The interaction between the brain and periphery might play a crucial role in the development of Alzheimer's disease (AD).

By using blood transcriptomic profile data from two independent AD cohorts, scientists performed expression quantitative trait locus (cis-eQTL) analysis of 29 significant genetic loci from a recent large-scale genome-wide association study to investigate the effects of the AD genetic variants on gene expression levels and identify their potential target genes.

They then performed differential gene expression analysis of identified AD target genes and linear regression analysis to evaluate the association of differentially expressed genes with neuroimaging biomarkers.

The authors performed a cis-eQTL analysis and identified and replicated significant associations in seven genes (APH1B, BIN1, FCER1G, GATS, MS4A6A, RABEP1, TRIM4). APH1B expression levels in the blood increased in AD and were associated with entorhinal cortical thickness and global cortical amyloid-β deposition.

They conclude that an integrative analysis of genetics, blood-based transcriptomic profiles, and imaging biomarkers suggests that APH1B expression levels in the blood might play a role in the pathogenesis of AD.

Read the original article on Pubmed

Vitamin A (VitA), via its active metabolite retinoic acid (RA), is critical for the maintenance of memory function with advancing age. Although its role in Alzheimer's disease (AD) is not well understood, data suggest that impaired brain Vitamin A signaling is associated with the accumulation of β-amyloid peptides (Aβ), and could thus contribute to the onset of AD.

Methods: We evaluated the protective action of a six-month-long dietary Vitamin A-supplementation (20 IU/g), starting at 8 months of age, on the memory and the neuropathology of the 3xTg-AD mouse model of AD (n = 11-14/group; including 4-6 females and 7-8 males). We also measured protein levels of Retinoic Acid Receptor β (RARβ) and Retinoid X Receptor γ (RXRγ) in homogenates from the inferior parietal cortex of 60 participants of the Religious Orders study (ROS) divided in three groups: no cognitive impairment (NCI) (n = 20), mild cognitive impairment (MCI) (n = 20) and AD (n = 20).

Results: Vitamin A enriched diet preserved spatial memory of 3xTg-AD mice in the Y maze. Vitamin A supplementation affected hippocampal RXR expression in an opposite way according to sex by tending to increase in males and decrease in females their mRNA expression. Vitamin A enriched diet also reduced the amount of hippocampal Aβ40 and Aβ42, as well as the phosphorylation of Tau protein at sites Ser396/Ser404 (PHF-1) in males. Vitamin A supplementation had no effect on tau phosphorylation in females but worsened their hippocampal amyloid load. However, the expression of Rxr-β in the hippocampus was negatively correlated with the amount of both soluble and insoluble Aβ in both males and females. Western immunoblotting in the human cortical samples of the ROS study did not reveal differences in RARβ levels. However, it evidenced a switch from a 60-kDa-RXRγ to a 55-kDa-RXRγ in AD, correlating with ante mortem cognitive decline and the accumulation of neuritic plaques in the brain cortex.

Conclusion: Our data suggest that (i) an altered expression of RXRs receptors is a contributor to β-amyloid pathology in both humans and 3xTg-AD mice, (ii) a chronic exposure of 3xTg-AD mice to a Vitamin A enriched diet may be protective in males, but not in females.

Read the original article on Pubmed

Estimating the clinical progression of a disease in a standardized way helps communication between medical specialists. For ALS there is the King's college clinical stage progression rate, which is adapted from Braak's staging. Yet it is very difficult in practice to evaluate correctly the stage where an ALS patient stands.

Scientists wanted to estimate King's college clinical stage progression rate (ΔKC) at first clinical evaluation in order to define its predictive and prognostic role on survival in a large cohort of Amyotrophic Lateral Sclerosis (ALS) patients.

They calculated ΔKC with the following formula: 0 - KC clinical stage at first clinical evaluation/disease duration from onset to first evaluation, and each result was reported as absolute value.

All the evaluations were performed in two cohorts: one from their tertiary health centre for motor neuron disease and the other one from a pooled resource open-access ALS clinical trials (PRO-ACT) database.

The tool C-statistic was used to evaluate the model discrimination of survival at different time points (1-3 years). Cox proportional hazard model was used to identify factors associated with survival.

The scientists found that ΔKC predicted survival at three years in their medical centre and in the PRO-ACT cohort. At multivariate analysis, ΔKC was independently associated with survival both in their cohort and in the PRO-ACT cohort.

Based on these results the authors think that ΔKC could be used as a novel measure of disease progression, hence as an accurate predictor of survival in ALS patients. Indeed, greater values of ΔKC were associated with a 3.5-fold higher risk to experience the event, confirming its robust prognostic value.

Read the original article on Pubmed

Contact the author

Advertisement

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.

A growing body of evidence suggests that aggregated α-synuclein, the major constituent of Lewy bodies, plays a key role in the pathogenesis of Parkinson's disease and related α-synucleinopathies.

Immunotherapies, both active and passive, against α-synuclein have been developed and are promising novel treatment strategies for such disorders.

Here, scientists report on the humanization and pharmacological characteristics of ABBV-0805, a monoclonal antibody that exhibits a high selectivity for human aggregated α-synuclein and very low affinity for monomers.

ABBV-0805 binds to a broad spectrum of soluble aggregated α-synuclein, including small and large aggregates of different conformations. Binding of ABBV-0805 to pathological α-synuclein was demonstrated in Lewy body-positive post mortem brains of Parkinson's disease patients.

The functional potency of ABBV-0805 was demonstrated in several cellular assays, including inhibition of both neurotoxicity in primary cortical neurons and Fcγ-receptor mediated uptake of soluble aggregated α-synuclein in microglia.

In vivo, the murine version of ABBV-0805 (mAb47) displayed significant dose-dependent decrease of α-synuclein aggregates in brain in several mouse models, both in prophylactic and therapeutic settings.

In addition, mAb47 treatment of α-synuclein transgenic mice resulted in a significantly prolonged survival. ABBV-0805 selectively targets soluble toxic α-synuclein aggregates with a picomolar affinity and demonstrates excellent in vivo efficacy.

Based on the strong preclinical findings described herein, ABBV-0805 has been progressed into clinical development as a potential disease-modifying treatment for Parkinson's disease.

Read the original article on Pubmed

The present study aimed to investigate the effects of dopaminergic medication on voice, speech motor functions, and motor impairment in patients with Parkinson's disease.

Twenty-five individuals with Parkinson disease underwent comprehensive assessment of voice, speech, and motor functions in levodopa medication ON and medication OFF conditions.

Frenchay Dysarthria Assessment and Unified Parkinson's Disease Rating Scale-III were used to evaluate speech motor and motor functions, respectively.

An improvement in lip and laryngeal functioning was found in the medication ON over medication OFF state in both males and females with Parkinson disease.

UPDRS-III scores reduced from the OFF state to the ON state, and no change in dysarthria severity or VHI was found in either gender or medication condition. No correlation was found between speech motor function and motor function or between VHI and acoustic parameters of voice in either medication condition.

Improvement in motor symptoms with levodopa was predominantly observed when compared with the minor improvements in a few aspects of speech motor function and vocal parameters. The results of this study suggest the need for speech therapy as a nonpharmacological treatment method for speech impairments in Parkinson disease.

Read the original article on Pubmed

Parkinson’s disease (PD) is characterized by rigidity, bradykinesia, resting tremor, and postural instability, freezing of gait, hypometria in aiming movements, and micrographia in writing and drawing.

The neural mechanisms and cognitive-motor aspects underlying characteristic deficits in PD remain unclear.

Heterogeneity in Parkinson’s disease presentation has challenged reconciliation of dopaminergic versus nondopaminergic deficits.

Contradictory results are wide spread across studies such as unclear segregation of motor and cognitive task demands.

Dopaminergic mechanisms regulating cognitive and motor control were evaluated comparing visuoperceptual and perceptuomotor functions in Parkinson's disease.

A total of 40 individuals with PD and 42 age and education matched healthy controls (ages range 50–75) consented for participation in this study.

The current study evaluated the role of dopamine in visuoperceptual accuracy versus spatial aspects of movement in idiopathic PD compared to age-matched healthy controls. In order to isolate dopaminergic medication effects on performance, subjects engaged in the experiment twice on and off-medications counterbalanced across visits 1 and 2 (sham on and sham off for controls) with an 8-week interval between visits.

Subjects were examined on computerized tasks of visuoperceptual judgments in vertical and horizontal orientations that were contrasted with spatial accuracy in cursor movement termination relative to targets in different locations. Experimental tasks were designed to segregate spatial accuracy in perception versus aiming movements of variable stimulus lengths (4, 8, and 12 cm lines).

The performance of Parkinson disease patients was contrasted with healthy controls across two separate visits on computerized tasks of perception and aiming to a target at variable stimulus lengths.

Novel visuoperceptual tasks of length equivalence and width interval estimations without motor demands were compared with tasks estimating spatial deviation in movement termination.

The findings support the presence of spatial deficits in early Parkinson disease, more pronounced with increased discrimination difficulty, and with shorter stimulus lengths of 4 cm for both visuoperceptual and perceptumotor functions.

Dopaminergic medication had an adverse impact on visuoperceptual accuracy in particular for length equivalence estimations, in contrast with dopaminergic modulation of perceptuomotor functions that reduced angular displacements toward the target.

The differential outcomes for spatial accuracy in perception versus movement termination in Parkinson disease are consistent with involvement of the direct pathway and models of progressive loss of dopamine through corticostriatal loops.

Future research should develop validated and sensitive standardized tests of perception and explore dopaminergic selective deficits in Parkinson disease to optimize medication titration for motor and cognitive symptoms of the disease.

Read the original article on Pubmed

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative brain disorder. Despite its prevalence and severity, early diagnosis of AD remains a considerable challenge.

Scientists from Duke University, report an integrated acoustofluidics-based diagnostic system (ADx), which combines triple functions of acoustics, microfluidics, and orthogonal biosensors for clinically accurate, sensitive, and rapid detection of AD biomarkers from human plasma.

They also designed and built a surface acoustic wave-based acoustofluidic separation device to isolate and purify Alzheimer's disease biomarkers to increase the signal-to-noise ratio.

Semiconductor metal oxide nanostructures have various compositions and morphologies such as single crystals, one dimensional, and thin or thick film form. Recently, 1D nanoarchitectors have much attraction for sensing due to their aspect ratio beside their thermal and chemical stabilities.

Nanostructures grown by these techniques could adopt the shape of nanowires, nanobelts, nanotubes, nanoneedles, nanorods, etc...

The modifications in surface morphology result in sensing of various kinds of oxidizing and reducing gases like CO, NH3, NO2, H2, O2, H2S, LPG, xylene, propane, toluene, triethylamine, methanol, and acetone.

Multimodal biosensors within the integrated acoustofluidics-based Alzheimer disease diagnostic system were fabricated by in-situ patterning of the ZnO nanorod array and deposition of Ag nanoparticles onto the ZnO nanorods for surface-enhanced Raman scattering (SERS) and electrochemical immunosensors.

This diagnostic system enabled the label-free detections of SERS and electrochemical immunoassay of clinical plasma samples from AD patients and healthy controls with high sensitivity and specificity.

The researchers believe that this efficient integration provides promising solutions for the early diagnosis of AD.

Read the original article on Pubmed

Scientists aimed to investigate the effects and potential mechanisms underlying the action of Shenqi Fuzheng Injection (a Chinese traditional medicine) on a well-established transgenic mouse model of Amyotrophic Lateral Sclerosis.

Shenqi Fuzheng Injection (SFI) is concocted from two kinds of Chinese medicinal herbs, Radix Codonopsis (the root of Codonopsis pilosula; Chinese name: Dangshen) and Radix Astragali (the root of Astragalus; Chinese name: Huangqi).

It is a drug approved by the State Food and Drug Administration of the People’s Republic of China primarily as an antitumor auxiliary injection and marketed in China by Livzon Pharmaceutical Group Inc.

Transgenic SOD1-G93A mice were intraperitoneally injected with SFI three times a week from 87 days of age.

Motor function, survival, pathological manifestations in the brain, and Nrf2 pathway-related assessments of the mice were performed.

SFI marginally reduced motor neuron loss and astrocytic activation in the motor cortex of the brain of SOD1-G93A mice at 130 days of age.

There was a decrease of the level of malondialdehyde and an increase of the levels of superoxide dismutase, Nrf2, heme oxygenase-1, and glutathione S-transferase in the SOD1-G93A mice.

The SFI treatment did not significantly extended the overall survival but improved the pathological manifestations of the brain alleviating the oxydative stress injury and activating the Nrf2 pathway in the animal model of Amyotrophic Lateral Sclerosis.

Read the original article on Pubmed