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.

With the increase in life expectancy, one of the most important topic for scientific research, especially for the elderly, is good nutrition.

In particular, with an advanced age and health issues because disorders such as Alzheimer and dementia, monitoring the subjects' dietary habits to avoid excessive or poor nutrition is a critical role.

It is possible to consider the following issues and typologies:

• Wearable sensors: usually represented by accelerometers positioned on human body parts, equipped with a battery and a wireless communication interface. The use of this technology requires the collaboration of the subjects wearing the device and recharging the battery, with the assumption that subjects affected by neurological problems could find it difficult to carry out these procedures.

  Ambient sensors: magnetic sensors for doors and windows, or bed and armchair sensors, which provide information on the interaction of the monitored subject with the objects. In contrast to the wearable sensors, this technology does not require subject collaboration.

  Video cameras: the classic technology for monitoring domestic and non-domestic environments. The advantage of the cameras is to have a wider field of view than sensors. Moreover, digital technologies allow privacy preservation, since it is possible to mask faces or other personal details.

The use of this type of sensor could generate problems in some situations. Firstly, because the video captured by the cameras depends on environmental lighting, sometimes strong variations in brightness make it difficult to capture images or videos of sufficient quality, and the installation of the cameras in rooms such as bathrooms or bedrooms can generate problems with privacy preservation.

Starting from an application aiming to monitor the food intake actions of people during a meal, already shown in a previously published paper, the present work describes some improvements that are able to make the application work in real time.

The considered solution exploits the Kinect v1 device that can be installed on the ceiling, in a top-down view in an effort to preserve privacy of the subjects.

The food intake actions are estimated from the analysis of depth frames. The innovations introduced in this document are related to the automatic identification of the initial and final frame for the detection of food intake actions, and to the strong revision of the procedure to identify food intake actions with respect to the original work, in order to optimize the performance of the algorithm.

Evaluation of the computational effort and system performance compared to the previous version of the application has demonstrated a possible real-time applicability of the solution presented in this document.

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Multifunctional ligands as an essential variant of polypharmacology are promising candidates for the treatment of multi-factorial diseases like Alzheimer's disease.

Based on clinical evidence and following the paradigm of multifunctional ligands the authors have rationally designed and synthesized a series of compounds targeting processes involved in the development of the disease.

The biological evaluation led to the discovery of two compounds with favorable pharmacological characteristics and ADMET profile. Compounds 17 and 35 are 5-HT6R antagonists (Ki = 13 nM and Ki = 15 nM respectively) and cholinesterase inhibitors with distinct mechanisms of enzyme inhibition.

The 5HT6 receptor is expressed almost exclusively in the brain. Despite the 5HT6 receptor having a functionally excitatory action, it is largely co-localized with GABAergic neurons and therefore produces an overall inhibition of brain activity.

Agents such as latrepirdine, idalopirdine (Lu AE58054), and intepirdine (SB-742,457/RVT-101) were evaluated as novel treatments for Alzheimer's disease and other forms of dementia. However, phase III trials of latrepirdine, idalopirdine, and intepirdine have failed to demonstrate efficacy.

Chemicals that interfere with the action of cholinesterase are potent neurotoxins (nerve gases), causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Anticholinesterases are used for reversing medication induced paralysis during anesthesia; as well as in the treatment of myasthenia gravis, glaucoma, and Alzheimer's disease.

Compound 17, a tacrine derivative is a reversible inhibitor of acetyl- and butyrylcholinesterase (IC50 = 8 nM and IC50 = 24 nM respectively), while compound 35 with rivastigmine-derived phenyl N-ethyl-N-methylcarbamate fragment is a selective, pseudo-irreversible inhibitor of butyrylcholinesterase (IC50 = 455 nM).

Both compounds inhibit aggregation of amyloid β in vitro (75% for compound 17 and 68% for 35 at 10 μM) moreover, compound 35 is a potent tau aggregation inhibitor in cellulo (79%).

In ADMET in vitro studies both compounds showed acceptable metabolic stability on mouse liver microsomes (28% and 60% for compound 17 and 35 respectively), no or little effect on CYP3A4 and 2D6 up to a concentration of 10 μM and lack of toxicity on HepG2 cell line (IC50 values of 80 and 21 μM, for 17 and 35 respectively).

Based on the pharmacological characteristics and favorable pharmacokinetic properties, the authors propose compounds 17 and 35 as an excellent starting point for further optimization and in-depth biological studies.

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Acetylcholinesterase inhibitors (AChEIs) are commonly used to treat mild to moderate cases of Alzheimer disease (AD).

There are probably no study estimating the risk of bleeding and cardiovascular events in patients with non-hypertensive AD. Therefore, this study aimed to estimate the association between AChEIs and the risk of bleeding and cardiovascular ischemic events in patients with non-hypertensive AD.

A nested case-control study was conducted to estimate the risk of bleeding and ischemic events (angina, myocardial infarction [MI], and stroke) in patients with AD.

This study was conducted using the UK Clinical Practice Research Datalink and Hospital Episode Statistics (HES) databases. The study cohort consisted of AD patients ≥65 years of age.

The case groups included all AD subjects in the database who had a bleeding or ischemic event during the cohort follow-up. Four controls were selected for each case.

Patients were classified as current users or past users based on a 60-day threshold of consuming the drug. Simple and multivariable conditional logistic regression analyses were used to calculate the adjusted odds ratio for bleeding events and cardiovascular events.

The scientists identified 507 cases and selected 2028 controls for the bleeding event cohort and 555 cases and 2220 controls for the ischemic event cohort. The adjusted odds ratio (OR) (95% confidence interval [CI]) for the association of AChEI use was 0.93 (0.75 to 1.16) for bleeding events, 2.58 (1.01 to 6.59) for angina, and 1.89 (1.07 to 3.33) for myocardial infarction. Past users of AChEIs were also at increased risk of stroke (1.51 [1.00 to 2.27]).

In conclusion: The use of AChEIs may be associated with a modest increase in the risk of myocardial infarction and angina in patients with non‐hypertensive AD.

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Prognostic studies in the context of Alzheimer's disease (AD) mainly predicted time to dementia. However, it is questionable whether onset of dementia is the most relevant outcome along the AD disease trajectory from the perspective of patients and their care partners. Therefore, the authors aimed to identify the most relevant outcomes from the viewpoint of patients and care partners.

They used a two-step, mixed-methods approach. As a first step they conducted four focus groups in the Netherlands to elicit a comprehensive list of outcomes considered important by patients (n = 12) and care partners (n = 14) in the prognosis of AD. The focus groups resulted in a list of 59 items, divided into five categories.

Next, in an online European survey, they asked participants (n = 232; 99 patients, 133 care partners) to rate the importance of all 59 items (5-point Likert scale). As participants were likely to rate a large number of outcomes as "important" (4) or "very important" (5), the scientists subsequently asked them to select the three items they considered most important.

The top-10 lists of items most frequently mentioned as "most important" by patients and care partners were merged into one core outcome list, comprising 13 items. Both patients and care partners selected outcomes from the category "cognition" most often, followed by items in the categories "functioning and dependency" and "physical health." No items from the category "behavior and neuropsychiatry" and "social environment" ended up in the core list of relevant outcomes.

Conclusion: The authors identified a core list of outcomes relevant to patients and care partner, and found that prognostic information related to cognitive decline, dependency, and physical health are considered most relevant by both patients and their care partners

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This paper aim at the analysis of the role of the circadian regulation of ghrelin levels in patients with Parkinson's disease.

Based on the literature data, patients with Parkinson's disease have clinical fluctuations in the symptoms of the disease, manifested by the diurnal changes in motor activity, autonomic functions, sleep-wake cycle, visual function, and the efficacy of dopaminergic therapy.

Biological rhythms are controlled by central and peripheral oscillators which links with dopaminergic neurotransmission - core of the pathogenesis of Parkinson's disease. Circadian system is altered in Parkinson's disease due to that ghrelin fluctuations may be changed.

Ghrelin is potential food-entrainable oscillator because it is linked with clock genes expression.

In Parkinson`s disease this hormone may induce eating behavior changing and as a result metabolic disorder.

The "hunger hormone" ghrelin can be a biomarker of the Parkinson's disease, and the study of its role in the pathogenesis, as well as its dependence on the period of the day, intake of levodopa medications to improve the effectiveness of treatment is promising.

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A randomized, placebo-controlled phase III study (AB10015) which ended in 2018 that orally administered masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable safety, in amyotrophic lateral sclerosis (ALS) patients having an ALS Functional Rating Scale-revised (ALSFRS-R) progression rate from disease onset to baseline of <1.1 points/month. As the 2018 study lasted roughly 3 years and a few months, this is not enough to create survival analysis. As patients were invited in a subsequent open label program, some information is known how they behaved during more than 6 years. This open label is under control of a local physician and dosing decisions are made solely by them.

In this article two employees of AB science, plus other contributeurs like the great ALS scientist Albert Ludolph reanalyzed the results from this 2018 trial. All investigational sites from study AB10015 were contacted with a request for an update on each patient’s vital (survival) status. From the 384 patients in the initial study, only 84 were available for the analysis.

The authors selected groups of patients between the patients that participated to this trial based on their survival. Some patients were eliminated from this new analysis, because they were too ill during the study.

Three enriched subgroups were defined: * patients with loss of ALSFR-R  < 1.1 regardless of their baseline ALSFRS-R score; * patients with ALSFRS-R ⩾2 on each baseline ALSFRS-R item, regardless of baseline ΔFS; * patients with ALSFRS-R ⩾2 on each baseline ALSFRS-R item and ΔFS < 1.1

What the authors found was that there was no real difference between patients who took masitinib 4.5 mg/kg/day versus the placebo group. So this what was found initially.

Yet when they compare a subgroup with the placebo they find a real difference. This subgroup is comprised of ALS patients that have not suffered a complete loss or severe impairment at the time of masitinib treatment initiation and have not experienced a rapid (ΔFS ⩾ 1.1) progression rate from disease onset to baseline.

In summary the authors selected a subgroup of patients (on their ALSFRS-R status) that did well and not surprisingly, they found these patients did well compared to the placebo.

So they conclude by this astonishing statement: A significant survival benefit of 25 months and 47% reduced risk of death (p = 0.025) was observed for patients receiving 4.5 mg/kg/day masitinib (n = 45) versus placebo (n = 62)

In an ideal world, scientists do not do that kind of analysis. Yet these reanalyzed studies have already been done; for example, the edaravone, rasagiline and high-fat intervention clinical trials.

There are many questions that could be asked about this study, in particular how could the small subsets of patients in sub-groups could statistically reflects the four times larger number of patients in the clinical study.

There is a lot of pressure on Biotechs, they are unfunded, actually most of them are on verge of bankrupt and the only way they could become profitable is if a big company buy them. There is also a lot hypocrisy on the part of large corporations as they do not do research on rare diseases (even Biogen works with Ionis). Instead as fat cats they wait for a succeeding trial to buy the biotech. So hundred biotech fail before one could be bought, this is an incredibly inefficient way to find new drugs.

So the reader of this blog is invited to take any enthusiastic statement by a biotech with a grain of salt.

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