Neuroinflammation, is characterized by excessively activated glial cells and overexpressed inflammatory factors in Alzheimer’s disease (AD).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are most widely used drugs in inhibiting NF-κB signaling pathway, and high-dose of ibuprofen have been confirmed to improve dementia-like symptoms in AD animal models.

Therefore, anti-neuroinflammatory treatment might undermine the positive feedback loop of neuroinflammation and neuronal dysfunction.

But ibuprofen can't make neuronal damages reversed to cure AD completely. So it is necessary to use additional neuroprotective drugs . Calcineurin inhibitor (tacrolimus, FK506), is one of the most effective neuroprotective drug in central nervous system diseases. Moreover, the amelioration of AD-like behavior has been observed in patients taking FK506 Xueqin He, Huile Gao from Sichuan and Macau universities, established an ibuprofen and FK506 encapsulated drug co-delivery system, which can target the receptor of advanced glycation endproducts and response to the high level of reactive oxygen species in Alzheimer's disease.

Methods used to get through the blood–brain barrier (BBB) may entail the use of endogenous transport systems, including carrier-mediated transporters (CMT), such as glucose and amino acid carriers, receptor-mediated transcytosis for insulin or transferrin, and the blocking of active efflux transporters such as p-glycoprotein.

Yet traditional CMT-based brain targeting delivery leads to unselective distribution in whole brain because of the homogenous expression of targeted receptors on BBB31. It is therefore important to find targets that are restrictively expressed on BBB of lesion. In AD lesion sites, the receptor of advanced glycation endproducts (RAGE) is specifically and highly expressed on the diseased neurovascular unit, including cerebral vascular endothelial cells, astrocytes and neurons.

As RAGE is highly and specifically expressed on the lesion neurovascular unit of Alzheimer's disease, this property helps to improve specificity of drug targeting the system and reduce unselective distribution in normal brain.

RAP peptide (sequence: CELKVLMEKEL) is a specific ligand of RAGE, which could assist with the transportation of nanoparticles into diseased brain parenchyma through CMT.

Thus, ibuprofen and FK506 delivery can be specifically released in astrocytes of Alzheimer's disease lesion in response to high levels of ROS.

As a result, the cognition of Alzheimer's disease mice was significantly improved and the quantity of A plaques was decreased. Neurotoxicity was also alleviated with structural regeneration and functional recovery of neurons. Besides, the neuroinflammation dominated by NF-B pathway was significantly inhibited with decreased NF-B and IL-1 in the brain. Overall, Ibu&FK@RNPs can efficiently and successively target diseased BBB and astrocytes in Alzheimer's disease lesion. Thus it significantly treats Alzheimer's disease by anti-neuroinflammation and neuroprotection.

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It's known since 2017 that some people with Type 2 diabetes have a higher risk of Alzheimer's disease.

A variant of the so-called Alzheimer’s gene, APOE4, seems to interfere with brain cells' ability to use insulin, which may eventually cause the cells to starve and die. Unofficially, it's called Type 3 diabetes. What it refers to is that their brain's insulin utilization or signaling is not functioning. Their risk of developing Alzheimer’s disease is about 10 to 15 times higher.

This new article by Gemma Salvadó and colleagues adds more information on this topic. Glial activation is one of the earliest mechanisms to be altered in Alzheimer's disease. Glial fibrillary acidic protein relates to reactive astrogliosis and can be measured in both cerebrospinal fluid and blood.

Plasma GFAP has been suggested to become altered earlier in Alzheimer's disease than its cerebrospinal fluid counterpart.

Although astrocytes consume approximately half of the glucose-derived energy in the brain, the relationship between reactive astrogliosis and cerebral glucose metabolism is poorly understood. Fluorodeoxyglucose (FDG) is a glucose analog labeled with a positron emitter isotope (18F) that allows measurement of regional cerebral glucose consumption using positron emission tomography (PET).

The Spanish authors aimed to investigate the association between fluorodeoxyglucose (FDG) uptake and reactive astrogliosis, by means of GFAP quantified in both plasma and cerebrospinal fluid for the same participants. GFAP is an astrocytic intermediate filament protein, mainly expressed in the brain.

The ALFA cohort characterized preclinical AD in 2743 cognitively unimpaired individuals, aged between 45 and 75 years old, and enriched for family history of sporadic AD. From this parent cohort, 419 ALFA + participants were selected to be preferentially APOE-ε4 carriers and/or to be adult children of AD patients. These participants underwent a more comprehensive evaluation including a lumbar puncture and an Aβ and [18F]FDG PET.

For this study, the authors included 314 cognitively unimpaired participants from the ALFA + cohort, 112 of whom were amyloid-β positive. Associations between GFAP markers and [18F]FDG uptake were studied.
The authors also investigated whether these associations were modified by Aβ and tau status.

Plasma GFAP was positively associated with glucose consumption in the whole brain, while cerebrospinal fluid GFAP associations with [18F]FDG uptake were only observed in specific smaller areas like temporal pole and superior temporal lobe. These associations persisted when accounting for biomarkers of Aβ pathology but became negative in Aβ-positive and tau-positive participants in similar areas of Alzheimer's disease-related hypometabolism.

Higher astrocytic reactivity, probably in response to early Alzheimer's disease pathological changes, is related to higher glucose consumption. With the onset of tau pathology, the observed uncoupling between astrocytic biomarkers and glucose consumption might be indicative of a failure to sustain the higher energetic demands required by reactive astrocytes.

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Over the years, the scientific community has sought improvements in the life quality of patients diagnosed with Alzheimer's disease. Synaptic loss and neuronal death observed in the regions responsible for cognitive functions represent an irreversible progressive disease that is clinically characterized by impaired cognitive and functional abilities, along with behavioral symptoms. Currently, image and body fluid biomarkers can provide early dementia diagnostic, being it the best way to slow the disease's progression. The first signs of Alzheimer's disease development are still complex, the existence of individual genetic and phenotypic characteristics about the disease makes it difficult to standardize studies on the subject. The answer seems to be related between Aβ and tau proteins. Aβ deposition in the medial parietal cortex appears to be the initial stage of Alzheimer's disease, but it does not have a strong correlation with neurodegeneration. The strongest link between symptoms occurs with tau aggregation, which antecede Aβ deposits in the medial temporal lobe, however, the protein can be found in cognitively healthy older people. The answer to the question may lie in some catalytic effect between both proteins. Amid so many doubts, Aducanumab was approved, which raised controversies and results intense debate in the scientific field. Abnormal singling of some blood biomarkers produced by adipocytes under high lipogenesis, such as TNFα, leptin, and interleukin-6, demonstrate to be linked to neuroinflammation worsens, diabetes, and also severe cases of COVID-19, howsoever, under higher lipolysis, seem to have therapeutic anti-inflammatory effects in the brain, which has increasingly contributed to the understanding of Alzheimer's disease. In addition, the relationship of severe clinical complications caused by Sars-CoV-2 viral infection and Alzheimer's disease, go beyond the term "risk group" and may be related to the development of dementia long-term.

Thus, this review summarized the current emerging pharmacotherapies, alternative treatments, and nanotechnology applied in clinical trials, discussing relevant points that may contribute to a more accurate look.

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Contrary to appearances, there is some links in this post with neurodegenerative diseases. Alcoholic liver injury are one kind of cellular stress. All drugs that can treat cellular stress, and especially Endoplasmic Reticulum (ER) stress, can probably be used against most common neurodegenerative diseases. The same is true for drugs with free radicals scavenging activity.

Euscaphis konishii Hayata is a traditional medicinal plant in China, and its leaves are usually used to make dishes for hepatic or gastrointestinal issues by Chinese She nationality. Hepatocellular carcinoma (hepatoma) is the most common type of primary liver cancer in adults. Hepatocellular carcinoma causes 662,000 deaths worldwide per year about half of them in China.

Pharmacological analysis showed that E. konishii leaves contain high levels of flavonoids and chromones with favorable anti-hepatoma effect. 8 flavonoids and 2 chromones were recognized in the chromone-rich extract. Chromones are found throughout the plant kingdom, where they serve as essential components of a number of structural polymers, provide protection from ultraviolet light, defend against herbivores and pathogens, and also mediate plant-pollinator interactions as floral pigments and scent compounds.

Alcohol-fed mice disease model were used to assess the hepatoprotective effects of these chromone-rich extract.

Chromone-rich extract represented strong free radicals scavenging activity in vitro. With oral administration, chromone-rich extract dose-dependently decreased the serum levels of alanine aminotransferase, alkaline phosphatase and aspartate aminotransferase in alcohol-fed mice.

Chromone-rich extract gradually increased the activity of superoxide dismutase and glutathione peroxidase in the alcohol-treated liver tissues. Chromone-rich extract also alleviated the hepatic inflammation, inhibited the hepatocyte apoptosis and lessened the alcohol-induced histological alteration and lipid accumulation in the liver tissues.

Chromone-rich extract administration inhibited the overexpression of endoplasmic reticulum chaperones signaling and unfolded protein response pathways to defense the ER-induced apoptosis. Pretreatment with chromone-rich extract also restored the mitochondrial membrane potentials andadenosine triphosphate levels, which in turn suppressed the Cytochrome C release and mitochondria-induced apoptosis.

Chromone-rich extract conferred great protection against alcoholic liver injury, which might be associated with its viability through suppressing reactive oxygen species stress and hepatocyte apoptosis.

It may be possible they also have positive effects in neurodegenerative diseases.

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What's in a name? Is Flail leg syndrome a variant of ALS or another disease? There are many anomalies in medicine, for example cancer sufferers in Western Europe could have a much different life expectancy when moving abroad, even when the new country is very similar to the country of origin.

It's a bit similar in ALS, it looks like ALS is not exactly the same disease in US, EU or Asia. Sometimes there is a understandable reason for example the statistical frequency of SOD1 mutations is different in Asia from US. Sometimes it is simply a matter of different semantics, some neurologists tell ALS is both upper and lower motor neurons, others have different opinions.

"Flail leg syndrome" is a Asian variant of amyotrophic lateral sclerosis with the characteristics of slow progression and the symptoms confined to the lumbosacral region for extended periods. In US it would have probably been called "Progressive Muscular Atrophy".

Yet there is no genetic background behind Flail leg syndrome, so why is it a regional appellation? In this new publication the scientists astonishingly decided that a slow progressing disease must be called "Flail leg syndrome".

The objective of a new study was to determine a cutoff time of disease progression that could differentiate Flail leg syndrome from the typical lower limb onset Amyotrophic Lateral Sclerosis.

A cutoff point analysis was performed with maximally selected log-rank statistics in patients with lower limb onset Amyotrophic Lateral Sclerosis registered from 2009 to 2013.

Based on the cutoff duration from the lower limb onset to second region (14 months), all patients were divided into the slowly progressive subtype of lower limb onset Amyotrophic Lateral Sclerosis group and the typical lower limb-onset Amyotrophic Lateral Sclerosis group.

Unsurprisingly the FLS was characterized by slower progression, less and later respiratory dysfunction, and a more benign prognosis than the typical lower limb onset Amyotrophic Lateral Sclerosis.

Patients with FLS exhibited a median diagnostic delay of 25 months, a median duration of 24 months from lower limb onset to second region, a forced vital capacity abnormity rate of 12.5% at the first visit to authors' department, and a median survival time of 80 months, which were significantly different from those of patients with typical lower limb onset Amyotrophic Lateral Sclerosis. The 5-year survival rate of the FLS group was much higher than that of the other group.

Now what all this mean? That if you select patients with a slow progression, you find they have a slow progression, is it high quality science?

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Despite recent studies suggesting a declining incidence and prevalence of dementia on a global scale, epidemiologic results with respect to Alzheimer's disease are lacking due to the methodological limitations inherent to conducting large-scale cohort investigations of this topic.

The aim of the current study was to investigate the incidence and prevalence of Alzheimer's disease in Korea.
The authors conducted a secondary analysis within the National Health Insurance System database, a unique resource that reports medical information for the entire Korean population.

Alzheimer's disease diagnoses as well as evaluations of vascular risks were defined based on International Statistical Classification of Diseases codes along with prescription records.

In this study, the incidence and prevalence of Alzheimer's disease in the Korean population aged 40 years or older showed an overall increase between 2006 and 2015.

Although both older and younger age groups showed an increase in the incidence and prevalence of Alzheimer's disease, the highest increase was observed in older age groups. Which is the inverse of the previous reports.

The average value for the diagnosis of Alzheimer's disease was found to be 69 years.

The incidence of Alzheimer's disease was higher in individuals with underlying vascular risks. However, in recent years, the prevalence of Alzheimer's disease was conversely found to be lower in individuals with hypertension or dyslipidemia.

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While amyotrophic lateral sclerosis is widely recognised as a multi-network disorder with extensive frontotemporal and cerebellar involvement, sensory dysfunction is most of the time denied as "ALS is a motor neuron disease", despite the wide reports of pain by patients and multiple MRI studies telling degeneration in many areas in the brain. This study complements the work in this area, hopefully many progress could be expected when scientists will stop to think of ALS as only "a motor neuron disease".

In a prospective neuroimaging study the authors have systematically evaluated cerebral grey and white matter structures involved in the processing, relaying and mediation of sensory information. Twenty two C9orf72 positive Amyotrophic Lateral Sclerosis patients, 138 C9orf72 negative Amyotrophic Lateral Sclerosis patients and 127 healthy controls were included.

Widespread cortical alterations were observed in C9+ Amyotrophic Lateral Sclerosis including both primary and secondary somatosensory regions. In C9- Amyotrophic Lateral Sclerosis, cortical thickness reductions were observed in the postcentral gyrus.

Thalamic nuclei relaying somatosensory information as well as the medial and lateral geniculate nuclei exhibited volume reductions. Diffusivity indices revealed posterior thalamic radiation pathology and a trend of left medial lemniscus degeneration was also observed in C9- Amyotrophic Lateral Sclerosis.

The authors' radiology data confirm the degeneration of somatosensory, visual and auditory pathways in Amyotrophic Lateral Sclerosis, which is more marked in GGGGCC hexanucleotide repeat expansion carriers.

In contrast to the overwhelming focus on motor system degeneration and frontotemporal dysfunction in recent research studies, authors' findings confirm that sensory circuits are also affected in Amyotrophic Lateral Sclerosis.

The involvement of somatosensory, auditory and visual pathways in Amyotrophic Lateral Sclerosis may have important clinical ramifications which are easily overlooked in the context of unremitting motor decline.

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Advanced therapies, including cell and gene therapies, are in development for Parkinson's disease. In many cases, the goal is to replace the lost dopamine, which is anticipated to improve motor dysfunctions associated with dopamine loss. This publication casts some doubts on this strategy.

For Mariah J Lelos from Cardiff University, it is not clear the extent to which these therapeutic interventions may impact on the wide range of cognitive symptoms that manifest as the disease progresses.

Although the accepted perception is that cognitive symptoms are predominately non-dopaminergic in origin, in this commentary, Lelos argues that several, specific cognitive processes, such as habit formation, working memory and reward processing, have been reported to be dopamine-dependent.

Furthermore, there is evidence of dopaminergic medications modulating these behaviors in Parkinson disease patients. Finally, the potential for cell and gene advanced therapies to influence these symptoms is considered.

Lelos concludes that dopamine replacement through advanced therapies is likely to improve certain dopamine-dependent symptoms, but only sparse clinical data are currently available and the ability to precisely titrate dopamine transmission is likely to be complex.

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