Astrocytes are key cellular partners for neurons in the central nervous system. Astrocytes react to virtually all types of pathological alterations in brain homeostasis by significant morphological ...and molecular changes. This response was classically viewed as stereotypical and is called astrogliosis or astrocyte reactivity. It was long considered as a nonspecific, secondary reaction to pathological conditions, offering no clues on disease‐causing mechanisms and with little therapeutic value. However, many studies over the last 30 years have underlined the crucial and active roles played by astrocytes in physiology, ranging from metabolic support, synapse maturation, and pruning to fine regulation of synaptic transmission. This prompted researchers to explore how these new astrocyte functions were changed in disease, and they reported alterations in many of them (sometimes beneficial, mostly deleterious). More recently, cell‐specific transcriptomics revealed that astrocytes undergo massive changes in gene expression when they become reactive. This observation further stressed that reactive astrocytes may be very different from normal, nonreactive astrocytes and could influence disease outcomes. To make the picture even more complex, both normal and reactive astrocytes were shown to be molecularly and functionally heterogeneous. Very little is known about the specific roles that each subtype of reactive astrocytes may play in different disease contexts. In this review, we have interrogated researchers in the field to identify and discuss points of consensus and controversies about reactive astrocytes, starting with their very name. We then present the emerging knowledge on these cells and future challenges in this field.
Main Points
Astrocytes react to brain homeostasis alteration by morphological and molecular changes.
This response is complex, heterogeneous and subject to controversies.
New tools, models and concepts will help better understand this widespread reaction.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract An estimated 47 million people worldwide are living with dementia in 2015, and this number is projected to triple by 2050. In the absence of a disease-modifying treatment or cure, reducing ...the risk of developing dementia takes on added importance. In 2014, the World Dementia Council (WDC) requested the Alzheimer's Association evaluate and report on the state of the evidence on modifiable risk factors for cognitive decline and dementia. This report is a summary of the Association's evaluation, which was presented at the October 2014 WDC meeting. The Association believes there is sufficient evidence to support the link between several modifiable risk factors and a reduced risk for cognitive decline, and sufficient evidence to suggest that some modifiable risk factors may be associated with reduced risk of dementia. Specifically, the Association believes there is sufficiently strong evidence, from a population-based perspective, to conclude that regular physical activity and management of cardiovascular risk factors (diabetes, obesity, smoking, and hypertension) reduce the risk of cognitive decline and may reduce the risk of dementia. The Association also believes there is sufficiently strong evidence to conclude that a healthy diet and lifelong learning/cognitive training may also reduce the risk of cognitive decline.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Due to a high prevalence of chronic non-degenerative diseases, it is suspected that COVID 19 poses a high risk of fatal complications for the Mexican population. The present study aims to estimate ...the risk factors for hospitalization and death in the Mexican population infected by SARS-CoV-2.
We used the publicly available data released by the Epidemiological Surveillance System for Viral Respiratory Diseases of the Mexican Ministry of Health (Secretaría de Salud, SSA). All records of positive SARS-CoV-2 cases were included. Two multiple logistic regression models were fitted to estimate the association between hospitalization and mortality, with other covariables. Data on 10,544 individuals (57.68% men), with mean age 46.47±15.62, were analyzed. Men were about 1.54 times more likely to be hospitalized than women (p<0.001, 95% C.I. 1.37-1.74); individuals aged 50-74 and ≥74 were more likely to be hospitalized than people aged 25-49 (OR 2.05, p<0.001, 95% C.I. 1.81-2.32, and OR 3.84, p<0.001, 95% C.I. 2.90-5.15, respectively). People with hypertension, obesity, and diabetes were more likely to be hospitalized than people without these comorbidities (p<0.01). Men had more risk of death in comparison to women (OR = 1.53, p<0.001, 95% C.I. 1.30-1.81) and individuals aged 50-74 and ≥75 were more likely to die than people aged 25-49 (OR 1.96, p<0.001, 95% C.I. 1.63-2.34, and OR 3.74, p<0.001, 95% C.I. 2.80-4.98, respectively). Hypertension, obesity, and diabetes presented in combination conveyed a higher risk of dying in comparison to not having these diseases (OR = 2.10; p<0.001, 95% C.I. 1.50-2.93). Hospitalization, intubation and pneumonia entail a higher risk of dying (OR 5.02, p<0.001, 95% C.I. 3.88-6.50; OR 4.27, p<0.001, 95% C.I. 3.26-5.59, and OR = 2.57; p<0.001, 95% C.I. 2.11-3.13, respectively). Our study's main limitation is the lack of information on mild (asymptomatic) or moderate cases of COVID-19.
The present study points out that in Mexico, where an important proportion of the population has two or more chronic conditions simultaneously, a high mortality rate is a serious risk for those infected by SARS-CoV-2.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's ...disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration AT(N). This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
How do the emotions of others affect us? The human anterior cingulate cortex (ACC) responds while experiencing pain in the self and witnessing pain in others, but the underlying cellular mechanisms ...remain poorly understood. Here we show the rat ACC (area 24) contains neurons responding when a rat experiences pain as triggered by a laser and while witnessing another rat receive footshocks. Most of these neurons do not respond to a fear-conditioned sound (CS). Deactivating this region reduces freezing while witnessing footshocks to others but not while hearing the CS. A decoder trained on spike counts while witnessing footshocks to another rat can decode stimulus intensity both while witnessing pain in another and while experiencing the pain first-hand. Mirror-like neurons thus exist in the ACC that encode the pain of others in a code shared with first-hand pain experience. A smaller population of neurons responded to witnessing footshocks to others and while hearing the CS but not while experiencing laser-triggered pain. These differential responses suggest that the ACC may contain channels that map the distress of another animal onto a mosaic of pain- and fear-sensitive channels in the observer. More experiments are necessary to determine whether painfulness and fearfulness in particular or differences in arousal or salience are responsible for these differential responses.
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•Rat ACC contains mirror-like neurons responding to pain experience and observation•Most do not respond to another salient negative emotion: fear•One can decode pain intensity in the self from a pattern decoding pain in others•Deactivating this region (area 24) impairs the social transmission of distress
Carrillo et al. show the rat anterior cingulate cortex contains emotional mirror neurons that respond when a rat experiences pain and witnesses another rat in pain but not while experiencing another salient emotion, fear. After cingulate deactivation, rats show reduced distress when witnessing another receive a shock.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary At the First WHO Ministerial Conference on Global Action Against Dementia in March, 2015, 160 delegates, including representatives from 80 WHO Member States and four UN agencies, agreed on a ...call for action to reduce the global burden of dementia by fostering a collective effort to advance research. To drive this effort, we completed a globally representative research prioritisation exercise using an adapted version of the Child Health and Nutrition Research Initiative method. We elicited 863 research questions from 201 participants and consolidated these questions into 59 thematic research avenues, which were scored anonymously by 162 researchers and stakeholders from 39 countries according to five criteria. Six of the top ten research priorities were focused on prevention, identification, and reduction of dementia risk, and on delivery and quality of care for people with dementia and their carers. Other priorities related to diagnosis, biomarkers, treatment development, basic research into disease mechanisms, and public awareness and understanding of dementia. Research priorities identified by this systematic international process should be mapped onto the global dementia research landscape to identify crucial gaps and inform and motivate policy makers, funders, and researchers to support and conduct research to reduce the global burden of dementia. Efforts are needed by all stakeholders, including WHO, WHO Member States, and civil society, to continuously monitor research investments and progress, through international platforms such as a Global Dementia Observatory. With established research priorities, an opportunity now exists to translate the call for action into a global dementia action plan to reduce the global burden of dementia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Blood‐based markers (BBMs) have recently shown promise to revolutionize the diagnostic and prognostic work‐up of Alzheimer's disease (AD), as well as to improve the design of interventional trials. ...Here we discuss in detail further research needed to be performed before widespread use of BBMs. We already now recommend use of BBMs as (pre‐)screeners to identify individuals likely to have AD pathological changes for inclusion in trials evaluating disease‐modifying therapies, provided the AD status is confirmed with positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. We also encourage studying longitudinal BBM changes in ongoing as well as future interventional trials. However, BBMs should not yet be used as primary endpoints in pivotal trials. Further, we recommend to cautiously start using BBMs in specialized memory clinics as part of the diagnostic work‐up of patients with cognitive symptoms and the results should be confirmed whenever possible with CSF or PET. Additional data are needed before use of BBMs as stand‐alone diagnostic AD markers, or before considering use in primary care.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
IMPORTANCE: Amyloid positron emission tomography (PET) detects amyloid plaques in the brain, a core neuropathological feature of Alzheimer disease. OBJECTIVE: To determine if amyloid PET is ...associated with subsequent changes in the management of patients with mild cognitive impairment (MCI) or dementia of uncertain etiology. DESIGN, SETTING, AND PARTICIPANTS: The Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study was a single-group, multisite longitudinal study that assessed the association between amyloid PET and subsequent changes in clinical management for Medicare beneficiaries with MCI or dementia. Participants were required to meet published appropriate use criteria stating that etiology of cognitive impairment was unknown, Alzheimer disease was a diagnostic consideration, and knowledge of PET results was expected to change diagnosis and management. A total of 946 dementia specialists at 595 US sites enrolled 16 008 patients between February 2016 and September 2017. Patients were followed up through January 2018. Dementia specialists documented their diagnosis and management plan before PET and again 90 (±30) days after PET. EXPOSURES: Participants underwent amyloid PET at 343 imaging centers. MAIN OUTCOMES AND MEASURES: The primary end point was change in management between the pre- and post-PET visits, as assessed by a composite outcome that included Alzheimer disease drug therapy, other drug therapy, and counseling about safety and future planning. The study was powered to detect a 30% or greater change in the MCI and dementia groups. One of 2 secondary end points is reported: the proportion of changes in diagnosis (from Alzheimer disease to non–Alzheimer disease and vice versa) between pre- and post-PET visits. RESULTS: Among 16 008 registered participants, 11 409 (71.3%) completed study procedures and were included in the analysis (median age, 75 years interquartile range, 71-80; 50.9% women; 60.5% with MCI). Amyloid PET results were positive in 3817 patients with MCI (55.3%) and 3154 patients with dementia (70.1%). The composite end point changed in 4159 of 6905 patients with MCI (60.2% 95% CI, 59.1%-61.4%) and 2859 of 4504 patients with dementia (63.5% 95% CI, 62.1%-64.9%), significantly exceeding the 30% threshold in each group (P < .001, 1-sided). The etiologic diagnosis changed from Alzheimer disease to non–Alzheimer disease in 2860 of 11 409 patients (25.1% 95% CI, 24.3%-25.9%) and from non–Alzheimer disease to Alzheimer disease in 1201 of 11 409 (10.5% 95% CI, 10.0%-11.1%). CONCLUSIONS AND RELEVANCE: Among Medicare beneficiaries with MCI or dementia of uncertain etiology evaluated by dementia specialists, the use of amyloid PET was associated with changes in clinical management within 90 days. Further research is needed to determine whether amyloid PET is associated with improved clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02420756
The Alzheimer's Association convened a multidisciplinary workgroup to develop appropriate use criteria to guide the safe and optimal use of the lumbar puncture procedure and cerebrospinal fluid (CSF) ...testing for Alzheimer's disease pathology detection in the diagnostic process.
The workgroup, experienced in the ethical use of lumbar puncture and CSF analysis, developed key research questions to guide the systematic review of the evidence and developed clinical indications commonly encountered in clinical practice based on key patient groups in whom the use of lumbar puncture and CSF may be considered as part of the diagnostic process. Based on their expertise and interpretation of the evidence from systematic review, members rated each indication as appropriate or inappropriate.
The workgroup finalized 14 indications, rating 6 appropriate and 8 inappropriate.
In anticipation of the emergence of more reliable CSF analysis platforms, the manuscript offers important guidance to health-care practitioners and suggestions for implementation and future research.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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