“Excessive dopamine neurotransmission underlies psychotic episodes as observed in patients with some types of bipolar disorder and schizophrenia. The dopaminergic hypothesis was postulated after the finding that antipsychotics were effective to halt increased dopamine tone. However, there is little evidence for dysfunction within the dopaminergic system itself. Alternatively, it has been proposed that excessive afferent activity onto ventral tegmental area dopaminergic neurons, particularly from the ventral hippocampus, increase dopamine neurotransmission, leading to psychosis.” Here, Tomasella and colleagues “show that selective dopamine D2 receptor deletion from parvalbumin interneurons in mouse causes an impaired inhibitory activity in the ventral hippocampus and a dysregulated dopaminergic system. Conditional mutant animals show adult onset of schizophrenia-like behaviors and molecular, cellular, and physiological endophenotypes as previously described from postmortem brain studies of patients with schizophrenia. (These) findings show that dopamine D2 receptor expression on parvalbumin interneurons is required to modulate and limit pyramidal neuron activity, which may prevent the dysregulation of the dopaminergic system.”
Tomasella E, Bechelli L, Ogando MB, Mininni C, Di Guilmi MN, De Fino F, Zanutto S, Elgoyhen AB, Marin-Burgin A, Gelman DM: Deletion of dopamine D2 receptors from parvalbumin interneurons in mouse causes schizophrenia-like phenotypes. Proc. Natl. Acad. Sci. USA pii: 201719897. doi: 10.1073/pnas.1719897115. [Epub ahead of print, March 12, 2018].
The purpose of this study was to investigate whether greater cardiovascular fitness in midlife is associated with decreased dementia risk in women followed for 44 years. A population-based sample of 1,462 women 38 to 60 years of age was examined in 1968. Of these, a systematic subsample comprising 191 women completed a stepwise-increased maximal ergometer cycling test to evaluate cardiovascular fitness. Subsequent examinations of dementia incidence were done in 1974, 1980, 1992, 2000, 2005, and 2009.
The study found that high cardiovascular fitness in midlife was associated with decreased risk of dementia. High compared to medium fitness decreased the risk of dementia by 88%. The authors suggest that promotion of high cardiovascular fitness may be included in strategies to combat dementia. Findings are not causal, and future research is needed on whether improved fitness could have positive effects on dementia risk and when during the life course a high cardiovascular fitness is the most important.
Hörder H, Johansson L, Guo X, Grimby G, Kern S, Östling S, Skoog I: Midlife cardiovascular fitness and dementia: A 44-year longitudinal population study in women. Neurology: pii: 10.1212/WNL.0000000000005290. doi: 10.1212/WNL.0000000000005290. [Epub ahead of print, March 14, 2018].
“New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons.” Here Sorrells and colleagues report that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. They also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18-77 years), young neurons were not detected in the dentate gyrus.
The authors concluded that “recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved.”
Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, James D, Mayer S, Chang J, Auguste KI, Chang EF, Gutierrez AJ, Kriegstein AR, Mathem GW, Oldham MC, Huang EJ, Garcia-Verdugo JM, Yang Z, Alvarez-Buylla A: Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature [ Epub ahead of print; March 7, 2018; doi: 10.1038/nature25975 ].
This study examined the risks of myocardial infarction, stroke, peripheral artery disease, venous thromboembolism, atrial fibrillation, and heart failure in patients with migraine and in a general population comparison cohort.
Higher risks were observed among patients with incident migraine than in the general population across most outcomes and follow-up periods. Migraine was positively associated with myocardial infarction, ischaemic stroke, and haemorrhagic stroke, as well as venous thromboembolism and atrial fibrillation or atrial flutter. No meaningful association was found with peripheral artery disease or heart failure. The associations, particularly for stroke outcomes, were stronger during the short term (0-1 years) after diagnosis than the long term (up to 19 years), in patients with aura than in those without aura, and in women than in men.
The authors concluded that migraine was associated with increased risks of myocardial infarction, ischaemic stroke, haemorrhagic stroke, venous thromboembolism, and atrial fibrillation or atrial flutter. They suggest that migraine may be an important risk factor for most cardiovascular diseases.
Adelborg K, Szépligeti SK, Holland-Bill L, Ehrenstein V, Horváth-Puhó E, Henderson VW, Sørensen HT: Migraine and risk of cardiovascular diseases: Danish population based matched cohort study. BMJ. 2018 Jan 31;360:k96. doi: 10.1136/bmj.k96.
The blood-brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet. The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning. BBB disruption allows influx of neurotoxic blood-derived debris, cells and microbial pathogens into the brain and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration.
This review by Sweeney and colleagues discusses the results of neuroimaging as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy. The mechanisms by which BBB breakdown leads to neuronal dysfunction and neurodegeneration are described. The importance of the BBB for therapeutic drug delivery and the adverse effects of BBB breakdown are noted, as well as opportunities to control the course of neurological diseases by targeting the BBB.
Sweeney MD, Sagare AP, Zlokovic BV: Blood-brain barrier breakdown in Alzheimer disease and neurodegenerative disorders. Nature Rev. Neurol. 14(3): 133-150 (2018).
“Schizophrenia is a disorder that involves hallucinations, delusions and cognitive impairment, and that affects nearly 1% of the global population. The mainstays of therapy have been drugs that block the activity of the D2 dopamine receptor (D2R), a member of the large G-protein-coupled receptor (GPCR) superfamily of membrane proteins. Unfortunately, most of these antipsychotic drugs come with a plethora of debilitating side effects, many of which are due to off-target interactions with other GPCRs. In a paper in Nature, Wang et al. now report the crystal structure of D2R in complex with the antipsychotic drug risperidone. The structure reveals features that might be useful for the design or discovery of drugs that have greater selectivity for D2R than existing therapeutics, and consequently have fewer side effects….”
Sibley DR and Shi L: A new era of rationally designed antipsychotics. Nature (News and Views, February 26, 2018).
“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.
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].
“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).