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.

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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