CX3CR1+ monocytes modulate learning and learning-dependent dendritic spine remodeling via TNF-[alpha] : Nature Medicine : Nature Research

Impaired learning and cognitive function often occurs during systemic infection or inflammation. Although activation of the innate immune system has been linked to the behavioral and cognitive effects that are associated with infection, the underlying mechanisms remain poorly understood. Here we mimicked viral immune activation with poly(I:C), a synthetic analog of double-stranded RNA, and longitudinally imaged postsynaptic dendritic spines of layer V pyramidal neurons in the mouse primary motor cortex using two-photon microscopy. We found that peripheral immune activation caused dendritic spine loss, impairments in learning-dependent dendritic spine formation and deficits in multiple learning tasks in mice. These observed synaptic alterations in the cortex were mediated by peripheral-monocyte-derived cells and did not require microglial function in the central nervous system. Furthermore, activation of CX3CR1highLy6Clow monocytes impaired motor learning and learning-related dendritic spine plasticity through tumor necrosis factor (TNF)-α-dependent mechanisms. Taken together, our results highlight CX3CR1high monocytes and TNF-α as potential therapeutic targets for preventing infection-induced cognitive dysfunction.

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A chronic low dose of [Delta]9-tetrahydrocannabinol (THC) restores cognitive function in old mice : Nature Medicine : Nature Research

Cannabis sativa plant (Photo credit: Wikipedia)

The balance between detrimental, pro-aging, often stochastic processes and counteracting homeostatic mechanisms largely determines the progression of aging. There is substantial evidence suggesting that the endocannabinoid system (ECS) is part of the latter system because it modulates the physiological processes underlying aging1, 2. The activity of the ECS declines during aging, as CB1 receptor expression and coupling to G proteins are reduced in the brain tissues of older animals3, 4, 5 and the levels of the major endocannabinoid 2-arachidonoylglycerol (2-AG) are lower6. However, a direct link between endocannabinoid tone and aging symptoms has not been demonstrated. Here we show that a low dose of Δ9-tetrahydrocannabinol (THC) reversed the age-related decline in cognitive performance of mice aged 12 and 18 months. This behavioral effect was accompanied by enhanced expression of synaptic marker proteins and increased hippocampal spine density. THC treatment restored hippocampal gene transcription patterns such that the expression profiles of THC-treated mice aged 12 months closely resembled those of THC-free animals aged 2 months. The transcriptional effects of THC were critically dependent on glutamatergic CB1 receptors and histone acetylation, as their inhibition blocked the beneficial effects of THC. Thus, restoration of CB1 signaling in old individuals could be an effective strategy to treat age-related cognitive impairments."



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Prenatal exposure to common air pollutants linked to cognitive and behavioral impairment

Neurotoxic PAH (polycyclic aromatic hydrocarbons) are ubiquitous in
the environment, in the home and in the workplace. Emissions from motor
vehicles, oil and coal burning for home heating or power generation,
wildfires and agricultural burning, hazardous waste sites, tobacco smoke
and charred foods are all sources of exposure. PAH readily crosses the
placenta and affects an unborn child's brain; earlier animal studies
showed that prenatal exposure impaired the development of behavior,
learning and memory.


Scientists led by Bradley S. Peterson, MD, director of the Institute
for the Developing Mind at The Saban Research Institute of CHLA, along
with Virginia Rauh, ScD, and Frederica Perera, DrPH, PhD, from Columbia
University's Mailman School of Public Health, conducted a study of
minority youth to test the effects on brain structure of PAH exposure
during the final trimester of pregnancy. They used magnetic resonance
imaging (MRI) to measure the brains of 40 children from a cohort of more
than 600 mother-baby pairs from minority communities in New York City.
The Columbia researchers had previously reported that exposure to
airborne PAH during gestation in this cohort was associated with
multiple neurodevelopmental disturbances, including development delay by
age 3, reduced verbal IQ at age 5, and symptoms of anxiety and
depression at age 7.

Molecular Psychiatry - Cigarette smoking and thinning of the brain/'s cortex

"Cigarette smoking is associated with cognitive decline and dementia, but the extent of the association between smoking and structural brain changes remains unclear. Importantly, it is unknown whether smoking-related brain changes are reversible after smoking cessation. We analyzed data on 504 subjects with recall of lifetime smoking data and a structural brain magnetic resonance imaging at age 73 years from which measures of cortical thickness were extracted. Multiple regression analyses were performed controlling for gender and exact age at scanning. To determine dose–response relationships, the association between smoking pack-years and cortical thickness was tested and then repeated, while controlling for a comprehensive list of covariates including, among others, cognitive ability before starting smoking. Further, we tested associations between cortical thickness and number of years since last cigarette, while controlling for lifetime smoking. There was a diffuse dose-dependent negative association between smoking and cortical thickness. Some negative dose-dependent cortical associations persisted after controlling for all covariates. Accounting for total amount of lifetime smoking, the cortex of subjects who stopped smoking seems to have partially recovered for each year without smoking. However, it took ~25 years for complete cortical recovery in affected areas for those at the mean pack-years value in this sample. As the cortex thins with normal aging, our data suggest that smoking is associated with diffuse accelerated cortical thinning, a biomarker of cognitive decline in adults. Although partial recovery appears possible, it can be a long process."

Persistent Viral Pathogens and Cognitive Impairment Across the Life Course in the Third National Health and Nutrition Examination Survey

Background. Herpesviruses have been linked to cognitive impairment in older individuals but little is known about the association in the general US population.

Methods. We determined whether cytomegalovirus (CMV) and herpes simplex virus 1 (HSV-1) seropositivity were associated with cognitive impairment among children (aged 6–16 years) and adults aged 20–59 or ≥60 years, using data from the National Health and Nutrition Examination Survey (NHANES) III. Linear and logistic regression models were used to examine the associations between pathogen seropositivity and cognitive impairment.

Results. Among children, HSV-1 seropositivity was associated with lower reading and spatial reasoning test scores (β, −0.69; 95% confidence interval [CI], −1.18 to −.21 and β, −0.82; 95% CI, −1.29 to −.36, respectively). Among middle-aged adults, HSV-1 and CMV seropositivity were associated with impaired coding speed (odds ratio [OR], 1.54; 95% CI, 1.13–2.11, and OR, 1.41; 95% CI, 1.09–1.82, respectively). CMV seropositivity was also associated with impaired learning and recall (OR, 1.43; 95% CI, 1.14–1.80). Among older
adults, HSV-1 seropositivity was associated with immediate memory impairment (OR, 3.26; 95% CI, 1.68–6.32).

Conclusions. Future studies examining the biological pathways by which herpesviruses influence cognitive impairment across the life course are warranted.

Persistent Viral Pathogens and Cognitive Impairment Across the Life Course in the Third National Health and Nutrition Examination Survey

Background. Herpesviruses have been linked to cognitive impairment in older individuals but little is known about the association in the general US population.

Methods. We determined whether cytomegalovirus (CMV) and herpes simplex virus 1
(HSV-1) seropositivity were associated with cognitive impairment among children (aged 6–16 years) and adults aged 20–59 or ≥60 years, using data from the National Health and Nutrition Examination Survey (NHANES) III. Linear and logistic regression models were used to examine the associations between pathogen seropositivity and cognitive impairment.

Results. Among children, HSV-1 seropositivity was associated with lower reading and spatial reasoning test scores (β, −0.69; 95% confidence interval [CI], −1.18 to −.21 and β, −0.82; 95% CI,
−1.29 to −.36, respectively).
Among middle-aged adults, HSV-1 and CMV seropositivity were associated with impaired coding speed (odds ratio [OR], 1.54; 95% CI, 1.13–2.11, and OR, 1.41; 95% CI, 1.09–1.82,
respectively). CMV seropositivity was also associated with impaired learning and recall (OR, 1.43; 95% CI, 1.14–1.80). Among older adults, HSV-1 seropositivity was associated with immediate
memory impairment (OR, 3.26; 95% CI, 1.68–6.32).

Conclusions. Future studies examining the biological pathways by which herpesviruses influence cognitive impairment across the life course are warranted.

Infections damage our ability to form spatial memories

n the first trial to image how inflammation impairs human memory, the team at Brighton and Sussex Medical School scanned 20 participants before and after either a benign salty water injection or typhoid vaccination, used to induce inflammation. Positron emission tomography (PET) was used to measure the effects of inflammation on the consumption of glucose in the brain and after each scan participants tested their spatial memory by performing a series of tasks in a virtual reality.

A reduction in glucose metabolism within the brain's memory centre, known as the Medial Temporal Lobe (MTL), was seen following inflammation. Participants also performed less well in spatial memory tasks, an effect that appeared to be directly mediated by the change in MTL metabolism.

Toxoplasma gondii impairs memory in infected seniors.

Almost 30% of humans present a Toxoplasma gondii positive antibody status and its prevalence increases with age. The central nervous system is the main target. However, little is known about the influence of asymptomatic i.e. latent Toxoplasmosis on cognitive functions in humans. To investigate neurocognitive dysfunctions in asymptomatic older adults with Toxoplasma gondii positive antibody status a double-blinded neuropsychological study was conducted. The participants were classified from a population-based sample (N=131) of healthy participants with an age of 65 years and older into two groups with 42 individuals each: Toxoplasmosis positive (T-pos; IgG50 IU/ml) and Toxoplasmosis negative (T-neg; IgG=0 IU/ml). The outcome measures were a computer-based working-memory test (2-back) and several standardized psychometric tests of memory and executive cognitive functions. T-pos seniors showed an impairment of different aspects of memory. The rate of correctly detected target symbols in a 2-back task was decreased by nearly 9% (P=0.020), corresponding to a performance reduction of about 35% in working memory relative to the T-neg group. Moreover, T-pos seniors had a lower performance in a verbal memory test, both regarding immediate recall (10% reduction; P=0.022), delayed recognition (6%; P=0.037) and recall from long-term memory assessed by the word fluency tests (12%; P=0.029). In contrast, executive functions were not affected. The effects remained mostly unchanged after controlling for medication. The impairment of memory functions in T-pos seniors was accompanied by a decreased self-reported quality of life. Because of the high prevalence of asymptomatic Toxoplasmosis and an increasing population of older adults this finding is of high relevance for public health.

Persistent Viral Pathogens and Cognitive Impairment across the Lifecourse in the Third National Health and Nutrition Examination Survey

Herpesviruses have been linked to cognitive impairment in older individuals but little is known about the association in the general U.S. population.

Methods. We examined whether cytomegalovirus (CMV) and herpes simplex virus-1 (HSV-1) seropositivity were associated with cognitive impairment among children 6-16, adults 20-59 and adults 60 years of age and older using data from the National Health and Nutrition Examination Survey (NHANES) III. Linear and logistic regression models were used to examine the associations between pathogen seropositivity and cognitive impairment.

Results. Among children, HSV-1 seropositivity was associated with lower reading and spatial reasoning test scores (β=-0.69, 95% Confidence Interval (CI), -1.18, -0.21 and β=-0.82, 95% CI, -1.29, -0.36, respectively). Among middle-aged adults, HSV-1 and CMV seropositivity were associated with impaired coding speed (Odds Ratio (OR)=1.54; 95% CI, 1.13, 2.11 and OR=1.41; 95% CI, 1.09, 1.82, respectively). CMV seropositivity was also associated with impaired learning and recall (OR=1.43; 95% CI, 1.14, 1.80). Among older adults, HSV-1 seropositivity was associated with immediate memory impairment (OR=3.26; 95% CI, 1.68, 6.32).

Conclusion. Future studies examining the biological pathways by which herpesviruses influence cognitive impairment across the lifecourse are warranted.

PCBs still affecting our health decades later

 Although Polychlorinated Biphenyls have been banned in the United States since 1979, University of Montreal and CHU Sainte-Justine researcher Maryse Bouchard has found that higher levels of the toxin was associated with lower cognitive performance in seniors. There is a significant association between PCB levels and cognitive abilities among individuals aged 70 to 84 years; the correlation was also detected to a lesser extent among people aged 60-69 years. This analysis also showed that the association differed by sex. Women in the older age group had the largest diminution in cognition in relation to exposure. "While most studies have looked at the impact of PCBs on infant development, our research shows that this toxin might affect us throughout our lives," Bouchard said.

Cognitive function improved by intranasal insulin in patients with type 2 diabetes - Medical News Today

"Previous studies had suggested that augmenting cerebral insulin may enhance cognitive function," says Novak, an Associate Professor of Neurology at Harvard Medical School. Intranasal administration delivers insulin directly to the brain, bypassing the blood-brain barrier and reaching receptors in multiple brain regions within minutes after administration.

In this pilot study, the authors tested whether similar effects would be observed in patients with diabetes. Fifteen patients with diabetes and 14 healthy older adults, average age 62, were administered a single 40-unit dose of insulin or saline in a randomized order on two subsequent days. Measurements of brain function were then made using regional perfusion and vasodilatation with 3 Tesla MRI and neuropsychological evaluation of learning and memory.

"We observed in both the healthy subjects and the patients with diabetes that there was an improvement in both verbal learning and visual-spatial learning and memory after they received the insulin," explains Novak. Through imaging tests, the investigators also learned that these improvements were dependent on the brain's vascular function.

PLOS ONE: Chronic Pravastatin but Not Atorvastatin Treatment Impairs Cognitive Function in Two Rodent Models of Learning and Memory

 Statins are some of the most commonly prescribed drugs and are used to reduce blood cholesterol. Recent evidence suggests that, in some patients, they may adversely influence cognitive function including causing memory impairments. These clinical observations have led to statin prescriptions now including a warning about possible cognitive impairments. In order to better understand the relationship between statin treatment and cognitive function, studies in animals are needed. The present study investigated the effects of chronic treatment with two statins, pravastatin and atorvastatin, in two rodent models of learning and memory. Adult rats were treated once daily with pravastatin (10mg/kg, orally) or atorvostatin (10mg/kg, orally) for 18 days. Before, during and after treatment, animals were tested in a simple discrimination and reversal learning task. On the last day of treatment and following one week withdrawal, animals were also tested in a task of novel object discrimination. Pravastatin tended to impair learning over the last few days of treatment and this effect was fully reversed once treatment ceased. In the novel object discrimination task, pravastatin significantly impaired object recognition memory. No effects were observed for atorvostatin in either task. These data suggest that chronic treatment with pravastatin impairs working and recognition memory in rodents. The reversibility of the effects on cessation of treatment is similar to what has been observed in patients, but the lack of effect of atorvostatin suggests that lipophilicity may not be a major factor influencing statin-induced cognitive impairments.

Exposure to herpes simplex virus, type 1 and reduced cognitive function.

 Herpes simplex virus, type 1 (HSV-1) causes cold sores, keratitis and rarely, fatal encephalitis. The infection is lifelong, with sensory ganglia serving as reservoirs of latent infection. Recently, exposure to HSV-1 has also been repeatedly associated with reduced cognitive function among healthy individuals without prior encephalitis. Though HSV-1 does not elevate risk for schizophrenia (SZ) per se, exposure is likewise associated with impaired cognitive functions among SZ patients. The range of cognitive changes observed in HSV-1 exposed persons has not been investigated systematically, nor is it known whether interaction between HSV-1 exposure and SZ related factors contributes to the impairment among SZ patients. Persons with or without schizophrenia/schizophreniform disorder (N = 298 total, DSM IV criteria) were assessed for HSV-1 exposure using serum HSV-1 antibody titers. The Penn Computerized Neurocognitive battery was used to assess eight cognitive domains with respect to accuracy and speed. There were no significant case-control differences in HSV-1 exposure. The SZ/schizophreniform disorder cases were significantly impaired in all cognitive domains compared with the controls. HSV-1 exposure was also associated with reduced cognitive function in the entire sample, but the magnitude of the effects and their patterns differed from the SZ related changes. Further, statistically significant interactions between HSV-1 exposure and SZ case status were not detected. HSV-1 exposure does not elevate risk for SZ, but it is associated with reduced function in specific cognitive domains regardless of SZ diagnostic status. An 'epidiagnostic' model for the association is proposed to explain the results.

Prenatal versus postnatal maternal factors in the development of infection-induced working memory impairments in mice.

Prenatal maternal infection is an environmental risk factor for neurodevelopmental psychiatric illness and disease-associated cognitive impairments. Modeling this epidemiological link in animals shows that prenatal immune challenge is capable of inducing long-lasting deficits in numerous cognitive domains. Here, we combined a neonatal cross-fostering design with a mouse model of prenatal immune challenge induced by maternal gestational treatment with the viral mimetic poly(I:C) to dissect the relative contribution of prenatal and postnatal maternal effects on the offspring. We show that offspring prenatally exposed to poly(I:C) display significant impairments in spatial matching-to-position working memory and spatial novelty presence regardless of whether they are raised by gestationally immune-challenged or non-challenged control surrogate mothers. Likewise, prenatally immune challenged offspring exhibit reduced glutamic acid decarboxylase 65-kDa (GAD65) and 67-kDa (GAD67) gene expression in the adult medial prefrontal cortex and dorsal hippocampus largely independently of the postnatal rearing conditions. In addition, we confirm that being raised by a gestationally immune-challenged surrogate mother is sufficient to increase the offspring's locomotor response to systemic amphetamine treatment. Our data thus suggest that prenatal infection-induced deficits in spatial short-term memory are mediated by prenatal maternal effects on the offspring. At the same time, our study adds further weight to the notion that being reared by a surrogate mother that experienced immune activation during pregnancy may constitute a risk factor for specific dopaminergic abnormalities.

Persistent infection with neurotropic herpes viruses and cognitive impairment.

Herpes virus infections can cause cognitive impairment during and after acute encephalitis. Although chronic, latent/persistent infection is considered to be relatively benign, some studies have documented cognitive impairment in exposed persons that is untraceable to encephalitis. These studies were conducted among schizophrenia (SZ) patients or older community dwellers, among whom it is difficult to control for the effects of co-morbid illness and medications. To determine whether the associations can be generalized to other groups, we examined a large sample of younger control individuals, SZ patients and their non-psychotic relatives (n=1852). Method Using multivariate models, cognitive performance was evaluated in relation to exposures to herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and cytomegalovirus (CMV), controlling for familial and diagnostic status and sociodemographic variables, including occupation and educational status. Composite cognitive measures were derived from nine cognitive domains using principal components of heritability (PCH). Exposure was indexed by antibodies to viral antigens.

RESULTS:

PCH1, the most heritable component of cognitive performance, declines with exposure to CMV or HSV-1regardless of case/relative/control group status (p = 1.09 × 10-5 and 0.01 respectively), with stronger association with exposure to multiple herpes viruses (β = -0.25, p = 7.28 × 10-10). There were no significant interactions between exposure and group status.

CONCLUSIONS:

Latent/persistent herpes virus infections can be associated with cognitive impairments regardless of other health status.

Persistent infection with neurotropic herpes viruses and cognitive impairment.

Herpes virus infections can cause cognitive impairment during and after acute encephalitis. Although chronic, latent/persistent infection is considered to be relatively benign, some studies have documented cognitive impairment in exposed persons that is untraceable to encephalitis. These studies were conducted among schizophrenia (SZ) patients or older community dwellers, among whom it is difficult to control for the effects of co-morbid illness and medications. To determine whether the associations can be generalized to other groups, we examined a large sample of younger control individuals, SZ patients and their non-psychotic relatives (n=1852). Method Using multivariate models, cognitive performance was evaluated in relation to exposures to herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and cytomegalovirus (CMV), controlling for familial and diagnostic status and sociodemographic variables, including occupation and educational status. Composite cognitive measures were derived from nine cognitive domains using principal components of heritability (PCH). Exposure was indexed by antibodies to viral antigens.

RESULTS:

PCH1, the most heritable component of cognitive performance, declines with exposure to CMV or HSV-1 regardless of case/relative/control group status (p = 1.09 × 10-5 and 0.01 respectively), with stronger association with exposure to multiple herpes viruses (β = -0.25, p = 7.28 × 10-10). There were no significant interactions between exposure and group status.

CONCLUSIONS:

Latent/persistent herpes virus infections can be associated with cognitive impairments regardless of other health status.

Obesity and metabolic syndrome associated with impaired brain function in adolescents

A new study by researchers at NYU School of Medicine reveals for the first time that metabolic syndrome (MetS) is associated with cognitive and brain impairments in adolescents and calls for pediatricians to take this into account when considering the early treatment of childhood obesity.