Lifelong bilingualism is associated with delayed dementia onset, suggesting a protective effect on the brain. Here, the authors aim to study the effects of lifelong bilingualism as a dichotomous and continuous phenomenon, on brain metabolism and connectivity in individuals with Alzheimer's dementia.

In the present study, the scientists from Italy and Switzerland modeled bilingualism with two complementary approaches, as either a dichotomous or a continuous phenomenon. They employed FDG-PET to evaluate brain glucose metabolism and brain dysfunction in large series of bilingual and monolingual individuals with AD to investigate the neural effects of lifelong bilingualism.

According to the brain reserve hypothesis, they expected more severe cerebral hypometabolism in the group of bilinguals with AD in comparison to the monolingual AD patients, at comparable levels of dementia severity.

A language background questionnaire measured the level of language use for conversation and reading. Severity of brain hypometabolism and strength of connectivity of the major neurocognitive networks was compared across monolingual and bilingual individuals, and tested against the frequency of second language life-long usage.

Cerebral hypometabolism was more severe in bilingual compared to monolingual patients; severity of hypometabolism positively correlated with the degree of second language use.

The metabolic connectivity analyses showed increased connectivity in the executive, language, and anterior default mode networks in bilingual compared to monolingual patients. The change in neuronal connectivity was stronger in subjects with higher second language use.

The neuroprotective effects of lifelong bilingualism act both against neurodegenerative processes and through the modulation of brain networks connectivity.

These findings highlight the relevance of lifelong bilingualism in brain reserve and compensation, supporting bilingual education and social interventions aimed at usage, and maintenance of two or more languages, including dialects, especially crucial in the elderly people.

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The electronic health record is designed principally to support the provision and documentation of clinical care, as well as billing and insurance claims.

Broad implementation of the EHR, however, also yields an opportunity to use EHR data for other purposes, including research and quality improvement. Indeed, effective use of clinical data for research purposes has been a longstanding goal of physicians who provide care for patients with Amyotrophic Lateral Sclerosis, but the quality and completeness of clinical data, as well as the burden of double data entry into the EHR and into a research database, have been persistent barriers.

These factors provided motivation for the development of the Amyotrophic Lateral Sclerosis Toolkit, a set of interactive digital forms within the EHR that enable easy, consistent, and structured capture of information relevant to Amyotrophic Lateral Sclerosis patient care during clinical encounters.

Routine use of the Amyotrophic Lateral Sclerosis Toolkit within the context of the CReATe Consortium's IRB-approved Clinical Procedures to Support Research in Amyotrophic Lateral Sclerosis study protocol, permits aggregation of structured Amyotrophic Lateral Sclerosis patient data, with the goals of empowering research and driving quality improvement.

Widespread use of the Amyotrophic Lateral Sclerosis Toolkit through the CAPTURE-Amyotrophic Lateral Sclerosis protocol will help to ensure that Amyotrophic Lateral Sclerosis clinics become a driving force for collecting and aggregating clinical data in a way that reflects the true diversity of the populations affected by this disease, rather than the restricted subset of patients that currently participate in dedicated research studies.

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MRi is a new way to diagnose ALS. It replaces the unreliable practice of old school neurologists with instantaneous, factual information.

Yet there is a need of specialists to analyze MRi pictures. In the long term it will disrupt the way neurologists work, and they may take a back seat in their relation with neurodegenerescent patients.

MRi also reintroduces anatomy in the global picture and scientists may notice what is obvious to patients: That muscle wasting is a central feature of ALS, and not a epiphenomenon.

MRi brings also a new vocabulary, T1, T2, relaxivity, FLAIR, STIR, STRATE. Source: KieranMaher at English Wikibooks

T relaxivity contrast imaging may serve as a potential imaging biomarker for amyotrophic lateral sclerosis by noninvasively quantifying the tissue microstructure.

In this preliminary longitudinal study, the authors investigated the Transverse Relaxivity at Tracer Equilibrium (TRATE, an MRI technique) in three muscle groups between SOD1-G93A rat and a control population at two different timepoints. The control group was time matched to the Amyotrophic Lateral Sclerosis group such that the second timepoint was the onset of disease. Other groups have as well experimented this new way to diagnose ALS with MRi on muscles.

They observed a statistically significant decrease in TRATE over time in the gastrocnemius, tibialis, and digital flexor muscles in the SOD1-G93A model, whereas TRATE did not change over time in the control group.

Immunofluorescent staining revealed a decrease in minimum fiber area and cell density in the SOD1-G93A model when compared to the control group. These microstructural changes observed from histology align with the theorized biophysical properties of TRATE.

The scientists here demonstrate that TRATE can longitudinally differentiate disease associated atrophy from healthy muscle and has potential to serve as a biomarker for disease progression and ultimately therapy response in patients with Amyotrophic Lateral Sclerosis.

Let's hope the usage of MRi whill shorten the diagnosis "black hole" that characterize old school neurologists practice.

Let's hope MRi will help to shift the paradigm of "ALS as a Motor Neuron Disease". Many signs hint a a disease striking the skeletal muscles as well, including the presence of TDP-43 aggregates.

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Neurodegenerative diseases are characterized by the selective degeneration of neuronal populations in different brain regions and frequently the formation of distinct protein aggregates that often overlap between diseases.

Contrary to most other cells, neurons cannot divide, and therefore cannot dilute misfolded/aggregated proteins that accumulate in their cytosol. Their removal is a complex task involving recognition proteins, chaperones, and eventually activation of degradation pathways such as the ubiquitin-proteasome system and the autophagy-lysosomal pathway.

Mechanisms to recycle proteins are complex, one of them uses lysosomes. A lysosome is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules.

Lysosomal health is crucial for the degradation of dysfunctional proteins and in particular for the clearance of autophagic vacuoles. An impaired lysosomal system contributes to autophagy stress, accumulation of damaged mitochondria, and restricts clearance of proteins aggregates.

Vacuolar protein sorting ortholog 35 (VPS35) is a protein involved in autophagy and is implicated in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). Yet it was not commonly associated with ALS.

VPS35 is part of a complex called the retromer, which is responsible for transporting select cargo proteins between vesicular structures (e.g., endosomes, lysosomes, vacuoles) and the Golgi apparatus.

So any defects in VPS35 is associated with neurodegenerative diseases. Indeed it is certainly not the unique cause of those diseases. Mutations in the VPS35 gene have been identified to cause late-onset, autosomal dominant familial Parkinson's disease, whereas reduced VPS35 protein levels are reported in vulnerable brain regions of subjects with Alzheimer's disease, neurodegenerative tauopathies such as progressive supranuclear palsy and Pick's disease, and amyotrophic lateral sclerosis.

Here, Dorian Sargent and colleagues develop conditional knockout mice with the selective deletion of in neurons to better elucidate its role in neuronal viability and its connection to neurodegenerative diseases.

Surprisingly, the pan-neuronal deletion of induces a progressive and rapid disease with motor deficits and early post-natal lethality. Neuronal loss is accompanied and preceded by the formation of p62-positive protein inclusions and robust reactive astrogliosis.

The authors' study reveals a critical yet unappreciated role for VPS35 function in the normal maintenance and survival of motor neurons during post-natal development that has important implications for neurodegenerative diseases, particularly amyotrophic lateral sclerosis.

In 2020 another team achieved a substantial reduction of CRC proteins in motor neurons of SOD1 G93A mice. They designed, synthetize and characterize a small array of bis-guanylhydrazones. Such retromer stabilizers possess good in vivo bioavailability, potency, and stability.

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Pure autonomic failure is a rare degenerative disease of the autonomic nervous system. Symptoms include dizziness and fainting (caused by orthostatic hypotension), visual disturbances and neck pain. Chest pain, fatigue and sexual dysfunction are less common symptoms that may also occur. ‘Pill-rolling’ rest tremor as found in Parkinson’s disease.

The autonomic nervous system is a control system that acts largely unconsciously and regulates bodily functions. It has a sequential organization: The preganglionic neuron synapse onto a postganglionic neuron before innervating the target organ. It's a bit similar to the upper/lower motor neuron/muscle assemblage.

Longitudinal studies have reported that Pure autonomic failure can phenoconvert to a central synucleinopathy with motor or cognitive involvement-i.e., to Parkinson disease, dementia with Lewy bodies, or multiple system atrophy.

Synucleinopathies are neurodegenerative diseases characterised by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibres or glial cells.

These longitudinal studies have classified patients clinically as having Pure autonomic failure based on neurogenic orthostatic hypotension without an identified secondary cause or clinical evidence of motor or cognitive impairment due to central neurodegeneration.

This approach lumps together two neurogenic orthostatic hypotension syndromes that are pathologically and neurochemically distinct.

• One is characterized by intraneuronal cytoplasmic alpha-synuclein aggregates and degeneration of postganglionic sympathetic neurons, as in Parkinson disease and Dementia with Lewy Bodies.
• The other is not, as in multiple system atrophy.

Clinical and postmortem data show that the form of Pure autonomic failure that involves sympathetic intraneuronal synucleinopathy and noradrenergic deficiency can phenoconvert to Parkinson disease or Dementia with Lewy Bodies-but not to multiple system atrophy.

Conversely, Pure autonomic failure without these features leaves open the possibility of premotor multiple system atrophy.

Multiple system atrophy is a rare neurodegenerative disorder characterized by autonomic dysfunction, tremors, slow movement, muscle rigidity, and postural instability (collectively known as parkinsonism) and ataxia. This is caused by progressive degeneration of neurons in several parts of the brain including the basal ganglia, inferior olivary nucleus, and cerebellum.

MSA generally show little response to the dopamine medications used to treat Parkinson's disease and only about 9% of MSA patients with tremor exhibit a true parkinsonian pill-rolling tremor.

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Replacing defective neurons is an attractive goal in diseases such as Parkinson's disease or ALS, but one that still seemed unrealistic. Recently impressive progress has been made.

Parkinson's disease is a neurodegenerative disorder caused by the selective degeneration of dopaminergic cells in the substantia nigra leading to major problems in the motor system. The substancia nigra is a tiny part of the mid brain. Source Wikipedia: FrozenMan - Own work

One futuristic therapeutic approach for Parkinson's disease is dopaminergic cell-replacement therapy, in which dopaminergic precursors are grafted into the striatum to restore the lost dopaminergic neurotransmission.

Previous clinical trials based on foetal dopamine neuron transplantation have shown promising results, but also significant limitations including the survival of grafted dopaminergic neurons, which is very poor.

A major limiting factor for cell therapy in Parkinson's disease is the poor survival and reinnervation capacity of grafted dopaminergic neurons.

Major factors responsible for the high levels of dopaminergic cell loss during the transplantation process and early post-transplantation period have not been totally clarified. However, grafting-related cell trauma, lack of growth factors, poor vascularization, neuroinflammation and other factors have been involved.

MSCs have been effective against several of the above-mentioned factors, and a neuroprotective effect on grafted dopaminergic neurons could be expected. Mesenchymal stromal cells are multipotent cells originally isolated from the stroma of the bone marrow. Different studies have shown their capability to regulate the local environment through the release of immunomodulatory, antiapoptotic and trophic factors. These properties make them an attractive cell source for repairing damaged tissue.

In this work, Jannette Rodriguez-Pallares and colleagues from Spain, investigated whether co-grafting of MSCs could improve the survival and reinnervation ability of dopaminergic precursors transplanted in animal models of Parkinson's disease.

Rats with total unilateral dopaminergic denervation were grafted with a cell suspension of rat dopaminergic precursors (500,000 cells) with or without a high (200,000 cells) or low (25,000 cells) number of MSCs. Eight weeks after grafting, rats were tested for motor behaviour and sacrificed for histological analysis.

Results showed that the survival of dopaminergic neurons and graft-derived striatal dopaminergic innervation was higher in rats that received co-grafts containing a low number of MSCs than in non-co-grafted controls.

Surprisingly, the increase in the number of co-grafted MSCs led to detrimental effects. The mechanisms responsible for this effect are still unclear. A high concentration of MSCs may induce MSC senescence, damaged mitochondrial transfer or dysregulation of pro-inflammatory cytokine production.

In conclusion, co-grafting with MSCs or MSCs-derived products may constitute a useful strategy to improve dopaminergic graft survival and function. However, a tight control of MSCs density or levels of MSCs-derived products is necessary.

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Premorbid body mass index, physical activity, diabetes and cardiovascular disease have been associated with an altered risk of developing amyotrophic lateral sclerosis (ALS).

A very large prospective on UK Biobank was published in BMJ. It permits the study of a range of metabolic parameters and the risk of subsequent diagnosis of ALS.

The UK Biobank is a prospective cohort study of over 500 000 people aged between 39 and 72 years (www.ukbiobank.ac.uk).

The risk of subsequent Amyotrophic Lateral Sclerosis diagnosis in those enrolled prospectively to the UK Biobank was examined in relation to baseline levels of blood high and low density lipoprotein, total cholesterol, total cholesterol:HDL ratio, apolipoproteins A1 and B, triglycerides, glycated haemoglobin A1c and creatinine, plus self-reported exercise and body mass index.

Controlling for age and sex, higher HDL and apoA1 were associated with a reduced risk of Amyotrophic Lateral Sclerosis.

High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Increasing concentrations of HDL particles are associated with decreasing accumulation of atherosclerosis within the walls of arteries, reducing the risk of vascular diseases. HDL particles are commonly referred to as "good cholesterol",

On contrary higher total cholesterol versus HDL was associated with an increased risk of Amyotrophic Lateral Sclerosis.

Coronary artery disease, cerebrovascular disease and increasing age were also associated with an increased risk of Amyotrophic Lateral Sclerosis.

The association of HDL, apoA1 and LDL levels with risk of Amyotrophic Lateral Sclerosis contributes to an increasing body of evidence that the premorbid metabolic landscape may play a role in ALS pathogenesis, at least for a subset of patients.

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Electrical impedance myography (EIM) technology is finding application in neuromuscular disease research as a tool to assess muscle health.

Correlations between electrical impedance myography outcomes, functional, imaging and histological data have been established in a variety of neuromuscular disorders.

Electrical impedance myography (EIM) is a non-invasive technique for the evaluation of neuromuscular disease that relies upon the application and measurement of high-frequency, low-intensity electrical current.

The EIM technique has proven useful in the diagnosis of radiculopathy, with specificity and sensitivity similar to that of needle electromyography (EMG).

Unlike needle EMG, however, there is no dichotomous outcome (e.g., presence vs absence of fibrillation potentials). For this reason and also because there is a fairly wide range of normal values, in order to employ EIM for this purpose, it is necessary to compare measures on the affected side to those on the unaffected side.

Differing results notwithstanding, the concept of using impedance to measure contractile properties in health and disease is attractive as it could offer new insights into the mechanics of muscle contraction, one area in which standard electrophysiologic techniques are relatively weak. In fact, current standard approaches such as needle EMG or nerve conduction studies only measure up to the point of muscle fiber depolarization, ignoring entirely the contractile process itself.

The tongue is an extraordinarily complex muscle, with fibres running through multiple planes. Thus, assessment of muscle impedance in a number of different directions using multiple frequencies should encapsulate maximal information.

Yet, a potential problem lies in interpreting this large amount of data to give an objective measure of disease. Thus, decomposition of the data is required in order to draw out the most important features and facilitate interpretation/graphical representation.

The authors of this article used a new dimension reduction technique (Non-negative tensor factorisation), to provide a framework for identifying clinically relevant features within a high dimensional EIM dataset.

Non-negative tensor factorisation was applied to the dataset for dimensionality reduction. It provides highly significant differentiation between healthy and Amyotrophic Lateral Sclerosis patients.

Similarly this new technique to analyze datasets differentiates between mild and severe disease states and significantly correlates with symptoms.

Tensor EIM thus can provide clinically relevant metrics for identifying Amyotrophic Lateral Sclerosis- related muscle disease.

This procedure has the advantage of using the whole spectral dataset, with reduced risk of overfitting. The process identifies spectral shapes specific to disease allowing for a deeper clinical interpretation.