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Delirium é uma síndrome neurocomportamental decorrente da quebra transitória da homeostase cerebral. Deve-se, invariavelmente, a perturbações sistêmicas ou do sistema nervoso central. No contexto médico geral, a ocorrência de delirium está associada à maior incidência de complicações clínico-cirúrgicas, maior tempo de permanência hospitalar e pior recuperação funcional. O envelhecimento e o comprometimento cognitivo são fatores de risco conhecidos para o delirium. Em pacientes idosos, a ocorrência aumenta o reconhecimento de quadros demenciais preexistentes. Em contrapartida, indivíduos idosos não-demenciados que desenvolvem um episódio de delirium durante uma dada internação hospitalar têm incidência aumentada de demência na evolução em longo prazo. Estudos prospectivos e controlados demonstraram uma associação significativa entre o diagnóstico prévio de delirium e o ulterior desenvolvimento de síndromes demenciais. Essa associação parece ser ainda maior em indivíduos muito idosos. O presente estudo de revisão aborda criticamente a natureza da associação entre delirium e demência. Hipotetiza-se que a sua ocorrência em indivíduos idosos cognitivamente preservados é fator preditivo de deterioração cognitiva, e de risco aumentado para o desenvolvimento de demência, no seguimento de longo termo. As bases neurobiológicas da associação entre delirium e demência são discutidas à luz da hipótese colinérgica da doença de Alzheimer, uma vez que o comprometimento da neurotransmissão colinérgica é denominador comum a essas duas perturbações neuropsíquicas.Delirium is a neurobehavioral syndrome caused by the transient disruption of cerebral homeostasis, which is invariably subsequent to systemic or central nervous system insults. In general medical settings, the occurrence of delirium is also associated with a higher incidence of post-operative complications, longer hospital stays, and poor functional recovery. Ageing and cognitive decline are known risk factors for the occurrence of delirium. In elderly patients, delirium has been shown to be associated with pre-existing dementia. Conversely, non-demented elderly subjects who develop a new delirium episode display an increased incidence of dementia in the long-term outcome. Prospective case-control studies have demonstrated a significant association between the previous diagnosis of delirium and the development of dementia. The association between delirium and dementia may be even higher among the eldest elderly. After reviewing the relevant literature on the association between delirium and dementia, we hypothesize that the occurrence of delirium in non-demented elderly individuals is predictive of a worse cognitive outcome, and increased risk of dementia, in the long-term follow-up. We further discuss the biological nature of this association in the light of the cholinergic deficit observed in the pathophysiology of both delirium and Alzheimer's disease.

O presente artigo de revisão aborda as perspectivas atuais e futuras no tratamento farmacológico da doença de Alzheimer. Os benefícios e limitações da terapia de reposição colinérgica, representada fundamentalmente pelos inibidores das colinesterases, são apresentados com base em dados de pesquisas neurobiológicas, farmacológicas e clínicas, ilustrados pelos principais estudos controlados por placebo e por estudos recentes de metanálise. O papel da memantina nos casos de demência moderada a grave, bem como as perspectivas de seu emprego em associação com os inibidores das colinesterases, são discutidos adicionalmente com base em achados clínicos e neurobiológicos. Discute-se o papel da reposição estrogênica, dos antioxidantes, das estatinas e dos antiinflamatórios no tratamento e na prevenção da demência, levando em consideração os resultados negativos oriundos de estudos clínico-epidemiológicos recentes. Finalmente, são apresentadas algumas perspectivas futuras do tratamento da doença de Alzheimer: entre as estratégias farmacológicas, que têm como objetivo modificar mecanismos patogênicos, são abordadas as diferentes modalidades da terapêutica antiamilóide, com destaque na imunoterapia da doença de Alzheimer.The current article provides a comprehensive overview of the current strategies and the future directions of the pharmacological treatment of Alzheimer's disease. The benefits and shortcomings of cholinergic replacement therapy is discussed in the light of its neurobiological, pharmacological and clinical data, illustrated by the most relevant randomised controlled trials and recent meta-analytical studies. The role of memantine in moderate to severe dementia, and the perspectives of combination therapy are further discussed both at clinical and neuro-pharmacological levels. In addition, the role of oestrogen replacement, antioxidants, statins, and non-steroidal anti-inflammatory drugs, in the management and prevention of dementia is discussed, considering the negative results of recent controlled trials. The last segment of this review explores the treatment approaches into the molecular pathogenesis of dementia, focusing on disease-modifying candidate therapies such as anti-amyloid strategies and the immunotherapy of Alzheimer's disease.

O delirium corresponde a uma das primeiras doenças mentais descritas na literatura médica, há mais de 2.500 anos. Nas classificações psiquiátricas, permaneceu como categoria nosológica independente até o final do século XIX, quando foi redefinida com base nos seus aspectos fenomenológicos e etiológicos, precipitando a reclassificação das insanidades funcionais em psicoses. os estados confusionais passaram a se referir a uma síndrome mais ampla que incluía o delirium, enfatizando a desorganização dos processos cognitivos e do pensamento, e tendo no turvamento da consciência e na desorientação temporoespacial a condição de base. Com o objetivo de descrever a evolução histórica do conceito de delirium, foram realizados levantamentos da literatura médica através do sistema Medline, além da pesquisa em publicações literárias específicas sobre os temas história da medicina e história da psiquiatria. Partiu-se de algumas observações dogmáticas praticadas na Antigüidade e Idade Média, para atingir as definições e práticas atuais, oferecendo uma análise crítica dos critérios diagnósticos vigentes (DSM-III, DSM-IIIR, DSM-IV e CID-10). Não obstante a evolução conceitual, o delirium continua sendo mal compreendido, do ponto de vista fisiopatológico e são poucas as opções terapêuticas. o diagnóstico de delirium é ato eminentemente clínico: baseia-se na observação cautelosa das manifestações psíquicas e comportamentais dos pacientes acometidos, além da análise dos fatores predisponentes e precipitantes. É freqüente o seu subdiagnóstico em contextos clínicos e cirúrgicos. o diagnóstico do delirium é estabelecido em apenas 30% a 50% dos pacientes, sendo a omissão diagnóstica menos freqüente em serviços que contam com a interconsulta psiquiátrica. o delirium é uma das complicações mais comuns entre pacientes idosos hospitalizados e está associado a maior morbimortalidade. Isso sustenta a importância do seu pronto reconhecimento e manejo.Delirium remained a stable psychiatric category until the early 19th century when it underwent etiological and phenomenological redefinition, precipitating the transformation of the functional insanities into psychoses. Confusion, introduced by French workers during the second half of the century, referred to a syndrome wider than (but including) delirium. It emphasized chaotic thinking and cognitive failure. The notion of clouding of consciousness (and temporo-spatial disorientation) established a common denominator for the two concepts, while Chaslin and Bonhoeffer redefined confusion and delirium as the stereotyped manifestations of acute brain failure.

Reduced phospholipase A₂ (PLA₂) activity has been reported in the brain and in blood cells of patients with Alzheimer's disease (AD). Individuals with mild cognitive impairment (MCI) are at increased risk of developing AD. In the present study, we determined the activity of distinct PLA₂ subgroups (iPLA₂, sPLA₂ and cPLA₂) in older adults with MCI as compared to patients with mild dementia due to AD and to cognitively healthy controls. We investigated whether decreased PLA₂ activity at baseline is associated with the progression of MCI to AD upon follow-up during a period of 4 years. The activity of PLA₂ subgroups was determined in platelets from 169 elderly adults. Progression of MCI to AD was ascertained by standard clinical criteria for AD upon follow-up. At baseline, iPLA₂ activity was significantly decreased (p = 0.001) in patients with AD and MCI as compared to controls. Patients with MCI who progressed to AD during follow-up showed significantly lower iPLA₂ activity at baseline as compared to patients with MCI who did not progress to AD (p = 0.009). Moreover, subjects from the control group at baseline who progressed to MCI during follow-up had lower sPLA₂ and cPLA₂ (p = 0.014 and p = 0.009, respectively). Our findings suggest that low platelet iPLA₂ activity may be a risk marker for AD in subjects with MCI. Moreover, low sPLA₂ and cPLA₂ were related to cognitive decline in healthy controls, suggesting a relationship with the very early stages of the disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease with well-defined pathophysiological mechanisms, mostly affecting medial temporal lobe and associative neocortical structures. Neuritic plaques and neurofibrillary tangles represent the pathological hallmarks of AD, and are respectively related to the accumulation of the amyloid-beta peptide (Aβ) in brain tissues, and to cytoskeletal changes that arise from the hyperphosphorylation of microtubule-associated Tau protein in neurons. According to the amyloid hypothesis of AD, the overproduction of Aβ is a consequence of the disruption of homeostatic processes that regulate the proteolytic cleavage of the amyloid precursor protein (APP). Genetic, age-related and environmental factors contribute to a metabolic shift favoring the amyloidogenic processing of APP in detriment of the physiological, secretory pathway. Aβ peptides are generated by the successive cleavage of APP by beta-secretase (BACE-1) and gamma-secretase, which has been recently characterized as part of the presenilin complex. Among several beta-amyloid isoforms that bear subtle differences depending on the number of C-terminal amino acids, Aβ (1-42) plays a pivotal role in the pathogenesis of AD. The neurotoxic potential of the Aβ peptide results from its biochemical properties that favor aggregation into insoluble oligomers and protofibrils. These further originate fibrillary Aβ species that accumulate into senile and neuritic plaques. These processes, along with a reduction of Aβ clearance from the brain, leads to the extracellular accumulation of Aβ, and the subsequent activation of neurotoxic cascades that ultimately lead to cytoskeletal changes, neuronal dysfunction and cellular death. Intracerebral amyloidosis develops in AD patients in an age-dependent manner, but recent evidence indicate that it may be observed in some subjects as early as in the third or fourth decades of life, with increasing magnitude in late middle age, and highest estimates in old age. According to recent propositions, three clinical phases of Alzheimer's disease may be defined: (i) pre-symptomatic (or pre-clinical) AD, which may last for several years or decades until the overproduction and accumulation of Aβ in the brain reaches a critical level that triggers the amyloid cascade; (ii) pre-dementia phase of AD (compatible with the definition of progressive, amnestic mild cognitive impairment), in which early-stage pathology is present, ranging from mild neuronal dystrophy to early-stage Braak pathology, and may last for several years according to individual resilience and brain reserve; (iii) clinically defined dementia phase of AD, in which cognitive and functional impairment is severe enough to surmount the dementia threshold; at this stage there is significant accumulation of neuritic plaques and neurofibrillary tangles in affected brain areas, bearing relationship with the magnitude of global impairment. New technologies based on structural and functional neuroimaging, and on the biochemical analysis of cerebrospinal fluid may depict correlates of intracerebral amyloidosis in individuals with mild, pre-dementia symptoms. These methods are commonly referred to as AD-related biomarkers, and the combination of clinical and biological information yields good diagnostic accuracy to identify individuals at high risk of AD. In other words, the characterization of pathogenic Aβ by means of biochemical analysis of biological fluids or by molecular neuroimaging are presented as diagnostic tools to help identify AD cases at the earliest stages of the disease process. The relevance of this early diagnosis of AD relies on the hypothesis that pharmacological interventions with disease-modifying compounds are more likely to produce clinically relevant benefits if started early enough in the continuum towards dementia. Therapies targeting the modification of amyloid-related cascades may be viewed as promising strategies to attenuate or even to prevent dementia. Therefore, the cumulative knowledge on the pathogenesis of AD derived from basic science models will hopefully be translated into clinical practice in the forthcoming years.

The Montreal Cognitive Assessment (MoCA) is a brief cognitive schedule that has been developed for the screening of patients with Mild Cognitive Impairment (MCI). MCI is recognized as a high-risk state for Alzheimer's disease. The aim of the present study is to examine the reliability and validity of the Brazilian version of the MoCA test (MoCA-BR) in a sample of older individuals with at least 4 years of education.The MoCA-BR was administered to 112 older adults who were classified into three diagnostic groups according to their cognitive state (Alzheimer's disease, n = 28; MCI, n = 43; normal controls, n = 41). This procedure was based on clinical and neuropsychological data. The performance in the MoCA-BR was compared with the Mini-mental state examination (MMSE) and the Cambridge Cognitive Examination. Diagnostic accuracy was examined with the receiver operating characteristic (ROC) curve analyses.Cronbach's alpha for the MoCA-BR was 0.75. Temporal stability (retesting after 3 months) using intraclass correlation coefficient was 0.75 (p0.001). The sensitivity and specificity of the MoCA-BR for MCI were 81% and 77%, respectively, with a cut-off score of 25 points. The area under the ROC curve for predicting MCI was 0.82 ± 0.06.The present results indicate that the MoCA-BR maintains its core diagnostic properties rendering it a valid and reliable tool for the screening of MCI among older individuals with at least 4 years of education.

The present recommendations and suggestions on "Treatment of Alzheimer's Disease" were elaborated by a work group constituted by participants of the IV Meeting of Researchers on Alzheimer's Disease and Related Disorders, sponsored by the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology. They comprise topics on pharmacological and non-pharmacological treatment of cognitive impairment and functional decline, as well as of behavioral and psychological symptoms of this dementing disease. Several levels of evidence and of recommendations and suggestions are used for the various proposed drugs, as well as for non-pharmacological treatment, underpinned by a wide national and international bibliographical review.