Deep Brain Stimulation (DBS) of the subthalamic nucleus or globus pallidus internus is used to treat the motor symptoms of Parkinson's disease.

The former can worsen impulsive and compulsive behaviors after controlling for the reduction of dopaminergic medications. However, the effect of pallidal DBS on such behaviors in PD patients is less clear.

The authors hypothesized that greater stimulation spread to the pallidum with prefrontal connectivity would reduce motor impulsivity.

Seven Parkinson's patients with stable globus pallidus internus DBS settings for 3 months, disease duration of 13 ± 1.3 years, and Montreal Cognitive Assessment of 26.8 ± 1.1 each had two stimulation settings defined based on reconstructions of lead placement and volume of tissue activation targeting either a dorsal or ventral position along the DBS electrode but still within the globus pallidus internus.

Subjects performed a stop signal reaction time task with the DBS turned off vs. on in each of the defined stimulation settings, which was correlated with the degree of stimulation effect on pallidal subregions.

Results: A shorter distance between the volume of tissue activation and the right prefrontally-connected GPi correlated with less impulsivity on the stop signal reaction time task (r = 0.69, p < 0.05). Greater volume of tissue activation overlap with the non-prefrontally-connected globus pallidus internus was associated with increased impulsivity.

Conclusion: These data can be leveraged to optimize DBS programming in PD patients with problematic impulsivity or in other disorders involving impulsive behaviors such as substance use disorders.disorders involving impulsive behaviors such as substance use disorders.

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" Background and purpose: The aim of this study was to investigate the role of the autonomic nervous system in Amyotrophic Lateral Sclerosis using a multimodal approach. NMS were studied with the NMS assessment scale for Parkinson's disease and an autonomic subscale was calculated. Cardioautonomic innervation at rest and while standing was assessed by different parameters of heart rate variability. NMS in general were more frequent in Amyotrophic Lateral Sclerosis patients and correlated inversely with the Amyotrophic Lateral Sclerosis functional rating scale whereas the autonomic subscore of NMSScale did not differ between both groups and was not related to functional impairment. Cardioautonomic assessment solely revealed an increased heart rate at rest in Amyotrophic Lateral Sclerosis patients, whereas the other HRV parameters did not differ from controls. Using a multimodal approach the authors found evidence for a rather mild cardio-sympathetic overactivity in Amyotrophic Lateral Sclerosis patients. Overall, autonomic dysfunction seems to be subtle and is not related to the functional state of Amyotrophic Lateral Sclerosis patients.

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Scientists and pharmaceutical industry have an interest in ultra-segmenting each disease despite the obvious overlap both clinically and at molecular level of most neurodegenerative diseases.

The motor unit number estimation (MUNE) method, reflects motor unit loss in motor neuron diseases, yet there is more and more doctors using it in other contexts.

The aim of this study was to evaluate the involvement of a peripheral motor neuron in Parkinson Disease using the motor unit number estimation method, which reflects motor unit loss in motor neuron diseases.

Multipoint incremental MUNE method was calculated in abductor pollicis brevis and abductor digiti minimi in forty one patients with Parkinson disease and forty five healthy volunteers.

From the analysis, the MUNE of APB was lower in Parkinson disease than in the control group, especially in the sub-group aged 60 years or older. MUNE was negatively correlated with the age of patientsfor APB, but not with the duration of the disease and advancement of Parkinson disease.

The loss of motor units in sporadic Parkinson's disease revealed by multipoint incremental MUNE method is considered a sign of lower motor neuron involvement, however, loss of motor neurons is slight and does not manifest equally in all muscles .

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Positron emission tomography (PET) amyloid imaging has become an important part of the diagnostic workup for patients with primary progressive aphasia (PPA) and uncertain underlying pathology.

Connected speech is a linguistic term that is quite a synonym of "conversation". Analysis of connected speech shows sound changes affecting linguistic units.

Here, scientists employ a semi-automated analysis of connected speech (CS) with a twofold objective.

• First, to determine if quantitative connected speech features can help select primary progressive aphasia (PPA) patients with a higher probability of a positive PET amyloid imaging result.
• Second, to examine the relevant group differences from a clinical perspective.

117 connected speech samples from a well-characterised cohort of PPA patients who underwent PET amyloid imaging were collected. Expert consensus established PET amyloid status for each patient, and 40% of the sample was amyloid positive.

The scientists found that leave-one-out cross-validation yields 77% classification accuracy (sensitivity: 74%, specificity: 79%).

Their results seem to confirm the potential of connected speech analysis as a screening tool. Discriminant connected speech features from lexical, syntactic, pragmatic, and semantic domains are discussed.

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by inclusions of aggregated α-synuclein (α-SYN) in the cytoplasmic region of neurons. Clinical evidence suggests that stimulation of pro-inflammatory cytokines leads to neuroinflammation in the affected brain regions.

The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death and tumour formation. Since the JAK-STAT pathway plays a major role in many fundamental processes, such as apoptosis and inflammation, dysfunctional proteins in the pathway may lead to a number of diseases. Yet it is rarely associated by scientists to Parkinson's disease. This review take the opposite point of view: The JAK-STAT signaling pathway is involved in Parkinson's disease.

The JAK-STAT pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through a process called transcription. There are three key parts of JAK-STAT signalling:

• Janus kinases (JAKs),
• signal transducer and activator of transcription proteins (STATs),
• receptors (which bind the chemical signals).

Upon neuroinflammation, the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway, and other transcription factors such as nuclear factor κB (NF-κB), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), mammalian target of rapamycin (mTOR), and toll-like receptors (TLRs) are upregulated and induce the microglial activation, contributing to Parkinson's disease via dopaminergic neuron autophagy.

Aberrant activation or phosphorylation of the components of JAK/STAT signaling pathway has been implicated in increased transcription of the inflammation-associated genes and many neurodegenerative disorders such as Parkinson's disease.

Interferon gamma (IFN-γ), and interleukine (IL)-6 are two of the most potent activators of the JAK/STAT pathway, and it was shown to be elevated in PD.

Stimulation of microglial cell with aggregated α-SYN results in production of nitric oxide (NO), tumor necrosis factor (TNF)-α, and IL-1β in PD.

Dysregulation of the JAK/STAT in PD and its involvement in various inflammatory pathways make it a promising PD therapy approach. So far, a variety of synthetic or natural small-molecule JAK inhibitors (Jakinibs) have been found promising in managing a spectrum of ailments, many of which are in preclinical research or clinical trials.

Janus kinase inhibitors, also known as JAK inhibitors or jakinibs, are a type of medication that functions by inhibiting the activity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2), thereby interfering with the JAK-STAT signaling pathway.

These inhibitors have therapeutic application in the treatment of cancer and inflammatory diseases such as rheumatoid arthritis. JAK3 inhibitors are attractive as a possible treatment of various autoimmune diseases since its functions is mainly restricted to lymphocytes.

Herein, scientists provided a perspective on the function of the JAK/STAT signaling pathway in Parkinson's disease progression and gathered data that describe the rationale evidence on the potential application of Jakinibs to improve neuroinflammation in Parkinson's disease.

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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.

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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.

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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.

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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.