Alzheimers disease. 2003;  5 189-195
• 26 Hyman B, Gomez-Isla T, Briggs M. et al . Apolipoprotein E and cognitive change in an elderly population.  Annals of Neurology. 1996;  40 55-66
• 27 Bickel H. Epidemiologie der Demenz. In: Beyreuther K, Einhäupl KM, Förstl H, Kurz A, eds. Demenzen - Grundlagen und Klinik. Stuttgart: Thieme 2002: 17-41
• 28 Corbo R M, Scacchi R. Apolipoprotein E (APOe) allele distribution in the world. Is APOE*4 a “thrifty” allele?.  Annals of Human Genetics. 1999;  63 301-310
• 29 Grant W B. Dietary Links to Alzheimer's Disease.  Alzheimer's Disease Review. 1997;  2 42-55
• 30 Lund J P, Mojon P, Pho M, Feine J S. Alzheimer's Disease and edentulism.  Age & Aging. 2003;  32 228-229
• 31 Launer L J, Andersen K, Dewey M E. et al . Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses.  Neurology. 1999;  52 78-84
• 32 Schulte P A, Burnett C A, Boeniger M F, Johnson J. Neurodegenerative diseases: occupational occurence and potential risk factors, 1982 through 1991.  Am J Public Health. 1996;  86 1281-1288
• 33 CSAH . The Canadian Study of Health and Aging: risk factors for Alzheimer's disease in Canada.  Neurology. 1994;  44 2073-2080
• 34 Olivieri G, Novakovic M, Savaskan E. et al . The effects of β-Estradiol on SHSY5Y neuroblastoma cells during heavy metal induced oxidative stress, neurotoxicity and β-Amyloid secretion.  Neuroscience. 2002;  113 849-855
• 35 Henderson V W. Oestrogens and dementia.  Novartis Foundation Symposium. 2000;  230 254-265
• 36 Henderson V W, Paganini-Hill A, Emanuel C K, Dunn M E, Buckwalter J G. Estrogen replacement therapy in older woman. Comparisons between Alzheimer's disease cases and nondemented control subjects.  Archives of Neurology. 1994;  51 896-900
• 37 Paganini-Hill A, Henderson V W. Estrogen deficiency and risk of Alzheimer's disease in women.  American Journal of Epidemiology. 1994;  140 256-261
• 38 Rapp S R, Espeland M A, Shumaker S A. et al . WHIMS Investigators: Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized trial.  JAMA. 2003;  289 2663-2672
• 39 Grant W B, Campell A, Itzhaki R F, Savory J. The significance of environmental factors in the etiology of Alzheimer's disease.  Journal of Alzheimers disease. 2002;  4 179-189
• 40 Clarke R, Smith A D, Jobst K A, Refsum H, Sutton L, Ueland P M. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease.  Archives of Neurology. 1998;  55 1449-1455
• 41 Kalmijn S, Launer L J, Ott A, Witteman J C, Hofman A, Breteler M M. Dietary fat intake and the risk of incident dementia in the Rotterdam study.  Annals of Neurology. 1997;  42 776-782
• 42 Morris M C, Evans D A, Bienias J L. et al . Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease.  Archives of Neurology. 2003;  60 940-946
• 43 Schober S E, Sinks T H, Jones R L. et al . Blood mercury levels in US children and women of childbearing age.  JAMA. 2003;  289 1667-1674
• 44 WHO .Environmental health criteria 118: inorganic mercury. (118). Ref Type: Serial (Book, Monograph) 1991
• 45 Christen Y. Oxidative stress and Alzheimer disease.  American Journal of Clinical Nutrition. 2000;  71 621S-629S
• 46 Perry G, Castellani R J, Hirai K, Smith M A. Reactive Oxygen Species Mediate Cellular Damage in Alzheimer disease.  Journal of Alzheimers disease. 1998;  1 45-55
• 47 Smith M A, Perry G, Richey P L. et al . Oxidative damage in Alzheimer's.  Nature. 1996;  382 120-121
• 48 Pizzichini M, Fonzi M, Giannerini F. et al . Influence of amalgam fillings on Hg levels and total antioxidant activity in plasma of healthy donors.  Science of the Total Environment. 2003;  301 43-50
• 49 McLachlan D R, Lukiw W J, Kruck T P. New evidence for an active role of aluminium in Alzheimer's disease.  Canadian Journal of Neurological Sciences. 1989;  16 490-497
• 50 Kruck T P. Aluminium - Alzheimer's link?.  Nature. 1993;  363 119
• 51 Kruck T P, McLachlan D R. Aluminium as a pathogenic factor in senile dementia of the Alzheimer type.  Progress in Clinical & Biological Research. 1989;  317 1155-1167
• 52 McLachlan D R, Smith W L, Kruck T P. Desferrioxamine and Alzheimer's disease: video home behavior assessment of clinical course and measures of brain aluminium.  Therapeutic Drug Monitoring. 1993;  15 602-607
• 53 Crapper McLachlan D R, Dalton A J, Kruck T P, Bell M Y, Kalow W, Andrews D F. Intramuscular desferrioxamine in patients with Alzheimer's disease.  Lancet. 1991;  337 1304-1308
• 54 Duhr E f, Pendergrass J C, Slevin J T, Haley B E. HgEDTA complex inhibits GTP interactions with the E-site of brain beta-tubulin.  Toxicology & Applied Pharmacology. 1993;  122 273-280
• 55 Leong C CW, Syed N I, Lorscheider F L. Retrograde degeneration of neurite membrane structural integrity of nerve growth cones following in vitro exposure to mercury.  NeuroReport. 2001;  12 733-737
• 56 Campell A, Bondy S C. Aluminium induces oxidative events and its relation to inflammation: a role for the metal in Alzheimer's disease.  Cellular & Molecular Biology. 2000;  46 721-730
• 57 Ganguli M, Burmeister L A, Seaberg E C, Belle S, DeKosky S T. Association between dementia and elevated TSH: a community-based study.  Biological Psychiatry. 1996;  40 714-725
• 58 Lindh U, Hudecek R, Danersund A. et al . Removal of dental amalgam and other metal alloys supported by antioxidant therapy alleviates symptoms and improves quality of life in patients with amalgam-associated ill health.  Neuro Endocrinol Lett. 2002;  23 459-482
• 59 Ehmann W D, Markesbery W R, Alauddin M. et al . Brain trace elements in Alzheimer’s disease.  Neurotoxicology. 1986;  7 197-206
• 60 Thompson C M, Markesbery W R, Ehmann W D. et al . Regional brain trace-element studies in Alzheimer’s disease.  Neurotoxicology. 1988;  9 1-8
• 61 Wenstrup D, Ehmann W D, Markesbery W R. Trace element imbalances in isolated subcellular fractions of Alzheimer’s disease brains.  Brain Research. 1990;  533 125-131
• 62 Cornett C R, Ehmann W D, Wekstein D R, Markesbery W R. Trace elements in Alzheimer’s disease pituitary glands.  Biol. Trace Element Res. 1998;  62 107-114
• 63 Samudralwar D L, Diprete C C, Ni B F, Ehmann W D, Markesbery W R. Elemental imbalances in the olfactory pathway in Alzheimer's disease.  Journal of Neurology Science. 1995;  130 139-145
• 64 Cornett C R, Markesbery W R, Ehmann W D. Imbalances of trace elements related to oxidative damage in Alzheimer’s disease brain.  Neurotoxicology. 1998;  19 339-346
• 65 Deibel M A, Ehmann W D, Markesbery W R. Institution. Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer’s disease: possible relation to oxidative stress.  Journal of the Neurological Sciences. 1996;  143 137-142
• 66 Fung Y K, Meade A G, Rack E P, Blotcky A J. Brain Mercury in Neurodegenerative Disorders.  Clinical Toxicology. 1997;  35 49-54
• 67 Saxe S R, Wekstein M W, Kryscio R J. et al . Alzheimer’s disease, dental amalgam and mercury.  JADA. 1999;  130 191-199
• 68 Danscher G, Hørsted-Bindsley P, Rungby J. Traces of mercury in organs from primates with amalgam fillings.  Experimental and Molecular Pathology. 1990;  52 291-299
• 69 Hahn L J, Kloiber R, Leininger R W, Vimy M J, Lorscheider F L. Whole-body imaging of the distribution of mercury released from dental fillings into monkey tissues.  FASEB Journal. 1990;  4 3256-3260
• 70 Hahn L J, Kloiber R, Vimy M J. et al . Dental “silver” tooth fillings: a source of mercury exposure revealedby whole-body image scan and tissue analysis.  FASEB Journal. 1989;  3 2641-2646
• 71 Lorscheider F L, Vimy M J, Summers A O. Mercury exposure from “silver” tooth fillings: emerging evidence questions a traditional dental paradigm.  FASEB Journal. 1995;  9 504-508
• 72 Lorscheider F L, Vimy M J. Mercury exposure from “silver” fillings.  Lancet. 1991;  337 1103
• 73 Vimy M J, Takahashi Y, Lorscheider F L. Maternal-fetal distribution of mercury (203 Hg) released from dental amalgam fillings.  American Journal of Physiology. 1990;  258 939-945
• 74 Drasch G, Schupp I, Hofl H. et al . Mercury burden of human fetal and infant tissues.  European Journal of Pediatrics. 1994;  153 607-610
• 75 Drasch G, Schupp I, Riedl G, Günther G. Einfluss von Amalgamfüllungen auf die Quecksilberkonzentration in menschlichen Organen.  Dtsch Zahnärztl Z. 1992;  47 490-496
• 76 Guzzi G, Grandi M, Cattaneo C. Should amalgam fillings be removed?.  Lancet. 2002;  360 2081
• 77 Nylander M. Mercury in pituitary glands of dentists.  Lancet. 1986;  22 442
• 78 Nylander M, Friberg L, Lind B. Mercury concentrations in the human brain and kidneys in relation to exposure from dental amalgam fillings.  Swedish Dental Journal. 1987;  11 179-187
• 79 Nylander M, Weiner J. Mercury and selenium concentrations and their interrelations in organs from dental staff and the general population.  British Journal of Industrial Medicine. 1991;  48 729-734
• 80 Eggleston D W, Nylander M. Correlation of dental amalgam with mercury in brain tissue.  Journal of Prosthetic Dentistry. 1987;  58 704-707
• 81 Weiner J A, Nylander M. The relationship between mercury concentration in human organs and different predictor variables.  Science of the Total Environment. 1993;  138 101-115
• 82 Hock C, Drasch G, Golombowski S. et al . Increased blood mercury levels in patients with Alzheimer’s disease.  Journal of Neural Transmission. 1998;  105 59-68
• 83 Basun H, Forssell L G, Wetterberg L, Winblad B. Metals and trace elements in plasma and cerebrospinal fluid in normal aging and Alzheimer's disease.  Journal of Neural Transmission. 1991;  3 231-258
• 84 Fung Y K, Meade A G, Rack E P. et al . Determination of blood mercury concentrations in Alzheimer’s patients.  Clinical Toxicology. 1995;  33 243-247
• 85 Vance D E, Ehmann W D, Markesbery W R. Trace element imbalances in hair and nails of Alzheimer’s disease patients.  Neurotoxicology. 1988;  9 197-208
• 86 Vance D E, Ehmann W D, Markesbery W R. A search for longitudinal variations in trace element levels in nails of Alzheimer’s disease patients.  Biol Trace Element Res. 1989;  26 - 27 461-470
• 87 Ask K, Akesson A, Berglund M, Vahter M. Inorganic mercury and methylmercury in placentas of Swedish women.  Environmental Health Perspectives. 2002;  110 523-526
• 88 Holmes A S, Blaxill M F, Haley B E. Reduced levels of mercury in first baby haircuts of autistic children.  Int J Toxicol. 2003;  22 277-285
• 89 Björklund G. Mercury as a potential source fot the etiology of Alzheimer's disease.  Trace Elements in Medicine. 1991;  8 208
• 90 Falconer M M, Vaillant A, Reuhl K R, Laferriere N, Brown D L. The molecular basis of microtubule stability in neurons.  Neurotoxicology. 1994;  15 109-122
• 91 Palkiewicz P, Zwiers H, Lorscheider F L. ADP-Ribosylation of brain neuronal proteins is altered by in vivo exposure to inorganic mercury.  Journal of Neurochemistry. 1994;  62 2049-2052
• 92 Vimy M J, Lorscheider F L. Serial measurements of intra-oral air mercury: estimation of daily dose from dental amalgam.  Journal of Dental Research. 1985;  64 1073-1085
• 93 Pendergrass J C, Haley B E. Mercury-EDTA Complex Specifically Blocks Brain-Tubulin-GTP Interactions:Similarity to Observations in Alzheimers's disease. Status Quo and Perspective of Amalgam and Other Dental Materials. International Symposium Proceedings. Stuttgart-New York: Thieme 1995: 98-105
• 94 Pendergrass J C, Haley B E. Inhibition of brain tubulin-guanosine 5’-triphosphate interactions by mercury: similarity to observations in Alzheimer’s diseased brain. In: Sigel A, Sigel H, eds. Mercury and its effects on environment and biology. Dekker 1997: 461-478
• 95 Olivieri G, Brack C, Muller-Spahn F. et al . Mercury induces cell cytotoxicity and oxidative stress and increases beta-amyloid secretion and tau phosphorylation in SHSY5Y neuroblastoma cells.  Journal of Neurochemistry. 2000;  71 231-236
• 96 Limson J, Nyokong T, Daya S. The interaction of melatonin and its precursors with aluminium, cadmium, copper, iron, lead, and zinc: an adsorptive voltammetric study.  J Pineal Res. 1998;  24 15-21
• 97 Olivieri G, Hess C, Savaskan E. et al . Melatonin protects SHSY5Y neuroblastoma cells from cobalt-induced oxidative stress, neurotoxicity and increased beta-amyloid secretion.  Journal of Pineal Research. 2001;  31 320-325
• 98 Cedrola S, Guzzi G, Ferrari D. et al . Inorganic mercury changes the fate of murine CNS stem cells.  FASEB Journal. 2003;  10.1096/fj.02 - 0491fj 17 869-871
• 99 Wataha J C, Nakajima H, Hanks C T, Okabe T. Correlation of cytotoxicity with element release from mercury- and gallium-based dental alloys in vitro.  Dental Materials. 1994;  10 298-303
• 100 Schubert J, Riley E J, Tyler S A. Combined effects in toxicology - a rapid systematic testing procedure: cadmium, mercury, and lead.  Journal of Toxicology & Environmental Health. 1978;  4 763-776
• 101 Aschner M, Yao C P, Allen J W, Tan K H. Methylmercury alters glutamate transport in astrocytes.  Neurochem Int. 2000;  37 199-206
• 102 Brookes N. In vitro evidence for the role of glutamate in the CNS toxicity of mercury.  Toxicology. 1992;  76 245-256
• 103 Sierra E M, Tiffany-Castiglioni E. Reduction of glutamine synthetase activity in astroglia exposed in culture to low levels of inorganic lead.  Toxicology. 1991;  65 295-304
• 104 Allen J W, Mutkus L A, Aschner M. Mercuric chloride, but not methylmercury, inhibits glutamine synthetase activity in primary cultures of cortial astrocytes.  Brain Research. 2001;  891 148-157
• 105 Butterfield D A, Hensley K, Cole P. et al . Oxidatively induces structural alteration of glutamine synthetase assessed by analysis of spin label incorporation kinetics: relevance to Alzheimer's disease.  Journal of Neurochemistry. 1997;  68 2451-2457
• 106 Gunnersen D, Haley B. Detection of glutamine synthetase in the cerebrospinal fluid of Alzheimer diseased patients:a potential diagnostic biochemical marker.  Proceedings of the National Acadamy of Sciences of the United States of America. 1992;  89 1149-1153
• 107 Tumani H, Shen G, Peter J B, Bruck W. Glutamine synthetase in cerebrospinal fluid, serum, and brain: a diagnostic marker for Alzheimer disease?.  Archives of Neurology. 1999;  56 1241-1246
• 108 David S, Shoemaker M, Haley B E. Abnormal properties of creatine kinase in Alzheimer’s disease brain: correlation of reduced enzyme activity and active site photolabeling with aberrant cytosol-membrane partitioning.  Molecular Brain Research. 1998;  54 276-287
• 109 Matsuoka M, Wispriyono B, Iryo Y, Igisu H. Mercury chloride activates c-Jun N-terminal kinase and induces c-jun expression in LLC-PK1 cells.  Toxicological Sciences. 2000;  53 361-368
• 110 Rajanna B, Chetty C S, Rajanna S. et al . Modulation of protein kinase C by heavy metals.  Toxicology Letters. 1995;  81 197-203
• 111 Saxe S R, Snowdon D A, Wekstein M W. et al . Dental amalgam and cognitive function in older women: findings from the nun study.  JADA. 1995;  126 1495-1501
• 112 Ahlqwist M, Bengtsson C, Furunes B. et al . Number of amalgam tooth fillings in relation to subjectively experienced symptoms in a study of Swedish women.  Community Dent Oral Epidemiol. 1988;  16 227-231
• 113 Ahlqwist M, Bengtsson C, Lapidus L. Number of amalgam fillings in relation to cardiovascular disease, diabetes, cancer and early death in Swedish women.  Community Dent Oral Epidemio. 1993;  21 40-44
• 114 Ahlqwist M, Bengtsson C, Lapidus L, Bergdahl I A, Schütz A. Serum mercury concentration in relation to survival, symptoms, and diseases: results from the prospective study of women in Gothenburg, Sweden.  Acta Odontol Scand. 1999;  57 168-174
• 115 Björkman L, Pedersen N L, Lichtenstein P. Physical and mental health related to dental amalgam fillings in Swedish twins.  Dentistry & Oral Epedemiology. 1996;  24 260-267
• 116 Mutter J, Naumann J, Walach H, Daschner F. Amalgam risk assessment with coverage of references up to 2005.  Gesundheitswesen. 2005;  67 204-216
• 117 Guzzi G, Grandi M, Cattaneo C, Calza S, Minoia C, Ronchi A, Gatti A, Severi G. Dental amalgam and mercury levels in autopsy tissues: food for thought.  Am J Forensic Med Pathol. 2006;  27 42-45
• 118 Mutter J, Naumann J, Walach H, Daschner F. Risikobewertung Amalgam: Antwort auf Prof. Halbachs Kommentar (Ausführliche Version: http://www.thieme-connect.de/ejournals/html/gesu/doi/10.1055/s-2006 - 926 707).  Gesundheitswesen. 2006;  68 277
• 119 Stoppe P, Pirk O, Haupt M. Treatment of Alzheimer’s disease utilising the best available evidence-based medicine - utopia?.  Gesundheitswesen. 2005;  67 20-26
• 120 Bush A I. Metal complexing agents as therapies for Alzheimer's disease.  The Neurobiology of Aging. 2002;  23 1031-1038
• 121 Finefrock A E, Bush A I, Doraiswamy P M. Current status of metals as therapeutic targets in Alzheimer's disease.  Journal of American Geriatric Society. 2003;  51 1143-1148
• 122 Helmuth L. New therapies. New Alzheimer's treatments that may ease the mind.  Science. 2002;  297 1260-1262
• 123 Drasch G, Mailänder S, Schlosser C, Roider G. Content of non-mercury-associated selenium in human tissues.  Biol Trace Element Res. 2000;  77 219-230
• 124 The Children's Amalgam Trial Study Group . The Children's Amalgam Trial Study Group. The Children's Amalgam Trial: design and methods.  Controlled Clinical Trials. 2003;  24 795-814
• 125 Drasch G. et al . Scientific comment on the German human biological monitoring values (HBM values) for mercury.  International Journal Hygiene Environmental Health. 2002;  205 509-512
• 126 Drasch G, Böse-O’Reilly S, Beinhoff C. et al . The Mt. Diwata study on the Philippines 1999 - assessing mercury intoxication of the population by small scale gold mining.  Sc Total Environ. 2001;  267 151-168
• 127 Harris H H, Pickering I J, George G N. The chemical form of mercury in fish.  Science. 2003;  301 1203
• 128 Bartova J, Prochazkova J, Kratka Z. et al . Dental amalgam as one of the risk factors in autoimmune diseases.  Neuro Endocrinol Lett. 2003;  24 65-67
• 129 Sterzl I, Procházková J, Hrdá P. et al . Mercury and nickel allergy: risk factors in fatigue and autoimmunity.  Neuro Endocrinol Lett. 1999;  20 221-228
• 130 Prochazkova J, Sterzl I, Kucerova H, Bartova J, Stejskal V DM. The beneficial effect of amalgam replacement on health in patients with autoimmunity.  Neuro Endocrinol Lett. 2004;  25 211-218