Systemic inflammation and Alzheimer's disease biomarkers

Orientador: Marcio Luiz Figueredo BalthazarDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: A demência na doença de Alzheimer (DA) é um grave problema de saúde pública que tende a se intensificar devido, sobretudo, ao envelhecimento da população. Quanto aos aspectos clínicos da doença, o primeiro sintoma geralmente observado é a dificuldade em armazenar informações novas, afetando principalmente a memória episódica, à medida que a doença progride, outras funções cognitivas também são afetadas. A fisiopatologia da DA é caracterizada por uma série de alterações neuropatológicas que incluem: placas senis que contêm em excesso depósitos extracelulares de peptídeo ß-amiloide (ßA) e emaranhados neurofibrilares intracelulares que contêm proteína Tau hiperfosforilada (p-Tau), levando a uma maciça perda sináptica, morte neuronal e alterações funcionais em redes neurais, como na Default Mode Network (DMN). A conectividade funcional (CF) da DMN é alterada na DA devido ao acumulo de ßA em suas regiões, contribuindo para severidade dos sintomas cognitivos e clínicos. Alterações estruturais como atrofia cerebral, principalmente atrofia do hipocampo, também são observadas na doença. Há crescente evidência de que a inflamação sistêmica, através de mediadores inflamatórios, como por exemplo, as citocinas, desempenha um papel importante na produção e regulação dessas proteínas (ßA e Tau) presentes no líquido cefalorraquidiano (LCR). Existem vias de comunicação entre o cérebro e o sistema imune periférico que podem estar alteradas desde da fase pré-demencial, favorecendo ou não a progressão da doença, decorrente disso a inflamação sistêmica também tem sido associada com a cognição e morfologia cerebral. Nosso objetivo principal foi verificar a hipótese se a inflamação sistêmica pode ser associada com os principais biomarcadores da DA (proteínas do LCR e neuroimagem). Para isso, adquirimos imagens de ressonância magnética em 3T de 25 controles saudáveis, 45 pacientes com Comprometimento Cognitivo Leve amnéstico (CCLa) e 28 pacientes com DA leve. Observamos que os pacientes com CCLa nos quais detectamos IL-12, TNF-'alfa' e IL-6 apresentaram aumento da CF das regiões da DMN; os pacientes do grupo DA nos quais detectamos IL-12, IL-6, IL-10 e TNF-'alfa' apresentaram maior volume do hipocampo, menos ßA1-42 e diminuição na CF da DMN. Nossos resultados podem indicar uma possível relação entre o perfil de inflamação sistêmica e os biomarcadores da DAAbstract: Dementia in Alzheimer's disease (AD) is a serious public health problem that tends to intensify, mainly due to the aging of the population. Regarding the clinical aspects of the disease, the first symptom usually observed is the difficulty in storing new information, affecting episodic memory, as the disease progresses, other cognitive functions are affected. The pathophysiology of AD is characterized by a series of neuropathological changes that include: senile plaques that contain excess extracellular deposits ß-amyloid peptide (Aß) and intracellular neurofibrillary tangles that contain hyperphosphorylated Tau protein (p-Tau), leading to a massive neuronal death, and functional abnormalities in neural network, such as in the Default Mode Network (DMN). The functional connectivity (FC) of DMN is altered in AD due to the accumulation of Aß in its regions, contributing to the severity of cognitive and clinical symptoms. Structural changes such as brain atrophy, especially hippocampal atrophy, are also seen in the disease. There is increasing evidence that systemic inflammation, through inflammatory mediators, such as cytokines, plays an important role in the production and regulation of these proteins (ßA and Tau) present in cerebrospinal fluid (CSF). There are pathways of communication between the brain and the peripheral immune system that may be altered from the pre-dementia phase, favoring or not the progression of the disease, as a result of which systemic inflammation has also been associated with cerebral cognition and morphology. Our main objective was to verify the hypothesis that sistemic inflammation may be associated with the main biomarkers of AD (CSF proteins and neuroimaging). For this, we acquired magnetic resonance imaging in 3T of 25 healthy controls, 45 amnestic Mild Cognitive Impairment (aMCI) and 28 patients with mild AD. We observed that patients with aMCI in whom we detected IL-12, TNF-'alpha' and IL-6 showed increased FC of the regions of the DMN; the patients in the mild AD group in which we detected IL-12, IL-6, IL-10 and TNF-'alpha' had higher hippocampal volume, less Aß1-42, and decreased FC in DMN. Our results may indicate a possible relationship between the systemic inflammation profile and the biomarkers of ADMestradoNeurologiaMestra em Ciências133343/2015-42011/17092-0CNPQFAPES

Cognitive Reserve Relates to Functional Network Efficiency in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia, with no means of cure or prevention. The presence of abnormal disease-related proteins in the population is, in turn, much more common than the incidence of dementia. In this context, the cognitive reserve (CR) hypothesis has been proposed to explain the discontinuity between pathophysiological and clinical expression of AD, suggesting that CR mitigates the effects of pathology on clinical expression and cognition. fMRI studies of the human connectome have recently reported that AD patients present diminished functional efficiency in resting-state networks, leading to a loss in information flow and cognitive processing. No study has investigated, however, whether CR modifies the effects of the pathology in functional network efficiency in AD patients. We analyzed the relationship between CR, pathophysiology and network efficiency, and whether CR modifies the relationship between them. Fourteen mild AD, 28 amnestic mild cognitive impairment (aMCI) due to AD, and 28 controls were enrolled. We used education to measure CR, cerebrospinal fluid (CSF) biomarkers to evaluate pathophysiology, and graph metrics to measure network efficiency. We found no relationship between CR and CSF biomarkers; CR was related to higher network efficiency in all groups; and abnormal levels of CSF protein biomarkers were related to more efficient networks in the AD group. Education modified the effects of tau-related pathology in the aMCI and mild AD groups. Although higher CR might not protect individuals from developing AD pathophysiology, AD patients with higher CR are better able to cope with the effects of pathology—presenting more efficient networks despite pathology burden. The present study highlights that interventions focusing on cognitive stimulation might be useful to slow age-related cognitive decline or dementia and lengthen healthy aging