“Flavonoids are a class of plant-derived dietary polyphenols that have attracted attention for their pro-cognitive and anti-inflammatory effects. The diversity of flavonoids and their extensive in vivo metabolism suggest that a variety of cellular targets in the brain are likely to be impacted by flavonoid consumption. Initially characterized as antioxidants, flavonoids are now believed to act directly on neurons and glia via the interaction with major signal transduction cascades, as well as indirectly via interaction with the blood-brain barrier and cerebral vasculature. This review discusses potential mechanisms of flavonoid action in the brain, with a focus on two critical transcription factors: cAMP response element-binding protein (CREB) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB).”

The authors advocate bioavailability studies to verify the identity and concentration of flavonoid metabolites reaching the brain after ingestion and to validate that these metabolites are produced not just in rodent models but also in humans. Development of new cell lines may also provide a useful tool for investigation of the mechanisms of action of flavonoid metabolites in humans.

 

Jaeger BN, Parvlak SL, Gage FH: Mechanisms of dietary flavonoid action in neuronal function and neuroinflammation. Mol. Aspects Med.Nov 9, 2017. pii: S0098-2997(17)30111-5. doi: 10.1016/j.mam.2017.11.003.

https://www.ncbi.nlm.nih.gov/pubmed/29117513

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The purpose of this study was to examine whether the APOE ε4 allele modifies the cognitive benefits of a multidomain lifestyle intervention. Participants (ages 60-77 years) were randomly assigned to a multidomain intervention group (diet, exercise, cognitive training, and vascular risk management) or a control group (general health advice). Intervention duration was 2 years. Group allocation was not actively disclosed to participants, and outcome assessors were masked to group allocation.

Results showed that APOE ε4 carriers and noncarriers were not significantly different at baseline, except for serum cholesterol level. The difference between the intervention and control groups in annual neuropsychological test battery total score change was 0.037 among carriers and 0.014 among noncarriers. Intervention effect was not significantly different between carriers and noncarriers.

The authors concluded that healthy lifestyle changes may be beneficial for cognition in older at-risk individuals even in the presence of APOE ε4 -related genetic susceptibility to dementia. Whether such benefits are more pronounced in APOE ε4 carriers compared with noncarriers needs to be further investigated. The authors also emphasized the importance of early prevention strategies that target multiple modifiable risk factors simultaneously.

Solomon A, Turunen H, Ngandu T, Peltonen M, Levälahti E, Helisalmi S, Antikainen R, Bäckman L, Hänninen T, Jula A, Laatikainen T, Lehtisalo J, Lindström J, Paajanen T, Pajala S, Stigsdotter-Neely A, Strandberg T, Tuomilehto J, Soininen H, Kivipelto M: Effect of the Apolipoprotein E Genotype on Cognitive Change During a Multidomain Lifestyle InterventionA Subgroup Analysis of a Randomized Clinical Trial. JAMA Neurol. [Epub ahead of print, January 22, 2018. doi:10.1001/jamaneurol.2017.4365].

https://www.ncbi.nlm.nih.gov/pubmed/29356827

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“During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease.” Here, Mattson and colleagues consider how “intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood.” This metabolic switching appears to impact resistance of the brain to injury and disease.

Mattson MP, Moehl K, Ghena N, Schmaedick M, Cheng A: Intermittent metabolic switching, neuroplasticity and brain health. Nature Rev. Neurosci. 19: 63-80 (2018).

https://www.ncbi.nlm.nih.gov/pubmed/29321682

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A diet rich in salt is linked to an increased risk of cerebrovascular diseases and dementia, but it remains unclear how dietary salt harms the brain. Faraco and colleagues report that, in mice, excess dietary salt suppresses resting cerebral blood flow and endothelial function, leading to cognitive impairment. The effect depends on expansion of TH17 cells in the small intestine, resulting in a marked increase in plasma interleukin-17 (IL-17). Circulating IL-17, in turn, promotes endothelial dysfunction and cognitive impairment by the Rho kinase–dependent inhibitory phosphorylation of endothelial nitric oxide synthase and reduced nitric oxide production in cerebral endothelial cells. The findings reveal a new gut–brain axis linking dietary habits to cognitive impairment through a gut-initiated adaptive immune response compromising brain function via circulating IL-17. The authors suggest that the TH17 cell–IL-17 pathway is a putative target to counter the deleterious brain effects induced by dietary salt.

Faraco G, Brea D, Garcia-Bonilla L, Wang G, Racchumi G,  Chang H, Buendia I, Santisteban MM, Segarra SG, Koizumi K,  Sugiyama Y, Murphy M, Voss H, Anrather J, Iadecola C: Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response. Nature Neurosci. 21: 240–249 (2018).

https://www.ncbi.nlm.nih.gov/pubmed/29335605

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“Superconducting computing chips modelled after neurons can process information faster and more efficiently than the human brain. That achievement, described in Science Advances below, is a key benchmark in the development of advanced computing devices designed to mimic biological systems. And (as described below), it could open the door to more natural machine-learning software ….”

https://www.nature.com/articles/d41586-018-01290-0

Schneider ML, Donnelly CA, Russek SE, Baek B, Pufall MR, Hopkins PF, Dresselhaus PD, Benz SP, Rippard WH: Ultralow power artificial synapses using nanotextured magnetic Josephson junctions. Science Advances 4(1): e1701329 (Jan 26, 2018); DOI: 10.1126/sciadv.1701329.

http://advances.sciencemag.org/content/4/1/e1701329

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http://www.sciencemag.org/collections/bridging-divide-interdisciplinary-research-vulnerable-populations-china

Bridging the divide: Interdisciplinary research into vulnerable populations in China

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“During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease.” Here, Mattson and colleagues consider how intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood. Such metabolic switching impacts multiple signaling pathways that promote neuroplasticity and resistance of the brain to injury and disease.

Mattson MP, Moehl K, Ghena N, Schmaedick M, Cheng A: Intermittent metabolic switching, neuroplasticity and brain health. Nature Reviews Neuroscience 19: 63-80 (2018).

https://www.ncbi.nlm.nih.gov/pubmed/29321682

 

 

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Learning reflects the influence of experience on genetically determined circuitry, but little is known about how experience and genetics interact to determine learned phenotypes. Here, Mets and Brainard use vocal learning in songbirds to study genetic influences on learned behavior. They first show that the tempo of learned song is strongly influenced by genetics. However, increasing richness of the learning experience from weak (tutoring by computer) to strong (tutoring by a live bird) reduces this genetic influence in favor of experiential influence. The results demonstrate a strong, heritable contribution to individual variation in song learning but that the degree of heritability depends profoundly on the quality of instructive experience. Therefore, increasing the richness of instruction can overcome even strong genetic bias.

Mets DG and Brainard MS: Genetic variation interacts with experience to determine interindividual differences in learned song. Proc. Natl. Acad. Sci. USA 115(2): 421-426 (2018).

https://www.ncbi.nlm.nih.gov/pubmed/29279376

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ABSTRACT SUMMARY AND GOALS:

To update the 2001 American Academy of Neurology (AAN) guideline on mild cognitive impairment (MCI).

METHODS and RESULTS:

The guideline panel systematically reviewed MCI prevalence, prognosis, and treatment articles according to AAN evidence classification criteria, and based recommendations on evidence and modified Delphi consensus.

MCI prevalence was 6.7% for ages 60-64, 8.4% for 65-69, 10.1% for 70-74, 14.8% for 75-79, and 25.2% for 80-84. Cumulative dementia incidence was 14.9% in individuals with MCI older than age 65 years followed for 2 years. No high-quality evidence exists to support pharmacologic treatments for MCI. In patients with MCI, exercise training (6 months) is likely to improve cognitive measures and cognitive training may improve cognitive measures.

MAJOR RECOMMENDATIONS:

Clinicians should assess for MCI with validated tools in appropriate scenarios (Level B). Clinicians should evaluate patients with MCI for modifiable risk factors, assess for functional impairment, and assess for and treat behavioral/neuropsychiatric symptoms (Level B). Clinicians should monitor cognitive status of patients with MCI over time (Level B). Cognitively impairing medications should be discontinued where possible and behavioral symptoms treated (Level B). Clinicians may choose not to offer cholinesterase inhibitors (Level B); if offering, they must first discuss lack of evidence (Level A). Clinicians should recommend regular exercise (Level B). Clinicians may recommend cognitive training (Level C). Clinicians should discuss diagnosis, prognosis, long-term planning, and the lack of effective medicine options (Level B), and may discuss biomarker research with patients with MCI and families (Level C).

Petersen RC, Lopez O, Armstrong MJ, Getchius TSD, Ganguli M, Gloss D, Gronseth GS, Marson D, Pringsheim T, Day GS, Sager M, Stevens J, Rae-Grant A: Practice guideline update summary: Mild cognitive impairment: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology  [Epub ahead of print December 27, 2017; doi: 10.1212/WNL.0000000000004826. ]

https://www.ncbi.nlm.nih.gov/pubmed/29282327

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The BDNF mimetic compound 7,8-dihydroxyflavone (7,8-DHF), a potent small molecular TrkB agonist, displays prominent therapeutic efficacy against Alzheimer’s disease. However, 7,8-DHF has only modest oral bioavailability and a moderate pharmacokinetic profile. To alleviate these preclinical obstacles, the authors used a prodrug strategy for elevating 7,8-DHF oral bioavailability and brain exposure, and found that the optimal prodrug R13 has favorable properties and dose-dependently reverses the cognitive defects in an Alzheimer’s mouse model. Chronic oral administration of R13 activated TrkB signaling and prevented Aβ deposition in Alzheimer model mice. Moreover, R13 inhibited the loss of hippocampal synapses and ameliorated memory deficits in a dose-dependent manner. The authors suggest that the prodrug R13 is a promising new therapeutic agent for treating Alzheimer’s Disease.

Chen C, Wang Z, Zhang Z, Liu X, Kang SS, Zhang Y and Ye K: The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer’s disease. Proc. Natl. Acad. Sci. USA [Epub ahead of print, January 2, 2018; doi:10.1073/pnas.1718683115].

http://www.pnas.org/content/early/2018/01/01/1718683115.abstract

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