•This review describes an integrated and multidisciplinary approach for the “early” diagnosis of Alzheimer's disease (AD).•An overview of epidemiology, genetic risk factors, and different biomarkers ...of AD is provided.•Latest findings suggest EEG rhythms analysis as a valid screening tool to predict AD conversion.
Alzheimer’s disease (AD) is the most common neurodegenerative disease among the elderly with a progressive decline in cognitive function significantly affecting quality of life. Both the prevalence and emotional and financial burdens of AD on patients, their families, and society are predicted to grow significantly in the near future, due to a prolongation of the lifespan. Several lines of evidence suggest that modifications of risk-enhancing life styles and initiation of pharmacological and non-pharmacological treatments in the early stage of disease, although not able to modify its course, helps to maintain personal autonomy in daily activities and significantly reduces the total costs of disease management. Moreover, many clinical trials with potentially disease-modifying drugs are devoted to prodromal stages of AD. Thus, the identification of markers of conversion from prodromal form to clinically AD may be crucial for developing strategies of early interventions. The current available markers, including volumetric magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebral spinal fluid (CSF) analysis are expensive, poorly available in community health facilities, and relatively invasive. Taking into account its low cost, widespread availability and non-invasiveness, electroencephalography (EEG) would represent a candidate for tracking the prodromal phases of cognitive decline in routine clinical settings eventually in combination with other markers. In this scenario, the present paper provides an overview of epidemiology, genetic risk factors, neuropsychological, fluid and neuroimaging biomarkers in AD and describes the potential role of EEG in AD investigation, trying in particular to point out whether advanced analysis of EEG rhythms exploring brain function has sufficient specificity/sensitivity/accuracy for the early diagnosis of AD.
Somatic variants are not inherited but acquired during an individual’s lifetime, and individuals are increasingly considered as complex mosaics of genetically distinct cells. Whereas this concept is ...long-recognized in cancer, this review focuses on the growing role of somatic variants in immune cells in nonmalignant immune-related disorders, such as primary immunodeficiency and autoimmune diseases. Older case reports described somatic variants early in development, leading to large numbers of affected cells and severe phenotypes. Thanks to technological evolution, it is now feasible to detect somatic variants occurring later in life and affecting fewer cells. Hence, only recently is the scale at which somatic variants contribute to monogenic diseases being uncovered and is their contribution to complex diseases being explored systematically.
Somatic variants arise frequently, at least one order of magnitude more often than germline variants. They can occur early in development or later in life, and lead to mosaicism in a wide range or a specific subset of cell lineages.Somatic mosaicism is an under-recognized cause of monogenic immune disorders. Moreover, gonosomal mosaicism in mostly unaffected or sometimes mildly affected parents can lead to vertical transmission of a presumed de novo germline variant.Somatic variants may act as stochastic factors increasing risk of complex diseases together with inherited germline variants and environmental risk factors.Somatic variants tagging cells involved in immune pathogenesis may act as biomarkers guiding treatment.Improving technologies will facilitate detection of somatic variants affecting smaller cell subsets. Integration of germline and somatic genomes may provide novel insights into disease pathogenesis.
In 2018, the US National Institute on Aging and the Alzheimer's Association proposed a purely biological definition of Alzheimer's disease that relies on biomarkers. Although the intended use of this ...framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. Furthermore, a positive Alzheimer's disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer's disease pathology is present as a comorbidity. In this Personal View, the International Working Group presents what we consider to be the current limitations of biomarkers in the diagnosis of Alzheimer's disease and, on the basis of this evidence, we propose recommendations for how biomarkers should and should not be used for diagnosing Alzheimer's disease in a clinical setting. We recommend that Alzheimer's disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer's disease phenotypes, whereas biomarker-positive cognitively unimpaired individuals should be considered only at-risk for progression to Alzheimer's disease.
It has been hypothesized that the composition of particulate matter (PM) may be a better predictor of health effects than PM mass alone. The regional differences in PM composition and the ...heterogeneity in PM risk estimates in large multi-city epidemiologic studies are consistent with this hypothesis. Since 2005, efforts have been made to relate apportioned components and sources of PM with human health outcomes in epidemiology, controlled human exposure and toxicology studies. We reviewed published studies that: 1) focused on short-term exposure to PM; 2) included at least five components of PM; 3) grouped them into factors or sources; and 4) used quantitative methods to examine the relationship between the factors or sources and health effects. We then examined whether specific groups of PM components or sources of PM are consistently linked to specific health effects across studies. Collectively, these studies suggest that cardiovascular effects may be associated with PM2.5 from crustal or combustion sources, including traffic, but at this time, no consistent relationships have emerged. Fewer studies evaluated respiratory health effects, and the evidence for associations was limited. Apportionment methods have linked a variety of health effects to multiple groups of PM components and sources of PM, but the collective evidence has not yet isolated factors or sources that would be closely and unequivocally related to specific health outcomes.
► PM chemical composition may better predict health effects than PM mass or size. ► We reviewed 29 studies that attempted this by using apportionment methods. ► Were specific sources or factors consistently linked to specific health effects? ► Apportionment methods have identified links, but we found little if any consistency.
Alzheimer's disease (AD) causes alterations of brain network structure and function. The latter consists of connectivity changes between oscillatory processes at different frequency channels. We ...proposed a multi-layer network approach to analyze multiple-frequency brain networks inferred from magnetoencephalographic recordings during resting-states in AD subjects and age-matched controls. Main results showed that brain networks tend to facilitate information propagation across different frequencies, as measured by the multi-participation coefficient (MPC). However, regional connectivity in AD subjects was abnormally distributed across frequency bands as compared to controls, causing significant decreases of MPC. This effect was mainly localized in association areas and in the cingulate cortex, which acted, in the healthy group, as a true inter-frequency hub. MPC values significantly correlated with memory impairment of AD subjects, as measured by the total recall score. Most predictive regions belonged to components of the default-mode network that are typically affected by atrophy, metabolism disruption and amyloid-β deposition. We evaluated the diagnostic power of the MPC and we showed that it led to increased classification accuracy (78.39%) and sensitivity (91.11%). These findings shed new light on the brain functional alterations underlying AD and provide analytical tools for identifying multi-frequency neural mechanisms of brain diseases.
Four decades after the passage of the US Clean Air Act, air-quality standards are set to protect ecosystems from damage caused by gas-phase nitrogen (N) and sulfur (S) compounds, but not from the ...deposition of these air pollutants to land and water. Here, we synthesize recent scientific literature on the ecological effects of N and S air pollution in the US. Deposition of N and S is the main driver of ecosystem acidification and contributes to nutrient enrichment in many natural systems. Although surface-water acidification has decreased in the US since 1990, it remains a problem in many regions. Perturbations to ecosystems caused by the nutrient effects of N deposition continue to emerge, although gas-phase concentrations are generally not high enough to cause phytotoxicity. In all, there is overwhelming evidence of a broad range of damaging effects to ecosystems in the US under current air-quality conditions.
After intense scientific exploration and more than a decade of failed trials, Alzheimer's disease (AD) remains a fatal global epidemic. A traditional research and drug development paradigm continues ...to target heterogeneous late-stage clinically phenotyped patients with single 'magic bullet' drugs. Here, we propose that it is time for a paradigm shift towards the implementation of precision medicine (PM) for enhanced risk screening, detection, treatment, and prevention of AD. The overarching structure of how PM for AD can be achieved will be provided through the convergence of breakthrough technological advances, including big data science, systems biology, genomic sequencing, blood-based biomarkers, integrated disease modeling and P4 medicine. It is hypothesized that deconstructing AD into multiple genetic and biological subsets existing within this heterogeneous target population will provide an effective PM strategy for treating individual patients with the specific agent(s) that are likely to work best based on the specific individual biological make-up.
The Alzheimer's Precision Medicine Initiative (APMI) is an international collaboration of leading interdisciplinary clinicians and scientists devoted towards the implementation of PM in Neurology, Psychiatry and Neuroscience. It is hypothesized that successful realization of PM in AD and other neurodegenerative diseases will result in breakthrough therapies, such as in oncology, with optimized safety profiles, better responder rates and treatment responses, particularly through biomarker-guided early preclinical disease-stage clinical trials.
Apathy is a very common behavioural and psychological symptom across brain disorders. In the last decade, there have been considerable advances in research on apathy and motivation. It is thus ...important to revise the apathy diagnostic criteria published in 2009. The main objectives were to: a) revise the definition of apathy; b) update the list of apathy dimensions; c) operationalise the diagnostic criteria; and d) suggest appropriate assessment tools including new technologies.
The expert panel (N = 23) included researchers and health care professionals working on brain disorders and apathy, a representative of a regulatory body, and a representative of the pharmaceutical industry. The revised diagnostic criteria for apathy were developed in a two-step process. First, following the standard Delphi methodology, the experts were asked to answer questions via web-survey in two rounds. Second, all the collected information was discussed on the occasion of the 26th European Congress of Psychiatry held in Nice (France).
Apathy was defined as a quantitative reduction of goal-directed activity in comparison to the patient’s previous level of functioning (criterion A). Symptoms must persist for at least four weeks, and affect at least two of the three apathy dimensions (behaviour/cognition; emotion; social interaction; criterion B). Apathy should cause identifiable functional impairments (criterion C), and should not be fully explained by other factors, such as effects of a substance or major changes in the patient’s environment (Criterion D).
The new diagnostic criteria for apathy provide a clinical and scientific framework to increase the validity of apathy as a clinical construct. This should also help to pave the path for apathy in brain disorders to be an interventional target.
To devise a short bedside cognitive and behavioral battery to assess frontal lobe functions.
The designed battery consists of six subtests exploring the following: conceptualization, mental ...flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. It takes approximately 10 minutes to administer. The authors studied 42 normal subjects and 121 patients with various degrees of frontal lobe dysfunction (PD, n = 24; multiple system atrophy, n = 6; corticobasal degeneration, n = 21; progressive supranuclear palsy, n = 47; frontotemporal dementia, n = 23).
The Frontal Assessment Battery scores correlated with the Mattis Dementia Rating Scale scores (rho = 0.82, p < 0.01) and with the number of criteria (rho = 0.77, p < 0.01) and perseverative errors (rho = 0.68, p < 0.01) of the Wisconsin Card Sorting Test. These variables accounted for 79% of the variance in a stepwise multiple regression, whereas age or Mini-Mental State Examination scores had no significant influence. There was good interrater reliability (kappa = 0.87, p < 0.001), internal consistency (Cronbach's coefficient alpha = 0.78), and discriminant validity (89.1% of cases correctly identified in a discriminant analysis of patients and controls).
The Frontal Assessment Battery is easy to administer at bedside and is sensitive to frontal lobe dysfunction.
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