“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

 

 

Posted in Uncategorized | Comments Off on Intermittent metabolic switching, neuroplasticity and brain health

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

Posted in Uncategorized | Comments Off on Genetic variation interacts with experience to determine interindividual differences in learning

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

Posted in Uncategorized | Comments Off on Mild cognitive impairment: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

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

Posted in Uncategorized | Comments Off on BDNF mimetic prodrug for treating Alzheimer’s disease

The neural causes of most complex behaviors are still not understood. It is thought that much of this is due to the fact that complex behavior depends on distributed neural control. Disruption in this causal web can produce effects that are difficult to trace back to their origin. Against this background, the finding that focal lesions of the ventromedial prefrontal cortex could lead to immoral and even criminal behavior has generated considerable interest. While a number of rare cases have now been described in which a focal lesion caused criminality, these are neither very consistent (the lesions occur in several different anatomical locations) nor at all reliable (only a small fraction of patients, for any lesion location, showed criminal behavior). To explain the effects of a lesion on criminal behavior, one needs to understand what it is that the lesion does to the rest of the brain. A network-level understanding of lesion effects is now provided by the new study of Darby and colleagues. In this study, all lesions were functionally connected to the same network of brain regions. This criminality-associated connectivity pattern was unique compared with lesions causing four other neuropsychiatric syndromes. The network includes regions involved in morality, value-based decision making, and theory of mind, but not regions involved in cognitive control or empathy. Finally, the results were replicated in a separate cohort of 23 cases in which a temporal relationship between brain lesions and criminal behavior was implied but not definitive. The results suggest that lesions in criminals occur in different brain locations but localize to a unique resting state network, providing insight into the neurobiology of criminal behavior.

 

Darby RR, Horn A, Cushman F and Fox MD: Lesion network localization of criminal behavior. Proc. Natl. Acad. Sci. USA  [Epub ahead of print, Dec. 18, 2017; doi: 10.1073/pnas.1706587115.]

https://www.ncbi.nlm.nih.gov/pubmed/29255017

Posted in Uncategorized | Comments Off on Searching for the neural causes of criminal behavior

“Early life adversities including harsh parenting, maternal depression, neighborhood deprivation, and low family economic resources are more prevalent in low-income urban environments and are potent predictors of psychopathology, including, for boys, antisocial behavior. However, little research has examined how these stressful experiences alter later neural function. Moreover, identifying genetic markers of greater susceptibility to adversity is critical to understanding biopsychosocial pathways from early adversity to later psychopathology.

Within a sample of 310 low-income boys followed from age 1.5 to 20, multimethod assessments of adversities were examined at age 2 and age 12. At age 20, amygdala reactivity to emotional facial expressions was assessed using fMRI, and symptoms of Antisocial Personality Disorder were assessed via structured clinical interview. Genetic variability in cortisol signaling (CRHR1) was examined as a moderator of pathways to amygdala reactivity.

Observed parenting and neighborhood deprivation at age 2 each uniquely predicted amygdala reactivity to emotional faces at age 20 over and above other adversities measured at multiple developmental periods. Harsher parenting and greater neighborhood deprivation in toddlerhood predicted clinically-significant symptoms of antisocial behavior via less amygdala reactivity to fearful facial expressions and this pathway was moderated by genetic variation in CRHR1. These results elucidate a pathway linking early adversity to less amygdala reactivity to social signals of interpersonal distress 18 years later, which in turn increased risk for serious antisocial behavior. Moreover, these findings suggest a genetic marker of youth more susceptible to adversity.”

Gard AM, Waller R, Shaw DS, Forbes EE, Hariri AR and Hyde LW: The long reach of early adversity: Parenting, stress, and neural pathways to antisocial behavior in adulthood. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 2(7):582-590 (2017).

https://www.ncbi.nlm.nih.gov/pubmed/29170760

and

https://www.ncbi.nlm.nih.gov/pubmed/26386294

Posted in Uncategorized | Comments Off on The long reach of early adversity: Parenting, stress, and neural pathways to antisocial behavior in adulthood

Abstract: Vortioxetine is a novel antidepressant with multimodal activity currently approved for the treatment of major depressive disorder. Vortioxetine is orally administered once daily at 5- to 20-mg doses. The pharmacokinetics of vortioxetine are linear and dose proportional, with a mean terminal half-life of approximately 66 h and steady-state plasma concentrations generally achieved within 2 weeks of dosing. The mean absolute oral bioavailability of vortioxetine is 75%. No food effect on pharmacokinetics was observed. Vortioxetine is metabolized by cytochrome P450 enzymes and subsequently by uridine diphosphate glucuronosyltransferase. The major metabolite is pharmacologically inactive, and the minor pharmacologically active metabolite is not expected to cross the blood-brain barrier, making the parent compound primarily responsible for in-vivo activity. No clinically relevant differences were observed in vortioxetine exposure by sex, age, race, body size, and renal or hepatic function. Dose adjustment is only recommended for cytochrome P450 2D6 poor metabolizers based on polymorphism of the cytochrome P450 enzymes involved. Similarly, except for bupropion, a strong cytochrome P450 2D6 inhibitor, and rifampin, a broad cytochrome P450 inducer, co-administration of other drugs evaluated did not affect the vortioxetine exposure or safety profile in any clinically meaningful way. Pharmacodynamic studies demonstrated that vortioxetine achieved high levels of serotonin transporter occupancy in relevant brain areas, affected neurotransmitter levels in the cerebrospinal fluid, and modified abnormal resting state networks in the brain over the therapeutic dose range. Overall, vortioxetine can be administered in most populations studied to date without major dose adjustments; however, dose adjustments should be considered on a patient-by-patient basis.

Chen G, Højer AM, Areberg J, Nomikos G: Vortioxetine: Clinical Pharmacokinetics and Drug Interactions. Clin. Pharmacokinet.  (Epub ahead of print, Nov. 30, 2017; doi: 10.1007/s40262-017-0612-7).

https://www.ncbi.nlm.nih.gov/pubmed/29189941

Posted in Uncategorized | Comments Off on Vortioxetine: Clinical Pharmacokinetics and Drug Interactions

The prefrontal cortex maintains working memory information in the presence of distracting stimuli. It has long been thought that sustained activity in individual neurons or groups of neurons was responsible for maintaining information in the form of a persistent, stable code. This study shows that, upon the presentation of a distractor, information in the lateral prefrontal cortex was reorganized into a different pattern of activity to create a morphed stable code without losing information. In contrast, the code in the frontal eye fields persisted across different delay periods but exhibited substantial instability and information loss after the presentation of a distractor. Neurons with mixed-selective responses were necessary and sufficient for the morphing of code and it was observed that these neurons were more abundant in the lateral prefrontal cortex than the frontal eye fields. The authors suggest that mixed selectivity provides populations with code-morphing capability, a property that may underlie cognitive flexibility.

Parthasarathy A, Herikstad R, Bong JH, Medina FS, Libedinsky C, Yen SC: Mixed selectivity morphs population codes in prefrontal cortex. Nature Neuroscience 20(12): 1770-1779 (2017).

https://www.ncbi.nlm.nih.gov/pubmed/29184197

Posted in Uncategorized | Comments Off on Working Memory: effect of distractors on neuronal activity patterns

Mutations in presenilin 1 and 2, which encode components of the γ-secretase complex, cause familial Alzheimer’s disease. It is hypothesized that altered γ-secretase mediated processing of the amyloid precursor protein to the Aβ42 fragment, which is accumulated in diseased brain, may be pathogenic. This paper describes an in vitro model system that enables analysis of neuronal disease mechanisms in non-neuronal patient cells using CRISPR gene activation of endogenous disease-relevant genes. In familial Alzheimer patient-derived fibroblast cultures, CRISPR activation of amyloid precursor protein or BACE unmasked an occult processivity defect in downstream γ-secretase -mediated carboxypeptidase cleavage of amyloid precursor protein, ultimately leading to higher Aβ42 levels. These data suggest that, selectively in neurons, relatively high levels of BACE1 activity lead to substrate pressure on familial Alzheimer-mutant γ-secretase complexes, promoting CNS Aβ42 accumulation. These results introduce an additional platform for analysis of neurological disease.

Inoue K, Oliveira LMA, Abeliovich A:  CRISPR Transcriptional Activation Analysis Unmasks an Occult γ-Secretase Processivity Defect in Familial Alzheimer’s Disease Skin Fibroblasts. Cell Rep. 21(7):1727-1736 (2017); doi: 10.1016/j.celrep.2017.10.075.

https://www.ncbi.nlm.nih.gov/pubmed/29141208

Posted in Uncategorized | Comments Off on Familial Alzheimer’s Disease: γ-Secretase Defect unmasked by CRISPR Transcriptional Activation Analysis

During exposure to chronic stress, some individuals engage in active coping behaviors that promote resiliency to stress. Other individuals engage in passive coping that is associated with vulnerability to stress and with anxiety and depression. In an effort to identify novel molecular mechanisms that underlie vulnerability or resilience to stress, the authors used nonbiased analyses of microRNAs in the ventral hippocampus to identify those miRNAs differentially expressed in active (long-latency (LL)/resilient) or passive (short-latency (SL)/vulnerable) rats following chronic social defeat.

Additionally, pharmacological approaches were used to determine the contribution of inflammatory processes in mediating vulnerability and resiliency. Administration of the pro-inflammatory cytokine vascular endothelial growth factor-164 increased vulnerability to stress, while the non-steroidal anti-inflammatory drug meloxicam attenuated vulnerability. The authors suggest that vulnerability to stress is determined by a re-designed neurovascular unit characterized by increased neural activity, vascular remodeling and pro-inflammatory mechanisms in the ventral hippocampus. Dampening inflammatory processes by administering anti-inflammatory agents appeared to reduce vulnerability to stress. These results have translational relevance as they suggest that administration of anti-inflammatory agents may reduce the impact of stress or trauma in vulnerable individuals.

Pearson-Leary J, Eacret D, Chen R, Takano H, Nicholas B, Bhatnagar S: Inflammation and vascular remodeling in the ventral hippocampus contributes to vulnerability to stress. Transl. Psychiatry 7(6):e1160 (2017); doi: 10.1038/tp.2017.122.

https://www.ncbi.nlm.nih.gov/pubmed/28654094

Posted in Uncategorized | Comments Off on Vulnerability to stress: role of inflammation and vascular remodeling