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A genômica geriatrica estuda as formas do envelhecimento, podendo ser adiantando ou retardado dependendo das ações e escolhas que fazemos para a nossa vida, possuindo por tanto muitos fatores externos que levam ao envelhecimento.

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Aspectos genéticos do envelhecimento e doenças associadas: uma complexa rede de interações entre genes e ambiente

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Resumo O envelhecimento é um processo dinâmico, no qual ocorrem modificações do nível molecular…

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As doenças degenerativas são as doenças que geram perda ou degeneração dos neurônios

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As mutações que originam o câncer são uma alteração de aminoácidos do DNA que podem ser germinativas, transmitidas hereditariamente, ou somáticas

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O rastreamento genético é recomendado para pessoas que tem uma pré-disposição ao câncer, tendo como exemplo a técnica de CGAH que rastreia vários genes ao mesmo tempo e que ajuda a detectar a melhor forma de tratamento, apesar disso, possui um pequena equidade de acesso

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Os erros inatos do metabolismo geram doenças metabolicamente primárias que em sua grande maioria são sistémicas, essas doenças são subdivididas em graus:
- I: Erro na síntese ou catabolismo de moléculas complexas
- II: Erro no metabolismo intermediário
- III: Erro na produção ou utilização de energia

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A genômica nutricional possui duas áreas de maior relevância a nutrigenética que estuda a genética do indivíduo e a nutrigenômica que estuda como os alimentos alteram a expressão genica

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As vacinas gênicas são vacinas feitas a partir de DNA ou RNA que possuem uma alta eficácia e possuem três gerações:
- Gen 1: Patógeno atenuado ou inativado
- Gen 2: Subunidades do patógeno
- Gen 3: Gênica, fragmento do DNA ou RNA do patógeno

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As terapias alvos são uma técnica de tratamento de câncer que não afeta as células saudáveis e impede a duplicação de células cancerígenas, mas essas técnicas não estão disponíveis para todos os tipos de câncer

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Doenças complexas são doença que não possuem uma herança genética definida ou uma mutação adquirida clara, ou seja, são multifatoriais.

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Dieta epigenética: alimentação dos pais pode neutralizar os "genes ruins" dos filhos?

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Vez ou outra, aparecem declarações confusas sobre o tema, como é o caso da ideia da dieta epigenética. Entenda melhor os conceitos que cercam a questão

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Essas patogenias são de difícil diagnóstico, mas se tratadas precocemente possuem um bom prognóstico. Para se fazer o diagnóstico dessas patogenias pode-se usar testes químicos ou testes físicos

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A vacina gênica feita a partir do DNA possui um fragmento desejado do trecho de um DNA viral ou bacteriano que dentro das nossas células vai passar por transcrição e tradução para expressar uma proteína, já a feita a partir de RNA também possui apenas um trecho do RNA original, mas essa passa apenas pela tradução para que possa expressar uma proteína

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O alzheimer precoce é quando a pessoa desenvolve a doença antes dos 65 anos e costuma ser associado a fatores genéticos. Já a tardia é a mais comum, sendo desenvolvida após os 65 anos.

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A  TERAPIA-ALVO  E  O  CÂNCER  DE  PULMÃO  DEPEQUENAS E DE NÃO PEQUENAS CÉLULAS

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As farmacêuticas Moderna e MSD anunciaram que o tratamento conjunto que estão desenvolvendo contra o melanoma, o tipo mais letal de câncer de pele, irá para a terceira e última fase de testes clínicos. Ele inclui uma nova vacina e um medicamento já utilizado contra a doença.

Serão recrutadas aproximadamente 1.089 pessoas maiores de 18 anos em cerca de 25 países para os testes. As primeiras inscrições já começaram na Austrália, segundo a nota conjunta das empresas. A pesquisa deve levar mais de um ano para ser concluída.

Dados de um estudo intermediário em 157 pacientes indicaram que a combinação da vacina com a imunoterapia Keytruda reduziu o risco de recorrência ou morte em 44% em pacientes com melanoma quando comparada com a utilização apenas de Keytruda, conforme noticiou a agência de notícias "Reuters".

Kyle Holen, vice-presidente sênior e chefe de desenvolvimento, terapêutica e oncologia da Moderna, classificou o início do estudo de fase 3 como "um marco empolgante e importante".

Ele destacou que os laboratórios continuarão trabalhando em conjunto para "investigar como a terapia individualizada com neoantígenos pode potencialmente transformar o tratamento da forma mais grave câncer de pele".

A Moderna e a MSD informaram que planejam expandir o programa para outros tipos de câncer, incluindo o de pulmão de células não pequenas.

Entenda como funciona o tratamento
A vacina experimental contra o câncer da Moderna foi projetada para preparar o sistema imunológico para gerar uma resposta a tumores específicos.

Ela utiliza a tecnologia de RNA mensageiro (mRNA) -que foi utilizado em algumas vacinas para a Covid-19, por exemplo-, uma espécie de "receita" que será decodificada pelo organismo do paciente para a produção de anticorpos.

Essa vacina é "individualizada", pois será produzida com base na sequência genética do tumor de cada paciente.

Neste caso, a vacina não será utilizada para a prevenção em pacientes que nunca tiveram o câncer, mas para evitar morte ou recorrência em quem já o teve.

A imunoterapia Keytruda, da MSD, já é usada no tratamento do melanoma. Ela estimula o sistema imunológico a atacar os tumores.

Entenda como funciona o teste
Esse estudo é randomizado (pacientes recebem o medicamento/vacina testado ou placebo de forma aleatória), duplo-cego (nem o aplicador, nem o paciente sabem se está sendo usado o placebo ou medicamento/vacina testado) e controlado por placebo e comparador ativo (há comparação entre o tratamento testado e outro já utilizado pela medicina).

A pesquisa visa testar a eficácia e segurança do imunizante. Serão recrutadas aproximadamente 1.089 pessoas maiores de 18 anos em cerca de 25 países para os testes. As primeiras inscrições já começaram na Austrália, segundo a nota conjunta das empresas.

Segundo a Moderna e a MSD, após "remoção cirúrgica completa", alguns pacientes receberão 1 mg a cada três semanas da vacina -até que sejam aplicadas 9 doses- e 400 mg de Keytruda a cada seis semanas.

Outros receberão apenas Keytruda por aproximadamente um ano "até a recorrência da doença ou toxicidade inaceitável, ou por uma duração total do tratamento de até aproximadamente 56 semanas, o que ocorrer primeiro".

Perigo do melanoma
Segundo as farmacêuticas, o melanoma é caracterizado pelo crescimento descontrolado de células produtoras de pigmento, com cada vez mais casos mundialmente nas últimas décadas.

Em 2020, ainda de acordo com a nota da Moderna e da MSD, cerca de 325 mil novos casos foram diagnosticados em todo o mundo.

As empresas ressaltam que especialistas estimam que serão diagnosticados cerca de 100 mil novos casos de melanoma e quase 8.000 mortes pela doença apenas nos Estados Unidos neste ano.

O câncer de pele é um dos tipos mais comuns de câncer diagnosticados nos EUA, e o melanoma é responsável pela grande maioria de mortes nos cânceres de pele, finaliza a nota das farmacêuticas.

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Vacina contra câncer de pele mais letal entra na última fase de teste; saiba como funciona - Instituto Oncoguia

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Estudo intermediário indicou que combinação com medicamento já utilizado reduziu o risco de recorrência ou morte em 44% em pacientes com melanoma

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Pesquisadores do Hospital das Clínicas (UFMG), da Universidade de George Washington, nos EUA, e da Fiocruz Minas estão participando de um grande estudo clínico de fase 2/2b de uma vacina experimental contra a infecção pelo vírus do Zika, em Belo Horizonte. Feito com parte do material genético do vírus, a vacina poderá produzir anticorpos capazes de promover uma resposta contra a infecção num indivíduo que é imunizado.

Chamada de " vacina de DNA contra Zika ", a substância experimental já foi testada em seres humanos nos EUA, e o estudo clínico foi aprovado pelos comitês de ética e agências regulatórias nacionais e internacionais. Agora, será avaliada numa população expandida com a finalidade de estudar novos dados sobre a sua eficácia e segurança. Para essa nova fase, serão recrutados voluntários sadios, entre 15 e 35 anos, que morem em Belo Horizonte ou região metropolitana e que tenham disponibilidade para participar do estudo pelos próximos dois anos.

Os voluntários serão selecionados após a realização de uma avaliação clínica e de exames laboratoriais que serão oferecidos gratuitamente pela equipe do Hospital das Clínicas. Já a Fiocruz Minas, ficará responsável pelo processamento do sangue e urina de todos os participantes da pesquisa, que serão testados para avaliar a eficácia, a resposta imune, e os efeitos da vacina no organismo.

"Faremos o processamento e armazenamento dos amostras dos participantes. Um dos objetivos do estudo é verificar se a vacina induz anticorpos que protejam contra o vírus do Zika", explica o pesquisador Rodrigo Corrêa Oliveira, coordenador do estudo na Fiocruz Minas.

Para se tornarem aptos a realizar o processamento das amostras, profissionais do Grupo de Imunologia Molecular e Celular da Fiocruz Minas passaram por um treinamento rigoroso e receberam um certificado internacional, habilitando-lhes a realizar esse tipo de trabalho. "É uma atividade que envolve uma série de protocolos a serem seguidos e, por isso, requer todo um preparo. No Brasil, pouquíssimas pessoas estão autorizadas a desenvolver esse tipo de processamento de amostras", afirma o pesquisador Jeffrey Michael Bethony, da Universidade de George Washington, que há cerca de 15 anos desenvolve projetos em parceria com a Fiocruz Minas como pesquisador visitante.

O estudo é liderado pelo Instituto Nacional de Alergia e Doenças Infecciosas do National Institutes of Health (NIH), organização do governo americano. Em Minas Gerais, a pesquisa está sob coordenação da infectologista Flávia Ribeiro, pesquisadora-chefe e coordenadora-técnica do Centro de Pesquisas Clínicas do Hospital das Clínicas da UFMG.

Informações adicionais sobre o vírus do Zika e a pesquisa clínica poderão ser obtidas na página facebook.com/vacinazikabh, por meio do telefone 0800 035 66 35 ou pelo email vacinazikabh@gmail.com.

A doença- A Zika é uma doença viral aguda, transmitida principalmente por mosquitos, tais como Aedes aegypti. Entre os sintomas podem estar erupção cutânea, acompanhada de coceira intensa, bem como febre intermitente, hiperemia conjuntival não purulenta e sem prurido (olhos vermelhos e lacrimejantes), dor nas articulações, dor muscular e dor de cabeça. A doença apresenta evolução benigna, e os sintomas geralmente desaparecem espontaneamente após 3 a 7 dias.

Entretanto, embora a infecção por Zika virus possa passar sem causar grandes transtornos, os casos confirmados de microcefalia indicam que as mães foram infectadas pelo vírusnos primeiros meses de gravidez. A criança é considerada portadora de microcefalia, quando seu perímetro cefálico é menor do que 32 cm.

Estudos indicam também uma ligação entre o Zika virus e a Síndrome de Guillain-Barré, doença autoimune que provoca fraqueza muscular e paralisia que, nos casos mais graves, pode colocar a vida do paciente em risco.

Ainda não há cura ou vacina para prevenir a infecção pelo Zika. A principal medida de prevenção, atualmente, é o controle dos mosquitos transmissores.

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Vacina contra o vírus Zika será testada em MG

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Pesquisadores do Hospital das Clínicas (UFMG), da Universidade de George Washington, nos EUA, e da Fiocruz Minas estão participando de um grande estudo clínico de fase 2/2b de uma vacina experimental contra a infecção pelo vírus do Zika, em Belo Horizonte.

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Resumo

Os erros inatos do metabolismo são alterações em alguma via metabólica do organismo e são os responsáveis pelas doenças metabólicas hereditárias. As doenças metabólicas hereditárias geralmente cursam com hipotonia, letargia, vômitos, redução da sucção e crises convulsivas em neonatos, e em casos mais tardios pode-se encontrar atraso no desenvolvimento neuropsicomotor, dismorfias e infecções de repetição. O exame que detecta essas doenças nos recém-nascidos é a triagem neonatal biológica, mais conhecido como "teste do pezinho". O vigente estudo tem por objetivo realizar uma revisão bibliográfica sobre a triagem neonatal no Brasil e os erros inatos do metabolismo que são pesquisados no exame, a fim de esclarecer os benefícios do diagnóstico e tratamento precoce das doenças pesquisadas. É de conhecimento que existem diversos erros inatos do metabolismo que ainda não são detectados no teste do pezinho, porém em 2021 o Ministério da Saúde iniciou o projeto de ampliação da triagem neonatal biológica. Os pais e pediatras devem estar atentos à realização da triagem neonatal no tempo correto e o seu resultado.

Palavras-chave: Doenças Metabólicas. Erros Inatos do Metabolismo. Hereditárias Triagem Neonatal. Teste do Pezinho.
NEONATAL SCREENING AND METABOLIC INBORN ERRORS: A BIBLIOGRAPHIC REVIEW ABSTRACT
Metabolism inborn errors are alterations in some metabolic pathway in the body and are responsible for inherited metabolic diseases. Inherited metabolic diseases are usually presented as hypotonia, lethargy, vomiting, reduced sucking, and seizures in neonates, and in later cases one may find delayed neuropsychomotor development, dysmorphisms, and recurrent infections. The test that detects these diseases in newborns is the biological neonatal screening, better known as the "heel prick". This paper aims to conduct a literature review on newborn screening in Brazil and the metabolism inborn errors that are investigated in the test, in order to clarify the benefits of early diagnosis and treatment of investigated diseases. It is known that there are several inborn errors of metabolism that are not yet detected in the guthrie test, but in 2021 the Ministry of Health started the project to expand the biological newborn screening. Parents and pediatricians should be aware of neonatal screening at the correct time and its results.

Key words: Newborn Screening. Inborn Errors of Metabolism. Hereditary Metabolic Diseases

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A TRIAGEM NEONATAL E OS ERROS INATOS DO METABOLISMO: UMA REVISÃO BIBLIOGRÁFICA | Teles | Tekhne e Logos

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A TRIAGEM NEONATAL E OS ERROS INATOS DO METABOLISMO: UMA REVISÃO BIBLIOGRÁFICA

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The association between Alzheimer's disease (AD) and sleep disturbances has received increasing scientific attention in the last decades. However, little is known about the impact of sleep and its disturbances on the development of preclinical AD stages, such as mild cognitive impairment. This review describes the evolution of knowledge about the potential bidirectional relationships between AD and sleep disturbances exploring recent large prospective studies and meta-analyses and studies of the possible mechanisms through which sleep and the neurodegenerative process could be associated. The review also makes a comprehensive exploration of the sleep characteristics of older people, ranging from cognitively normal individuals, through patients with mild cognitive impairment, up to the those with dementia with AD.

Keywords:
Alzheimer disease; sleep initiation and maintenance disorders; cognitive dysfunction

A associação entre Doença de Alzheimer (DA) e distúrbios do sono vem recebendo atenção crescente nas últimas décadas. No entanto, pouco se sabe sobre o impacto do sono e suas alterações no desenvolvimento de estágios pré-clínicos da doença, como é o caso do Comprometimento Cognitivo Leve (CCL). Esta revisão descreve a evolução do conhecimento sobre as relações potencialmente bidirecionais entre DA e distúrbios do sono, explorando grandes estudos prospectivos e meta-análises, assim como estudos dos possíveis mecanismos da associação entre o sono e as doenças neurodegenerativas. Também revisamos amplamente as características do sono de pessoas idosas, incluindo indivíduos cognitivamente normais, com CCL e com demência por DA.

Palavras-chave:
Doença de Alzheimer; distúrbios do início e da manutenção do sono; disfunção cognitiva

Understanding this interaction is of utmost importance because it would increase knowledge about the role of sleep in the development of AD, and about the impact AD has on sleep quality. This could offer cues about how sleep interferes with cognitive and behavioural symptoms of dementia. Additionally, understanding the association between AD and sleep could lead to insights into the pathophysiological mechanisms of AD.

The scientific community has widely discussed sleep disturbances in normal aging. From the late '70s to early '80s, interest in the characteristics of the sleep of patients with dementia started to increase. Studies using polysomnography to compare AD patients in the healthy elderly provided knowledge about sleep-disordered breathing and changes in sleep structure (especially in rapid eye movement [REM] sleep) in AD. The REM sleep behavioral disorder was described late in the 1980s, but its association with Lewy bodies dementia and Parkinson's disease was uncovered only a decade later.

The knowledge in this area has developed impressively, but the direction of the relationship between sleep disturbances and AD remains unknown. Initially, the dominant hypothesis was that the incidence of both disorders increased with age and they merely coexisted. However, since the beginning of the 21 st century, many prospective longitudinal studies have been published, revealing an association of sleep disorders and an increased risk of dementias.

The study of sleep disorders demands the conduction of an arsenal of diagnostic methods. Two types of tools are commonly used: subjective and objective. Among the subjective methods are methods registering behaviour and scales of sleep. The main objective methods are polysomnography and actigraphy.

On the other hand, polysomnography is a more accurate test for diagnosing multiple kinds of sleep disorders (such as sleep-disordered breathing, periodic limb movement syndrome, and REM sleep behavioural disorder) and alterations in sleep structure. However, it is more challenging to perform because of the higher costs and the need to keep the patients in a sleep laboratory overnight. Moreover, polysomnography does not allow the assessment of habitual sleep patterns, mainly in older adults, who have a higher frequency of circadian rhythm changes and daytime naps. In Table 1, we compare the potential differences and advantages of the one subjective and two objective methods.

Studies assessing characteristics of sleep in individuals of many age groups have shown that several sleep changes occur in older adults compared with younger ones. Changes in sleep structure occur and progress as the age advances.

Sleep structure and aging

Polysomnography studies describe a reduction in slow-wave sleep and a compensatory increase in the lighter sleep stages (N1 and N2) in the elderly compared with young and middle-aged people,,,. Figure 1 shows the sleep phases organization with age published by Moraes et al..

Electroencephalographic (EEG) sleep changes

Are sleep impairments part of normal aging?

In patients with non-amnestic MCI, sleep problems are also common. Sleep fragmentation has been associated with memory dysfunction and increased wake time after sleep onset with executive dysfunctions (impairments in attention, response inhibition, concept forming, and problem-solving). Studies assessing sleep architecture revealed that patients with MCI had decreased slow-wave sleep compared with the normal elderly, and increased fragmentation of non-REM sleep. Moreover, borderline changes have been found in REM, wake time after sleep onset, REM latency, and sleep efficiency.

Electroencephalographic studies on AD patients in the 1980s and 1990s provided valuable information about sleep patterns in AD dementia compared with the healthy elderly and neuropsychiatric disorders, such as depression. Sleep disturbances in patients with AD dementia were qualitatively similar to those seen in the healthy elderly. However, the severity of the changes was usually higher, and the REM sleep had specific alterations. Wakefulness commonly increased and, consequently, sleep was more disrupted at night in AD dementia, with an increase in number and duration of awakenings, resulting in a shorter total sleep time and lower sleep efficiency. As a result, a higher percentage of stage 1 and 2 sleep and lower percentage of slow-wave sleep was observed in these patients.

Additionally, AD dementia is related to reductions of specific features of the N2 light sleep stage, such as sleep spindles and K complexes, which become poorly formed, with lower amplitudes and frequencies. These alterations have been reported to worsen with the severity of dementia, and, as the disease progresses, distinguishing N1 and N2 becomes a challenge. Because of this, some authors classify the sleep without distinguishable stages observed in late AD as indeterminate nonEEM,,.

The first studies evaluating sleep structure in AD patients were made without segmentation by severity. However, further studies have also been done characterizing sleep in patients with mild stage AD dementia. Overall, the main change in sleep/wake patterns observed was the marked intrusion of wakefulness into sleep time. In Table 2 we show the sleep characteristics in the healthy elderly, MCI and AD patients.

Despite some early studies in the 20 th century hypothesizing that the sleep disturbances could act as a risk factor to the incidence of dementia, initially, the dominant theory was that both conditions occurred in parallel as aging advanced. This hypothesis changed recently when some prospective cohort studies of incident dementia showed that people with a history of sleep complaints in middle age had an increased risk of developing AD than those without sleep complaints. Moreover, more recently, meta-analyses have confirmed the potential role of poor sleep and sleep disorders as predictors of AD development.

Epidemiological studies

Prospective cohort studies assessing the hypothesis that sleep deterioration and disorders may increase the risk of cognitive impairment and dementia began being published around the year 2000. They provided information on many different aspects of sleep disturbances, and most of them showed an association with the development of dementia. For example, insomnia, excessive daytime sleepiness,, long sleep duration, and short sleep duration,, have been linked to the development of cognitive impairment and/or dementia. Moreover, studies assessing sleep time revealed both short and long sleep times as risk factors, suggesting a U-shaped association between sleep duration and cognitive impairment/dementia,.

Report on systematic reviews and meta-analyses

Biomarkers

Potential mechanisms linking sleep disorders and AD risk

Finally, other negative consequences of disordered sleep have been studied, such as increases in neuronal oxidative stress, impairment in the blood-brain barrier and reduction in the hippocampal neurogenesis. In Figure 2 we show a diagram with the proposed causal mechanisms.

Amyloid plaque formation occurs in various brain areas, including regions that control sleep, which would worsen the sleep disturbances, perpetuating the cycle. Likewise, many behavioural symptoms occur as AD dementia develops, such as changes in lifestyle, less exposure to daylight and use of polypharmacy, also interfering in the sleep quality of the demented individuals. On the other hand, the sleep disturbances impair their cognitive functions directly. Another cause of sleep disorders that could interfere directly in the pathogenesis of AD is sleep-disordered breathing, through hypoxia and inflammatory cascades.

The interface of neurodegenerative disorders and sleep is a topic with increasing relevance. Scientific evidence toward the refinement or stratification of dementia risk among subgroups of the older population, such as those with MCI, requires further investigation of potential predictors that are still under-recognized. Indicators of poor sleep or sleep disorders may play a role in the cascade of AD pathology and, consequently, increase the incidence of dementia among those with higher risk, including people with MCI. Therefore, the study of the sleep-related factors that occur precisely when MCI is established is of the utmost importance to the development of future interventions that could impact the natural history of AD and other neurodegenerative diseases.

³

Reynolds CF 3rd, Kupfer DJ, Taska LS, Hoch CC, Sewitch DE, Restifo K, et al. Sleep apnea in Alzheimer's dementia: correlation with mental deterioration. J Clin Psychiatry. 1985 Jul;46(7):257-61.

³³

Vitiello M V, Prinz PN, Williams DE, Frommlet MS, Ries RK. Sleep disturbances in patients with mild-stage Alzheimer's disease. J Gerontol. 1990;45(4):M131-8.

⁴⁶

Loerbroks A, Debling D, Amelang M, Stürmer T. Nocturnal sleep duration and cognitive impairment in a population-based study of older adults. Int J Geriatr Psychiatry. 2010 Jan;25(1):100-9.

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Alzheimer's disease and sleep disturbances: a review

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ABSTRACT The association between Alzheimer's disease (AD) and sleep disturbances has...

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Brazil has the second highest age-standardized prevalence of Alzheimer's disease worldwide. However, information about Alzheimer's disease-related hospitalizations in Brazil is scarce despite its economic and social impact. We described temporal trends in hospitalizations related to Alzheimer's disease in Brazil from 2010 to 2019. We conducted a time-series, retrospective, descriptive, national-based study using data from the DATASUS database of the Brazilian Ministry of Health. Hospitalizations, mean days hospitalized, and economic costs from those hospitalizations were extracted from 2010 to 2019. Hospitalizations by Alzheimer's disease increased 87.7% from 2010 to 2019, with greater increase among men (97.4%), mixed ethnicity (224%), 80 years or older (115.1%), and in the Northeast (172.1%) and Central West (144.2%) regions. Although mean days hospitalized decreased in all subgroups, an increasing time trend in hospital admission was observed in the Central West Region. Costs per hospitalization increased for patients aged 50 years or younger and in admissions related to emergency services. Compared with other non-communicable chronic diseases, Alzheimer's disease had the highest increase in absolute number and rate of hospitalizations in Brazil from 2010 to 2019. AD is a public health problem in Brazil. Strategies to reduce its burden are necessary but only if accompanied by greater equality and awareness of this disease.

Keywords:
Alzheimer Disease; Hospitalization; Time Series Studies

O Brasil tem a segunda maior prevalência ajustada para idade da doença de Alzheimer no mundo. Entretanto, são escassas as informações sobre internações hospitalares por doença de Alzheimer no Brasil, apesar dos impactos econômicos e sociais da doença. O artigo descreve as tendências temporais nas internações hospitalares relacionadas à doença de Alzheimer no Brasil entre 2010 e 2019. Realizamos um estudo de séries temporais, retrospectivo, descritivo e de base nacional, usando dados DATASUS do Ministério da Saúde. As internações, média de dias de internação e custos econômicos das hospitalizações foram extraídos para os anos de 2010 a 2019. As internações hospitalares por doença de Alzheimer aumentaram em 87,7% entre 2010 e 2019, com os maiores aumentos entre homens (97,4%), pardos (224%), indivíduos com 80 anos ou mais (115,1%) e as regiões Nordeste (172,1%) e Centro-oeste (144,2%). Embora as médias de dias de internação tenham diminuído em todos os subgrupos, foi observada uma tendência temporal crescente nas internações na Região Centro-oeste. O custo por hospitalização aumentou para pacientes de 50 anos ou menos e nas internações relacionadas aos serviços de emergência. Em comparação às outras doenças crônicas não transmissíveis, a doença de Alzheimer mostrou o maior aumento no número absoluto e taxa de internações hospitalares no Brasil entre 2010 e 2019. A doença de Alzheimer é um problema de saúde pública no Brasil. São necessárias estratégias para reduzir a carga da doença, porém só serão eficazes se forem acompanhadas por maior igualdade e conscientização em relação a essa doença.

Palavras-chave:
Doença de Alzheimer; Hospitalização; Estudos de Séries Temporais

Brasil cuenta con la segunda prevalencia más alta por edad estandarizada de enfermedad de Alzheimer en todo el mundo. No obstante, la información sobre las hospitalizaciones relacionadas con la enfermedad de Alzheimer en Brasil es escasa, pese a su impacto económico y social. Describimos las tendencias temporales en hospitalizaciones relacionadas con la enfermedad de Alzheimer en Brasil, desde 2010 a 2019. Realizamos un estudio de series temporales, retrospectivo, descriptivo, de base nacional, usando datos procedentes del DATASUS del Ministerio de Salud de Brasil. Las hospitalizaciones, la media de días hospitalizados, y los costes económicos de estas hospitalizaciones se extrajeron desde 2010 a 2019. Las hospitalizaciones por enfermedad de Alzheimer se incrementaron un 87,7%, desde 2010 a 2019, con un incremento más grande entre hombres (97,4%), origen étnico mixto (224%), 80 años o mayores (115,1%), y en las regiones del Nordeste (172,1%) y Centro-oeste (144,2%). A pesar de que la media de días hospitalizados decreció en todos los subgrupos, se observó una tendencia creciente en el tiempo respecto a las admisiones hospitalarias en la Región del Centro-oeste. El coste económico por hospitalización se incrementó en el caso de pacientes con 50 años o más jóvenes en las admisiones relacionadas con los servicios de emergencia. Comparado con otras enfermedades crónicas no transmisibles, la enfermedad de Alzheimer tuvo el incremento más alto en el número absoluto y tasa de hospitalizaciones en Brasil desde 2010 a 2019. La enfermedad de Alzheimer es un problema de salud público en Brasil. Las estrategias para reducir su carga son necesarias pero solamente si están acompañadas de una mayor equidad y concienciación sobre esta enfermedad.

Palabras-clave:
Enfermedad de Alzheimer; Hospitalización; Estudios de Series Temporales

According to the Scientific Department for Cognitive Neurology and Aging of the Brazilian Academy of Neurology , the diagnosis of Alzheimer's disease occurs when cognitive or behavioral symptoms affects at least two of the following domains: memory, executive functions, visual and spatial skills, language, and personality or behavior. Usually together with loss of functional capacity, these problems increased the frequency of hospitalizations in Alzheimer's disease patients ,,. This is particularly concerning since these patients may have an irreversible cognitive and functional decline during hospitalization .

Although information about hospitalization due to ischemic heart disease , overweight, and obesity is available, the information concerning Alzheimer's disease-related hospitalizations in Brazil is scarce despite its economic and social impact ,,. As such, this study describes the trend of number, duration, and economic cost from hospitalizations related to Alzheimer's disease in Brazil from 2010 to 2019.

For this time-series, retrospective, descriptive study, we collected data from Brazilian Informatics Department of SUS (DATASUS. http://www.datasus.gov.br). We extracted the number of hospital admissions, total days hospitalized, and total costs of hospitalizations from 2010 to 2019, which was the latest year with available data.

Total hospitalizations were considered as any new authorized hospitalization form, transferences, and re-hospitalization related to Alzheimer's disease. To account for population size and growth, we divided the number of hospital admissions by the total population size. For stratified analysis, we divided the number of hospitalizations by the population size in each subgroup (i.e., sex, age group, ethnicity, and region) for each year. The number of inhabitants was obtained using the 2010 National Census (Instituto Brasileiro de Geografia e Estatística. http://www.ibge.gov.br) and the Continuous Brazilian National Household Survey (PNAD Contínua, in Portuguese. https://www.ibge.gov.br/en/statistics/social/labor/16833-monthly-dissemination-pnadc1.html?=&t=o-que-e, accessed on 10/Mar/2020).

Mean days hospitalized was calculated by dividing the total in-hospital days of all hospitalizations by the number of hospital admissions during the 10-year period. Hospitalization duration was calculated based on admission and discharge. For example, if the patient was admitted on January 15st and discharged on January 18th, that would be a 3-days hospitalization.

Total costs was considered as the value referred to all hospitalizations during a specific period. Values from each year were adjusted to the inflation rate based on the Extended National Consumer Price Index (IPCA) (Banco Central do Brasil. Correção de valores. https://www3.bcb.gov.br/CALCIDADAO/publico/exibirFormCorrecaoValores.do?method=exibirFormCorrecaoValores&aba=1, accessed on 13/Oct/2020), enabling direct comparison among the years.

The cause of hospitalizations was informed as the main diagnosis, defined as what caused the hospitalization. For Alzheimer's disease, we considered all hospitalizations from which the main diagnose were Alzheimer's Disease defined as G30.0 to G30.9 according to the International Classification of Disease, 10th revision (ICD-10) .

We also stratified these outcomes by sex (male/female), age groups based on birth and admission days (less than 50, 50-59, 60-69, 70-79, 80 or older), ethnicity (white, black, mixed, yellow, and indigenous), type of admission (emergency or elective), and region (South, Southeast, North, Northeast, and Central West). After data collection, we calculated the percent changes in our outcomes from 2010 to 2015 and then from 2015 to 2019. Values from Asian and indigenous people were not shown due to missing data in most of the years for all outcomes.

Total hospitalizations, rate of hospitalization, mean days hospitalized, and absolute and relative costs from these hospitalizations were also collected from DATASUS for hospitalizations due to ischemic heart disease (ICD-10: I20-I25), cerebrovascular disease (ICD-10: I60-I69), diabetes mellitus (E10-E14), and chronic obstructive pulmonary disease (J40-J44), that were the first, second, fifth, and seventh leading causes of death in Brazil in 2017, and with Alzheimer's disease they were the top-5 non-communicable chronic diseases that served as cause of death (Departamento de Análise em Saúde e Vigilância das Doenças Não Transmissíveis, Secretaria de Vigilância em Saúde. Principais causas de morte. http://svs.aids.gov.br/dantps/centrais-de-conteudos/paineis-de-monitoramento/mortalidade/gbd-brasil/principais-causas/, accessed on 16/Oct/2020). We used those data to compare changes of our outcomes from 2010 to 2019 among these diseases. After importing into Stata 13.1 ( https://www.stata.com), data was reported in absolute and relative values, and changes were described in percent.

To test time trend in number, duration, and cost of hospitalizations due to Alzheimer's disease from 2010 to 2019 in Brazil, the Prais-Winsten regression method was used, with Corchrane-Orcutt transformation and search for rho to minimize the sum-of-squared errors of the transformed equation. This test corrects the first-order autocorrelation effect and quantifies the annual variation in number, rate (per 100,000 inhabitants), duration (days), and cost (BRL) of hospitalization due to Alzheimer's disease in Brazil throughout that period . Regression coefficients classified time trend as increased or decreased if p < 0.05 and coefficient higher or lower than 0, respectively. If p > 0.05, trend was classified as stationary. Since public data were available in DATASUS and in Brazilian Institute of Geography ansd Statistics (IBGE, in Portuguese) website, approval by the Ethics Research Committee was not needed.

We observed an increase of 87.7% in hospitalizations due to Alzheimer's disease in Brazil from 2010 to 2019 ( Table 1). This increase was even greater among men (97.4%), mixed ethnicity (224%), those aged 80 years or older (115.1%), and in Northeast (172.1%), Central West (144.2%), and Southeast (91.6%) regions of Brazil. Further, the time trend of the number of hospital admissions during that 10-year period did not achieve statistical significance only in patients aged 50 years or younger (p = 0.105), admitted as elective (p = 0.099), and in the Southeast (p = 0.057) and North (p = 0.097) regions.

Even though there was a decrease in hospitalizations due to Alzheimer's disease among black individuals from 2010 to 2015 (-20.4%), this ethnicity was more hospitalized from 2015 to 2019 (105.1%). On the other hand, women, subjects aged 79 or less, admission on hospital by elective, and patients from the Southeast and North regions had an increase in hospitalizations from 2010 to 2015, followed by decrease from 2015 to 2019.

Furthermore, Table 2 summarizes the hospitalization rate attributable to Alzheimer's disease from 2010 to 2019 in Brazil. Our findings showed that, in this 10-year period, the hospitalization rate increased 75.3% in the country, with higher values in patients self-declared white (76.7%) and mixed ethnicity (192.8%), from Southeast (91.6%), Central West (119.2%), and Northeast (158.9%). Nevertheless, only patients aged 50 years or younger presented a decrease in this indicator (-43.6%).

We also revealed an increasing trend in the rate of hospitalizations per 100,000 inhabitants from 2010 to 2019 in Brazil (0.04; 95%CI: 0.01; 0.08) and in the South (0.03; 95%CI: 0.03; 0.05), Northeast (0.03; 95%CI: 0.02; 0.04), and Central West (0.07; 95%CI: 0.05; 0.09) regions. This trend was also identified in all sex and ethnic groups. On the other hand, no trend in hospitalization rate was identified by different age groups.

Table 3 summarizes the trend in mean duration of hospitalizations. Our findings revealed a reduction in mean days hospitalized from 2010 to 2019 in all groups, with remarkable changes in patients aged between 60 and 69 years old (54.8%), mixed ethnicity (64.5%), patients in the Northeast Region (67.7%) and aged 50 or younger (71.2%). Nevertheless, in patients aged 50 and 59 years old the mean duration of hospital admissions raised by 26.7% between 2015 and 2019.

Likewise, mean days hospitalized have been decreasing annually among white (4.3; 95%CI: -8.02; -0.65) and mixed ethnicity patients (2.54; 95%CI: -3.47; -1.60). Significant annual changes were also observed in patients aged 60-69 (-5.40; 95%CI: -8.12; -2.68) and 80 or older (-1.61; 95%CI: -2.63; -0.59) and were independent of type of admission. While four of five regions revealed briefer hospital stays during the 10-year period, only the Central West Region indicates an increasing trend in days hospitalized per year (0.75; 95%CI: 0.30; 1.19).

The economic cost from hospitalizations due to Alzheimer's disease in Brazil increased 41.6% from 2010 to 2019, as shown in Table 4. In hospitalizations whose patients were from the South Region (43%), men (51.9%), aged 80 years or older (87.3%), admitted by emergency services (98.9%), and from the Central West Region (793.4%), the increase was higher than the average.

Furthermore, black people had a decrease in service costs at the hospital (-9.6%) from 2010 to 2015. Nevertheless, between 2015 and 2019, these values increased by 31.8%. A similar pattern was observed from patients younger than 50 years where the values increased by 69.6% between 2015 to 2019.

The variation coefficient indicates the cost from hospitalizations due to Alzheimer's disease increased annually from 2010 to 2019 among women (BRL 65.99; 95%CI: 11.30; 1220.68), black (BRL 23.09; 95%CI: 13.29; 32.90) and mixed (BRL 20.22; 95%CI: 5.13; 35.32) ethnic groups, patients aged between 70 and 79 years (BRL 35.79; 95%CI: 12.81; 58.76), and in emergency-related hospital admissions (BRL 122.74; 95%CI: 97.08; 148.41). Likewise, while costs from those hospital services increased annually in the North (BRL 1.56; 95%CI: 0.29; 2.82) and Central West regions (BRL 12.02; 95%CI: 6.51; 17.53), it decreased in elective admission (BRL -722,29; 95%CI: -1,190.40; -240,18).

Moreover, Supplementary Material ( http://cadernos.ensp.fiocruz.br/static//arquivo/suppl-e000733-20_7798.pdf) describes the mean cost per hospital admission by Alzheimer's disease in Brazil from 2010 to 2019. In contrast with the absolute values, the mean cost of these hospitalizations had a decreasing trend from 2009 to 2019 in women (BRL -93,02; 95%CI: -156.91; -29.12) and mixed ethnicity people (BRL -170,11; 95%CI: -250.81; -89.41). Also, only patients aged 50 or younger (BRL 214.19; 95%CI: 46.40; 381.98) presented increasing annual variation in this indicator. The highest decreasing trend was observed in patients admitted by elective services (BRL -1,004.42; 95%CI: -1,613.69; -395.14), followed by those aged 60 to 69 years (BRL -335.93; 95%CI: -543.64; -128.21), and those living in the Southeast Region (BRL -272.87; 95%CI: -421.59; -124.15).

Compared to the top-5 non-communicable chronic diseases that serve as cause of death in Brazil, Alzheimer's disease showed the highest and third-highest increase in disease-related hospitalization rate per 100,000 inhabitants ( Figure 1a; 75%) and total costs from hospitalizations ( Figure 1c; 42%), respectively. On the other hand, the greatest reduction in mean days hospitalized and costs per admission were from patients with Alzheimer's disease ( Figure 1b; 41%; Figure 1 d; 25%).

This was the first national-based, time-series study that described hospital admissions from Alzheimer's disease in Brazil. We reported that total (87.7%) and rate (75.3%) of hospitalizations and total cost from hospitalization (41.6%) due to Alzheimer's disease increased from 2010 to 2019 in Brazil, indicating an increase in hospitalizations over this 10-year interval in Brazil. On the other hand, mean days hospitalized (-37%) and costs per hospitalization (-24.5%) decreased during the same period.

Although 66% of all hospitalization from Alzheimer's disease in 2019 were among females, the increase in hospital admission rate was higher in men (84.2%) than women (71.9%). Also, the annual variation coefficient indicates a time trend of increase in the absolute number and rate of hospitalization in both sexes from 2010 to 2019. In Brazil, prevalence and morbidity attributable to Alzheimer's disease and other dementia were, respectively, 69% and 68% higher among women in 2017 (Institute for Health Metrics and Evaluation. GBD results tool. http://ghdx.healthdata.org/gbd-results-tool%20, accessed on Oct/2020). On the other hand, women tend to present longer survival time but more affective symptoms and disability , while men reported more comorbidity, decline in behavior control, and higher mortality rates , which may led to an increasing need of hospital admissions.

Regarding ethnicity, white subjects accounted for 66.1% of hospitalizations due to Alzheimer's disease in 2019 at Brazil. Moreover, this ethnic group had a hospitalization rate 2.2 and 2.7 times higher than black and mixed ethnicity patients, respectively. However, we observed an increase of about 105.1% and 208.6% of hospitalization in black subjects from 2015 to 2019 and in mixed ethnicity from 2010 to 2019. This relative change was corroborated by the positive and significant annual percentage change in those ethnic groups. Husaini et al. reported that besides a gender disparity in prevalence of dementia, there is also an ethnic disparity, with higher prevalence among black women and men compared to whites. According to the IBGE , the self-declared black population increased 7.4% from 2012 to 2015, and 23.1% from 2015 to 2018, and mixed ethnicity became the most prevalent ethnicity in Brazil (46.5%).

The Brazilian population is ageing. From 2000 to 2050, the prevalence of people living with at least 60 years will increase by 280% . The most important risk factor for Alzheimer's disease is age, with the prevalence of the disease doubling every 5 years after age 65 . This fact could explain the 115.1% increase in hospitalization for patients aged 80 or older. Although the youngest age group (< 50 years-old) had a decrescent trend from 2010 to 2019 in hospitalization rate, the mean economic cost changed in the opposite direction. Early-onset Alzheimer's disease included cases of Alzheimer's disease onset before age 65 and is associated in most cases with genetic mutations ,. People with this condition are more likely to present more brain changes related to Alzheimer's disease ,, which could be associated with the increased cost per admission. Although it is estimated to represent about 5% of all Alzheimer's disease cases in the world , no data about the prevalence of this type of Alzheimer's disease in the Brazilian population is available . Early-onset Alzheimer's disease is poorly understood, underdiagnosed, and inadequately treated, leading to underestimation of the impact of this condition on the healthcare system ,. Future population-based studies that aim to describe the people with Alzheimer's disease and its sub-types in Brazil are encouraged.

The prevalence of Alzheimer's disease and other dementia in 2017 were higher in subjects aged from 60 to 74 years old in Brazil compared to United States, Canada, and Australia (Institute for Health Metrics and Evaluation. GBD results tool. http://ghdx.healthdata.org/gbd-results-tool%20, accessed on Oct/2020), which could be related to earlier onset of disease in most prevalent ethnicities . Also, the country has made progress in the public health agenda concerning dementia control, especially in providing high cost medication free of charge for patients with dementia . However, the difficult diagnosis for Alzheimer's disease and related disorders may lead to longer hospital stays and more screenings to possible diagnoses. Then, more training and resources for diagnosis of dementia, better long-term management provide by health professionals, and improved knowledge about risk factors for dementia and how to control them need to be done to reduce the hospital-related burden of Alzheimer in all age groups .

Our findings indicate an annual rise in hospitalization rate from 2010 to 2019 in the South, Northeast, Central West, and Southeast regions. Regarding hospitalization duration, we observed an annual reduction in four of the five Brazilian regions, with the only crescent trend being observed in the Central West Region. Similarly, the morbidity associated with Alzheimer's disease increased by 153% from 2010 to 2019 in Central West Region while it decreased by 6% in the Southeast in the same period (Institute for Health Metrics and Evaluation. GBD results tool. http://ghdx.healthdata.org/gbd-results-tool%20, accessed on Oct/2020). Indeed, older population in the Central West Region increased 42% from 2010 to 2017 primarily due to migration of people from other Brazilian regions . Together, those facts may explain the change of hospitalizations due to Alzheimer's disease in those regions.

From 2010 to 2019, Alzheimer's disease had the highest increase in number and rate of hospitalizations among the top-5 causes of death by non-communicable disease in Brazil. For example, the observed increase in hospitalization per 100,00 inhabitants attributable to Alzheimer's disease was 330% and 263% higher than for cerebrovascular and ischemic heart diseases, respectively. Based on annual rate change, we projected that in 2050, more people will be hospitalized in Brazil due to Alzheimer's disease than chronic obstructive pulmonary disease. At Central West and Northeast regions, Alzheimer's disease will overcome diabetes in number of hospital admissions in 2048 and 2035, respectively.

Similarly, the growth in costs of Alzheimer's disease in hospital settings from 2010 to 2019 was 785% higher than chronic obstructive pulmonary disease and 53% higher than diabetes mellitus. Although mortality rate by Alzheimer's disease decreased from 19.1 to 13.7 between 2010 to 2015, it increased throughout the following years by up to 24.2 in 2019, the highest increase in mortality rate from 2015 to 2019 (DATASUS. http://www.datasus.gov.br). That made Alzheimer's disease the disease with the third-highest all-cause mortality rate in Brazil in 2019 (24.1%), followed by septicemia (44.7%) and malignant neoplasia in the trachea, lungs, and bronchus (26.8%). In the United States, the percentage of death by Alzheimer's disease increased by 145% from 2000 to 2017 , killing more than breast and prostate cancer combined .

The main limitation of this study is its descriptive design. Nevertheless, this type of investigation is relevant in Brazil as it led to a broader view of the current situation of Alzheimer's disease in Brazil. This is the first time-series national-based study that descripted total number of hospitalizations, hospitalized days and the related costs attributable to Alzheimer's disease in Brazil. The prevalence of this disease will triple by 2050 , affecting more than 3 million people, and only 1 in 4 cases of dementia are diagnosed . As a result, public health policies, such as high-cost medication available free-of-charge, have been delineated to reduce the burden of Alzheimer's disease in the country. Nevertheless, much more needs to be done. Alzheimer's disease in underdiagnosed, undertreated, and much of these come from under-recognition and undermanagement .

In conclusion, Alzheimer's disease is already a public health problem in Brazil. The number, duration, and the costs of hospitalizations due to this disease increased more than other top-5 causes of death by non-communicable chronic diseases from 2010 to 2019. Strategies to reduce the burden of Alzheimer's disease in Brazil are necessary but only if followed by greater equality and awareness of this disease.

This study was funded in part by the Brazilian Graduate Studies Coordinationg Board (CAPES).

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# data[].attributes.attachment_link.title
Ten-year trends in hospitalizations due to Alzheimer's disease in Brazil: a national-based study

# data[].attributes.attachment_link.description
Abstract: Brazil has the second highest age-standardized prevalence of Alzheimer's disease...