In most neurodegenerative diseases there are contradictory explanations of where the disease strikes and how it progresses. For a majority of scientists it begins somewhere in the brain, while for a minority it appears in guts, mucous membranes or muscles.

Aggregation of alpha-synuclein into inclusion bodies, termed Lewy pathology, is a defining feature of Parkinson's disease (PD) and Dementia with Lewy bodies (LBD), a less agressive form of the Parkinson's disease.

The Braak staging system is based on the idea that Lewy pathology starts in the olfactory bulb and enteric nervous system, and invades the brain via the vagus nerve. Alternative hypotheses propose that Lewy pathology does not start in the gut but inside the central nervous system (CNS), or possibly via an isolated olfactory entry route followed by intra-cerebral propagation.

A potential problem with both the Braak and DLB consortium staging systems is that relatively little emphasis is put on the magnitude of Lewy pathology in a given region. Assignment of a case to a specific category or stage is based mainly on the spatial distribution of pathology. Thus, two patients who display Lewy pathology in the same anatomical regions, but who have quite different levels of pathology in those regions, will nevertheless be labeled with the same Braak or DLB consortium stage.

A recent paper analyzed 124 Lewy pathology-positive post mortem cases in a population-based sample of subjects aged over 85 years (Raunio et al., 2019). The authors showed that approximately two-thirds of the cases conformed to a caudo-rostral pattern with relatively more pathology in the brainstem than in the telencephalon.

The remaining one-third showed an amygdala-centered pattern with a peak of pathology in the “center of the brain”, including the amygdala, entorhinal cortex, and SN, and then relatively less pathology in the lower brainstem, spinal intermediolateral column (IML), and also in neocortical regions.

Here, the authors use two existing post mortem datasets to explore the possibility that clinical body-first and brain-first subtypes are equivalent to the caudo-rostral and amygdala-centered patterns of Lewy pathology seen at post mortem.

In summary, caudo-rostral and amygdala-centered profiles of Lewy pathology seem to be the two most common patterns seen in post mortem studies. In cases with a low global burden of Lewy pathology, thought to be early prodromal disease, the patterns are particularly clear. Therefore, it seems likely that patients with Lewy body disorders most commonly evolve from one of these two initial conditions.

Using in vivo, multi-modal imaging, it was recently shown that patients with prodromal and de novo PD can be divided into two clusters compatible with brain-first and body-first etiology.

In this paper the authors argue that body-first patients, in whom the sympathetic system degenerates before the dopamine system, are equivalent to post mortem cases with a caudo-rostral distribution of Lewy pathology. In early caudo-rostral cases, the autonomic structures display more pathology than the substantia nigra and limbic structures.

In contrast, brain-first patients show dopaminergic degeneration before sympathetic denervation. The scientists remarked that these patients are equivalent to post mortem cases with an amygdala-centered distribution of Lewy pathology, where limbic structures and the nigra show more pathology than do the autonomic structures.

This hypothesis could be tested in future studies, especially once a PET tracer targeting alpha-synuclein becomes available.

This line of reasoning suggests that the gut-first hypothesis posed by Braak and colleagues is only valid for that part of LBD patients, which the authors refer to as the body-first subtype.

Importantly, if the Lewy pathology in the remaining part of patients truly originates inside the brain or olfactory bulb and generally shows a top-down direction of propagation, it will be much more difficult to identify brain-first LBD at the prodromal stage.

These patients will generally not develop the most recognizable prodromal symptoms such as RBD and autonomic dysfunction until after parkinsonism or dementia have manifested.

If correct, this further emphasizes the importance of developing robust biomarkers in body fluids to detect brain-first LBD at an early stage, where neuroprotective treatments will be most effective.

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Tau protein belongs to an heterogeneous group of proteins that are associated with neurodegenerative diseases. While scientists have hoped that each protein would be associated with only one disease, actually most of those diseases cases display several harmful proteins aggregates at the same time.

These aggregates are misfolded, mislocated often partial proteins in the cytosol of neurons, including in mitochondria. Most experimental therapies that target those proteins have shown excellent pre-clinical results.

Previous studies have demonstrated that mitochondrial dysfunction is a key pathogenetic event in ALS. Interestingly, studies in Alzheimer's disease (AD) post-mortem brain and animal models link alterations in mitochondrial function to interactions between hyperphosphorylated tau and dynamin-related protein 1 (DRP1), the GTPase involved in mitochondrial fission.

Recent evidence suggest that tau may be involved in ALS pathogenesis, therefore, we sought to determine whether hyperphosphorylated tau may lead to mitochondrial fragmentation and dysfunction in ALS and whether reducing tau may provide a novel therapeutic approach.

The findings of the authors demonstrated that pTau-S396 is mis-localized to synapses in post-mortem motor cortex (mCTX) across ALS subtypes. Additionally, the treatment with ALS synaptoneurosomes (SNs), enriched in pTau-S396, increased oxidative stress, induced mitochondrial fragmentation, and altered mitochondrial connectivity without affecting cell survival in vitro.

Furthermore, pTau-S396 interacted with DRP1, and similar to pTau-S396, DRP1 accumulated in SNs across ALS subtypes, suggesting increases in mitochondrial fragmentation in ALS.

Reducing tau levels with QC-01-175, a selective tau degrader, prevented ALS SNs-induced mitochondrial fragmentation and oxidative stress in vitro. QC-01-175 is sometimes used in cerebral malaria, a severe complication of malaria.

Collectively, their findings suggest that increases in pTau-S396 may lead to mitochondrial fragmentation and oxidative stress in ALS and decreasing tau may provide a novel strategy to mitigate mitochondrial dysfunction in ALS.

pTau-S396 mis-localizes to synapses in ALS. ALS synaptoneurosomes (SNs), enriched in pTau-S396, increase oxidative stress and induce mitochondrial fragmentation in vitro. pTau-S396 interacts with the pro-fission GTPase DRP1 in ALS.

Reducing tau with a selective degrader, QC-01-175, mitigates ALS SNs-induced mitochondrial fragmentation and increases in oxidative stress in vitro.

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The CMAP idealizes the summation of a group of almost simultaneous action potentials from several muscle fibers in the same area. These are usually evoked by stimulation of the peripheral motor nerve.

Scientists wanted to determine which compound muscle action potential (CMAP) scan-derived electrophysiological markers are most sensitive for monitoring disease progression in amyotrophic lateral sclerosis (ALS), and whether they hold value for clinical trials.

Theye used four independent patient cohorts to assess longitudinal patterns of a comprehensive set of electrophysiological markers including their association with the ALS functional rating scale (ALSFRS-R).

The scientists recorded 225 thenar CMAP scan in 65 patients.

Electrophysiological markers showed extensive variation in their longitudinal trajectories. Expressed as standard deviations per month, motor unit number estimation (MUNE) values declined by 0.09, D50, a measure that quantifies CMAP scan discontinuities, declined by 0.09 and maximum CMAP by 0.05.

ALSFRS-R declined fastest, however the between-patient variability was larger compared to electrophysiological markers, resulting in larger sample sizes. MUNE reduced the sample size by 19.1% (n = 388 vs n = 314) for a 6-month study compared to the ALSFRS-R.

Conclusions: CMAP scan-derived markers show promise in monitoring disease progression in ALS patients, where MUNE may be its most suitable derivate.

Yet this study is weird, as it is known that electrophysiology (an very indirect measure of lower motor neuron activity done on muscle surface) is not accurate as it relies much on interpretation by the practitioner. In addition comparing electrophysiological markers to the unreliable ALSFRS-R looks like a very bad idea.

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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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