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      Imaging Alzheimer's disease pathophysiology with PET Translated title: A FISIOPATOLOGIA DA DOENÇA DE ALZHEIMER ATRAVÉS DO PET

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          ABSTRACT

          Alzheimer's disease (AD) has been reconceptualised as a dynamic pathophysiological process characterized by preclinical, mild cognitive impairment (MCI), and dementia stages. Positron emission tomography (PET) associated with various molecular imaging agents reveals numerous aspects of dementia pathophysiology, such as brain amyloidosis, tau accumulation, neuroreceptor changes, metabolism abnormalities and neuroinflammation in dementia patients. In the context of a growing shift toward presymptomatic early diagnosis and disease-modifying interventions, PET molecular imaging agents provide an unprecedented means of quantifying the AD pathophysiological process, monitoring disease progression, ascertaining whether therapies engage their respective brain molecular targets, as well as quantifying pharmacological responses. In the present study, we highlight the most important contributions of PET in describing brain molecular abnormalities in AD.

          RESUMO

          A doença de Alzheimer tem sido reconceitualizada como um processo patofisiológico dinâmico caracterizado pelos estágios pré-clínico, comprometimento cognitivo leve e demência. A tomografia por emissão de pósitrons associada a vários agentes de imagem molecular revela numerosos aspectos da patofisiologia da demência tais como amiloidose cerebral, acúmulo de tau, mudanças em neurorreceptores, anormalidades de metabolismo e neuroinflamação nestes pacientes. No contexto de um crescimento em direção ao diagnóstico precoce pré-sintomático e intervenções modificadores da doença, a imagem de PET com agentes moleculares fornece meio para quantificar o processo patofisiológico da DA sem precedentes, monitorizar a progressão da doença, bem como quantificar resposta farmacológica. Aqui, nós realçamos as mais importantes contribuições do PET na descrição de anormalidades moleculares cerebrais na DA.

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          Most cited references222

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          Classification and basic pathology of Alzheimer disease.

          The lesions of Alzheimer disease include accumulation of proteins, losses of neurons and synapses, and alterations related to reactive processes. Extracellular Abeta accumulation occurs in the parenchyma as diffuse, focal or stellate deposits. It may involve the vessel walls of arteries, veins and capillaries. The cases in which the capillary vessel walls are affected have a higher probability of having one or two apoepsilon 4 alleles. Parenchymal as well as vascular Abeta deposition follows a stepwise progression. Tau accumulation, probably the best histopathological correlate of the clinical symptoms, takes three aspects: in the cell body of the neuron as neurofibrillary tangle, in the dendrites as neuropil threads, and in the axons forming the senile plaque neuritic corona. The progression of tau pathology is stepwise and stereotyped from the entorhinal cortex, through the hippocampus, to the isocortex. The neuronal loss is heterogeneous and area-specific. Its mechanism is still discussed. The timing of the synaptic loss, probably linked to Abeta peptide itself, maybe as oligomers, is also controversial. Various clinico-pathological types of Alzheimer disease have been described, according to the type of the lesions (plaque only and tangle predominant), the type of onset (focal onset), the cause (genetic or sporadic) and the associated lesions (Lewy bodies, vascular lesions, hippocampal sclerosis, TDP-43 inclusions and argyrophilic grain disease).
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            Brain glucose metabolism in the early and specific diagnosis of Alzheimer's disease. FDG-PET studies in MCI and AD.

            The demographics of aging suggest a great need for the early diagnosis of dementia and the development of preventive strategies. Neuropathology and structural MRI studies have pointed to the medial temporal lobe (MTL) as the brain region earliest affected in Alzheimer's disease (AD). MRI findings provide strong evidence that in mild cognitive impairments (MCI), AD-related volume losses can be reproducibly detected in the hippocampus, the entorhinal cortex (EC) and, to a lesser extent, the parahippocampal gyrus; they also indicate that lateral temporal lobe changes are becoming increasingly useful in predicting the transition to dementia. Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) imaging has revealed glucose metabolic reductions in the parieto-temporal, frontal and posterior cingulate cortices to be the hallmark of AD. Overall, the pattern of cortical metabolic changes has been useful for the prediction of future AD as well as in distinguishing AD from other neurodegenerative diseases. FDG-PET on average achieves 90% sensitivity in identifying AD, although specificity in differentiating AD from other dementias is lower. Moreover, recent MRI-guided FDG-PET studies have shown that MTL hypometabolism is the most specific and sensitive measure for the identification of MCI, while the utility of cortical deficits is controversial. This review highlights cross-sectional, prediction and longitudinal FDG-PET studies and attempts to put into perspective the value of FDG-PET in diagnosing AD-like changes, particularly at an early stage, and in providing diagnostic specificity. The examination of MTL structures, which has so far been exclusive to MRI protocols, is then examined as a possible strategy to improve diagnostic specificity. All told, there is considerable promise that early and specific diagnosis is feasible through a combination of imaging modalities.
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              Body Fluid Cytokine Levels in Mild Cognitive Impairment and Alzheimer’s Disease: a Comparative Overview

              This article gives a comprehensive overview of cytokine and other inflammation associated protein levels in plasma, serum and cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). We reviewed 118 research articles published between 1989 and 2013 to compare the reported levels of 66 cytokines and other proteins related to regulation and signaling in inflammation in the blood or CSF obtained from MCI and AD patients. Several cytokines are evidently regulated in (neuro-) inflammatory processes associated with neurodegenerative disorders. Others do not display changes in the blood or CSF during disease progression. However, many reports on cytokine levels in MCI or AD are controversial or inconclusive, particularly those which provide data on frequently investigated cytokines like tumor necrosis factor alpha (TNF-α) or interleukin-6 (IL-6). The levels of several cytokines are possible indicators of neuroinflammation in AD. Some of them might increase steadily during disease progression or temporarily at the time of MCI to AD conversion. Furthermore, elevated body fluid cytokine levels may correlate with an increased risk of conversion from MCI to AD. Yet, research results are conflicting. To overcome interindividual variances and to obtain a more definite description of cytokine regulation and function in neurodegeneration, a high degree of methodical standardization and patients collective characterization, together with longitudinal sampling over years is essential. Electronic supplementary material The online version of this article (doi:10.1007/s12035-014-8657-1) contains supplementary material, which is available to authorized users.
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                Author and article information

                Journal
                Dement Neuropsychol
                Dement Neuropsychol
                dn
                Dementia & Neuropsychologia
                Associação de Neurologia Cognitiva e do Comportamento
                1980-5764
                Apr-Jun 2016
                Apr-Jun 2016
                : 10
                : 2
                : 79-90
                Affiliations
                [1 ]Translational Neuroimaging Laboratory (TNL), McGill Center for Studies in Aging (MCSA), Douglas Mental Health Research Institute, Montreal, Canada.
                [2 ]Alzheimer's Disease Research Unit, MCSA, Douglas Mental Health Research Institute, Montreal, Canada.
                [3 ]Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre RS, Brazil.
                [4 ]Department of Biochemistry, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre RS, Brazil.
                [5 ]Department NVS, Centre for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, Stockholm, Sweden.
                Author notes
                Pedro Rosa-Neto. McGill Center for Studies in Aging, 6825 LaSalle Boulevad, Montreal, H4H 1R3 Quebec - Canada. E-mail: ac.lligcm@ 123456asor.ordep

                Author contribution. Lucas Porcello Schilling collected and critically analysed literature, contributed with tables and wrote the paper; Eduardo R. Zimmer collected and critically analysed literature, contributed with figures and wrote the paper; Monica Shin collected and critically analysed literature and wrote the paper. Antoine Leuzy collected and critically analysed literature, contributed with figures and wrote the paper; Tharick A. Pascoal collected and critically analysed literature and wrote the paper; Andréa L. Benedet collected and critically analysed literature and wrote the paper. Wyllians V. Borelli collected and critically analysed literature and wrote the paper. André Palmini collected and critically analysed literature and wrote the paper; Serge Gauthier collected and critically analysed literature and wrote the paper; Pedro Rosa Neto collected and critically analysed literature and wrote and reviewed the paper.

                Disclosure: The authors report no conflicts of interest.

                Article
                10.1590/S1980-5764-2016DN1002003
                5642398
                29213438
                ef1bdf62-3e1b-4235-a98b-061289b44e1f

                This is an open-access article distributed under the terms of the Creative Commons Attribution License

                History
                : 10 December 2015
                : 16 March 2016
                Page count
                Figures: 2, Tables: 2, Equations: 0, References: 146, Pages: 12
                Categories
                Views & Reviews

                alzheimer's disease,positron emission tomography,amyloid imaging,neuroinflammation,neurodegeneration,tau

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