Cerebrospinal fluid irisin and lipoxin A4 are reduced in elderly Brazilian individuals with depression: Insight into shared mechanisms between depression and dementia.

INTRODUCTION: Depression is frequent among older adults and is a risk factor for dementia. Identifying molecular links between depression and dementia is necessary to shed light on shared disease mechanisms. Reduced brain-derived neurotrophic factor (BDNF) and neuroinflammation are implicated in the pathophysiology of depression and dementia. The exercise-induced hormone, irisin, increases BDNF and improves cognition in animal models of Alzheimer's disease. Lipoxin A4 is a lipid mediator with anti-inflammatory activity. However, the roles of irisin and lipoxin A4 in depression remain to be determined. METHODS: In the present study, blood and CSF were collected from 61 elderly subjects, including individuals with and without cognitive impairment. Screening for symptoms of depression was performed using the 15-item Geriatric Depression Scale (GDS-15). RESULTS: CSF irisin and lipoxin A4 were positively correlated and reduced, along with a trend of BDNF reduction, in elderly individuals with depression, similar to previous observations in patients with dementia. DISCUSSION: Our findings provide novel insight into shared molecular signatures connecting depression and dementia.

Changes in neuroinflammatory biomarkers correlate with disease severity and neuroimaging alterations in patients with COVID-19 neurological complications.

COVID-19 induces acute and persistent neurological symptoms in mild and severe cases. Proposed concomitant mechanisms include direct viral infection and strain, coagulopathy, hypoxia, and neuroinflammation. However, underlying molecular alterations associated with multiple neurological outcomes in both mild and severe cases are majorly unexplored. To illuminate possible mechanisms leading to COVID-19 neurological disease, we retrospectively investigated in detail a cohort of 35 COVID-19 mild and severe hospitalized patients presenting neurological alterations subject to clinically indicated cerebrospinal fluid (CSF) sampling. Clinical and neurological investigation, brain imaging, viral sequencing, and cerebrospinal CSF analyses were carried out. We found that COVID-19 patients presented heterogeneous neurological symptoms dissociated from lung burden. Nasal swab viral sequencing revealed a dominant strain at the time of the study, and we could not detect traces of SARS-CoV-2's spike protein in patients' CSF by multiple reaction monitoring analysis. Patients presented ubiquitous systemic hyper-inflammation and broad alterations in CSF proteomics related to inflammation, innate immunity, and hemostasis, irrespective of COVID-19 severity or neuroimaging alterations. Elevated CSF interleukin-6 (IL6) correlated with disease severity (sex-, age-, and comorbidity-adjusted mean Severe 24.5 pg/ml, 95% confidence interval (CI) 9.62-62.23 vs. Mild 3.91 pg/mL CI 1.5-10.3 patients, p = 0.019). CSF tumor necrosis factor-alpha (TNFα) and IL6 levels were higher in patients presenting pronounced neuroimaging alterations compared to those who did not (sex-, age-, and comorbidity-adjusted mean TNFα Pronounced 3.4, CI 2.4-4.4 vs. Non-Pronounced 2.0, CI 1.4-2.5, p = 0.022; IL6 Pronounced 33.11, CI 8.89-123.31 vs Non-Pronounced 6.22, CI 2.9-13.34, p = 0.046). Collectively, our findings put neuroinflammation as a possible driver of COVID-19 acute neurological disease in mild and severe cases.

Age-linked suppression of lipoxin A4 associates with cognitive deficits in mice and humans.

Age increases the risk for cognitive impairment and is the single major risk factor for Alzheimer's disease (AD), the most prevalent form of dementia in the elderly. The pathophysiological processes triggered by aging that render the brain vulnerable to dementia involve, at least in part, changes in inflammatory mediators. Here we show that lipoxin A4 (LXA4), a lipid mediator of inflammation resolution known to stimulate endocannabinoid signaling in the brain, is reduced in the aging central nervous system. We demonstrate that genetic suppression of 5-lipoxygenase (5-LOX), the enzyme mediating LXA4 synthesis, promotes learning impairment in mice. Conversely, administration of exogenous LXA4 attenuated cytokine production and memory loss induced by inflammation in mice. We further show that cerebrospinal fluid LXA4 is reduced in patients with dementia and positively associated with cognitive performance, brain-derived neurotrophic factor (BDNF), and AD-linked amyloid-ß. Our findings suggest that reduced LXA4 levels may lead to vulnerability to age-related cognitive disorders and that promoting LXA4 signaling may comprise an effective strategy to prevent early cognitive decline in AD.

Cerebrospinal Fluid Neurotransmitters, Cytokines, and Chemokines in Alzheimer's and Lewy Body Diseases.

BACKGROUND: Alzheimer's disease (AD) and Lewy body disease (LBD) are complex neurodegenerative disorders that have been associated with brain inflammation and impaired neurotransmission. OBJECTIVE: We aimed to determine concentrations of multiple cytokines, chemokines, and neurotransmitters previously associated with brain inflammation and synapse function in cerebrospinal fluid (CSF) from AD and LBD patients. METHODS: We examined a panel of 50 analytes comprising neurotransmitters, cytokines, chemokines, and hormones in CSF in a cohort of patients diagnosed with mild cognitive impairment (MCI), AD, LBD, or non-demented controls (NDC). RESULTS: Among neurotransmitters, noradrenaline (NA) was increased in AD CSF, while homovanillic acid (HVA), a dopamine metabolite, was reduced in both AD and LBD CSF relative to NDC. Six cytokines/chemokines out of 30 investigated were reliably detected in CSF. CSF vascular endothelial growth factor (VEGF) was significantly reduced in LBD patients relative to NDC. CONCLUSIONS: CSF alterations in NA, HVA, and VEGF in AD and LBD may reflect pathogenic features of these disorders and provide tools for improved diagnosis. Future studies are warranted to replicate current findings in larger, multicenter cohorts.

Cerebrospinal fluid irisin correlates with amyloid-ß, BDNF, and cognition in Alzheimer's disease.

INTRODUCTION: Irisin is a novel hormone originally identified for its role as a regulator of peripheral metabolism and recently found to protect synapses and rescue memory in mouse models of Alzheimer's disease (AD). However, whether and how cerebrospinal fluid (CSF) irisin varies in relation to canonical AD biomarkers and cognition in humans remains unknown. METHODS: We determined CSF levels of irisin and brain-derived neurotrophic factor (BDNF) and examined their correlations with CSF amyloid beta (Aß)42, total tau, and Mini-Mental State Exam (MMSE) scores in a cohort comprising AD patients (n = 14) and non-demented controls (NDC; n = 25). RESULTS: CSF irisin correlated positively with BDNF, Aß42, and MMSE scores, but not with CSF total tau. DISCUSSION: Results indicate that CSF irisin and BDNF are directly correlated with Aß pathology and cognition in AD.

What are the boundaries of legal guardianship in Alzheimer's disease? An evidence-based update in the context of the Brazilian Civil Code.

The Brazilian Civil Code, which came into force in 2002, established a functional criterion for guardianship proceedings and introduced the concept of "limited guardianship," applied to cases in which incapacity to exercise civil rights is partial. With population aging and the growth in the number of older people with cognitive impairments, such as Alzheimer's disease (AD), the need to invoke legal remedies against elder abuse increased; however, difficulties in assessing capacity still lead to a majority of decisions in favor of plenary guardianship. The present article compiled data on capacity in AD subjects. The varying degrees of decision-making impairment at different stages of AD might be compatible with limited guardianship in milder cases of the disease.

Structural neuroimaging findings in major depressive disorder throughout aging: a critical systematic review of prospective studies.

Clinical manifestations of major depressive disorder (MDD) have been linked to structural and functional alterations in fronto-limbic circuits and white matter microstructural abnormalities. However, little is known about how brain pathological changes in volume and microstructure are related to illness progression throughout aging, including course deterioration and treatment response. A comprehensive review of the literature regarding midlife- and late-onset MDD was performed through PubMed/Medline, ISI, and EMBASE electronic databases from January 2000 to May 2014. Eligible references included prospective studies in which structural neuroimaging assessments were performed in MDD samples. The course of MDD may be associated with brain aging modifications, including hippocampal, amigdalar and frontal volume reductions. White matter changes associated with MDD progression have been reported in the corpus callosum, frontal and temporal regions and may be associated with poorer response to treatment. The data suggest that both cortical and subcortical alterations may interact along the progression of MDD. Further knowledge brought by neuroimaging studies, through the integration of multimodal techniques, may help to improve the accuracy of diagnosis, disease monitoring and treatment response in MDD.

What are the boundaries of legal guardianship in Alzheimer's disease? An evidence-based update in the context of the Brazilian Civil Code

The Brazilian Civil Code, which came into force in 2002, established a functional criterion for guardianship proceedings and introduced the concept of “limited guardianship,” applied to cases in which incapacity to exercise civil rights is partial. With population aging and the growth in the number of older people with cognitive impairments, such as Alzheimer’s disease (AD), the need to invoke legal remedies against elder abuse increased; however, difficulties in assessing capacity still lead to a majority of decisions in favor of plenary guardianship. The present article compiled data on capacity in AD subjects. The varying degrees of decision-making impairment at different stages of AD might be compatible with limited guardianship in milder cases of the disease.

CAMCOG - valores das subescalas em idosos normais com níveis diferentes de escolaridade. Aspectos preliminares / CAMCOG – Subscales values in normal elderly with different educational levels – Preliminary aspects

Introdução: O Exame Cognitivo Cambridge (CAMCOG) é um instrumento breve para avaliação cognitiva. É composto por subescalas que representam diversos domínios cognitivos (orientação, linguagem, memória, atenção, praxia, percepção, cálculo e pensamento abstrato). Escores totais adequados permitem definir comprometimento em nível de demência. Entretanto, tais escores totais nem sempre representam o desempenho real de um indivíduo, pois é possível obter escores baixos em determinado(s) domínio(s) e ainda manter um escore total dentro da variação normal. Objetivo: Obter valores do CAMCOG total e das subescalas de indivíduos idosos normais com diferentes níveis de escolaridade. O interesse crescente na definição de estágios pré-demência é uma razão importante do presente estudo. Métodos: Foram avaliados com CAMCOG idosos normais residindo na comunidade, divididos em três grupos de acordo com o nível de escolaridade. Foi realizada análise estatística para comparar a significância dos escores (total e subescalas) entre os grupos. Resultados: Os valores médios do CAMCOG total mostraram aumento com a escolaridade, o mesmo tendo sido observado em relação aos escores das subescalas. Conclusão: As subescalas do CAMCOG relacionados com os níveis de escolaridade são necessárias para identificar indivíduos que apresentam diminuição de valores em um ou mais domínios cognitivos, apesar de apresentar o escore total dentro da variação da normalidade, o que pode caracterizar um estado de comprometimento cognitivo pré-demência...

Introduction: The Cambridge Cognitive Examination (CAMCOG) is a brief tool for cognitive assessment. It is composed of subscales that represent various cognitivedomains (orientation, language, memory, attention, praxis, perception, calculation and abstract thinking). Appropriate total scores permit to define impairment in the dementia level. However, such total scores do not always represent the real performance of the subject as it is possible to obtain low scores in certain domain(s) yet maintaining a total score in the normal range. Objective: To obtain data of CAMCOG total and subscales scores of normal elderly subjects with different educational levels. The growing interest in defining pre-dementia stages is an important reason of the present study. Methods: Community living normal elderly, divided in three groups according to their education level were assessed with CAMCOG. Statistic analysis was performed to compare significance of the scores (total and subscales) among the groups. Results: Total CAMCOG mean values increased with education, and the same was observed in relation to the subscales scores. Conclusion: CAMCOG subscales related to education levels are necessary to identify subjects who present decreased values on one or more cognitive domain despite total scores within normal range, which may characterize a pre-dementia cognitive impairment state...