Objectives: Dementia of the Alzheimer's type (DAT) is the most common chronic neurodegenerative disease. At present, the pathogenesis of Alzheimer's disease is not completely clear, and there are no drugs that can cure the disease. Once an individual is diagnosed with Alzheimer's disease, the survival time is only 3 to 9 years.

Therefore, there is an urgent need to determine the etiology of Alzheimer's disease and the associated influencing factors to find a breakthrough in the treatment of DAT.

Methods: We studied the relationship between polymorphisms in several genes (including BIN1 and APOE) and Alzheimer's disease susceptibility and the effects of sex differences on Alzheimer's disease.

Our study included 137 patients with Alzheimer's disease and 509 healthy controls (HCs). Results: The APOE rs429358 polymorphism CC and CT genotypes were associated with an increased risk of Alzheimer's disease in women.

We found a significant association between APOE ε4 and Alzheimer's disease. The frequency of the ε4 allele in the Alzheimer's disease group (15.5%) was higher than that in the HC group (8.7%). The BIN1 rs7561528 polymorphism was associated with a decreased risk of DAT in men.

Conclusions: APOE gene rs429358 and BIN1 gene 7561528 genes may affect the susceptibility to Alzheimer's disease in a Chinese Han population.

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Polygenic risk scores (PRS) aggregating results from genome-wide association studies are the state of the art in the prediction of susceptibility to complex traits or diseases, yet their predictive performance is limited for various reasons, not least of which is their failure to incorporate the effects of gene-gene interactions.

Novel machine learning algorithms that use large amounts of data promise to find gene-gene interactions in order to build models with better predictive performance than PRS.

Here, we present a data preprocessing step by using data-mining of contextual information to reduce the number of features, enabling machine learning algorithms to identify gene-gene interactions.

We applied our approach to the Parkinson's Progression Markers Initiative (PPMI) dataset, an observational clinical study of 471 genotyped subjects (368 cases and 152 controls). With an AUC of 0.85 (95% CI = [0.72; 0.96]), the interaction-based prediction model outperforms the PRS (AUC of 0.58 (95% CI = [0.42; 0.81])).

Furthermore, feature importance analysis of the model provided insights into the mechanism of Parkinson's disease. For instance, the model revealed an interaction of previously described drug target candidate genes TMEM175 and GAPDHP25.

These results demonstrate that interaction-based machine learning models can improve genetic prediction models and might provide an answer to the missing heritability problem.

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Here we will discuss about two recent studies about the relation between protocatechuic acid and Alzheimer's disease.

Diet appears to be have some relation with the progression of Alzheimer's disease, maybe related to the gut microbiome. There is a clear relation between gut's microbiome and Alzheimer's disease which was formalized in Braak's stages.

The aims of the first study were to detect the main anthocyanins of blueberry extract; then to verify the protective effects of anthocyanin-rich blueberry extract on hippocampal neurons and the promotion of autophagy; and finally to investigate the main protective effects and mechanisms of protocatechuic acid, a major metabolite of blueberry extract, for promoting autophagy and thus playing a neuroprotective role.

Protocatechuic acid is a type of phenolic acid increasing bringing plants resistance against fungus. It is a major metabolite of antioxidant polyphenols found in green tea. It has mixed effects on normal and cancer cells in in vitro and in vivo studies. Açaí oil, obtained from the fruit of the açaí palm (Euterpe oleracea), is rich in protocatechuic acid (630±36 mg/kg).

Protocatechuic acid is regarded as an active component in traditional Chinese herbal medicine. For example the dried and mature fruits of the Zingiberaceae plant Alpinia oxyphylla Miq, is a choice in traditional Chinese medicine to treat Alzheimer's disease.

Recent studies have demonstrated its potent activities in modulating multiple signaling pathways associated with β-amyloid deposition, tau protein phosphorylation, chronic inflammation, oxidative stress.

In this study mice models of Alzheimer's disease (APP/PS1) were given 150 mg/kg blueberry extract daily for 16 working days. The mice were then sacrificed and morphology of neurons was observed under transmission electron microscope and autophagy-related proteins were detected.

Protocatechuic acid also promoted autophagy of neurons and the mechanism was mainly involved in increasing autophagosome degradation.

Neuron damage in morphology was reduced and the expression of autophagy-related proteins in APP/PS1 mice were promoted after blueberry extract treatment. In vitro, Aβ25-35-induced cytotoxicity, including decreased neuron viability and increased levels of lactate dehydrogenase and reactive oxygen species, was effectively reversed by protocatechuic acid.

Furthermore, by adding autophagy inducers rapamycin and autophagy inhibitors Bafilomycin A1, it was verified that degradation of autophagosomes was upregulated and autophagy was promoted by protocatechuic acid.

Yet it seems unlikely that any chemical coumpound would dramatically improve Alzheimer's disease in a few weeks and we all know that few results like that are credible. However other recent studies have hinted at similar results.

Protocatechuic acid is a dihydroxybenzoic acid with is a precursor of some insecticides and neurotransmitters like catecholamines, so it is indeed a potent and possibly dangerous drug.

In the treatment of Alzheimer's disease, it is important to develop alternative cholinesterase inhibitors with antioxidant properties that will reduce acetylcholine deficiency and free radical formation.

The aim of this other study was to investigate the effect of hydroquinone, 4-hydroxybenzoic acid, 3,5-dihydroxybenzoic acid, caffeic acid, vanillic acid and chlorogenic acid against acetylcholinesterase (AChE), partially purified from serum.

Binding of compounds with effective inhibitory potential to the AChE active site as competitive was illuminated by molecular docking.

Hydroquinone, chlorogenic acid and 4-hydroxybenzoic acid have been found to have higher inhibitory potential than others against the AChE. IC50 and KI values of the phenolic compounds against AChE were found in the range of 0.26 ± 0.01-36.34 ± 2.72 mM and 0.72 ± 0.00-29.23 ± 2.62 mM, respectively.

The effectiveness of the compounds has been associated with its structure. Consequently, the phenolic compounds, which have AChE inhibitory potential and antioxidant properties, can be considered as alternative drugs in the treatment of Alzheimer's disease.

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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