New “omic” technologies are revealing shared and distinct biological pathways within and across neurodegenerative diseases (NDDs), allowing a better understanding of endophenotypes that exceeds the ...boundaries of the current diagnostic criteria. Moreover, a diagnostic framework is needed that can accommodate the co‐pathology and the clinical overlap and heterogeneity of NDDs. Apart from dissecting the reasons for a revolution in how we conceive NDD, this article aims to prompt a change in how we diagnose and classify NDD, drafting a general scheme for a new nosology. As identifying a cause is the key to using the term “disease” properly, we propose using a tridimensional classification based on three axes: (1) etiology or pathogenic mechanism, (2) pathology markers and molecular biomarkers, (3) anatomic–clinical; and three hierarchical levels of etiology: (1) genetic/sporadic (2) cellular pathways and processes, and function of fluidic brain systems, and (3) risk factors.
Previous studies have suggested a relationship between the number of CAG triplet repeats in the HTT gene and neurodegenerative diseases not related to Huntington's disease (HD). This study seeks to ...investigate whether the number of CAG repeats of HTT is associated with the risk of developing certain tauopathies and its influence as a modulator of the clinical and neuropathological phenotype. Additionally, it aims to evaluate the potential of polyglutamine staining as a neuropathological screening. We genotyped the HTT gene CAG repeat number and APOE‐ℰ isoforms in a cohort of patients with neuropathological diagnoses of tauopathies (n=588), including 34 corticobasal degeneration (CBD), 98 progressive supranuclear palsy (PSP) and 456 Alzheimer's disease (AD). Furthermore, we genotyped a control group of 1070 patients, of whom 44 were neuropathologic controls. We identified significant differences in the number of patients with pathological HTT expansions in the CBD group (2.7%) and PSP group (3.2%) compared to control subjects (0.2%). A significant increase in the size of the HTT CAG repeats was found in the AD compared to the control group, influenced by the presence of the Apoliprotein E (APOE)‐ℰ4 isoform. Post‐mortem assessments uncovered tauopathy pathology with positive polyglutamine aggregates, with a slight predominance in the neostriatum for PSP and CBD cases and somewhat greater limbic involvement in the AD case. Our results indicated a link between HTT CAG repeat expansion with other non‐HD pathology, suggesting they could share common neurodegenerative pathways. These findings support that genetic or histological screening for HTT repeat expansions should be considered in tauopathies.
Assessment of neuropathological findings in individuals affected by pathological expansion of CAG HTT.
Intestinal organoids capture essential features of the intestinal epithelium such as crypt folding, cellular compartmentalization and collective movements. Each of these processes and their ...coordination require patterned forces that are at present unknown. Here we map three-dimensional cellular forces in mouse intestinal organoids grown on soft hydrogels. We show that these organoids exhibit a non-monotonic stress distribution that defines mechanical and functional compartments. The stem cell compartment pushes the extracellular matrix and folds through apical constriction, whereas the transit amplifying zone pulls the extracellular matrix and elongates through basal constriction. The size of the stem cell compartment depends on the extracellular-matrix stiffness and endogenous cellular forces. Computational modelling reveals that crypt shape and force distribution rely on cell surface tensions following cortical actomyosin density. Finally, cells are pulled out of the crypt along a gradient of increasing tension. Our study unveils how patterned forces enable compartmentalization, folding and collective migration in the intestinal epithelium.
Background:
Identifying neuropsychiatric disorders is essential for prompt treatment to reduce morbidity. Among these disorders, anxiety and depression have been frequently associated with Parkinson ...disease (PD), particularly among elderly population.
Objective:
The objective of this study is to determine the prevalence of anxiety and depression in a series of community-based PD cases in Spain, their relationship with different clinical and sociodemographic characteristics, and quality of life.
Methods:
This is an observational, descriptive, survey-based study with 95 community-based patients with PD diagnosis at different disease stages. Anxiety and depression were assessed using the State-Trait Anxiety Inventory and the Beck Depression Inventory II, respectively. Quality of life was assessed using the Parkinson’s Disease Questionnaire 39.
Results:
The prevalence of depression and anxiety was 32.63% and 68.42%, respectively. Concomitant depression and anxiety were observed in 31.58% of patients. Patients with longer than 10 years’ PD duration had an increased risk of depression. We found a relationship between the presence of anxiety, depression, and the patient’s quality of life.
Conclusions:
Depression is present in one-third and anxiety in two-thirds of PD cases in community settings in Spain. Depression and anxiety have a very negative impact on quality of life in PD. Both anxiety and depression are independent from sociodemographic characteristics, patient’s comorbidities, or antiparkinsonian treatments; presenting as intrinsic symptoms in PD.
Leptomeningeal disease (LMD) is a devastating sequela of many cancers, with an extremely poor prognosis. Barriers to improving outcomes are related to the inability of many traditional therapies to ...effectively reach the cerebrospinal fluid (CSF) space within the central nervous system. Liquorpheresis is an emerging treatment modality specific to CSF diseases, the primary mechanism of action of which is direct targeted filtration of CSF content by neurosurgical access. In this review, we highlight the principles of liquorpheresis and detail how LMD can be amenable to this treatment. Further, we summarize the current in vitro and in vivo evidence supporting liquorpheresis as a feasible method to treat LMD and other central nervous system diseases as well as describe its conceivable limitations.
More than 50% of patients diagnosed with multiple sclerosis report problems with manipulative function and impairments in their daily lives due to this disorder. Therefore, the aim of the present ...study is to determine how pinch strength, prey strength and manipulative dexterity affect the quality of life and personal autonomy of people diagnosed with multiple sclerosis and to study whether there is a difference in these aspects between different types of multiple sclerosis.
There was a total sample of 126 participants, of which 57 were controls and 69 cases. All of them were assessed with a Multiple Sclerosis Quality of Life-54 test, Nine-Hole Peg Test and Barthel Index.
People with multiple sclerosis have worse pinch strength, prey strenght, manipulative dexterity, performance in basic activities of daily living and quality of life (p < 0.001). Prey strength is a conditioning factor for performance and quality of life in people with multiple sclerosis. As for the type of multiple sclerosis, relapsing-remitting multiple sclerosis presented better values (p < 0.001).
The findings of this study point to the fact that patients diagnosed with multiple sclerosis have a decrease in prey strength, pinch strength, manipulative dexterity, quality of life and autonomy in activities of daily living compared to the healthy population.
We have previously proposed a radical change in the current strategy to clear pathogenic proteins from the central nervous system (CNS) based on the cerebrospinal fluid (CSF)-sink therapeutic ...strategy, whereby pathogenic proteins can be removed directly from the CNS via CSF. To this aim, we designed and manufactured an implantable device for selective and continuous apheresis of CSF enabling, in combination with anti-amyloid-beta (Aβ) monoclonal antibodies (mAb), the clearance of Aβ from the CSF. Here, we provide the first proof of concept in the APP/PS1 mouse model of Alzheimer’s disease (AD). Devices were implanted in twenty-four mice (seventeen APP/PS1 and seven Wt) with low rates of complications. We confirmed that the apheresis module is permeable to the Aβ peptide and impermeable to mAb. Moreover, our results showed that continuous clearance of soluble Aβ from the CSF for a few weeks decreases cortical Aβ plaques. Thus, we conclude that this intervention is feasible and may provide important advantages in terms of safety and efficacy.
Alzheimer’s disease (AD) is a global health problem, with incidence and prevalence considered to increase during the next decades. However, no currently available effective treatment exists despite ...numerous clinical trials in progress. Moreover, although many hypotheses are accepted regarding the pathophysiological mechanisms of AD onset and evolution, there are still many unknowns about the disorder. A relatively new approach, based on the amyloid-beta dynamics among different biological compartments, is currently intensely discussed, as it seems to offer a promising solution with significant therapeutic impact. Known as the “cerebrospinal-fluid-sink therapeutic strategy”, part of the “three-sink therapeutic strategy”, this theoretical model focuses on the dynamics of amyloid-beta among the three main liquid compartments of the human body, namely blood, cerebrospinal fluid, and the (brain) interstitial fluid. In this context, this article aims to describe in detail the abovementioned hypothesis, by reviewing in the first part the most relevant anatomical and physiological aspects of amyloid-beta dynamics. Subsequently, explored therapeutic strategies based on the clearance of amyloid-beta from the cerebrospinal fluid level are presented, additionally highlighting their limitations. Finally, the originality and novelty of this work rely on the research experience of the authors, who focus on implantable devices and their utility in AD treatment.
This study investigates the tensile failure mechanisms in granitic rock samples at different scales by means of different types of tests. To do that, we have selected a granitic rock type and ...obtained samples of different sizes with the diameter ranging from 30 mm to 84 mm. The samples have been subjected to direct tensile strength (DTS) tests, indirect Brazilian tensile strength (BTS) tests and to two fracture toughness testing approaches. Whereas DTS and fracture toughness were found to consistently grow with sample size, this trend was not clearly identified for BTS, where after an initial grow, a plateau of results was observed. This is a rather complete database of tensile related properties of a single rock type. Even if similar databases are rare, the obtained trends are generally consistent with previous scatter and partial experimental programs. However, different observations apply to different types of rocks and experimental approaches. The differences in variability and mean values of the measured parameters at different scales are critically analysed based on the heterogeneity, granular structure and fracture mechanics approaches. Some potential relations between parameters are revised and an indication is given on potential sample sizes for obtaining reliable results. Extending this database with different types of rocks is thought to be convenient to advance towards a better understanding of the tensile strength of rock materials.
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