Brain bank of the Brazilian aging brain study group a milestone reached and more than 1,600 collected brains

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1 Cell Tissue Banking (2007) 8: DOI /s z Brain bank of the Brazilian aging brain study group a milestone reached and more than 1,600 collected brains Lea Tenenholz Grinberg Æ Renata Eloah de Lucena Ferretti Æ José Marcelo Farfel Æ Renata Leite Æ Carlos Augusto Pasqualucci Æ Sérgio Rosemberg Æ Ricardo Nitrini Æ Paulo Hilário Nascimento Saldiva Æ Wilson Jacob Filho Æ Brazilian Aging Brain Study Group Received: 16 April 2006 / Accepted: 5 July 2006 / Published online: 31 October 2006 Ó Springer Science+Business Media B.V Abstract Introduction Brain banking remains a necessity for the study of aging brain processes and related neurodegenerative diseases. In the present paper, we report the methods applied at and the first results of the Brain Bank of the Brazilian Aging Brain Study Group (BBBABSG) which has two main aims: (1) To collect a large number of brains of elderly comprising non-demented subjects and a large spectrum of pathologies related to aging brain processes, (2) To provide quality material to a multidisciplinar research network unraveling multiple aspects of aging brain processes and related neurodegenerative diseases. Methods The subjects are selected from the Sao Paulo Autopsy Service. Brain parts are L. T. Grinberg (&) Æ R. E. de Lucena Ferretti Æ R. Leite Æ C. A. Pasqualucci Æ S. Rosemberg Æ P. H. N. Saldiva Department of Pathology, University of Sao Paulo Medical School, Avenida Dr. Arnaldo, 455 1st floor, room 1351, Sao Paulo, SP , Brazil leagrinberg@usp.br J. M. Farfel Æ W. Jacob Filho Division of Geriatrics, University of Sao Paulo Medical School, Sao Paulo, SP, Brazil R. Nitrini Department of Neurology, University of Sao Paulo Medical School, Sao Paulo, SP, Brazil frozen and fixated. CSF, carotids, kidney, heart and blood are also collected and DNA is extracted. The neuropathological examinations are carried out based on accepted criteria, using immunohistochemistry. Functional status are assessed through a collateral source based on a clinical protocol. Protocols are approved by the local ethics committee and a written informed consent form is obtained. Results During the first 21 months, 1,602 samples were collected and were classified by Clinical Dementia Rating as CDR0: 65.7%; CDR0.5:12.6%, CDR1:8.2%, CDR2:5.4%, and CDR3:8.1%. On average, the cost for the processing each case stood at US$400. To date, 14 laboratories have been benefited by the BBBABSG. Conclusion The high percentage of nondemented subjects and the ethnic diversity of this series may be significantly contributive toward aging brain processes and related neurodegenerative diseases understanding since BBBABSG outcomes may provide investigators the answers to some additional questions. Keywords Aging Æ Alzheimer s disease Æ Brain banking Æ Dementia Æ Geriatrics Æ Neurodegenerative diseases Æ Neurology Æ Neuropathology

2 152 Cell Tissue Banking (2007) 8: Abbreviations BBASG Brazilian Brain Aging Study Group BBBABSG Brain Bank of the Brazilian Aging Brain Study Group CNS Central nervous system CS Collateral source ICF Informed consent form NOK Next-of-kin PMI Postmortem interval SPAS Sao Paulo autopsy service USPMS University of Sao Paulo Medical School Introduction The world s elderly population is expected to increase four times from 2000 to 2050 (UN Population Division 2000). This will inevitably be followed by a great increase in the prevalence of related neurodegenerative diseases particularly, in developing countries (Ferri et al. 2005; Herrera et al. 2002). Animal models on age-related human diseases mimic the complex pathogenic interactions within the highly evolved human CNS only in a limited manner. Therefore, in order to elucidate environmental, genetic, and endogenous processes in human aging and in neurodegenerative diseases investigation on human brain tissue is precondition. For that reason, brain banks gained an important function during the last years as autopsy is the only practical way in which human brain tissue can be assessed (Cruz-Sanchez and Tolosa 1993). However, considering the high complexity of the brain anatomy and function, a proper brain bank have to be a scientific facility, conducted by multiprofessional experts who assess the subject s cognitive and functional status, and where the material is processed following high standard protocols (Love 2004). Although there are many successful brain banks (Hulette 2003; Orr et al. 2005), the majority of them are affected by the inhered consequences of the worldwide dramatic decreased autopsy rates of past decades resulting in: a low number of enrolled subjects, mainly the non-demented cases; a lack of objective information about comorbidities in brain-only autopsies; and long postmortem interval (PMI). In the present paper, we report the methods applied at and the first results of the Brain Bank of the Brazilian Aging Brain Study Group (BBBABSG). This brain bank has two main aims: (1) To perform a large number of autopsies of elderly individuals; the donors come to autopsy through a general autopsy service, followed by specific dissection protocols. The collected cases should comprise a large number of non-demented subjects and a vast spectrum of pathologies related to aging brain processes. (2) To provide high quality material to a multidisciplinar research network unraveling multiple aspects of aging brain processes and related neurodegenerative diseases. Methods Core board The BBBABSG has been created in September 2003 by the core board of the Brazilian Brain Aging Study Group (BBASG). BBASG is composed by a group of different specialists from the University of Sao Paulo Medical School (USPMS) (Fig. 1). Quality control The first months were fully dedicated to the study design and pilot tests. Clinical scales and questionnaires were discussed and tested in the USPMS Cognitive Study Center, a multidisciplinar research facility. Meanwhile, both the pathological protocol and the electronic database were formatted based on previous successful experiences (Cruz-Sanchez and Tolosa 1993). In 2004, following a study involving all the clinical and pathological steps, BBBABSG began to work under full power. In order to keep the BBBABSG up-to-date and improve its quality, communication with other brain banks like the Netherlands Brain Bank and the Washington University in St. Louis Brain Bank is carefully maintained, including on-site visits and fellowships.

3 Cell Tissue Banking (2007) 8: Fig. 1 Brazilian Brain Aging Study Group s board members Ethical issues BBBABSG s procedures are approved by the Ethical Board of USPMS and by the Brazilian Federal Health Department. The ethical principles follow Brazilian requirements (1996), which are based on international standards, such as The Belmont Report (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1978) and The Helsinki Declaration (1964). A voluntary Informed Consent Form (ICF) is obtained by the interviewer and must be signed by each next-of-kin (NOK) before any procedure. The ICF details research procedures (including image, molecular and genetic studies), purposes, risks and benefits, as well as a statement offering the NOK the opportunity to ask questions and to withdraw at any time from the study. If any of the procedures is refused by the NOK, the case is not banked. All the material used for any purpose is anonymous and the specimens are coded by number. However, specimen identification can be retrieved in case of legal or public health requirements, according to Brazilian regulations. Source of subjects In Sao Paulo, autopsies are compulsory for those who have died in the metropolitan areas with no established cause of death, at no charge to the family. The Sao Paulo Autopsy Service (SPAS) is the site of all autopsies of natural deaths from this city of 11 million people. SPAS has functioned 24 h a day since 1931 and is located within USPMS, adjacent to the BBBABSG s facilities. All autopsies complete and documented, are performed by a medically qualified pathologist assisted by nationally certified technicians. Brains are obtained at autopsy of subjects aged 50 years or older and sourced from the SPAS. BBBABSG s procedures Only the centralized Municipal Autopsy Service is allowed to transport deceased bodies. The time frame is 2 6 h from the hospital or home to SPAS resulting in a short PMI mean of 10.4 h (4 20 h). BBBABSG is structured into five areas (Fig. 2). Reception, selection and informed consent Reception and selection (Fig. 3) Subjects are enrolled from Monday through Friday, between 8 and 18 h. Two rotating teams of two experienced gerontologists each are on shift at the SPAS during this period. Deceased

4 154 Cell Tissue Banking (2007) 8: B B B A B S G RECEPTION, SELECTION AND INFORMED CONSENT CLINICAL AND FUNTIONAL ASSESSMENT NEUROPATHOLOGICAL PROCEDURES DNA BANK ELETRONIC DATABASE Fig. 2 Brain Bank of the Brazilian Aging Brain Study Group structure. Sao Paulo, 2006 information is received in SPAS before the corpse s arrival, allowing a subject pre-selection. The NOK must come personally to SPAS in order to give release of the body. Upon arrival, the NOK waits around 3 h for autopsy procedures and the release of documents. If the consent is granted and a satisfactory collateral source (CS) is on-site, the clinical and functional interview is conducted in a private room. The NOK and the CS are not necessarily the same person. During the interview, the gerontologist judges whether there is enough information available to rate the subject, as well as whether the CS is reliable. The subject is excluded from the study if any of these criteria is not fulfilled. Selection criteria Inclusion criteria: (i) Subjects aged 50 years old and older. Exclusion criteria: (i) Subjects with macroscopically detectable acute brain infarctions, hemorrhages or trauma, since an immediate examination is required for filling the death certificate. (ii) Subjects with severe chronic conditions that might damage cognitive function prior to death by interfering in brain homeostasis. These conditions include severe heart failure, chronic kidney failure and brain metastasis. (iii) Subjects without reliable CS to provide enough information or to appropriately answer the clinical and functional interview. Eligible CS are expected to have at least close weekly contact with the diseased subject during the last 6 months. (iv) Subjects with indication of acidosis due to severe agonal status (CSF ph < 6.5), which makes the tissue incompatible for biochemical and molecular studies (Ravid et al. 1992; Harrison 1996). Fig. 3 Flowchart of the Brain Bank of the Brazilian Aging Brain Study Group s procedures 2006

5 Cell Tissue Banking (2007) 8: Clinical and functional assessment Although the 40 min interview is usually done during the waiting period at SPAS, it may be rescheduled for a later date during the following few days, in case of any impediment. The subject s clinical and functional statuses are assessed through the CS. The protocol includes a series of semi-structured scales and questionnaires that cover major functional abilities and are validated for assessment with an informant (Table 1) (Morris et al. 1991; Isella et al. 2006). Additional information is collected from medical records when available. Moreover, information concerning demographics, medication, medical history, cardiovascular risk factors, and family history of dementia is also collected. Neuropathological procedures (Fig. 3) The procedures are divided into three steps: (1) during autopsy procedure, (2) immediately after autopsy, and (3) during post-fixation (Fig. 3). Steps 1 and 2 are done by three alternating teams composed of three biomedicine undergraduates and one graduate student each. During Step 3, tissue processing and staining are performed by histotechnicians. The materials are analyzed macroscopically and microscopically by the pathologists (Fig. 3). Autopsy is performed by the SPAS pathologist on shift. Step 1 Body weight, height and skull size are measured. CSF is extracted in situ, from the lateral ventricles by transcallosal puncture. Blood is taken from the aorta. Brain, heart, cervical carotids and a kidney sample are removed. Step 2 The brain and heart are measured (weight and volume) and digitally photographed. Three samples of 1 1 cm each are taken from selected areas are snap frozen in labeled cryotubes (Table 2). The Circle of Wills is dissected, photographed and fixed. Subsequently, the brain (suspended), heart, and carotids are fixed. All the material is fixed in 4% buffered paraformaldehyde for 3 weeks. Step 3 All the procedures are done in the BBBABSG s laboratory, located one floor above the SPAS. Any surplus tissue is discarded and buried according to Brazilian regulations. Macroscopic analyzes Brain After cerebellum and brainstem separation by a cut at the level of the superior colliculus, the brain Table 1 Scales used in Brain Bank of the Brazilian Aging Brain Study Group for the clinical and functional assessment 2006 Domain Scales Cognitive Clinical Dementia Rating Scale CDR (Morris 1993) Informant questionnaire of the cognitive decline in the elderly IQCODE (Jorm 1994) Behavioral changes Neuropsychiatric Inventory NPI (Cummings et al. 1994) Affective disorders DSM IV SCID for depression and manic disorders (Del-Ben et al. 1996; Spitzer et al. 1992) Functional assessment The Katz Index (Katz et al. 1963) Instrumental activities of daily living (Lawton and Brody 1969) Parkinson disease Tanner et al. (1990) Social information ABIPEME a Brazilian scale used to determine social-economic condition (Almeida and Wickerhauser 1991)

6 156 Cell Tissue Banking (2007) 8: Table 2 Types of tissues collected and their respective procedure of sampling Brain Bank of the Brazilian Aging Brain Study Group. Sao Paulo, 2006 Area Brain Other tissue Middle frontal (BA46) Superior and inferior parietal lobule (BA 39/40) Superior and middle temporal (BA21/22) Superior frontal (BA8/9) and anterior cingulate (BA24), at the level of the anterior basal ganglia Occipital lobe (BA17/18) Anterior hippocampal formation, entorhinal region (BA27/28) and the inferior temporal (BA20) Amygdala Thalamus Basal ganglia, including the nucleus basalis of Meynert, at the level of the anterior commissure Midbrain including the substantia nigra Pons including locus ceruleus Medulla oblongata Cerebellum, including the dentate nucleus Circle of Willis Cervical carotids Heart Kidney sample CSF Arterial blood Stored at 80 C Stored at 4 C X X X X X X X b b b b u u Fixed X X X X X X X X X X X X X X X X X Embedded X X X X X X X X X X X X X X X X in paraffin X X = sampled; b = bilateral; u = unilateral Note: Paraffin blocks measure cm each

7 Cell Tissue Banking (2007) 8: is coronally sliced in 1 cm slabs. A minimal set of 13 areas is represented and embedded in paraffin blocks (Table 2). The remaining tissue is stored in covered plastic boxes. Cardiovascular In order to assess cardiovascular changes which might be related to cognitive impairment, carotids, coronaries and Circle of Willis arteries are examined semiquantitatively, both macroscopically and microscopically. In every artery, the atherosclerosis level is graded as: none, mild, moderate or severe, and the most obstructed part is sampled and measured microscopically. The ventricular thickness is measured and the heart valves are examined for assessing the occurrence of high blood pressure effects over the heart. These procedures are performed by a specialist following a protocol. Histological technique and staining methods All paraffin blocks are sectioned 8 lm thick and stained with hematoxylin-eosin (HE) and modified Bielschowsky silver impregnation methods. Routine immunohistochemistry is performed on selected areas (Table 3) using antibodies against the following peptides or proteins: b-amyloid, phosphorylated tau, a-synuclein and ubiquitin (Table 4). If suspected lesions are found in the other samples, additional immunostaining is performed. The kidney sample is stained with HE and Masson s trichromic for assessing signs of kidney damage due pressure and atherosclerosis. Histological assessment and diagnosis criteria The histological assessments are based on the most accepted criteria for age-related neurodegenerative diseases (Mirra et al. 1991; Braak and Braak 1991; Braak et al. 2004; McKeith et al. 1996; NIA-RR 1997; McKhann et al. 2001; Saito et al. 2004). Vascular pathology is recorded by area, size and type. DNA bank DNA is extracted from blood samples up to 7 days after the autopsy and is frozen at 80 C. The DNA procedure is coordinated by Mayana Zatz, Ph.D., Director of the Human Genomics Research Center. Eletronic database An SQL-based database was built to store and analyze the data. This work is coordinated by Helena Brentani, MD, Ph.D., Director of the Bioinformatics Laboratory of Hospital A.C Camargo Sao Paulo. This laboratory has contributed to the building of the Sao Paulo Cancer Genomics Project s database (Brentani et al. 2003). Data are loaded in each procedure step. The database is password protected, and backups are done daily. Table 3 Antibodies used routinely in Brain Bank of the Brazilian Aging Brain Study Group Protein name Clone (source) Dilution Antigenal-retrieval treatment Detecton system Chromogen b-amyloid Tau a-synuclein Ubiquitin 4G8 (Signet Pathology Systems) PHF-1 (Gift of P. Davies) a-synuclein (Chemicon) Anti-ubiquitin polyclonal (DAKO) 1:10,000 Steam, citrate ph 6 1:2,000 Steam, citrate ph 6 Vectastain ABC Kit Vectastain ABC Kit (Mouse IgG) Vector Laboratories (Mouse IgG) 1:500 Steam, citrate ph 6 Vectastain ABC Kit (Mouse IgG) 1:5,000 Steam, citrate ph 6 Vectastain ABC Kit (Mouse IgG) DAB DAB DAB DAB

8 158 Cell Tissue Banking (2007) 8: Table 4 Staining protocol for brain areas. Brain Bank of the Brazilian Aging Brain Study Group 2006 Cerebellum Medulla oblongata Midbrain Pons including locus ceruleus Amygdala Thalamus Basal ganglia, including the nucleus basalis of Meynert, Anterior hippocampal formation, entorhinal region (BA27/28) and the inferior temporal (BA20) Occipital lobe (BA17/18) Superior frontal (BA8/9) and anterior cingulate (BA24) Superior and middle temporal (BA21/22) Superior and inferior parietal lobule (BA 39/40) Area Middle frontal (BA46) 4G8 X X X X X X X X X Tau 2 X X X X X X X X X X X X a-synuclein X X X X X X X X X X = stained. Ubiquitin immunohistochemistry is performed if Frontotemporal Lobar Degeneration is suspected Tissue request Research groups may access material for studies on the aging process and related neurodegenerative diseases. The request, together with the proof of ethics approval from the parent institution, is evaluated by the BBBABSG core board. An annual report from each participating research group should be done. No tissue may be redistributed without authorization from the BBBABSG. Results Sample characteristics From April 2004 to December 2005, 1,602 out of the 2,769 possible subjects were enrolled. The number of deaths in older age groups as well as enrolled subjects increased during the winter. Although the percentage of possible subjects successfully banked is around 50%, approximately 9% of the NOKs declined to participate in this study, mainly due a lack of interest in the proposed study. Possible subjects are excluded by either CS or subject-dependent variables, such as lack of reliability or agonal state severity, respectively. (Fig. 4) The series mean age is 71.2 years for females and 66.5 years for males, following the life expectancy data for Sao Paulo City. However, males are slightly more represented in general (Fig. 5). Table 5 summarizes additional results regarding ethnic distribution. It is noteworthy that 2/3 of the subjects are non-cognitive impaired (CDR = 0) (Fig. 6). The cost per successfully banked specimen was about US$400 per case. Tissue request To date, BBBAGSG is providing tissue for five kinds of studies: neuropathological, neurochemical, molecular, neuroimaging and epidemiological, which are being conducted in 14 research laboratories from both USPMS and outside.

9 Cell Tissue Banking (2007) 8: Fig. 4 Time line of Brain Bank of the Brazilian Aging Brain Study Group series from April 2004 to December 2005 (in absolute numbers) Possible subjects = 2, Enrolled subjects = 1, Excluded due to selection criteria = Excluded due to CS = Refused =148 0 jul/04ago/04set/04out/04nov/04dez/04jan/05 fev/05mar/05abr/05mai/05jun/05 jul/05ago/05set/05out/05nov/05dez/05jan/06 Discussion Our first results show the feasibility of brain bank based on a large general autopsy service that prospectively prepares and stores specimens to satisfy most research requirements for aging processes and related neurodegenerative studies. Furthermore, the large amount of available subjects affords strict selection criteria minimizing the pitfalls related to this kind of study design. In summary, some local characteristics are positive assets to BBBABSG, such as: (a) (b) (c) The large number of autopsies done at SPAS, leading to a large number of possible subjects, consequently facilitating control-case matching and continuous specimen replacement, The location of SPAS within the USPMS, adjacent to the Pathology Department, narrowing postmortem delay and avoiding transportation damage, The broad heterogeneity of the Sao Paulo population, resulting in an ethnically diverse sample (BBBABSG hosts 160 African and 19 Oriental subjects.), Fig. 5 Brain Bank of the Brazilian Aging Brain Study Group series. Subjects distribution by gender and age group

10 160 Cell Tissue Banking (2007) 8: Table 5 Ethnic group distribution Brain Bank of the Brazilian Aging Brain Study Group Ethnic group (%) 65.7% African 10 Caucasian 76.6 Mixed 11 Orientals 1.2 Not available 1.2 (d) The large amount of control subjects (65.7%), a group extremely important to neurodegenerative disease studies and scarcely represented in some series (Murphy and Ravina 2003; Ravid et al. 1995). Furthermore, most of the mild affected subjects are drug-naïve, (e) The high quality of material obtained with low maintenance costs. Each successfully banked specimen cost US$400 in direct and indirect cost, while in the USA the costs range from $10,000 to $30,000 (Hulette 2003). Given that SPAS is an already-established service which boasts structured technical support, the costs are due to consumables, and (f) Complete autopsy results and objective cardiovascular evaluation even careful clinical and laboratory assessment may show discrepancies with autopsy data (Roulson et al. 2005). Given that some cardiovascular risk factors are implied in dementia (Luchsinger et al. 2005), a number of studies stress the importance of objective vascular evaluation through autopsy. The desirable design for a neurodegenerative brain bank is based on longitudinally assessed subjects. However, most brain banks are affected by low rates of subject enrollment. These low rates result in a lack of matching control cases, and long periods are needed to gather a reasonable amount of samples. Therefore, a cross-sectional design could solve some of the cited problems and even complement the other series through collaborations. We try to tackle the following questions/issues: (1) Is a cross-sectional brain bank in which clinical and functional assessment is based on CS information able to provide reliable data? 12.6% 8.2% 5.4% 8.1% CDR0 CDR 0.5 CDR 1 CDR 2 CDR 3 Fig. 6 Subject distribution according to the Clinical Rating Scale of Dementia. Brain Bank of the Brazilian Aging Brain Study Group Cognitive function is a difficult assessment area, especially in the absence of the subject. Therefore, aiming to gather reliable data from the CS, our protocol comprises only scales which are widely recognized as reliable for informantbased assessment (Morris et al. 1991; Jorm 1997; Winblad et al. 2004), including two cognitive scales: the IQCODE (Jorm 1994) and the CDR (Morris 1993). A study performed in Sao Paulo City verifies the IQCODE high sensitivity and specificity to the local population (Bustamante et al. 2003). Furthermore, evidence demonstrates these scales to be reliable even for subjects having mild cognitive impairment (Isella et al. 2006). An assessment done by experienced gerontologists is considered as accurate as one done by physicians (McCulla et al. 1989). (2) Is the period during autopsy suitable for clinical and functional assessment? Both the previous pilot studies and the current experience demonstrate that CSs are cooperative and provide accurate information in this period. Around 90% of the families voluntarily consent to participate, and just 15% of the assessments are reassigned for a few days later. (3) Is a structured brain bank affordable in local research conditions? USPMS is a government-supported school. The BBBABSG is sponsored by grants from the Pathology Department and minor grants from

11 Cell Tissue Banking (2007) 8: the Brazilian Research Institutes; SPAS structure and staff is paid by public funds. Moreover, the majority of the collecting and storing procedures are performed by supervised undergraduate biomedical students enrolled in a certificated Research Training Program. These students spend 20 h per week in training, and 30% of that time is dedicated to BBBABSG. The students receive a scholarship, and the remaining time is dedicated to their research projects, seminars and lectures. Those students are more academically prepared and motivated than technicians. Furthermore, several requests for grants are under evaluation by both national and international associations, as well as private companies which might benefit from tax breaks. Conclusions The high percentage of control subjects and the ethnic diversity of this series might make a significant contribution toward understanding aging brain processes and related neurodegenerative diseases. BBBABSG is not another brain bank in competition with the established facilities; rather, BBBABSG outcomes may provide investigators the answers to some additional questions. Finally, the BBBABSG series has the potential to advance the knowledge and understanding of the mechanisms underlying aging brain processes and related neurodegenerative diseases. Acknowledgements We are grateful to Prof. H. Heinsen (Julius Maximilians University Wurzburg, Germany) and to Larenda Mielke (Washington University in St Louis, USA) for them critical review. We also thank Sao Paulo Autopsy Service physicians and staff for unconditional support, BBASG s students for outstanding assistance and the staff of Pathology Department of University of Sao Paulo Medical School for technical support.support for this work was provided by grants from the Pathology Department and Geriatrics Division of University of Sao Paulo Medical School Research and Teaching Institute of Albert Einstein Hospital (Sao Paulo), Toxicology Department of Butantan Institute (Sao Paulo), Coordenadoria de Apoio ao Pessoal de Nivel Superior CAPES Scholarship (to LTG), and Fundação de Apoio à Pesquisa do Estado de São Paulo FAPESP Scholarship (to LTG). References Almeida P, Wickerhauser H (1991) [O Critério ABA/ ABIPEME em Busca de Uma Atualização. Um estudo e uma proposta submetidos à ABA e à ABI- PEME]. Editora da Associação Brasileira dos Institutos de Pesquisa de Mercado, Sao Paul Sao Paulo Braak H, Braak E (1991) Neuropathological stageing of alzheimer-related changes. Acta Neuropathol (Berl) 82: Braak H, Ghebremedhin E, Rub U et al (2004) Stages in the development of Parkinson s disease-related pathology. Cell Tissue Res 318(1): Brasil Conselho Nacional de Saúde (1996) [Resolução n 196 de 10 de outubro de Diretrizes e normas regulamentadoras de pesquisas envolvendo seres humanos]. In: Diário Oficial da República Federativa do Brasil, Brasília Brentani H, Caballero OL, Camargo AA et al (2003) The generation and utilization of a cancer-oriented representation of the human transcriptome by using expressed sequence tags. Proc Natl Acad Sci USA 100: Bustamante SE, Bottino CM, Lopes MA et al (2003) [Combined instruments on the evaluation of dementia in the elderly: preliminary results]. Arq Neuropsiquiatr 61: Cruz-Sanchez FF, Tolosa E (1993) The need of a consensus for brain banking. J Neural Transm Suppl 39:1 4 Cummings JL, Mega M, Gray K et al (1994) The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology 44: Declaration of Helsinki (1964) Ethical principles for medical research involving human subjects. Adopted by the 18th World Medical Assembly. Helsinki, Finland Del-Ben CM, Rodrigues CR, Zuardi AW (1996) Reliability of the Portuguese version of the structured clinical interview for DSM-III-R (SCID) in a Brazilian sample of psychiatric outpatients. Braz J Med Biol Res 29: Ferri CP, Prince M, Brayne C et al (2005) Global prevalence of dementia: a Delphi consensus study. Lancet 366: Harrison PJ (1996) Advances in post mortem molecular neurochemistry and neuropathology: examples from schizophrenia research. Br Med Bull 52: Herrera E Jr, Caramelli P, Silveira AS et al (2002) Epidemiologic survey of dementia in a communitydwelling Brazilian population. Alzheimer Dis Assoc Disord 16: Hulette C (2003) Brain banking in the United States. J Neuropathol Exp Neurol 62: Isella V, Villa L, Russo A et al (2006) Discriminative and predictive power of an informant report in mild cognitive impairment. J Neurol Neurosurg Psychiatr 77:

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