Yet another in-vitro and mice study was recently published. So even if there is eventually a positive outcome, it is many years in the future. Basically it tells about experimentation done on the axon of in-vitro and in a mice model. The conclusion is that TDP-43 (which is found in misfolded aggregates in >95% of ALS patients) impairs local mitochondria in neuromotor junctions (NMJ).

However some questions could be asked: * The authors say TDP-43 in ALS plays an important role at NMJ. This is certainly NOT a mainstream statement: For most (but not all) scientists, ALS starts in the brain (upper motor neurons), not in the NMJs (lower motor neurons).

• They use transgenic mice expressing the human TDP-43 lacking the nuclear-localization-signal (∆NLS). No wonder TDP-43 goes in weird places into the cell. To remind, once a protein is produced by the ribosomes and folded by the endoplasmic reticulum (ER), it is packaged and sent to its final destination (the nucleus for TDP-43) by the Golgi apparatus. If there is no NLS, then the newly protein is not sent somewhere, it just accumulates and moves at random pushed by the Brownian movement, but it is correctly folded because it went through the ER. This is not what scientists tell, for them in ALS the TDP-43 proteins do not enter in the ER, or the ER is dysfunctional, so they stay misfolded.

• They confirm that misfolded TDP-43 is found in mitochondria, but this was first found by Gao and al at Case Western Uni in 2016.

• When they reintroduce doxycycline in mice diet (a classic trick to switch ON/OFF a gene in a genetically modified mice), the TDP-43 got again its NLS and the mice health improved. Again this was shown in the past, specially by Gao and al in 2016 who designed a credible TDP-43 genetic therapy by adding a NLS signal to neuron cells. It remain to see in real life in humans if this would improve their health. After all "normal" TDP-43 got its NLS signal in the Golgi apparatus, so why this is not the case in ALS patients?

• Something really interesting is that when they used TAT-fused peptide corresponding to residues 190-208 of G3BP1, a decrease in translation was reversed by axonal-exclusive application of (G3BP1 peptide) and mice health improved. This result mirrors other several experiments, yet this is done with peptides, not with costly genetic therapeis. This is something very low cost that could be easily tried in other labs in pre-clinical studies and may lead to a future therapy.

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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.

SGLT2 inhibitors, also called gliflozins, are a class of medications that alter essential physiology of the nephron. It inhibits reabsorption of glucose in the kidney and therefore lower blood sugar.

DPP-4 inhibitors increase incretin levels (GLP-1 and GIP), which inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels.

The effects of sodium-glucose cotransporter 2 inhibitors (SGLT2I) and dipeptidyl peptidase-4 inhibitors (DPP4I) on new-onset cognitive dysfunction in type 2 diabetes mellitus remain unknown.

This study aimed to evaluate the effects of the two novel antidiabetic agents on cognitive dysfunction by comparing the rates of dementia between SGLT2I and DPP4I users.

This was a population-based cohort study of type 2 diabetes mellitus patients treated with SGLT2I and DPP4I between January 1, 2015 and December 31, 2019 in Hong Kong. Exclusion criteria were <1-month exposure or exposure to both medication classes, or prior diagnosis of dementia or major neurological/psychiatric diseases. * Primary outcomes were new-onset dementia, Alzheimer's, and Parkinson's. * Secondary outcomes were all-cause, cardiovascular, and cerebrovascular mortality.

Results: A total of 13,276 SGLT2I and 36,544 DPP4I users were studied, SGLT2I users had lower incidences of dementia , Alzheimer's, Parkinson's disease, all-cause, cerebrovascular, and cardiovascular mortality.

In conclusions the use of SGLT2I is associated with lower risks of dementia, Parkinson's disease, and cerebrovascular mortality compared with DPP4I use after 1:2 ratio propensity score matching.

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Some years ago there were great hopes in Pramipexole hydrochloride, a dopamine agonist. A phase III, multicenter, randomized, double-blind, placebo-controlled study of RPPX (EMPOWER) was conducted in ALS patients in the US, Canada, Australia, and Europe; however, regrettably, the results were clinically insignificant.

In 2018 Japanese scientists used induced pluripotent stem cell (iPSC) technology to generate stem and differentiated cells retaining the patients' full genetic information. They thus established a large number of in vitro cellular models of SALS. These models showed phenotypic differences in their pattern of neuronal degeneration, types of abnormal protein aggregates, cell death mechanisms, and onset and progression of these phenotypes in vitro among cases.

The researchers therefore developed a system for case clustering capable of subdividing these heterogeneous SALS models by their in vitro characteristics. They further evaluated multiple-phenotype rescue of these subclassified SALS models using agents selected from non-SOD1 FALS models, and identified ropinirole, a drug similar to Pramipexole, as a potential therapeutic candidate.

As a result, ropinirole hydrochloride was eventually selected. Therefore, the scientists wanted to explore the safety, tolerability and efficacy of ropinirole hydrochloride as an ALS treatment in this clinical trial.

Patient recruitment began in December 2018 and the scientists published their results on MedArXiv. Twenty one participants with Amyotrophic Lateral Sclerosis FRS-R scores greater than 2 points were randomly assigned using dynamic allocation to receive ropinirole or placebo for 24 weeks in the double-blind period.

Upon completion, participants could choose to participate in the following 24-week open-label active extension period. The primary outcomes were safety and tolerability. The secondary outcomes for the feasibility trial objective were the change in the ALS FRS-R) score, composite functional endpoint, combined assessment of function and survival, event-free survival, and time to [≤]50% forced vital capacity (blinded outcome assessment).

The participants were randomized into two groups (ropinirole group; n=14) and received ropinirole (n=13) or placebo (n=7) and the data of all participants were analysed using mixed-effects models for repeated measures together.

The incidence of gastrointestinal disorders (mainly, temporary mild nausea and diarrhoea) was high at 77% in the ropinirole group versus 14% in the placebo group). This is common in this type of clinical trial yet it is a major problem to keep long term adherence to the treatment.

Regarding the feasibility of verifying efficacy, there were no significant differences in the ALS FRS-R score and combined assessment of function and survival scores during the double-blind period for 6 months, while the participants in the ropinirole group had lived an additional 28 weeks without disease progression events compared with the placebo group at 12 months. It seems the effect of ropinorole became obvious only after 24 weeks.

Ropinirole is thus found (by the authors) safe and tolerable for patients with ALS and this trial indicates feasibility for a subsequent large-scale trial.

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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.

This study investigated the criterion and construct validity of a novel, acoustic-based framework composed of five key components of motor control: Coordination, Consistency, Speed, Precision, and Rate.

Acoustic and kinematic analyses were performed on audio recordings from 22 subjects with amyotrophic lateral sclerosis during a sequential motion rate task. Perceptual analyses were completed by two licensed speech-language pathologists, who rated each subject's speech on the five framework components and their overall severity. Analytical and clinical validity were assessed by comparing performance on the acoustic features to their kinematic correlates and to clinician ratings of the five components, respectively.

Divergent validity of the acoustic-based framework was then assessed by comparing performance on each pair of acoustic features to determine whether the features represent distinct articulatory constructs. Bivariate correlations and partial correlations with severity as a covariate were conducted for each comparison.

Results revealed moderate-to-strong analytical validity for every acoustic feature, both with and without controlling for severity, and moderate-to-strong clinical validity for all acoustic features except Coordination, without controlling for severity. When severity was included as a covariate, the strong associations for Speed and Precision became weak.

Divergent validity was supported by weak-to-moderate pairwise associations between all acoustic features except Speed (second-formant [F2] slope of consonant transition) and Precision (between-consonant variability in F2 slope).

This study demonstrated that the acoustic-based framework has potential as an objective, valid, and clinically useful tool for profiling articulatory deficits in individuals with speech motor disorders. The findings also suggest that compared to clinician ratings, instrumental measures are more sensitive to subtle differences in articulatory function. With further research, this framework could provide more accurate and reliable characterizations of articulatory impairment, which may eventually increase clinical confidence in the diagnosis and treatment of patients with different articulatory phenotypes.

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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.

Mild Cognitive Impairment (MCI) is fraught with high false positive diagnostic errors. The high rate of false positive diagnosis hampers attempts to identify reliable and valid biomarkers for MCI.

Recent research suggests that aberrant functional neurocircuitries emerge prior to significant cognitive deficits. The aim of the present study was to examine this in clinically confirmed multi-domain amnestic-MCI (mdaMCI) using an established, multi-time point, methodology for minimizing false positive diagnosis.

Structural and resting-state functional MRI data were acquired in healthy controls (HC, n=24), clinically-confirmed multi-domain amnestic-MCI (mdaMCI, n=14) and mild Alzheimer's Dementia (mAD, n=6).

Group differences in cortical thickness, hippocampal volume and functional connectivity were investigated. Hippocampal subvolumes differentiated mAD from HC and mdaMCI.

Functional decoupling of fronto-temporal networks implicated in memory and executive function differentiated HC and mdaMCI.

Decreased functional connectivity in these networks was associated with poorer cognitive performance scores.

Preliminary findings suggest the large-scale decoupling of fronto-temporal networks associated with cognitive decline precedes measurable structural neurodegeneration in clinically confirmed MCI and may represent a potential biomarker for disease progression.

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Alzheimer's disease is a progressive neurodegenerative disease characterized by the deposition of amyloid β peptide, but given the lack of clinical efficacy of amyloid β inhibitors, this is increasingly disputed.

Yet neprilysin-deficient knockout mice exhibit both Alzheimer's-like behavioral alteration and beta-amyloid deposition in the brain. Since neprilysin is considered to be the step limiting the rate of degradation of beta-amyloid, it has been considered as a potential therapeutic target.

Scientists have previously shown that somatostatin, a neuropeptide, regulates Aβ42 levels in the brain via upregulation of neprilysin. Somatostatin mRNA levels are significantly decreased with aging, especially in Alzheimer's disease. This suggests that the aging-induced downregulation of somatostatin expression may be a trigger for amyloid β peptide pathology in late-onset Alzheimer's disease.

However, the mechanism by which somatostatin signaling regulates neprilysin activity remains unclear. In the present study, the authors used in vitro and in vivo experimental paradigms to identify α-endosulfine (ENSA) as a negative regulator of neprilysin activity downstream of somatostatin signaling.

In vitro and in vivo experiments revealed that neprilysin degrades α-endosulfine (ENSA) as a substrate, suggesting that neprilysin and α-endosulfine (ENSA) form a negative feedback loop. This hypothesis is based on the fact that opioids and substance P, cell-specific ligands in monocytes and bone marrow cells, respectively, regulate neprilysin via a feedback mechanism. It is possible that amyloid β peptide and α-endosulfine (ENSA) compete against each other in neprilysin-mediated degradation, additively exacerbating this feedback loop and inducing a vicious cycle.

A selective KATP channel agonist such as diazoxide (Dz) could serve as a beneficial approach to break this vicious cycle since diazoxide is sometimes used as a drug for antihypertensive and hypoglycemic properties, and has the potential in the preclinical setting. 'improve amyloid β peptide pathology and behavioral abnormalities in Alzheimer's disease.

Diazoxide is used as a vasodilator in the treatment of acute hypertension or malignant hypertension. Diazoxide also inhibits insulin secretion by opening the ATP-sensitive potassium channel of pancreatic beta cells;

The mechanism by which diazoxide (Dz) attenuated amyloid peptide plaque deposition was not clear, however. Their results indicate that diazoxide (Dz) reduced amyloid deposition in AppNL-F mice via the regulation of neprilysin activity in the anterior cortex and the hippocampus. This regional selectivity of the action of neprilysin by diazoxide (Dz) may depend on the dopaminergic system in the brain.

The authors have therefore demonstrated a new preventive approach at the preclinical stage of Alzheimer's disease based on the function of α-endosulfine (ENSA). This negative regulator of neprilysin and of the KATP channel could be a new therapeutic target for lowering the amyloid β peptide.

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This study evaluates the incidence, prevalence and survival trends of motor neurone disease (MND) in Northern Ireland from 2015 to 2019.

A capture-recapture analysis was performed using five independent data sources. Incidence and prevalence rates were standardized to the European Standard Population. Survival outcomes were analysed using Kaplan-Meier curves and Cox regression analysis.

Amongst 254 total cases of MND. Age standardized incidence of captured cases was 3.12 per 100,000 while in 2006 it was 1.4 per 100,000. Of identified cases, 133 (52.4%) were male; 94.5% had amyotrophic lateral sclerosis; median age of onset was 67 years; median time to diagnosis was 12 months; survival from diagnosis was 12 months.

25 people (9.8%) reported a family history of MND or frontotemporal dementia; and a known MND-associated genetic mutation was identified in 7.9% of total cases, of which the most common was C9orf72 (5.7% of all patients).

Factors associated with improved survival were younger age at onset, longer time to diagnosis, attendance at regional MND clinic, and initial neurology presentation as outpatient (all p < 0.001).

Conclusion: The incidence and prevalence of MND in Northern Ireland has increased over the last 10 years, in line with increasing rates reported from other European countries. Improved survival was associated with younger age at onset, longer time to diagnosis, attendance at a regional MND clinic and outpatient presentation to a Neurology Department.

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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.

The Amyotrophic Lateral Sclerosis diagnostic challenges necessitate more robust diagnostic and prognostic methods. A potential biomarker in this regard is the alterations of ferritin levels in the serum and cerebrospinal fluid of patients compared to controls.

The cerebrospinal fluid and serum ferritin levels were measured in 50 Amyotrophic Lateral Sclerosis cases and 50 control patients with predefined exclusion criteria. The ELISA method was utilized for laboratory measurement and was statistically analyzed using the SPSS.

Heightened serum ferritin levels in cases were not statistically significant, however, cerebrospinal fluid ferritin levels were significantly higher in Amyotrophic Lateral Sclerosis patients.

Serum ferritin levels were significantly negatively correlated with the disease duration and were significantly positively correlated with the disease progression rate.

Heightened cerebrospinal fluid ferritin levels can be used for the diagnosis of Amyotrophic Lateral Sclerosis. The correlation between the serum ferritin levels with the DPR and its correlation with the disease duration suggests potential prognostic utilities.

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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.