Diagnosis of Alzheimer’s disease: recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology

Schilling, Lucas Porcello; Balthazar, Marcio Luiz Figueredo; Radanovic, Márcia; Forlenza, Orestes Vicente; Silagi, Marcela Lima; Smid, Jerusa; Barbosa, Breno José Alencar Pires; Frota, Norberto Anízio Ferreira; Souza, Leonardo Cruz de; Vale, Francisco Assis Carvalho; Caramelli, Paulo; Bertolucci, Paulo Henrique Ferreira; Chaves, Márcia Lorena Fagundes; Brucki, Sonia Maria Dozzi; Damasceno, Benito Pereira; Nitrini, Ricardo

doi:10.1590/1980-5764-DN-2022-S102EN

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Dementia & Neuropsychologia

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Consensus • Dement. neuropsychol. 16 (3 Suppl 1) • Sept 2022 • https://doi.org/10.1590/1980-5764-DN-2022-S102EN copy

Diagnosis of Alzheimer’s disease: recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

This paper presents the consensus of the Scientific Department of Cognitive Neurology and Aging from the Brazilian Academy of Neurology on the diagnostic criteria for Alzheimer’s disease (AD) in Brazil. The authors conducted a literature review regarding clinical and research criteria for AD diagnosis and proposed protocols for use at primary, secondary, and tertiary care levels. Within this clinical scenario, the diagnostic criteria for typical and atypical AD are presented as well as clinical, cognitive, and functional assessment tools and complementary propaedeutics with laboratory and neuroimaging tests. The use of biomarkers is also discussed for both clinical diagnosis (in specific conditions) and research.

Keywords:
Alzheimer Disease; Dementia; Diagnosis

Type of instrument	Main tests and normative studies
Screening tests
Brief tests	Mini-Mental State Examination (MMSE) ⁽³⁹39. Folstein MF, Folstein SE, Folstein, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-98. doi:10.1016/0022-3956(75)90026-6 https://doi.org/10.1016/0022-3956(75)900... ^),(⁴⁰40. Brucki SM, Nitrini R, Caramelli P, Bertolucci PH, Okamoto IH. Suggestions for utilization of the mini-mental state examination in Brazil. Arq Neuropsiquiatr. 2003;61(3B):777-81. doi:10.1590/s0004-282x2003000500014 https://doi.org/10.1590/s0004-282x200300... , Montreal Cognitive Assessment (MoCA) ⁽⁴¹41. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-9. Errata em: J Am Geriatr Soc. 2019;67(9):1991. doi:10.1111/j.1532-5415.2005.53221.x https://doi.org/10.1111/j.1532-5415.2005... ^),(⁴²42. Memória CM, Yassuda MS, Nakano EY, Forlenza OV. Brief screening for mild cognitive impairment: validation of the Brazilian version of the Montreal cognitive assessment. Int J Geriatr Psychiatry. 2013;28(1):34-40. doi:10.1002/gps.3787 https://doi.org/10.1002/gps.3787... , Cognitive Abilities Screening Instrument - Short Version (CASI-S) ⁽⁴³43. Teng EL, Larson EB, Lin KN, Graves AB, Liu HC. Screening for dementia: the Cognitive Abilities Screening Instrument - short version (CASI Short). Proceedings of the 106th Annual Convention of the American Psychological Association; 1998 Aug 14-18; San Francisco, US. Washington, DC: American Psychological Association; 1998.^),(⁴⁴44. Damasceno A, Delicio AM, Mazo DFC, Zullo JFD, Scherer P, Ng RTY, et al. Validation of the Brazilian version of mini-test CASI-S. Arq Neuropsiquiatr. 2005;63(2b): 416-21. doi:10.1590/S0004-282X2005000300010 https://doi.org/10.1590/S0004-282X200500... , Brief Cognitive Screening Battery (BBRC) ⁽⁴⁵45. Nitrini R, Lefèvre BH, Mathias SC, Caramelli P, Carrilho PE, Sauaia N, et al. Neuropsychological tests of simple application for diagnosing dementia. Arq Neuropsiquiatr. 1994;52(4):457-65. doi:10.1590/ s0004-282x1994000400001 https://doi.org/10.1590/... ^),(⁴⁶46. Nitrini R, Brucki SMD, Yassuda MS, Fichman HC, Caramelli P. The Figure Memory Test: diagnosis of memory impairment in populations with heterogeneous educational background. Dement. Neuropsychol. 2021;15(2):173-85. doi:10.1590/1980-57642021dn15-020004 https://doi.org/10.1590/1980-57642021dn1...
Multi-functional batteries	Addenbrooke’s Cognitive Examination - revised version (ACE-R) ⁽⁴⁷47. Mioshi E, Dawson K, Mitchell J, Arnold R, Hodges JR. The Addenbrooke's Cognitive Examination Revised (ACE-R): a brief cognitive test battery for dementia screening. Int J Geriatr Psychiatry. 2006;21(11):1078-85. doi:10.1002/gps.1610 https://doi.org/10.1002/gps.1610... ^),(⁴⁸48. Carvalho VA, Caramelli P. Brazilian adaptation of the Addenbrooke's Cognitive Examination-Revised (ACE-R). Dement Neuropsychol. 2007;1(2):212-216. doi:10.1590/S1980-57642008DN10200015 https://doi.org/10.1590/S1980-57642008DN... , Cambridge Cognitive Examination (CAMCOG) ⁽⁴⁹49. Roth M, Tym E, Mountjoy CQ, Huppert FA, Hendrie H, Verma S, et al. CAMDEX. A standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia. Br J Psychiatry. 1986;149:698-709. doi:10.1192/bjp.149.6.698 https://doi.org/10.1192/bjp.149.6.698... ^)-(⁵¹51. Aprahamian I, Martinelli JE, Cecato J, Izbicki R, Yassuda MS. Can the CAMCOG be a good cognitive test for patients with Alzheimer's disease with low levels of education? Int Psychogeriatr. 2011;23(1):96-101. doi:10.1017/S104161021000116X https://doi.org/10.1017/S104161021000116... , Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-COG) ⁽⁵²52. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984;141(11):1356-64. doi:10.1176/ajp.141.11.1356 https://doi.org/10.1176/ajp.141.11.1356... ^),(⁵³53. Schultz RR, Siviero MO, Bertolucci PH. The cognitive subscale of the "Alzheimer's Disease Assessment Scale" in a Brazilian sample. Braz J Med Biol Res. 2001;34(10):1295-1302. doi:10.1590/ S0100-879X2001001000009 https://doi.org/10.1590/... , Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) ⁽⁵⁴54. Morris JC, Heyman A, Mohs RC, Hughes JP, van Belle G, Fillenbaum G, et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer's disease. Neurology. 1989;39(9):1159-65. doi:10.1212/wnl.39.9.1159 https://doi.org/10.1212/wnl.39.9.1159... ^),(⁵⁵55. Bertolucci PHF, Okamoto IH, Brucki SMD, Siviero MO, Toniolo J Neto, Ramos LR. Applicability of the CERAD neuropsychological battery to Brazilian elderly. Arq Neuropsiquiatr. 2001;59(3A):532-36. doi:10.1590/S0004-282X2001000400009 https://doi.org/10.1590/S0004-282X200100... , Mattis Dementia Rating Scale (MDRS) ⁽⁵⁶56. Vitaliano PP, Breen AR, Russo J, Albert M, Vitiello MV, Prinz PN. The clinical utility of the dementia rating scale for assessing Alzheimer patients. J Chronic Dis. 1984;37(9-10):743-53. doi:10.1016/0021-9681(84)90043-2 https://doi.org/10.1016/0021-9681(84)900... ^),(⁵⁷57. Porto CS, Fichman HC, Caramelli P, Bahia VS, Nitrini R. Brazilian version of the Mattis dementia rating scale: diagnosis of mild dementia in Alzheimer's disease. Arq Neuropsiquiatr. 2003;61(2B):339-45. doi:10.1590/s0004-282x2003000300004 https://doi.org/10.1590/s0004-282x200300...
Evaluation of single cognitive domains
Verbal episodic memory	Rey Auditory Verbal Learning Test (RAVLT) ⁽⁵⁸58. Rey A. L'examen clinique en psychologie [The clinical examination in psychology]. Paris (France): Presses Universitaires de France; 1964. French.^),(⁵⁹59. Malloy-Diniz LF, Lasmar VA, Gazinelli LS, Fuentes D, Salgado JV. The Rey Auditory-Verbal Learning Test: applicability for the Brazilian elderly population. Braz J Psiquiatry. 2007;29(4):324-29. doi:10.1590/S1516-44462006005000053 https://doi.org/10.1590/S1516-4446200600... , CERAD Battery Word List Learning Subtest
Nonverbal memory	Subtest “figure recognition” (BBRC), Subtest “geometric figure recall” (CERAD Battery), Rey-Osterrieth Complex Figure⁶⁰60. Osterrieth PA. Le test de copie d'une figure complexe; contribution à l'étude de la perception et de la mémoire [Test of copying a complex figure; contribution to the study of perception and memory]. Arch Psychol. 1944;30:206-356.^),(⁶¹61. Foss MP, Bastos-Formigheri MS, Speciali JG. Rey's complex figures for the elderly. Aval Psicol. 2010;9(1):53-61.
Language	Verbal Fluency Test (phonemic and semantic) ⁽⁶²62. Hazin I, Leite G, Oliveira RM, Alencar JC, Fichman HC, Marques PN, et al. Brazilian Normative Data on Letter and Category Fluency Tasks: effects of gender, age, and geopolitical region. Front Psychol. 2016;7:684. doi:10.3389/fpsyg.2016.00684 https://doi.org/10.3389/fpsyg.2016.00684... ^),(⁶³63. Caramelli P, Carthery-Goulart MT, Porto CS, Fichman HC, Nitrini R. Category fluency as a screening test for Alzheimer disease in illiterate and literate patients. Alzheimer Dis Assoc Disord. 2007;21(1):65-7. doi:10.1097/WAD.0b013e31802f244f https://doi.org/10.1097/WAD.0b013e31802f... , Boston Naming Test (BNT) ⁽⁶⁴64. Kaplan EF, Goodglass H, Weintraub S. The Boston Naming Test. 2a ed. Philadelphia: Lippincott Williams & Wilkins; 2001.^),(⁶⁵65. Mansur LL, Radanovic M, Araújo GC, Taquemori LY, Greco LL. Boston Naming Test: performance of Brazilian population from São Paulo. Pro Fono. 2006;18(1):13-20. doi:10.1590/S0104-56872006000100003 https://doi.org/10.1590/S0104-5687200600...
Attention control and executive function	Digit Span Task in forward and inverse order⁶⁶66. Wechsler D. Wechsler Adult Intelligence Scale-III. San Antonio: The Psychological Corporation; 1997.^),(⁶⁷67. Zimmermann N, Cardoso CO, Trentini CM, Grassi-Oliveira R, Fonseca RP. Brazilian preliminary norms and investigation of age and education effects on the Modified Wisconsin Card Sorting Test, Stroop Color and Word test and Digit Span test in adults. Dement Neuropsychol. 2015;9(2):120-7. doi:10.1590/1980-57642015DN92000006 https://doi.org/10.1590/1980-57642015DN9... , Clock Drawing Test⁶⁸68. Shulman KI, Shedletsky R, Silver IL. The challenge of time: clock-drawing and cognitive function in the elderly. Int J Geriatr Psychiatry. 1986;1(2):135-40. doi:10.1002/gps.930010209 https://doi.org/10.1002/gps.930010209... ^),(⁶⁹69. Fuzikawa C, Lima-Costa MF, Uchoa E, Barreto SM, Shulman K; Bambuí Health and Ageing Study. A population based study on the intra and inter-rater reliability of the clock drawing test in Brazil: the Bambuí Health and Ageing Study. Int J Geriatr Psychiatry. 2003;18(5):450-6. doi:10.1002/gps.863 https://doi.org/10.1002/gps.863... , Verbal Fluency Test
Visual-spatial / visual-constructive abilities	CERAD / MoCA Figure Copy Subtest, Clock Drawing Test
Functional assessment
Instrumental activities of daily living	Functional Activities Questionnaire (FAQ) ⁽⁷⁰70. Pfeffer RI, Kurosaki TT, Harrah CH Jr, Chance JM, Filos S. Measurement of functional activities in older adults in the community. J Gerontol. 1982;37(3):323-9. doi:10.1093/geronj/37.3.323 https://doi.org/10.1093/geronj/37.3.323... ^),(⁷¹71. Herrera E Jr, Caramelli P, Silveira AS, Nitrini R. Epidemiologic survey of dementia in a community-dwelling Brazilian population. Alzheimer Dis Assoc Disord. 2002;16(2):103-8. doi:10.1097/00002093-200204000-00007 https://doi.org/10.1097/00002093-2002040... , Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) ⁽⁷²72. Jorm AF, Jacomb PA. The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): socio-demographic correlates, reliability, validity and some norms. Psychol Med. 1989;19(4):1015-22. doi:10.1017/s0033291700005742 https://doi.org/10.1017/s003329170000574... ^),(⁷³73. Sanchez MA, Lawrence RA. Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): adaptação transcultural para uso no Brasil. Cad Saude Publica. 2009; 25(7):1455-65. doi:10.1590/S0102-311X2009000700003 https://doi.org/10.1590/S0102-311X200900... , Direct Assessment of Functional Status-Revised (DAFS-R) ⁽⁷⁴74. Loewnstein DA, Bates CB. The Direct Assessment of Functional Status-Revised (DAFS-R). Manual for administration and scoring. Miami: Mount Sinai Medical Center; 2006.^),(⁷⁵75. Pereira FS, Oliveira AM, Diniz BS, Forlenza OV, Yassuda MS. Cross-cultural adaptation, reliability and validity of the DAFS-R in a sample of Brazilian older adults. Arch Clin Neuropsychol. 2010;25(4):335-43. doi:10.1093/arclin/acq029 https://doi.org/10.1093/arclin/acq029... , Disability Assessment for Dementia (DAD) ⁽⁷⁶76. Gauthier L, Gélinas I, McIntyre M, Gauthier S, Laberge H, Dauphinee SW. Disability Assessment for Dementia (DAD) user's guide; 1994.^),(⁷⁷77. Bahia VS, Carthery-Goulart MT, Novelli MM, Kato-Narita EM, Areza-Fegyveres R, Caramelli P, et al. Functional disability in Alzheimer disease: a validation study of the Brazilian version of Disability Assessment for Dementia (DAD-Br). Alzheimer Dis Assoc Disord. 2010;24(3):291-5. doi:10.1097/WAD.0b013e3181cfc878 https://doi.org/10.1097/WAD.0b013e3181cf... , Activities of Daily Living Questionnaire (ADLQ) ⁽⁷⁸78. Johnson N, Barion A, Rademaker A, Rehkemper G, Weintraub S. The Activities of Daily Living Questionnaire: a validation study in patients with dementia. Alzheimer Dis Assoc Disord. 2004;18(4):223-30.^),(⁷⁹79. Medeiros ME, RO Guerra. Translation, cultural adaptation and psychometric analysis of the Activities of Daily Living Questionnaire (ADLQ) for functional assessment of patients with Alzeimer's disease. Braz J Phys Ther. 2009;13(3):257-66. doi:10.1590/S1413-35552009005000027 https://doi.org/10.1590/S1413-3555200900... , Bayer Activities of Daily Living Scale (B-ADL) ⁽⁸⁰80. Hindmarch I, Lehfeld H, Jongh P, Erzigkeit H. The Bayer Activities of Daily Living Scale (B-ADL). Dement Geriatr Cogn Disord. 1998;9(Suppl 2):20-6. doi:10.1159/000051195 https://doi.org/10.1159/000051195... ^),(⁸¹81. Folquitto JC, Bustamante SEZ, Barros SB, Azevedo D, Lopes MA, Hototian SR, et al. The Bayer: Activities of Daily Living Scale (B-ADL) in the differentiation between mild to moderate dementia and normal aging. Braz J Psychiatry . 2007;29(4):350-3. doi:10.1590/S1516-44462006005000037 https://doi.org/10.1590/S1516-4446200600... , AD8 Dementia Screening Interview⁸²82. Galvin JE, Roe CM, Powlishta KK, Coats MA, Muich SJ, Grant E, et al. The AD8: a brief informant interview to detect dementia. Neurology. 2005;65(4):559-64. doi:10.1212/01.wnl.0000172958.95282.2a https://doi.org/10.1212/01.wnl.000017295...
Basic activities of daily living	Katz scale⁸³83. Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of illness in the aged. The index of ADL: a standardized measure of biological and psychosocial function. JAMA. 1963;185:914-9. doi:10.1001/jama.1963.03060120024016 https://doi.org/10.1001/jama.1963.030601... ^),(⁸⁴84. Lino VTS, Pereira SRM, Camacho LAB, Ribeiro ST Filho, Buksman S. Cross-cultural adaptation of the Independence in Activities of Daily Living Index (Katz Index). Cad Saude Publica. 2008;24(1):103-12. doi:10.1590/s0102-311x2008000100010 https://doi.org/10.1590/s0102-311x200800... , Functional Activities Questionnaire (FAQ) ⁽⁷⁰70. Pfeffer RI, Kurosaki TT, Harrah CH Jr, Chance JM, Filos S. Measurement of functional activities in older adults in the community. J Gerontol. 1982;37(3):323-9. doi:10.1093/geronj/37.3.323 https://doi.org/10.1093/geronj/37.3.323... ^),(⁷²72. Jorm AF, Jacomb PA. The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): socio-demographic correlates, reliability, validity and some norms. Psychol Med. 1989;19(4):1015-22. doi:10.1017/s0033291700005742 https://doi.org/10.1017/s003329170000574...
Dementia staging	Clinical Dementia Rating scale (CDR) ⁽⁸⁵85. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia. Br J Psychiatry. 1982;140:566-72. doi:10.1192/bjp.140.6.566 https://doi.org/10.1192/bjp.140.6.566... ^),(⁸⁶86. Chaves ML, Camozzato AL, Godinho C, Kochhann R, Schuh A, Almeida VL, et al. Validity of the clinical dementia rating scale for the detection and staging of dementia in Brazilian patients. Alzheimer Dis Assoc Disord. 2007;21(3):210-7. doi:10.1097/WAD.0b013e31811ff2b4 https://doi.org/10.1097/WAD.0b013e31811f...

Diagnosis in Primary Care
Anamnesis	Ask the patient and their relative/caregiver about cognitive, neuropsychiatric, and behavioral symptoms. The interviews should be preferably conducted separately.
Clinical examination	Perform general physical examination looking for signs of systemic diseases and a complete neurological examination attentive to focal signs.
Laboratory tests	Perform laboratory tests to detect causes of secondary dementias and comorbidities that may contribute to the clinical picture.
Cognitive assessment	Applying a brief cognitive screening test, such as MoCA, BBRC, or CASI-S is suggested. BBRC stands out due to its easy application and high sensitivity, even for individuals with low schooling levels. Moreover, applying brief highly sensitive tasks, such as semantic verbal fluency (animals) and a word-learning test, which are highly accurate to detect dysfunction of the hippocampal system (amnesia), is recommended. Data on functionality can be addressed in the anamnesis or specific brief questionnaires, such as the Functional Activities Questionnaire (FAQ).
Structural neuroimaging	A brain CT is essential to rule out other causes of dementia (such as tumors, hydrocephalus, or cerebral infarctions) and to identify, within the limitations of the method, patterns of atrophy compatible with AD.
Diagnosis in Secondary Care
Anamnesis	Ask the patient and their relative/caregiver about cognitive, neuropsychiatric, and behavioral symptoms.
Clinical examination	Perform general physical examination looking for signs of systemic diseases and a complete neurological examination attentive to focal signs.
Laboratory tests	Perform laboratory tests to detect causes of secondary dementias and comorbidities that may contribute to the clinical picture. If chronic meningitis is suspected, a lumbar puncture should be performed for CSF analysis.
Cognitive assessment	Using a brief test of cognitive screening or multifunctional battery of medium coverage is suggested, with at least one task to examine each cognitive domain; complement by applying a functional assessment tool, as described above.
Structural neuroimaging	Brain CT or MRI (preferably) is essential to rule out other causes of dementia and further investigate mesial structures, with visual scales or manual or automated volumetry.
Biomarker assessment	Using biomarkers is indicated in cases of diagnostic doubt between AD and other neurodegenerative dementias not in the amyloid spectrum, such as FTD, to correctly follow the guidelines for the use of AD approved medications, such as cholinesterase inhibitors and memantine. Other situations are referred to in biomarkers sections. Importantly, the future emergence and availability of potentially disease-modifying drugs will require evaluating all patients with mild AD as potential candidates for these treatments. Biomarkers can be requested from the secondary level of health care if they are reserved for selected cases and requested and interpreted by trained professionals.
Diagnosis in Tertiary Care
Anamnesis	Conduct a detailed initial interview with the patient and their relative/caregiver.
Clinical examination	Perform a general physical examination looking for signs of systemic diseases and a complete neurological examination attentive to focal signs.
Laboratory tests	Perform laboratory tests to detect causes of secondary dementias and comorbidities that may contribute to the clinical picture and other tests if suspecting a relevant systemic disease. If chronic meningitis is suspected, a lumbar puncture should be performed for CSF analysis.
Cognitive assessment	A comprehensive neuropsychological evaluation using a cognitive screening test is suggested for applying instruments to further examine all cognitive domains and to assess functionality and neuropsychiatric disorders.
Structural neuroimaging	Brain MRI is essential to rule out other causes of dementia and further investigate the mesial temporal and other brain regions using visual scales or manual or automated volumetry.
Functional neuroimaging	FDG-PET or single-photon emission computerized tomography (SPECT) studies may show regional alterations in brain metabolism or changes in blood flow in cases of incipient and/or mild dementia, even in the absence of structural changes in neuroimaging.
Biomarker assessment	Using biomarkers is indicated in cases of diagnostic doubt between AD and other neurodegenerative dementias not in the amyloid spectrum, such as FTD, to correctly follow the guidelines for the use of AD approved medications, such as cholinesterase inhibitors and memantine. Other situations are referred to in biomarkers sections. Importantly, the future emergence and availability of potentially disease-modifying drugs will require evaluating all patients with mild AD as potential candidates for these treatments.

Academia Brasileira de Neurologia, Departamento de Neurologia Cognitiva e Envelhecimento R. Vergueiro, 1353 sl.1404 - Ed. Top Towers Offices, Torre Norte, São Paulo, SP, Brazil, CEP 04101-000, Tel.: +55 11 5084-9463 | +55 11 5083-3876 - São Paulo - SP - Brazil
E-mail: revistadementia@abneuro.org.br | demneuropsy@uol.com.br

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[1] Corresponding Author: Lucas Porcello Schilling; Email: lucas.schilling@pucrs.br.