Acting Before; A Combined Strategy to Counteract the Onset and Progression of Dementia.

Brain aging and aging-related neurodegenerative disorders are posing a significant challenge for health systems worldwide. To date, most of the therapeutic efforts aimed at counteracting dementiarelated behavioral and cognitive impairment have been focused on addressing putative determinants of the disease, such as ß-amyloid or tau. In contrast, relatively little attention has been paid to pharmacological interventions aimed at restoring or promoting the synaptic plasticity of the aging brain. The review will explore and discuss the most recent molecular, structural/functional, and behavioral evidence that supports the use of non-pharmacological approaches as well as cognitive-enhancing drugs to counteract brain aging and early-stage dementia.

Proof of principle: Preoperative cognitive reserve and brain integrity predicts intra-individual variability in processed EEG (Bispectral Index Monitor) during general anesthesia.

BACKGROUND: Preoperative cognitive reserve and brain integrity may explain commonly observed intraoperative fluctuations seen on a standard anesthesia depth monitor used ubiquitously in operating rooms throughout the nation. Neurophysiological variability indicates compromised regulation and organization of neural networks. Based on theories of neuronal integrity changes that accompany aging, we assessed the relative contribution of: 1) premorbid cognitive reserve, 2) current brain integrity (gray and white matter markers of neurodegenerative disease), and 3) current cognition (specifically domains of processing speed/working memory, episodic memory, and motor function) on intraoperative neurophysiological variability as measured from a common intraoperative tool, the Bispectral Index Monitor (BIS). METHODS: This sub-study included participants from a parent study of non-demented older adults electing unilateral Total Knee Arthroplasty (TKA) with the same surgeon and anesthesia protocol, who also completed a preoperative neuropsychological assessment and preoperative 3T brain magnetic resonance imaging scan. Left frontal two-channel derived EEG via the BIS was acquired preoperatively (un-medicated and awake) and continuously intraoperatively with time from tourniquet up to tourniquet down. Data analyses used correlation and regression modeling. RESULTS: Fifty-four participants met inclusion criteria for the sub-study. The mean (SD) age was 69.5 (7.4) years, 54% were male, 89% were white, and the mean (SD) American Society of Anesthesiologists score was 2.76 (0.47). We confirmed that brain integrity positively and significantly associated with each of the cognitive domains of interest. EEG intra-individual variability (squared deviation from the mean BIS value between tourniquet up and down) was significantly correlated with cognitive reserve (r = -.40, p = .003), brain integrity (r = -.37, p = .007), and a domain of processing speed/working memory (termed cognitive efficiency; r = -.31, p = .021). Hierarchical regression models that sequentially included age, propofol bolus dose, cognitive reserve, brain integrity, and cognitive efficiency found that intraoperative propofol bolus dose (p = .001), premorbid cognitive reserve (p = .008), and current brain integrity (p = .004) explained a significant portion of intraoperative intra-individual variability from the BIS monitor. CONCLUSIONS: Older adults with higher premorbid reserve and less brain disease were more stable intraoperatively on a depth of anesthesia monitor. Researchers need to replicate findings within larger cohorts and other surgery types.

Activity in the Ventral Medial Prefrontal Cortex Is Necessary for the Therapeutic Effects of Extinction in Rats.

Poor response and high relapse rates remain problematic in the treatment of stress-related psychiatric disorders such as depression and post-traumatic stress disorder. Although mechanisms of pharmacotherapies are intensely studied, little is known about mechanisms of behavioral therapy that could inform improved treatments. We have previously demonstrated the therapeutic effects of extinction learning as a behavioral intervention modeling exposure therapy in rats. In the present study, we tested the hypothesis that activity in the ventral medial prefrontal cortex (vmPFC) during extinction is necessary for its therapeutic effects. The inhibitory Gi-coupled designer receptor exclusively activated by designer drug CaMKIIα-hM4Di was expressed in vmPFC before administering chronic unpredictable stress (CUS). vmPFC projection neurons were then inhibited during extinction treatment by administering clozapine-N-oxide. Coping behavior and cognitive flexibility were assessed 24 h later on the shock-probe defensive burying test and attentional set-shifting test, respectively. Replicating previous results, extinction reversed the CUS-induced deficits in coping behavior and cognitive flexibility. Inhibiting vmPFC during extinction blocked these therapeutic effects. Further, increasing vmPFC activity with the excitatory Gq-coupled designer receptor exclusively activated by designer drug hM3Dq 24 h before testing was sufficient to reverse the CUS-induced deficits. CUS reduced mPFC responsivity, assessed by measuring afferent-evoked field potentials in the mPFC, and this reduction was reversed by extinction treatment 24 h before testing. These results demonstrate the necessity of vmPFC activity in the therapeutic effects of extinction as a model of exposure therapy, and suggest that increased vmPFC activity induced by extinction is sufficient to produce lasting plastic changes that underlie its beneficial effects.SIGNIFICANCE STATEMENT Stress-related psychiatric disorders remain poorly treated. Psychotherapies can be effective, but their mechanisms remain unknown, hindering progress toward improved treatment. We used a rat model of behavioral therapy to identify potential targets for enhancing treatment. Fear extinction as a therapeutic behavioral intervention reversed stress-induced cognitive dysfunction and passive coping in rats, modeling components of stress-related psychiatric disease. Extinction also reversed stress-induced attenuation of mPFC responsivity. The therapeutic effects were prevented by blocking activity of glutamatergic neurons in the mPFC during extinction, and were mimicked by inducing activity in lieu of extinction. Thus, activity and plasticity in the mPFC underlie the beneficial effects of extinction on cognitive flexibility and coping behavior compromised by stress, and could be targets to enhance behavioral therapy.

The neurobiology of HIV and its impact on cognitive reserve: A review of cognitive interventions for an aging population.

The medications used to treat HIV have reduced the severity of cognitive deficits; yet, nearly half of adults with HIV still exhibit some degree of cognitive deficits, referred to as HIV-associated neurocognitive disorder or HAND. These cognitive deficits interfere with everyday functioning such as emotional regulation, medication adherence, instrumental activities of daily living, and even driving a vehicle. As adults are expected to live a normal lifespan, the process of aging in this clinical population may exacerbate such cognitive deficits. Therefore, it is important to understand the neurobiological mechanisms of HIV on cognitive reserve and develop interventions that are either neuroprotective or compensate for such cognitive deficits. Within the context of cognitive reserve, this article delivers a state of the science perspective on the causes of HAND and provides possible interventions for addressing such cognitive deficits. Suggestions for future research are also provided.

[Neuroenhancement]. / Neuroenhancement.

BACKGROUND: Cognitive enhancement or neuroenhancement describes the increase in cognitive performance in humans by means of psychotropic drugs or brain stimulation methods, such as transcranial magnetic stimulation (TMS). PROBLEM: This article discusses the potential of pharmacological cognitive enhancement with some of the most common drugs. METHODS: A selective literature search was performed taking into account the most important groups of substances (i.e. caffeine, nicotine, stimulants including modafinil, and acetylcholine esterase inhibitors) for which studies on the pharmacological elevation of cognitive performance in healthy subjects are available. RESULTS: The extent of the effects that can be pharmacologically achieved is essentially genetically determined. Some of the best-characterized polymorphisms are described here. Pharmacological enhancement of cognitive performance is currently possible with all of the compounds described here and caffeine and nicotine are used by millions of people without the explicit intention of most consumers of cognitive enhancement. DISCUSSION: Clinical neuroscientists are required to share their expertise to a greater extent in the social discourse on cognitive enhancement in the future in order to influence opinion-forming and decision-making processes.

The cognitive consequences of stigma, social withdrawal, and depression in adults aging with HIV.

In addition to the immune system, HIV also affects the nervous system. Even with highly active antiretroviral therapy helping reduce the impact of HIV on the body and brain, approximately 50% of individuals with HIV experience cognitive problems. As people age with HIV, there is growing concern that they will be at increased risk of developing cognitive problems that may have an impact on their everyday functioning (e.g., medication adherence) and quality of life. Unfortunately, HIV-related stigma, social withdrawal, and depression, which are common to the HIV experience, can also have direct and indirect negative consequences on cognition. Research and practice implications concerning these relationships are posited.

Occupational solvent exposure and cognition: does the association vary by level of education?

OBJECTIVE: Chronic occupational solvent exposure is associated with long-term cognitive deficits. Cognitive reserve may protect solvent-exposed workers from cognitive impairment. We tested whether the association between chronic solvent exposure and cognition varied by educational attainment, a proxy for cognitive reserve. METHODS: Data were drawn from a prospective cohort of French national gas and electricity (GAZEL) employees (n = 4,134). Lifetime exposure to 4 solvent types (chlorinated solvents, petroleum solvents, benzene, and nonbenzene aromatic solvents) was assessed using a validated job-exposure matrix. Education was dichotomized at less than secondary school or below. Cognitive impairment was defined as scoring below the 25th percentile on the Digit Symbol Substitution Test at mean age 59 (SD 2.8; 88% of participants were retired at testing). Log-binomial regression was used to model risk ratios (RRs) for poor cognition as predicted by solvent exposure, stratified by education and adjusted for sociodemographic and behavioral factors. RESULTS: Solvent exposure rates were higher among less-educated patients. Within this group, there was a dose-response relationship between lifetime exposure to each solvent type and RR for poor cognition (e.g., for high exposure to benzene, RR = 1.24, 95% confidence interval 1.09-1.41), with significant linear trends (p < 0.05) in 3 out of 4 solvent types. Recency of solvent exposure also predicted worse cognition among less-educated patients. Among those with secondary education or higher, there was no significant or near-significant relationship between any quantification of solvent exposure and cognition. CONCLUSIONS: Solvent exposure is associated with poor cognition only among less-educated individuals. Higher cognitive reserve in the more-educated group may explain this finding.