Diagnostic Performance of Muscle Echo Intensity and Fractal Dimension for the Detection of Frailty Phenotype.

To determine the relationship between muscle echo intensity (EI) and fractal dimension (FD), and the diagnostic performance of both ultrasound parameters for the identification of frailty phenotype. A retrospective interpretation of ultrasound scans from a previous cohort (November 2014-February 2015) was performed. The sample included healthy participants <60 years old, and participants ≥60 divided into robust, pre-frail, and frail groups according to Fried frailty criteria. A region of interest of the rectus femoris from the ultrasound scan was segmented, and histogram function was applied to obtain EI. For fractal analysis, images were processed using two-dimensional box-counting techniques to calculate FD. Statistical analyses were performed with diagnostic performance tests. A total of 102 participants (mean age 63 ± 16, 57 men) were evaluated. Muscle fractal dimension correlated with EI (r = .38, p < .01) and showed different pattern in the scatter plots when participants were grouped by non-frail (control + robust) and frail (pre-frail + frail). The diagnostic accuracy for EI to categorize frailty was of 0.69 (95%CI: 0.59-0.78, p = .001), with high intra-rater (ICC: 0.98, 95%CI: 0.98-0.99); p < .001) and inter-rater (ICC: 0.89, 95%CI: 0.75-0.95; p < .001) reliability and low measurement error for both parameters (EI: -0.18, LOA95%: -10.8 to 10.5; FD: 0.00, LOA95%: -0.09 to 0.10) in arbitrary units. The ROC curve combining both parameters was not better than EI alone (p = .18). Muscle FD correlated with EI and showed different patterns according to frailty phenotype, with EI outperforming FD as a possible diagnostic tool for frailty.

Electroencephalography as a Non-Invasive Biomarker of Alzheimer's Disease: A Forgotten Candidate to Substitute CSF Molecules?

Biomarkers for disease diagnosis and prognosis are crucial in clinical practice. They should be objective and quantifiable and respond to specific therapeutic interventions. Optimal biomarkers should reflect the underlying process (pathological or not), be reproducible, widely available, and allow measurements repeatedly over time. Ideally, biomarkers should also be non-invasive and cost-effective. This review aims to focus on the usefulness and limitations of electroencephalography (EEG) in the search for Alzheimer's disease (AD) biomarkers. The main aim of this article is to review the evolution of the most used biomarkers in AD and the need for new peripheral and, ideally, non-invasive biomarkers. The characteristics of the EEG as a possible source for biomarkers will be revised, highlighting its advantages compared to the molecular markers available so far.

Is Sleep Disruption a Cause or Consequence of Alzheimer's Disease? Reviewing Its Possible Role as a Biomarker.

In recent years, the idea that sleep is critical for cognitive processing has gained strength. Alzheimer's disease (AD) is the most common form of dementia worldwide and presents a high prevalence of sleep disturbances. However, it is difficult to establish causal relations, since a vicious circle emerges between different aspects of the disease. Nowadays, we know that sleep is crucial to consolidate memory and to remove the excess of beta-amyloid and hyperphosphorilated tau accumulated in AD patients' brains. In this review, we discuss how sleep disturbances often precede in years some pathological traits, as well as cognitive decline, in AD. We describe the relevance of sleep to memory consolidation, focusing on changes in sleep patterns in AD in contrast to normal aging. We also analyze whether sleep alterations could be useful biomarkers to predict the risk of developing AD and we compile some sleep-related proposed biomarkers. The relevance of the analysis of the sleep microstructure is highlighted to detect specific oscillatory patterns that could be useful as AD biomarkers.

The Effectiveness of Vitamin E Treatment in Alzheimer's Disease.

Vitamin E was proposed as treatment for Alzheimer's disease many years ago. However, the effectiveness of the drug is not clear. Vitamin E is an antioxidant and neuroprotector and it has anti-inflammatory and hypocholesterolemic properties, driving to its importance for brain health. Moreover, the levels of vitamin E in Alzheimer's disease patients are lower than in non-demented controls. Thus, vitamin E could be a good candidate to have beneficial effects against Alzheimer's. However, evidence is consistent with a limited effectiveness of vitamin E in slowing progression of dementia; the information is mixed and inconclusive. The question is why does vitamin E fail to treat Alzheimer's disease? In this paper we review the studies with and without positive results in Alzheimer's disease and we discuss the reasons why vitamin E as treatment sometimes has positive results on cognition but at others, it does not.

When Does Alzheimer's Disease Really Start? The Role of Biomarkers.

While Alzheimer's disease (AD) classical diagnostic criteria rely on clinical data from a stablished symptomatic disease, newer criteria aim to identify the disease in its earlier stages. For that, they incorporated the use of AD's specific biomarkers to reach a diagnosis, including the identification of Aß and tau depositions, glucose hypometabolism, and cerebral atrophy. These biomarkers created a new concept of the disease, in which AD's main pathological processes have already taken place decades before we can clinically diagnose the first symptoms. Therefore, AD is now considered a dynamic disease with a gradual progression, and dementia is its final stage. With that in mind, new models were proposed, considering the orderly increment of biomarkers and the disease as a continuum, or the variable time needed for the disease's progression. In 2011, the National Institute on Aging and the Alzheimer's Association (NIA-AA) created separate diagnostic recommendations for each stage of the disease continuum-preclinical, mild cognitive impairment, and dementia. However, new scientific advances have led them to create a unifying research framework in 2018 that, although not intended for clinical use as of yet, is a step toward shifting the focus from the clinical symptoms to the biological alterations and toward changing the future diagnostic and treatment possibilities. This review aims to discuss the role of biomarkers in the onset of AD.

Redox-associated changes in healthy individuals at risk of Alzheimer's disease. A ten-year follow-up study.

Carrying an allele 4 of the apolipoprotein E (ApoE) is the best-established genetic risk factor to develop Alzheimer's disease (AD). Fifty percent of ApoE4/4 individuals develop the disease at 70 years of age. ApoE3/4 carriers have a lower risk of developing the disease, still 50% of them suffer AD at around 80 years. In a previous study we showed that healthy young individuals, who had a parent with AD and were carriers of at least one ApoE4 allele displayed reductive stress. This was evidenced as a decrease in oxidative markers, such as oxidized glutathione, p-p38, and NADP+/NADPH ratio, and an increase of antioxidant enzymes, such as glutathione peroxidase (Gpx1) and both the catalytic and regulatory subunits of glutamyl-cysteinyl (GCLM and GCLC). Moreover, we found an increase in stress-related proteins involved in tau physiopathology. Now, 10 years later, we have conducted a follow-up study measuring the same parameters in the same cohort. Our results show that reductive stress has reversed, as we could now observe an increase in lipid peroxidation and in the oxidation of glutathione along with a decrease in the expression of Gpx1 and SOD1 antioxidant enzymes in ApoE4 carriers. Furthermore, we found an increase in plasma levels of IL1ß levels and in PKR (eukaryotic translation initiation factor 2 alpha kinase 2) gene expression in isolated lymphocytes. Altogether, our results suggest that, in the continuum of Alzheimer's disease, people at risk of developing the disease go through different redox phases, from stablished reductive stress to oxidative stress.

Multifactorial Causation of Alzheimer's Disease Due to COVID-19.

There are several implications of the surge in the incidence of pandemics and epidemics in the last decades. COVID-19 being the most remarkable one, showed the vulnerability of patients with neurodegenerative diseases like Alzheimer's disease (AD). This review studies the pathological interlinks and triggering factors between the two illnesses and proposes a multifactorial pathway of AD causation due to COVID-19. The article evaluates and describes all the postulated hypotheses which explain the etiology and possible pathogenesis of the disease in four domains: Inflammation & Neurobiochemical interactions, Oxidative Stress, Genetic Factors, and Social Isolation. We believe that a probable hypothesis of an underlying cause of AD after COVID-19 infection could be the interplay of all these factors.

When Does Alzheimer's Disease Really Start? The Role of Biomarkers.

(Appeared originally in Int J Mol Sci 2019, 20 5536).

Is Oxidative Stress the Link Between Cerebral Small Vessel Disease, Sleep Disruption, and Oligodendrocyte Dysfunction in the Onset of Alzheimer's Disease?

Oxidative stress is an early occurrence in the development of Alzheimer's disease (AD) and one of its proposed etiologic hypotheses. There is sufficient experimental evidence supporting the theory that impaired antioxidant enzymatic activity and increased formation of reactive oxygen species (ROS) take place in this disease. However, the antioxidant treatments fail to stop its advancement. Its multifactorial condition and the diverse toxicological cascades that can be initiated by ROS could possibly explain this failure. Recently, it has been suggested that cerebral small vessel disease (CSVD) contributes to the onset of AD. Oxidative stress is a central hallmark of CSVD and is depicted as an early causative factor. Moreover, data from various epidemiological and clinicopathological studies have indicated a relationship between CSVD and AD where endothelial cells are a source of oxidative stress. These cells are also closely related to oligodendrocytes, which are, in particular, sensitive to oxidation and lead to myelination being compromised. The sleep/wake cycle is another important control in the proliferation, migration, and differentiation of oligodendrocytes, and sleep loss reduces myelin thickness. Moreover, sleep plays a crucial role in resistance against CSVD, and poor sleep quality increases the silent markers of this vascular disease. Sleep disruption is another early occurrence in AD and is related to an increase in oxidative stress. In this study, the relationship between CSVD, oligodendrocyte dysfunction, and sleep disorders is discussed while focusing on oxidative stress as a common occurrence and its possible role in the onset of AD.

Serum Levels of Clusterin, PKR, and RAGE Correlate with Amyloid Burden in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia and biomarkers are essential to help in the diagnosis of this disease. Image techniques and cerebrospinal fluid (CSF) biomarkers are limited in their use because they are expensive or invasive. Thus, the search for blood-borne biomarkers is becoming central to the medical community. OBJECTIVE: The main objective of this study is the evaluation of three serum proteins as potential biomarkers in AD patients. METHODS: We recruited 27 healthy controls, 19 mild cognitive impairment patients, and 17 AD patients. Using the recent A/T/N classification we split our population into two groups (AD and control). We used ELISA kits to determine Aß42, tau, and p-tau in CSF and clusterin, PKR, and RAGE in serum. RESULTS: The levels of serum clusterin, PKR, and RAGE were statistically different in the AD group compared to controls. These proteins showed a statistically significant correlation with CSF Aß42. So, they were selected to generate an AD detection model showing an AUC-ROC of 0.971 (CI 95%, 0.931-0.998). CONCLUSION: The developed model based on serum biomarkers and other co-variates could reflect the AD core pathology. So far, not one single blood-biomarker has been described, with effectiveness offering high sensitivity and specificity. We propose that the complexity of AD pathology could be reflected in a set of biomarkers also including clinical features of the patients.

COVID-19 Infection Process in Italy and Spain: Are Data Talking? Evidence From ARMA and Vector Autoregression Models.

COVID-19 (coronavirus disease 2019) has spread successfully worldwide in a matter of weeks. After the example of China, all the affected countries are taking hard-confinement measures to control the infection and to gain some time to reduce the significant amount of cases that arrive at the hospital. Although the measures in China reduced the percentages of new cases, this is not seen in other countries that have taken similar measures, such as Italy and Spain. After the first weeks, the worry was whether or not the healthcare system would collapse rather than its response to the patient's needs who are infected and require hospitalization. Using China as a mirror of what could happen in our countries and with the data available, we calculated a model that forecasts the peak of the curve of infection, hospitalization, and ICU bed numbers. We aimed to review the patterns of spread of the virus in the two countries and their regions, looking for similarities that reflect the existence of a typical path in this expansive virulence and the effects of the intervention of the authorities with drastic isolation measures, to contain the outbreak. A model based on Autorregressive and moving average models (ARMA) methodology and including Chinese disease pattern as a proxy, predicts the contagious pattern robustly. Based on the prediction, the hospitalization and intensive care unit (ICU) requirements were also calculated. Results suggest a reduction in the speed of contagion during April in both countries, earlier in Spain than in Italy. The forecast advanced a significant increase in the ICU needs for Spain surpassing 8,000 units by the end of April, but for Italy, ICU needs would decrease in the same period, according to the model. We present the following predictions to inform political leaders because they have the responsibility to maintain the national health systems away from collapsing. We are confident these data could help them into decision-taking and place the capitals (from hospital beds to human resources) into the right place.

Increased basal antioxidant levels in RCAN1 - deficient mice lowers oxidative injury after acute paraquat insult.

RCAN1 is an inhibitor of the phosphatase calcineurin, which is involved in the regulation of oxidative stress and apoptosis, among other important cell processes. Here we have used RCAN1 deficient mice (RCAN1-/-) to elucidate its role after an acute oxidative insult such as paraquat injection. We have observed that RCAN1-/- mice show less oxidative damage than wildtype (WT) mice after treatment. Under basal conditions, RCAN1-/- animals express more calcineurin, heme oxygenase-1, Nrf2, and catalase compared to WT mice (controls). This may explain the less severe effect of paraquat treatment on RCAN1-/- mice compared to WT. We showed that oxidative stress is involved in the early stages of apoptosis, thus we determined the apoptotic effector BAD and found that decreases in RCAN1-/- mice after treatment with paraquat compared with WT in similar experimental conditions. Our results suggest that RCAN1 may be involved in the balance between oxidant and antioxidant species production in vivo.

Obesity as a Risk Factor for Alzheimer's Disease: Implication of Leptin and Glutamate.

Obesity is known to induce leptin and insulin resistance. Leptin is a peptide hormone synthesized in adipose tissue that mainly regulates food intake. It has been shown that insulin stimulates the production of leptin when adipocytes are exposed to glucose to encourage satiety; while leptin, via a negative feedback, decreases the insulin release and enhances tissue sensitivity to it, leading to glucose uptake for energy utilization or storage. Therefore, resistance to insulin is closely related to leptin resistance. Obesity in middle age has also been related to Alzheimer's disease (AD). In recent years, the relation between impaired leptin signaling pathway and the onset of AD has been studied. In all this context the role of the blood brain barrier (BBB) is crucial. Slow excitotoxicity happens in AD due to an excess of the neurotransmitter glutamate. Since leptin has been shown to regulate N-methyl-D-aspartate (NMDA) receptors, we want to review the link between these pathological pathways, and how they are affected by other AD triggering factors and its role in the onset of AD.

Oxidative signature of cerebrospinal fluid from mild cognitive impairment and Alzheimer disease patients.

BACKGROUND: Several studies suggest that pathological changes in Alzheimer's disease (AD) brain begin around 10-20 years before the onset of cognitive impairment. Biomarkers that can support early diagnosis and predict development of dementia would, therefore, be crucial for patient care and evaluation of drug efficacy. Although cerebrospinal fluid (CSF) levels of Aß42, tau, and p-tau are well-established diagnostic biomarkers of AD, there is an urgent need to identify additional molecular alterations of neuronal function that can be evaluated at the systemic level. OBJECTIVES: This study was focused on the analysis of oxidative stress-related modifications of the CSF proteome, from subjects with AD and amnestic mild cognitive impairment (aMCI). METHODS: A targeted proteomics approach has been employed to discover novel CSF biomarkers that can augment the diagnostic and prognostic accuracy of current leading CSF biomarkers. CSF samples from aMCI, AD and control individuals (CTR) were collected and analyzed using a combined redox proteomics approach to identify the specific oxidatively modified proteins in AD and aMCI compared with controls. RESULTS: The majority of carbonylated proteins identified by redox proteomics are found early in the progression of AD, i.e., oxidatively modified CSF proteins were already present in aMCI compared with controls and remain oxidized in AD, thus suggesting that dysfunction of selected proteins initiate many years before severe dementia is diagnosed. CONCLUSIONS: The above findings highlight the presence of early oxidative damage in aMCI before clinical dementia of AD is manifested. The identification of early markers of AD that may be detected peripherally may open new prospective for biomarker studies.