Dynamic amyloid and metabolic signatures of delayed recall performance within the clinical spectrum of Alzheimer’s disease

Associations between pathophysiological events and cognitive measures provide insights regarding brain networks affected during the clinical progression of Alzheimer’s disease (AD). In this study, we assessed patients’ scores in two delayed episodic memory tests, and investigated their associations with regional amyloid deposition and brain metabolism across the clinical spectrum of AD. We assessed the clinical, neuropsychological, structural, and positron emission tomography (PET) baseline measures of participants from the Alzheimer’s Disease Neuroimaging Initiative. Subjects were classified as cognitively normal (CN), or with early (EMCI) or late (LMCI) mild cognitive impairment, or AD dementia. The memory outcome measures of interest were logical memory 30 min delayed recall (LM30) and Rey Auditory Verbal Learning Test 30 min delayed recall (RAVLT30). Voxel-based [18F]florbetapir and [18F]FDG uptake-ratio maps were constructed and correlations between PET images and cognitive scores were calculated. We found that EMCI individuals had LM30 scores negatively correlated with [18F]florbetapir uptake on the right parieto-occipital region. LMCI individuals had LM30 scores positively associated with left lateral temporal lobe [18F]FDG uptake, and RAVLT30 scores positively associated with [18F]FDG uptake in the left parietal lobe and in the right enthorhinal cortex. Additionally, LMCI individuals had LM30 scores negatively correlated with [18F]florbetapir uptake in the right frontal lobe. For the AD group, [18F]FDG uptake was positively correlated with LM30 in the left temporal lobe and with RAVLT30 in the right frontal lobe, and [18F]florbetapir uptake was negatively correlated with LM30 scores in the right parietal and left frontal lobes. The results show that the association between regional brain metabolism and the severity of episodic memory deficits is dependent on the clinical disease stage, suggesting a dynamic relationship between verbal episodic memory deficits, AD pathophysiology, and clinical disease stages

Avaliação Da Sirtuína 2 Sérica Como Biomarcador Da Doença De Alzheimer

ntroduction: Alzheimer's disease (AD) is the most prevalent form of degenerative dementia and there is no effective treatment to prevent its progression. An important step in the search for a cure is the identification of a biomarker able to diagnose the disease early in the pathological process, at which point a pharmacological intervention would be effective. Sirtuins are proteins present in most living organisms and their functions have been related to the control of healthy longevity, neuroprotection and the pathophysiology of dementia. Sirtuin 1 is altered in the serum and plasma of AD patients representing a potential biomarker for the disease. It has already been showed that the T allele of the rs10410544 polymorphism of the Sirtuin 2 (SIRT2) gene is associated with a greater risk of development of AD, but the potential of SIRT2 as a biomarker of AD needs to be better investigated. Objective: To evaluate the association between serum SIRT2 and AD. Evaluate the impact of SIRT2 on risk factors of AD and the correlation of SIRT2 with clinical parameters of the disease. Methods: we conducted a case-control study, which included patients with AD and controls without cognitive deficit. Clinical information was obtained through medical consultation and clinical and neuropsychological tests. The serum level of SIRT2 was measured by the ELISA method, fasting glucose was measured by colorimetric assay and glycated hemoglobin by HPLC. Results: Thirty patients with AD and 14 subjects without cognitive deficit were included. No difference was found in the level of serum SIRT2 between AD and controls (p = 0.247). The logistic model that used SIRT2 levels to predict whether an individual would be in the case group or control group was not different than 50%. SIRT2 levels showed no difference according to the diagnosis of hypertension, hyperlipidemia, anxiety or depression. SIRT2 levels were not correlated with age, sex, length of evolution and severity of the disease or fasting glucose levels. We found that serum SIRT2 levels were significantly increased in patients with type 2 diabetes compared to non-diabetic patients (p=0.027). There was also a positive correlation between the levels of glycated hemoglobin and SIRT2 (p=0.027). Conclusion: No association was found between serum SIRT2 and AD. The findings suggest a role of SIRT2 on the pathophysiology of type 2 diabetes that deserves to be further investigated.Introdução: A doença de Alzheimer (DA) é a demência degenerativa mais prevalente e não existe nenhum tratamento capaz de impedir sua evolução. Um passo importante na busca da cura da DA é a identificação de um biomarcador capaz de diagnosticar a doença no início do processo patológico, momento em que uma intervenção farmacológica seria eficaz. As Sirtuínas são proteínas presentes na maioria dos seres vivos e suas funções já foram relacionadas com controle da longevidade saudável, neuroproteção e fisiopatologia das demências. A Sirtuína 1 está diminuída no soro e no plasma de pacientes com DA representando um potencial biomarcador. O alelo T do polimorfismo rs10410544 do gene da Sirtuína 2 (SIRT2) está associado a um maior risco de desenvolvimento da DA, mas o potencial da SIRT2 como biomarcador da DA ainda precisa ser melhor investigado. Objetivos: Avaliar a associação entre o nível sérico de SIRT2 e DA. Avaliar o impacto da SIRT2 nos fatores de risco da DA e a correlação da SIRT2 com parâmetros clínicos da doença. Métodos: Foi realizado um estudo caso-controle, onde foram incluídos pacientes com diagnóstico de DA e controles sem déficit cognitivo. As informações clínicas foram obtidas através de consulta médica e de exame clínico e neuropsicológico. O nível sérico da SIRT2 foi medido pelo método ELISA, a glicemia de jejum foi medida pelo método colorimétrico-enzimático e a hemoglobina glicada por HPLC. Resultados: Foram incluídos 30 pacientes com DA e 14 idosos sem déficit cognitivo. Não foi encontrada diferença no nível sérico de SIRT2 entre os grupos DA e controle (p=0,247). O modelo logístico que utilizou os níveis de SIRT2 para predizer se um indivíduo seria do grupo caso ou controle não se apresentou diferente de 50%. Os níveis de SIRT2 não apresentaram diferença de acordo com o diagnóstico de HAS, dislipidemia, ansiedade ou depressão nem correlação com idade, sexo, tempo de evolução e gravidade da doença ou glicemia de jejum. Foi encontrado aumento significativo dos níveis de SIRT2 em pacientes com Diabetes Mellitus tipo II (p= 0,027) e uma correlação positiva entre o nível de SIRT2 e hemoglobina glicada (p= 0,027). Conclusão: Não foi encontrada associação entre o nível sérico de SIRT2 e DA. Os achados sugerem um papel da SIRT2 na fisiopatologia do Diabetes Mellitus tipo II que merece ser melhor investigado.Dados abertos - Sucupira - Teses e dissertações (2017

Dissociation between Brain Amyloid Deposition and Metabolism in Early Mild Cognitive Impairment

Alzheimer’s disease (AD) is characterized by a progressive accumulation of amyloid plaques, neurofibrillary tangles and neuronal depletion associated with a slow deterioration of cognition and functional status. Numerous technological advances have made possible the quantification of amyloid accumulation and neurodegeneration in vivo using imaging and fluid biomarkers. In AD, biomarkers are classified as biomarkers of amyloid accumulation (i.e CSF Aβ1–42, [11C] Pittsburgh compound B (PIB) Positron Emission Tomography (PET), [18F]AV45 PET) and neurodegeneration (i.e CSF tau, [18F] fluorodeoxyglucose(FDG) PET and structural MRI) [...

Summary of the imaging analysis methods.

<p>Summary of the imaging analysis methods.</p

Images represent statistical parametric mapping depicting (spectrum color bars) t-statistical contrast overlaid on a group structural MRI.

<p>Right images represent voxel-based statistical differences comparing [¹⁸F]AV45 retention (LMCI > EMCI). Left images represents voxel-based statistical differences comparing [¹⁸F]FDG uptake (LMCI < EMCI).</p

Global [¹⁸F]AV45 and [¹⁸F]FDG uptake in all groups.

<p>All values are indicated as mean ± standard deviation. p value indicates the value for the main effect of each group, as assessed with analyses of variance(ANOVA) for each variable. Statistics for post hoc 2-by-2 group comparisons are provided as significant differences:</p>a<p>from CN at p<0.01;</p>b<p>from CN at p<0.05.</p>c<p>from EMCI at p<0.01;</p>d<p>from EMCI at p<0.05;</p>e<p>from LMCI at p<0.01.</p

Demographics and neuropsychological data for all groups.

<p>All values are indicated as mean ± standard deviation except gender. p value indicates the value for the main effect of each group, as assessed with analyses of variance(ANOVA) for each variable except for gender, where a contingency chi-square was performed. Statistics for post hoc 2-by-2 group comparisons are provided as significant differences:</p>a<p>from CN at p<0.01;</p>b<p>from CN at p<0.05.</p>c<p>from EMCI at p<0.01;</p>d<p>from EMCI at p<0.05;</p>e<p>from LMCI at p<0.01.</p><p>MMSE =  mini mental state examination; CDR = clinical dementia rating scale; ADAS  =  Alzheimer’s disease assessment scale; RAVLT =  Rey auditory verbal learning test; FAQ =  functional activities questionnaire.</p

Images represent statistical parametric mapping depicting (spectrum color bars) t-statistical contrast overlaid on a group structural MRI. Right images represent voxel-based statistical differences comparing [¹⁸F]AV45 retention (EMCI > CN).

<p>Left images represents voxel-based statistical differences comparing [¹⁸F]FDG uptake (EMCI < CN).</p

Images represent statistical parametric mapping depicting (spectrum color bars) t-statistical contrast overlaid on a group structural MRI.

<p>Right images represent voxel-based statistical differences comparing [¹⁸F]AV45 retention (AD > LMCI). Left images represents voxel-based statistical differences comparing [¹⁸F]FDG uptake (AD < LMCI).</p

[¹⁸F]AV45 (left) and [¹⁸F]FDG (right) average images obtained from controls (CN), early MCI (EMCI), late MCI (LMCI) and Alzheimer’s dementia patients (AD).

<p>In [¹⁸F]AV45, there is a reduction of gray and white matter contrast in EMCI, LMCI and AD in comparison with CN. Note the PCC and IPC [¹⁸F]FDG SUVR reduction in LMCI and AD in comparison with CN.</p