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.

Applying machine-learning algorithms to large datasets such as those available in Huntington's disease offers the opportunity to discover hidden patterns, often not discernible to clinical observation.

A computer model of Huntington's disease progression is missing.

Longitudinal data encompassing 2079 assessment measures from four observational studies were integrated and machine-learning methods were applied to develop a probabilistic model of disease progression. The model was validated using a separate Enroll-HD dataset and compared with existing clinical reference assessments and CAG-age product.

Nine disease states were discovered based on 44 motor, cognitive, and functional measures, which correlated with reference assessments.

The validation set included 3158 participants of whom 61.5% had manifest disease. Analysis of transition times showed that "early-disease" states 1 and 2, which occur before motor diagnosis, lasted ~16 years.

Increasing numbers of participants had motor onset during "transition" states 3 to 5, which collectively lasted ~10 years, and the "late-disease" states 6 to 9 also lasted ~10 years. The annual probability of conversion from one of the nine identified disease states to the next ranged from 5% to 27%.

The natural history of Huntington's disease can be described by nine disease states of increasing severity. The ability to derive characteristics of disease states and probabilities for progression through these states will improve trial design and participant selection. © 2021 International Parkinson and Movement Disorder Society.

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To determine the long-term prognosis of the cognitive deficits progression in elderly people with amnestic mild cognitive impairment based on the analysis of the initial clinical and immunological parameters.

This study is based on a clinical and follow-up study of 252 outpatients with aMCI, who were observed in the Federal State Budgetary Scientific Institution «Mental Health Research Center» from 2018 to 2020.

The psychometric assessment complex included the following scales and tests: MMSE, MoCA, The 10 words test, BNT, David Wechsler's Scale, subtest 6, CDT, Memory test of 5 geometric shapes, BVRT Test, DRS - Mattis Dementia Rating Scale: Verbal fluency, DRS - Mattis Dementia Rating Scale, The Munsterberg Test.

As part of the study, the level of cytokines in the blood serum was determined in all patients by enzyme immunoassay, using diagnostic kits manufactured by Cytokine LLC.

In patients with a progression of aMCI syndrome, an increase in proinflammatory cytokines IL-1, IL-6, IL-8, TNF-α is initially detected, which may reflect the level of systemic inflammation or functional insufficiency of anti-inflammatory mechanisms.

In turn, the group with a subsequent improvement in cognitive functioning, on the contrary, is distinguished by an initially increased level of the anti-inflammatory interleukin system.

The scientists here provide new data on the presence of systemic inflammation and immune disturbances and their association with clinical course of disease in the majority of elderly patients with aMCI.

Signs of a chronic low-level systemic inflammatory response in patients with aMCI is the unfavorable prognosis criterion: in such patients, cognitive deficit significantly progresses or dementia due to Alzheimer disease develops within three years.

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Pramipexole or levodopa treatment has been suggested as a therapeutic method for Parkinson disease. Nonetheless, the combined effects of 2 drugs for Parkinson disease patients are not completely understood.The aim of this systematic review was to evaluate the clinical efficacy and safety of Pramipexole plus levodopa combination therapy in the treatment of Parkinson disease compared to that of levodopaL monotherapy, in order to confer a reference for clinical practice.

Randomized controlled trials of Pramipexole plus levodopa for Parkinson disease published up to April, 2020 were retrieved. Standardized mean difference, odds ratio, and 95% confidence interval were calculated and heterogeneity was measured with the I2 test. Sensitivity analysis was also carried out. The outcomes of interest were as follows: the efficacy, unified Parkinson disease rating scale scores, Hamilton depression rating scale score or adverse events.

Twenty-four RCTs with 2171 participants were included. Clinical efficacy of Pramipexole plus levodopa combination therapy was significantly better than levodopa monotherapy.

The Hamilton depression rating scale score showed significant decrease in the Pramipexole plus levodopa combination therapy compared to L monotherapy. In contrast to levodopa monotherapy, Pramipexole plus levodopa combination therapy reduced the number of any adverse events obviously in Parkinson disease patients.

Moreover, the safety profile of Pramipexole plus levodopa combination therapy was found to be better than that of levodopa monotherapy. Further well-designed, multicenter RCTs are needed to confirm the findings of this systematic review of the literature of the field.

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