Argyrophilic grain disease: An update on a frequent cause of dementia

Grinberg, Lea T.; Heinsen, Helmut

doi:10.1590/S1980-57642009DN30100002

Abstract

Argyrophilic grain disease (AGD) is a sporadic, very late-onset tauopathy, accounting for approximately 4-13% of neurodegenerative dementias. AGD may manifest with a range of symptoms such as cognitive decline and behavioral abnormalities. To date, no study has been able to demonstrate a distinct clinical syndrome associated with AGD. The diagnosis is exclusively based on postmortem findings, the significance of which remains controversial because up to 30% of AGD cases are diagnosed in subjects without any cognitive impairment, while AGD findings often overlap with those of other neurodegenerative processes. Nevertheless, the presence of AGD is likely to have a significant effect on cognitive decline. The neuropathological hallmarks of AGD are argyrophilic grains, pre-neurofibrillary tangles in neurons and coiled bodies in oligodendrocytes found mainly in the entorhinal cortex and hippocampus. This review aims to provide an up-to-date overview of AGD, emphasizing pathological aspects. Additionally, the findings of a Brazilian case series are described.

Key words:
pathology; brain; neurology; argyrophilic grain disease; tau

Resumo

Doença com grãos argirofílicos (DGA) é uma taupatia, não-familial, de início tardio que corresponde a cerca de 4 a 13% das demências neurodegenerativas. DGA se manifesta com uma gama de sintomas como déficit cognitivo e distúrbios comportamentais. Até o momento, não se conhece nenhuma característica clínica que distinga DGA de outras demências. O diagnóstico é baseado nos achados anatomopatológicos, cujo significado é controverso, quer porque cerca de 30% dos casos de DGA não apresentam sintomas, quer porque DGA é freqüentemente encontrada junto a outras alterações neurodegenerativas. Entretanto, acredita-se que a presença de DGA impacte a cognição. Os marcadores neuropatológicos de DGA são: grãos argirofílicos, pré-emaranhados neurofibrilares e corpúsculos em forma de vibrião em oligodendrócitos. As áreas mais afetadas são o córtex entorrinal, hipocampo e estruturas límbicas. Essa revisão almeja sumarizar o conhecimento mais atual sobre DGA e descrever brevemente achados de uma casuística brasileira.

Palavras-chave:
patologia; encéfalo; neurologia; doença com grãos argirofílicos

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Full text available only in PDF format.

References

¹
Tolnay M, Mistl C, Ipsen S, Probst A. Argyrophilic grains of Braak: occurrence in dendrites of neurons containing hyperphosphorylated tau protein. Neuropathol Appl Neurobiol 1998;24:53-59.
²
Saito Y, Ruberu NN, Sawabe M, et al. Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol. 2004;63:911-918.
³
Ding ZT, Wang Y, Jiang Y P. Argyrophilic grain disease frequency and neuropathology in centenarians. Acta Neuropathol. 2006;111:320-328.
⁴
Tolnay M, Clavaguera F. Argyrophilic grain disease: a late-onset dementia with distinctive features among tauopathies. Neuropathology 2004;24:269-283.
⁵
Ferrer I, Santpere G, van Leeuwen FW. Argyrophilic grain disease. Brain 2008;131:1416-1432.
⁶
Braak H, Braak E. Argyrophilic grains: characteristic pathology of cerebral cortex in cases of adult onset dementia without Alzheimer changes. Neurosci Lett 1987;76:124-127.
⁷
Ikeda K, Akiyama H, Arai T, Matsushita M, Tsuchiya K, Miyazaki H. Clinical aspects of argyrophilic grain disease. Clin Neuropathol. 2000;19:278-284.
⁸
Martinez-Lage P, Munoz DG. Prevalence and disease associations of argyrophilic grains of Braak. J Neuropathol Exp Neurol 1997;56:157-164.
⁹
Jicha GA, Petersen RC, Knopman DS, et al. Argyrophilic grain disease in demented subjects presenting initially with amnestic mild cognitive impairment. J Neuropathol Exp Neurol 2006;65:602-609.
¹⁰
Botez G, Schultz C, Ghebremedhin E, Bohl J, Braak E, Braak H. Clinical aspects of argyrophilic grain disease. Nervenarzt 2000;71:38-43.
¹¹
Togo T, Isojima D, Akatsu H, et al. Clinical features of argyrophilic grain disease: a retrospective survey of cases with neuropsychiatric symptoms. Am J Geriatr Psychiatry 2005;13: 1083-1091.
¹²
Tolnay M, Schwietert M, Monsch AU, Staehelin HB, Langui D, Probst A. Argyrophilic grain disease: distribution of grains in patients with and without dementia. Acta Neuropathol 1997;94:353-358.
¹³
Braak H, Braak E. Cortical and subcortical argyrophilic grains characterize a disease associated with adult onset dementia. Neuropathol Appl Neurobiol 1989;15:13-26.
¹⁴
Knopman DS, Parisi JE, Salviati A, et al. Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol 2003;62: 1087-1095.
¹⁵
Togo T, Cookson N, Dickson DW. Argyrophilic grain disease: neuropathology, frequency in a dementia brain bank and lack of relationship with apolipoprotein E. Brain Pathol 2002;12:45-52.
¹⁶
Jellinger KA. Dementia with grains (argyrophilic grain disease). Brain Pathol. 1998;8:377-386.
¹⁷
Saito Y, Yamazaki M, Kanazawa I, Murayama S. Severe involvement of the ambient gyrus in a case of dementia with argyrophilic grain disease. J Neurol Sci 2002;196:71-75.
¹⁸
Braak H, Braak E. Argyrophilic grain disease: frequency of occurrence in different age categories and neuropathological diagnostic criteria. J Neural Transm 1998;105:801-819.
¹⁹
Cairns NJ, Grinberg LT, Lisic R, et al. Expanding the neuropathological spectrum of frontotemporal lobar degenerations: review of 833 prospectively assessed dementia cases. J Neural Transm 2006;113:7.
²⁰
Petersen RC, Parisi JE, Dickson DW, et al. Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 2006;63:665-672.
²¹
Steuerwald GM, Baumann TP, Taylor KI, et al. Clinical characteristics of dementia associated with argyrophilic grain disease. Dement Geriatr Cogn Disord 2007;24:229-234.
²²
Kovacs GG, Pittman A, Revesz T, et al. MAPT S305I mutation: implications for argyrophilic grain disease. Acta Neuropathol 2008;116:103-118.
²³
Cairns NJ, Bigio EH, Mackenzie IR, et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 2007;114:5-22.
²⁴
Thal DR, Schultz C, Botez G, et al. The impact of argyrophilic grain disease on the development of dementia and its relationship to concurrent Alzheimer's disease-related pathology. Neuropathol Appl Neurobiol 2005;31:270-279.
²⁵
Josephs KA, Whitwell JL, Parisi JE, et al. Argyrophilic grains: a distinct disease or an additive pathology? Neurobiol Aging 2008;29:566-573.
²⁶
Uchihara T. Silver diagnosis in neuropathology: principles, practice and revised interpretation. Acta Neuropathol 2007; 113:483-499.
²⁷
Schultz C, Koppers D, Sassin I, Braak E, Braak H. Cytoskeletal alterations in the human tuberal hypothalamus related to argyrophilic grain disease. Acta Neuropathol 1998;96: 596-602.
²⁸
Ikeda K, Akiyama H, Kondo H, Haga C. A study of dementia with argyrophilic grains: possible cytoskeletal abnormality in dendrospinal portion of neurons and oligodendroglia. Acta Neuropathol 1995;89:409-414.
²⁹
Braak E, Braak H, Mandelkow EM. A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol 1994;87:554-567.
³⁰
Tau and ubiquitin immunoreactivity at different stages of formation of Alzheimer neurofibrillary tangles. New York: Alan R. Liss; 1989.
³¹
Komori T. Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Pick's disease. Brain Pathol 1999;9:663-679.
³²
Ikeda K, Akiyama H, Arai T, Nishimura T. Glial tau pathology in neurodegenerative diseases: their nature and comparison with neuronal tangles. Neurobiol Aging 1998;19(1 Suppl):S85-91.
³³
Tolnay M, Villoz N, Probst A, Miserez AR. Apolipoprotein E genotype in senile dementia with tangles differs from Alzheimer's disease. Neuropathol Appl Neurobiol 2003;29: 80-84.
³⁴
Fujino Y, Delucia MW, Davies P, Dickson DW. Ballooned neurones in the limbic lobe are associated with Alzheimer type pathology and lack diagnostic specificity. Neuropathol Appl Neurobiol 2004;30:676-682.
³⁵
Togo T, Dickson DW. Ballooned neurons in progressive supranuclear palsy are usually due to concurrent argyrophilic grain disease. Acta Neuropathol 2002;104:53-56.
³⁶
Cras P, Perry G. Dementia with argyrophilic grains. Ann Neurol 1991;30:853-854.
³⁷
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239-259.
³⁸
Fujino Y, Wang DS, Thomas N, Espinoza M, Davies P, Dickson DW. Increased frequency of argyrophilic grain disease in Alzheimer disease with 4R tau-specific immunohistochemistry. J Neuropathol Exp Neurol 2005;64:209-214.
³⁹
Tolnay M, Calhoun M, Pham HC, Egensperger R, Probst A. Low amyloid (Abeta) plaque load and relative predominance of diffuse plaques distinguish argyrophilic grain disease from Alzheimer's disease. Neuropathol Appl Neurobiol 1999;25:295-305.
⁴⁰
Tsuchiya K, Mitani K, Arai T, et al. Argyrophilic grain disease mimicking temporal Pick's disease: a clinical, radiological, and pathological study of an autopsy case with a clinical course of 15 years. Acta Neuropathol 2001;102:195-199.
⁴¹
Maurage CA, Sergeant N, Schraen-Maschke S, et al. Diffuse form of argyrophilic grain disease: a new variant of four-repeat tauopathy different from limbic argyrophilic grain disease. Acta Neuropathol 2003;106:575-583.
⁴²
Ishihara K, Araki S, Ihori N, et al. Argyrophilic grain disease presenting with frontotemporal dementia: a neuropsychological and pathological study of an autopsied case with presenile onset. Neuropathology 2005;25:165-170.
⁴³
Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 1989;3:519-526.
⁴⁴
Himmler A, Drechsel D, Kirschner MW, Martin Jr DW. Tau consists of a set of proteins with repeated C-terminal microtubule-binding domains and variable N-terminal domains. Mol Cell Biol 1989;9:1381-1388.
⁴⁵
Hanger DP, Mann DM, Neary D, Anderton BH. Tau pathology in a case of familial Alzheimer's disease with a valine to glycine mutation at position 717 in the amyloid precursor protein. Neurosci Lett 1992;145:178-180.
⁴⁶
Mandelkow E, Mandelkow EM. Kinesin motors and disease. Trends Cell Biol. 2002;12:585-591.
⁴⁷
Goedert M, Spillantini MG, Davies SW. Filamentous nerve cell inclusions in neurodegenerative diseases. Curr Opin Neurobiol 1998;8:619-632.
⁴⁸
Lovestone S, Reynolds CH. The phosphorylation of tau: a critical stage in neurodevelopment and neurodegenerative processes. Neuroscience 1997;78:309-324.
⁴⁹
Reynolds CH, Nebreda AR, Gibb GM, Utton MA, Anderton BH. Reactivating kinase/p38 phosphorylates tau protein in vitro. J Neurochem 1997;69:191-198.
⁵⁰
Reynolds CH, Utton MA, Gibb GM, Yates A, Anderton BH. Stress-activated protein kinase/c-jun N-terminal kinase phosphorylates tau protein. J Neurochem 1997;68:1736-1744.
⁵¹
Togo T, Sahara N, Yen SH, et al. Argyrophilic grain disease is a sporadic 4-repeat tauopathy. J Neuropathol Exp Neurol 2002;61:547-556.
⁵²
Ishizawa T, Ko LW, Cookson N, Davias P, Espinoza M, Dickson DW. Selective neurofibrillary degeneration of the hippocampal CA2 sector is associated with four-repeat tauopathies. J Neuropathol Exp Neurol 2002;61:1040-1047
⁵³
Andreadis, A, Brown, WM, Kosik, KS. Structure and novel exons of the human tau gene. Biochemistry (Mosc.). 1992;31: 10626-10633.
⁵⁴
Kovacs GG, Pittman A, Revesz T, et al. MAPT S305I mutation: implications for argyrophilic grain disease. Acta Neuropathol 2008;116:103-118
⁵⁵
Tolnay M, Probst A, Monsch AU, Staehelin HB, Egensperger R. Apolipoprotein E allele frequencies in argyrophilic grain disease. Acta Neuropathol 1998;96:225-227.
⁵⁶
Ghebremedhin E, Schultz C, Botez G, et al. Argyrophilic grain disease is associated with apolipoprotein E epsilon 2 allele. Acta Neuropathol. 1998;96:222-224.
⁵⁷
Ferrer I, Barrachina M, Tolnay M, et al. Phosphorylated protein kinases associated with neuronal and glial tau deposits in argyrophilic grain disease. Brain Pathol 2003;13:62-78.
⁵⁸
Masliah E, Hansen LA, Quijada S, et al. Late onset dementia with argyrophilic grains and subcortical tangles or atypical progressive supranuclear palsy? Ann Neurol 1991;29:389-396.
⁵⁹
Ikeda K, Akiyama H, Kondo H, et al. Thorn-shaped astrocytes: possibly secondarily induced tau- positive glial fibrillary tangles. Acta Neuropathol 1995;90:620-625.
⁶⁰
Beach TG, Sue L, Scott S, et al. Hippocampal sclerosis dementia with tauopathy. Brain Pathol 2003;13:263-278.
⁶¹
Uchikado H, Tsuchiya K, Tominaga I, et al. Argyrophilic grain disease clinically mimicking Parkinson's disease with dementia: report of an autopsy case. No To Shinkei 2004;56:785-788.

Publication Dates

Publication in this collection
Jan-Mar 2009

History

Received
01 Nov 2008
Accepted
05 Feb 2009

This is an open-access article distributed under the terms of the Creative Commons Attribution License

[1] ¹
Tolnay M, Mistl C, Ipsen S, Probst A. Argyrophilic grains of Braak: occurrence in dendrites of neurons containing hyperphosphorylated tau protein. Neuropathol Appl Neurobiol 1998;24:53-59.

[2] ²
Saito Y, Ruberu NN, Sawabe M, et al. Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol. 2004;63:911-918.

[3] ³
Ding ZT, Wang Y, Jiang Y P. Argyrophilic grain disease frequency and neuropathology in centenarians. Acta Neuropathol. 2006;111:320-328.

[4] ⁴
Tolnay M, Clavaguera F. Argyrophilic grain disease: a late-onset dementia with distinctive features among tauopathies. Neuropathology 2004;24:269-283.

[5] ⁵
Ferrer I, Santpere G, van Leeuwen FW. Argyrophilic grain disease. Brain 2008;131:1416-1432.

[6] ⁶
Braak H, Braak E. Argyrophilic grains: characteristic pathology of cerebral cortex in cases of adult onset dementia without Alzheimer changes. Neurosci Lett 1987;76:124-127.

[7] ⁷
Ikeda K, Akiyama H, Arai T, Matsushita M, Tsuchiya K, Miyazaki H. Clinical aspects of argyrophilic grain disease. Clin Neuropathol. 2000;19:278-284.

[8] ⁸
Martinez-Lage P, Munoz DG. Prevalence and disease associations of argyrophilic grains of Braak. J Neuropathol Exp Neurol 1997;56:157-164.

[9] ⁹
Jicha GA, Petersen RC, Knopman DS, et al. Argyrophilic grain disease in demented subjects presenting initially with amnestic mild cognitive impairment. J Neuropathol Exp Neurol 2006;65:602-609.

[10] ¹⁰
Botez G, Schultz C, Ghebremedhin E, Bohl J, Braak E, Braak H. Clinical aspects of argyrophilic grain disease. Nervenarzt 2000;71:38-43.

[11] ¹¹
Togo T, Isojima D, Akatsu H, et al. Clinical features of argyrophilic grain disease: a retrospective survey of cases with neuropsychiatric symptoms. Am J Geriatr Psychiatry 2005;13: 1083-1091.

[12] ¹²
Tolnay M, Schwietert M, Monsch AU, Staehelin HB, Langui D, Probst A. Argyrophilic grain disease: distribution of grains in patients with and without dementia. Acta Neuropathol 1997;94:353-358.

[13] ¹³
Braak H, Braak E. Cortical and subcortical argyrophilic grains characterize a disease associated with adult onset dementia. Neuropathol Appl Neurobiol 1989;15:13-26.

[14] ¹⁴
Knopman DS, Parisi JE, Salviati A, et al. Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol 2003;62: 1087-1095.

[15] ¹⁵
Togo T, Cookson N, Dickson DW. Argyrophilic grain disease: neuropathology, frequency in a dementia brain bank and lack of relationship with apolipoprotein E. Brain Pathol 2002;12:45-52.

[16] ¹⁶
Jellinger KA. Dementia with grains (argyrophilic grain disease). Brain Pathol. 1998;8:377-386.

[17] ¹⁷
Saito Y, Yamazaki M, Kanazawa I, Murayama S. Severe involvement of the ambient gyrus in a case of dementia with argyrophilic grain disease. J Neurol Sci 2002;196:71-75.

[18] ¹⁸
Braak H, Braak E. Argyrophilic grain disease: frequency of occurrence in different age categories and neuropathological diagnostic criteria. J Neural Transm 1998;105:801-819.

[19] ¹⁹
Cairns NJ, Grinberg LT, Lisic R, et al. Expanding the neuropathological spectrum of frontotemporal lobar degenerations: review of 833 prospectively assessed dementia cases. J Neural Transm 2006;113:7.

[20] ²⁰
Petersen RC, Parisi JE, Dickson DW, et al. Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 2006;63:665-672.

[21] ²¹
Steuerwald GM, Baumann TP, Taylor KI, et al. Clinical characteristics of dementia associated with argyrophilic grain disease. Dement Geriatr Cogn Disord 2007;24:229-234.

[22] ²²
Kovacs GG, Pittman A, Revesz T, et al. MAPT S305I mutation: implications for argyrophilic grain disease. Acta Neuropathol 2008;116:103-118.

[23] ²³
Cairns NJ, Bigio EH, Mackenzie IR, et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 2007;114:5-22.

[24] ²⁴
Thal DR, Schultz C, Botez G, et al. The impact of argyrophilic grain disease on the development of dementia and its relationship to concurrent Alzheimer's disease-related pathology. Neuropathol Appl Neurobiol 2005;31:270-279.

[25] ²⁵
Josephs KA, Whitwell JL, Parisi JE, et al. Argyrophilic grains: a distinct disease or an additive pathology? Neurobiol Aging 2008;29:566-573.

[26] ²⁶
Uchihara T. Silver diagnosis in neuropathology: principles, practice and revised interpretation. Acta Neuropathol 2007; 113:483-499.

[27] ²⁷
Schultz C, Koppers D, Sassin I, Braak E, Braak H. Cytoskeletal alterations in the human tuberal hypothalamus related to argyrophilic grain disease. Acta Neuropathol 1998;96: 596-602.

[28] ²⁸
Ikeda K, Akiyama H, Kondo H, Haga C. A study of dementia with argyrophilic grains: possible cytoskeletal abnormality in dendrospinal portion of neurons and oligodendroglia. Acta Neuropathol 1995;89:409-414.

[29] ²⁹
Braak E, Braak H, Mandelkow EM. A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol 1994;87:554-567.

[30] ³⁰
Tau and ubiquitin immunoreactivity at different stages of formation of Alzheimer neurofibrillary tangles. New York: Alan R. Liss; 1989.

[31] ³¹
Komori T. Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Pick's disease. Brain Pathol 1999;9:663-679.

[32] ³²
Ikeda K, Akiyama H, Arai T, Nishimura T. Glial tau pathology in neurodegenerative diseases: their nature and comparison with neuronal tangles. Neurobiol Aging 1998;19(1 Suppl):S85-91.

[33] ³³
Tolnay M, Villoz N, Probst A, Miserez AR. Apolipoprotein E genotype in senile dementia with tangles differs from Alzheimer's disease. Neuropathol Appl Neurobiol 2003;29: 80-84.

[34] ³⁴
Fujino Y, Delucia MW, Davies P, Dickson DW. Ballooned neurones in the limbic lobe are associated with Alzheimer type pathology and lack diagnostic specificity. Neuropathol Appl Neurobiol 2004;30:676-682.

[35] ³⁵
Togo T, Dickson DW. Ballooned neurons in progressive supranuclear palsy are usually due to concurrent argyrophilic grain disease. Acta Neuropathol 2002;104:53-56.

[36] ³⁶
Cras P, Perry G. Dementia with argyrophilic grains. Ann Neurol 1991;30:853-854.

[37] ³⁷
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239-259.

[38] ³⁸
Fujino Y, Wang DS, Thomas N, Espinoza M, Davies P, Dickson DW. Increased frequency of argyrophilic grain disease in Alzheimer disease with 4R tau-specific immunohistochemistry. J Neuropathol Exp Neurol 2005;64:209-214.

[39] ³⁹
Tolnay M, Calhoun M, Pham HC, Egensperger R, Probst A. Low amyloid (Abeta) plaque load and relative predominance of diffuse plaques distinguish argyrophilic grain disease from Alzheimer's disease. Neuropathol Appl Neurobiol 1999;25:295-305.

[40] ⁴⁰
Tsuchiya K, Mitani K, Arai T, et al. Argyrophilic grain disease mimicking temporal Pick's disease: a clinical, radiological, and pathological study of an autopsy case with a clinical course of 15 years. Acta Neuropathol 2001;102:195-199.

[41] ⁴¹
Maurage CA, Sergeant N, Schraen-Maschke S, et al. Diffuse form of argyrophilic grain disease: a new variant of four-repeat tauopathy different from limbic argyrophilic grain disease. Acta Neuropathol 2003;106:575-583.

[42] ⁴²
Ishihara K, Araki S, Ihori N, et al. Argyrophilic grain disease presenting with frontotemporal dementia: a neuropsychological and pathological study of an autopsied case with presenile onset. Neuropathology 2005;25:165-170.

[43] ⁴³
Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 1989;3:519-526.

[44] ⁴⁴
Himmler A, Drechsel D, Kirschner MW, Martin Jr DW. Tau consists of a set of proteins with repeated C-terminal microtubule-binding domains and variable N-terminal domains. Mol Cell Biol 1989;9:1381-1388.

[45] ⁴⁵
Hanger DP, Mann DM, Neary D, Anderton BH. Tau pathology in a case of familial Alzheimer's disease with a valine to glycine mutation at position 717 in the amyloid precursor protein. Neurosci Lett 1992;145:178-180.

[46] ⁴⁶
Mandelkow E, Mandelkow EM. Kinesin motors and disease. Trends Cell Biol. 2002;12:585-591.

[47] ⁴⁷
Goedert M, Spillantini MG, Davies SW. Filamentous nerve cell inclusions in neurodegenerative diseases. Curr Opin Neurobiol 1998;8:619-632.

[48] ⁴⁸
Lovestone S, Reynolds CH. The phosphorylation of tau: a critical stage in neurodevelopment and neurodegenerative processes. Neuroscience 1997;78:309-324.

[49] ⁴⁹
Reynolds CH, Nebreda AR, Gibb GM, Utton MA, Anderton BH. Reactivating kinase/p38 phosphorylates tau protein in vitro. J Neurochem 1997;69:191-198.

[50] ⁵⁰
Reynolds CH, Utton MA, Gibb GM, Yates A, Anderton BH. Stress-activated protein kinase/c-jun N-terminal kinase phosphorylates tau protein. J Neurochem 1997;68:1736-1744.

[51] ⁵¹
Togo T, Sahara N, Yen SH, et al. Argyrophilic grain disease is a sporadic 4-repeat tauopathy. J Neuropathol Exp Neurol 2002;61:547-556.

[52] ⁵²
Ishizawa T, Ko LW, Cookson N, Davias P, Espinoza M, Dickson DW. Selective neurofibrillary degeneration of the hippocampal CA2 sector is associated with four-repeat tauopathies. J Neuropathol Exp Neurol 2002;61:1040-1047

[53] ⁵³
Andreadis, A, Brown, WM, Kosik, KS. Structure and novel exons of the human tau gene. Biochemistry (Mosc.). 1992;31: 10626-10633.

[54] ⁵⁴
Kovacs GG, Pittman A, Revesz T, et al. MAPT S305I mutation: implications for argyrophilic grain disease. Acta Neuropathol 2008;116:103-118

[55] ⁵⁵
Tolnay M, Probst A, Monsch AU, Staehelin HB, Egensperger R. Apolipoprotein E allele frequencies in argyrophilic grain disease. Acta Neuropathol 1998;96:225-227.

[56] ⁵⁶
Ghebremedhin E, Schultz C, Botez G, et al. Argyrophilic grain disease is associated with apolipoprotein E epsilon 2 allele. Acta Neuropathol. 1998;96:222-224.

[57] ⁵⁷
Ferrer I, Barrachina M, Tolnay M, et al. Phosphorylated protein kinases associated with neuronal and glial tau deposits in argyrophilic grain disease. Brain Pathol 2003;13:62-78.

[58] ⁵⁸
Masliah E, Hansen LA, Quijada S, et al. Late onset dementia with argyrophilic grains and subcortical tangles or atypical progressive supranuclear palsy? Ann Neurol 1991;29:389-396.

[59] ⁵⁹
Ikeda K, Akiyama H, Kondo H, et al. Thorn-shaped astrocytes: possibly secondarily induced tau- positive glial fibrillary tangles. Acta Neuropathol 1995;90:620-625.

[60] ⁶⁰
Beach TG, Sue L, Scott S, et al. Hippocampal sclerosis dementia with tauopathy. Brain Pathol 2003;13:263-278.

[61] ⁶¹
Uchikado H, Tsuchiya K, Tominaga I, et al. Argyrophilic grain disease clinically mimicking Parkinson's disease with dementia: report of an autopsy case. No To Shinkei 2004;56:785-788.

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