No treatment options are currently available to counteract cognitive deficits and/or delay progression towards dementia in older people with mild cognitive impairment (MCI). The 'Train the Brain' programme is a combined motor and cognitive intervention previously shown to markedly improve cognitive functions in MCI individuals compared to non-trained MCI controls, as assessed at the end of the 7-month intervention. Here, we extended the previous analyses to include the long-term effects of the intervention and performed a data disaggregation by gender, education and age of the enrolled participants. We report that the beneficial impact on cognitive functions was preserved at the 14-month follow-up, with greater effects in low-educated compared to high-educated individuals, and in women than in men.

A deterioration in cognitive performance accompanies brain aging, even in the absence of neurodegenerative pathologies. However, the rate of cognitive decline can be slowed down by enhanced cognitive and sensorimotor stimulation protocols, such as environmental enrichment (EE). Understanding how EE exerts its beneficial effects on the aged brain pathophysiology can help in identifying new therapeutic targets. In this regard, the inflam-matory chemokine ccl11/eotaxin-1 is a marker of aging with a strong relevance for neurodegenerative processes. Here, we demonstrate that EE in both elderly humans and aged mice decreases circulating levels of ccl11. Interfering, in mice, with the ccl11 decrease induced by EE ablated the beneficial effects on long-term memory retention, hippocampal neurogenesis, activation of local microglia and of ribosomal protein S6. On the other hand, treatment of standard-reared aged mice with an anti-ccl11 antibody resulted in EE-like improvements in spatial memory, hippocampal neurogenesis, and microglial activation. Taken together, our findings point to a decrease in circulating ccl11 concentration as a key mediator of the enhanced hippocampal function resulting from exposure to EE.

Cognitive impairments associated with aging and dementia are major sources of neuropsychiatric symptoms (NPs) and deterioration in quality of life (QoL). Preventive measures to both reduce disease and improve QoL in those affected are increasingly targeting individuals with mild cognitive impairment (MCI) at early disease stage. However, NPs and QoL outcomes are too commonly overlooked in intervention trials. The purpose of this study was to test the effects of physical and cognitive training on NPs and QoL in MCI. Baseline data from an MCI court (N = 93, mean age 74.9 ± 4.7) enrolled in the Train the Brain (TtB) study were collected. Subjects were randomized in two groups: a group participated to a cognitive and physical training program, while the other sticked to usual standard care. Both groups underwent a follow-up re-evaluation after 7 months from baseline. NPs were assessed using the Neuropsychiatric Inventory (NPI) and QoL was assessed using Quality of Life-Alzheimer’s Disease (QOL-AD) scale. After 7 months of training, training group exhibited a significant reduction of NPs and a significant increase in QOL-AD with respect to no-training group (p = 0.0155, p = 0.0013, respectively). Our preliminary results suggest that a combined training can reduce NPs and improve QoL. Measuring QoL outcomes is a potentially important factor in ensuring that a person with cognitive deficits can ‘live well’ with pathology. Future data from non-pharmacological interventions, with a larger sample and a longer follow-up period, could confirm the results and the possible implications for such prevention strategies for early cognitive decline.

Background: Dementia has been recently viewed as a predominantly vascular disorder. Indeed, reduced brain NO availability causes increased ß-amyloid deposition by several mechanisms, including hypoperfusion. Purpose: To investigate the relationship between cerebral blood flow in the hippocampal and parahippocampal regions (CBF-hipp and CBF-parahipp), crucial areas for memory and processing of non-verbal/spatial information, and systemic endothelial function in individuals with mild cognitive impairment (MCI), a subclinical condition predisposing to dementia. Methods: CBF-hipp and CBF-parahipp were evaluated by magnetic resonance imaging (arterial spin labeling, GE HDxt 1.5 T Signa Neuro-optimized System) and systemic endothelial function by flow-mediated dilation (FMD) in the brachial artery. Results: Complete data about CBF and FMD at enrollment were available for 66 individuals with MCI and 32 without (non-MCI). The two groups were matched for age (75 ± 5 vs 74 ± 5 years, p = 0.22), sex (men 45 vs 50%, p = 0.18) and mean BP (96 ± 10 vs 97 ± 9 mmHg, p = 0.41). FMD was significantly lower in MCI than in non-MCI (2.93 ± 2.18 vs 3.74 ± 2.03%, p = 0.02); CBF-hipp (64.3 ± 9.43 vs 69.5 ± 7.03 ml/100 gr/min, p = 0.002) and CBF-parahipp (66.3 ± 8.02 vs 70.0 ± 8.12 ml/100 gr/min, p = 0.002) were significantly lower in MCI as well. Among MCI, FMD was significantly correlated with CBF-parahipp (r = 0.26, p = 0.03) and CBF-hipp (r = 0.32, p = 0.009). In multiple regression models, including age, sex, mean BP, BMI, brachial artery diameter as confounders, FMD remained an independent determinant of CBF-parahipp (beta = 0.93, r2 = 0.063, p = 0.04) and CBF-hipp (beta = 1.31, r2 = 0.089, p = 0.01). Nor CBF-parahipp (r = −0.13, p = 0.48) neither CBF-hipp (r = 0.05, p = 0.80) were correlated with FMD in non-MCI group. Conclusions: An independent association between hippocampal and parahippocampal CBF and systemic endothelial function is present in individuals with MCI.

Amblyopia is a neurodevelopmental disorder characterized by visual acuity and contrast sensitivity loss, refractory to pharmacological and mechanical treatments in adulthood. In animal models, the corpus callosum (CC) plays a critical role in the development of the ocular dominance, thus strengthening the hypothesis of an involvement of both striate and extrastriate areas in the pathogenesis of amblyopia. To investigate the role of interhemispheric pathways in amblyopia, we studied the response of the visual cortex to transcranial Direct Current Stimulation (tDCS) applied over the primary visual area (V1) contralateral to the amblyopic eye. Visual evoked potentials (VEPs) triggered by grating stimuli of different contrasts (K90%, K50%, K20%) were recorded in both hemispheres before and after inactivation of the occipital cortex of one side via cathodal tDCS (2.0 mA, 20′). VEPs were recorded before (T0), immediately after (T1) and 60′ following tDCS (T2). The display was either centered on the vertical meridian (central stimulation) or positioned in the right hemifield (with its inner edge at a distance of 1 degree from the fixation point). Visual acuity was tested at each time interval, to assess behavioral changes between active and sham stimulation. Cathodal tDCS improved visual acuity respect to baseline (recovery of 8.4 ± 3.3 letters, Holm-Sidak post hoc method p < 0.01), whereas sham polarization had no significant effect. At T1, tDCS produced an inhibitory effect on VEPs amplitudes at all contrasts in the targeted side and a concurrent facilitation of responses in the hemisphere ipsilateral to the amblyopic eye; compared with controls, the facilitation persisted at T2 for mid-high contrasts (K50%-K90%; Holm-Sidak post hoc method, p < 0.001), while the stimulated hemisphere recovered more quickly from the inhibition. tDCS is a promising treatment for amblyopia in adults. The rapid recovery of excitability and the persistent transcallosal disinhibition following perturbation of cortical activity strongly supports a critical role of interhemispheric balance in the pathophysiology of amblyopia.

Environmental enrichment may slow cognitive decay possibly acting through an improvement in vascular function. Aim of the study was to assess the effects of a 7-month cognitive, social, and physical training program on cognitive and vascular function in patients with mild cognitive impairment. In a single-center, randomized, parallel-group study, 113 patients (age, 65–89 years) were randomized to multidomain training (n=55) or usual care (n=58). All participants underwent neuropsychological tests and vascular evaluation, including brachial artery flow-mediated dilation, carotid–femoral pulse wave velocity, carotid distensibility, and assessment of circulating hematopoietic CD34+ and endothelial progenitor cells. At study entry, an age-matched control group (n=45) was also studied. Compared with controls, patients had at study entry a reduced flow-mediated dilation (2.97±2.14% versus 3.73±2.06%; P=0.03) and hyperemic stimulus (shear rate area under the curve, 19.1±15.7 versus 25.7±15.1×10−3; P=0.009); only the latter remained significant after adjustment for confounders (P=0.03). Training improved Alzheimer disease assessment scale cognitive (training, 14.0±4.8 to 13.1±5.5; nontraining, 12.1±3.9 to 13.2±4.8; P for interaction visit×training=0.02), flow-mediated dilation (2.82±2.19% to 3.40±1.81%, 3.05±2.08% to 2.24±1.59%; P=0.006; P=0.023 after adjustment for diameter and shear rate area under the curve), and circulating hematopoietic CD34+ cells and prevented the decline in carotid distensibility (18.4±5.3 to 20.0±6.6, 23.9±11.0 to 19.5±7.1 Pa−1; P=0.005). The only clinical predictor of improvement of cognitive function after training was established hypertension. There was no correlation between changes in measures of cognitive and vascular function. In conclusion, a multidomain training program slows cognitive decline, especially in hypertensive individuals. This effect is accompanied by improved systemic endothelial function, mobilization of progenitor CD34+ cells, and preserved carotid distensibility. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01725178.

Decline in declarative learning and memory performance is a typical feature of normal aging processes. Exposure of aged animals to an enriched environment (EE) counteracts this decline, an effect correlated with reduction of age-related changes in hippocampal dendritic branching, spine density, neurogenesis, gliogenesis, and neural plasticity, including its epigenetic underpinnings. Declarative memories depend on the medial temporal lobe system, including the hippocampus, for their formation, but, over days to weeks, they become increasingly dependent on other brain regions such as the neocortex and in particular the prefrontal cortex (PFC), a process known as system consolidation. Recently, it has been shown that early tagging of cortical networks is a crucial neurobiological process for remote memory formation and that this tagging involves epigenetic mechanisms in the recipient orbitofrontal (OFC) areas. Whether EE can enhance system consolidation in aged animals has not been tested; in particular, whether the early tagging mechanisms in OFC areas are deficient in aged animals and whether EE can ameliorate them is not known. This study aimed at testing whether EE could affect system consolidation in aged mice using the social transmission of food preference paradigm, which involves an ethologically based form of associative olfactory memory. We found that only EE mice successfully performed the remote memory recall task, showed neuronal activation in OFC, assessed with c-fos immunohistochemistry and early tagging of OFC, assessed with histone H3 acetylation, suggesting a defective system consolidation and early OFC tagging in aged mice which are ameliorated by EE.

The influence of exposure to impoverished environments on brain development is unexplored since most studies investigated how environmental impoverishment affects adult brain. To shed light on the impact of early impoverishment on developmental trajectories of the nervous system, we developed a protocol of environmental impoverishment in which dams and pups lived from birth in a condition of reduced sensory-motor stimulation. Focusing on visual system, we measured two indexes of functional development, that is visual acuity, assessed by using Visual Evoked Potentials (VEPs), and VEP latency. In addition, we assessed in the visual cortex levels of Insulin-Like Growth Factor 1 (IGF-1) and myelin maturation, together with the expression of the GABA biosynthetic enzyme GAD67. We found that early impoverishment strongly delays visual acuity and VEP latency development. These functional changes were accompanied by a significant reduction of IGF-1 protein and GAD67 expression, as well as by delayed myelination of nerve fibers, in the visual cortex of impoverished pups. Thus, exposure to impoverished living conditions causes a significant alteration of developmental trajectories leading to a prominent delay of brain maturation. These results underscore the significance of adequate levels of environmental stimulation for the maturation of central nervous system.

Hypothalamic proopiomelanocortin (POMC) neurons are important players in the regulation of energy homeostasis; we previously demonstrated that environmental stimulation excites arcuate nucleus circuits to undergo plastic remodeling, leading to altered ratio between excitatory and inhibitory synaptic contacts on these neurons. The widely used selective serotonin reuptake inhibitor fluoxetine (FLX) is known to affect body weight. On the other hand, FLX administration mimics the effects of environmental stimulation on synaptic plasticity in the hippocampus and cortex. The mammalian target of rapamycin (mTOR) pathway is instrumental in these phenomena. Thus, we aimed at investigating whether and how FLX affects POMC neurons activity and hypothalamic mTOR function. Adult mice expressing green fluorescent protein (GFP) under the POMC promoter were treated with FLX for 3 weeks resulting in diminished body weight. Patch clamp recordings performed on POMC neurons indicate that FLX increases their firing rate and the excitatory AMPA-mediated transmission, and reduces the inhibitory GABAergic currents at presynaptic level. Immunofluorescence studies indicate that FLX increases the ratio between excitatory and inhibitory synaptic contacts on POMC neurons. These changes are associated with an increased activity of the hypothalamic mTOR pathway. Use of the mTOR inhibitor rapamycin blunts the effects of FLX on body weight and on functional and structural plasticity of POMC neurons. Our findings indicate that FLX is able to remodel POMC neurons, and that this may be partly mediated by the mTOR signaling pathway.

Leptin and Brain Derived Neurotrophic Factor (BDNF) pathways are critical players in body weight homeostasis. Noninvasive treatments like environmental stimulation are able to increase response to leptin and induce BDNF expression in the brain. Emerging evidences point to the antidepressant selective serotonin reuptake inhibitor Fluoxetine (FLX) as a drug with effects similar to environmental stimulation. FLX is known to impact on body weight, with mechanisms yet to be elucidated. We herein asked whether FLX affects energy balance, the leptin system and BDNF function. Adult lean male mice chronically treated with FLX showed reduced weight gain, higher energy expenditure, increased sensitivity to acute leptin, increased hypothalamic BDNF expression, associated to changes in white adipose tissue expression typical of "brownization". In the Ntrk2tm1Ddg/J model, carrying a mutation in the BDNF receptor Tyrosine kinase B (TrkB), these effects are partially or totally reversed. Wild type obese mice treated with FLX showed reduced weight gain, increased energy output, and differently from untreated obese mice, a preserved acute response to leptin in terms of activation of the intracellular leptin transducer STAT3. In conclusion, FLX impacts on energy balance and induces leptin sensitivity and an intact TrkB function is required for these effects to take place.

Environmental enrichment may slow cognitive decay possibly acting through an improvement in vascular function. Aim of the study was to assess the effects of a 7-month cognitive, social, and physical training program on cognitive and vascular function in patients with mild cognitive impairment. In a single-center, randomized, parallel-group study, 113 patients (age, 65–89 years) were randomized to multidomain training (n=55) or usual care (n=58). All participants underwent neuropsychological tests and vascular evaluation, including brachial artery flow-mediated dilation, carotid–femoral pulse wave velocity, carotid distensibility, and assessment of circulating hematopoietic CD34+ and endothelial progenitor cells. At study entry, an age-matched control group (n=45) was also studied. Compared with controls, patients had at study entry a reduced flow-mediated dilation (2.97±2.14% versus 3.73±2.06%; P =0.03) and hyperemic stimulus (shear rate area under the curve, 19.1±15.7 versus 25.7±15.1×10 −3 ; P =0.009); only the latter remained significant after adjustment for confounders ( P =0.03). Training improved Alzheimer disease assessment scale cognitive (training, 14.0±4.8 to 13.1±5.5; nontraining, 12.1±3.9 to 13.2±4.8; P for interaction visit×training=0.02), flow-mediated dilation (2.82±2.19% to 3.40±1.81%, 3.05±2.08% to 2.24±1.59%; P =0.006; P =0.023 after adjustment for diameter and shear rate area under the curve), and circulating hematopoietic CD34 + cells and prevented the decline in carotid distensibility (18.4±5.3 to 20.0±6.6, 23.9±11.0 to 19.5±7.1 Pa −1 ; P =0.005). The only clinical predictor of improvement of cognitive function after training was established hypertension. There was no correlation between changes in measures of cognitive and vascular function. In conclusion, a multidomain training program slows cognitive decline, especially in hypertensive individuals. This effect is accompanied by improved systemic endothelial function, mobilization of progenitor CD34 + cells, and preserved carotid distensibility. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01725178.

Objective: Amblyopia is a neurodevelopmental disorder characterized by visual acuity and contrast sensitivity loss, refractory to pharmacological and optical treatments in adulthood. In animals, the corpus callosum (CC) contributes to suppression of visual responses of the amblyopic eye. To investigate the role of interhemispheric pathways in amblyopic patients, we studied the response of the visual cortex to transcranial Direct Current Stimulation (tDCS) applied over the primary visual area (V1) contralateral to the "lazy eye." Methods: Visual acuity (logMAR) was assessed before (T0), immediately after (T1) and 60' following the application of cathodal tDCS (2.0 mA, 20') in 12 amblyopic patients. At each time point, Visual Evoked Potentials (VEPs) triggered by grating stimuli of different contrasts (K90%, K20%) were recorded in both hemispheres and compared to those obtained in healthy volunteers. Results: Cathodal tDCS improved visual acuity respect to baseline (p < 0.0001), whereas sham polarization had no significant effect. At T1, tDCS induced an inhibitory effect on VEPs amplitudes at all contrasts in the targeted side and a facilitation of responses in the hemisphere ipsilateral to the amblyopic eye; compared with controls, the facilitation persisted at T2 for high contrasts (K90%; Holm-Sidak post hoc method, p < 0.001), while the stimulated hemisphere recovered more quickly from inhibition (Holm-Sidak post hoc method, p < 0.001). Conclusions: tDCS is a promising treatment for amblyopia in adults. The rapid recovery of excitability and the concurrent transcallosal disinhibition following perturbation of cortical activity may support a critical role of interhemispheric balance in the pathophysiology of amblyopia.

Environmental enrichment (EE) has a remarkable impact on brain development. Continuous exposure to EE from birth determines a significant acceleration of visual system maturation both at retinal and cortical levels. A pre-weaning enriched experience is sufficient to trigger the accelerated maturation of the visual system, suggesting that factors affected by EE during the first days of life might prime visual circuits towards a faster development. The search for such factors is crucial not only to gain a better understanding of the molecular hierarchy of brain development but also to identify molecular pathways amenable to be targeted to correct atypical brain developmental trajectories. Here, we showed that IGF-1 levels are increased in the visual cortex of EE rats as early as P6 and this is a crucial event for setting in motion the developmental program induced by EE. Early intracerebroventricular (i.c.v.) infusion of IGF-1 in standard rats was sufficient to mimic the action of EE on visual acuity development, whereas blocking IGF-1 signaling by i.c.v. injections of the IGF-1 receptor antagonist JB1 prevented the deployment of EE effects. Early IGF-1 decreased the ratio between the expression of NKCC1 and KCC2 cation/chloride transporters, and the reversal potential for GABAAR-driven Cl− currents (ECl) was shifted toward more negative potentials, indicating that IGF-1 is a crucial factor in accelerating the maturation of GABAergic neurotransmission and promoting the developmental switch of GABA polarity from excitation to inhibition. In addition, early IGF-1 promoted a later occurring increase in its own expression, suggesting a priming effect of early IGF-1 in driving post-weaning cortical maturation.

Age-related cognitive impairment and dementia are an increasing societal burden. Epidemiological studies indicate that lifestyle factors, e.g. physical, cognitive and social activities, correlate with reduced dementia risk; moreover, positive effects on cognition of physical/cognitive training have been found in cognitively unimpaired elders. Less is known about effectiveness and action mechanisms of physical/cognitive training in elders already suffering from Mild Cognitive Impairment (MCI), a population at high risk for dementia. We assessed in 113 MCI subjects aged 65–89 years, the efficacy of combined physical-cognitive training on cognitive decline, Gray Matter (GM) volume loss and Cerebral Blood Flow (CBF) in hippocampus and parahippocampal areas, and on brain-blood-oxygenation-level-dependent (BOLD) activity elicited by a cognitive task, measured by ADAS-Cog scale, Magnetic Resonance Imaging (MRI), Arterial Spin Labeling (ASL) and fMRI, respectively, before and after 7 months of training vs. usual life. Cognitive status significantly decreased in MCI-no training and significantly increased in MCI-training subjects; training increased parahippocampal CBF, but no effect on GM volume loss was evident; BOLD activity increase, indicative of neural efficiency decline, was found only in MCI-no training subjects. These results show that a non pharmacological, multicomponent intervention improves cognitive status and indicators of brain health in MCI subjects.

Minipump infusions into visual cortex in vivo at the onset of the critical period have revealed that the proinflammatory cytokine leukemia inhibitory factor (LIF) delays the maturation of thalamocortical projection neurons of the lateral geniculate nucleus, and tecto-thalamic projection neurons of the superior colliculus, and cortical layer IV spiny stellates and layer VI pyramidal neurons. Here, we report that P12–20 LIF infusion inhibits somatic maturation of pyramidal neurons and of all interneuron types in vivo. Likewise, DIV 12–20 LIF treatment in organotypic cultures prevents somatic growth GABA-ergic neurons. Further, while NPY expression is increased in the LIF-infused hemispheres, the expression of parvalbumin mRNA and protein, Kv3.1 mRNA, calbindin D-28k protein, and GAD-65 mRNA, but not of GAD-67 mRNA or calretinin protein is substantially reduced. Also, LIF treatment decreases parvalbumin, Kv3.1, Kv3.2 and GAD-65, but not GAD-67 mRNA expression in OTC. Developing cortical neurons are known to depend on neurotrophins. Indeed, LIF alters neurotrophin mRNA expression, and prevents the growth promoting action of neurotophin-4 in GABA-ergic neurons. The results imply that LIF, by altering neurotrophin expression and/or signaling, could counteract neurotrophin-dependent growth and neurochemical differentiation of cortical neurons.

Objective: Environmental enrichment obtained by a multidomain training may slow cognitive decay possibly acting through an improvement in vascular function. Aim of the study is to assess the effects of a 7-month cognitive, social and physical training on cognitive and vascular function in patients with mild cognitive impairment (MCI). Design and method: In a single-center, randomized parallel-group study, 113 MCI (age 65–89 years) were randomized to multidomain training (N = 55), or usual care (N = 58). All participants underwent neuropsychological tests (including Alzheimer's Disease Assessment Scale-cognitive - ADAS-cog) and vascular evaluation, including brachial artery flow mediated dilation (FMD), carotid-femoral pulse wave velocity (PWV), and carotid intima-media thickness and distensibility. At study entry, an age-matched control group (n = 45) was also studied. Results: Compared to controls, MCI had at study entry a reduced FMD (2.97 ± 2.14 vs 3.73 ± 2.06%, p = 0.03) and hyperemic stimulus (shear rate AUC, 25.9 ± 21.2 36.7 ± 22.5 × 10–3, p = 0.008); the latter remained significantly different in covariate analysis adjusted for confounders (p = 0.04). Training improved ADAS-cog (MCI-training: 14.0 ± 4.8 to 13.1 ± 5.5; MCI-no training: 12.1 ± 3.9 to 13.2 ± 4.8; p for interaction time-treatment = 0.02) and FMD (2.82 ± 2.19 to 3.40 ± 1.81; 3.05 ± 2.08 to 2.24 ± 1.59%; p = 0.006) and prevented decline in carotid distensibility (18.4 ± 5.3 to 20.0 ± 6.6; 23.9 ± 11.0 to 19.5 ± 7.1 Pa-1; p = 0.005). The only clinical predictor of improvement of ADAS-cog in MCI-training was established hypertension (delta ADAS-cog in hypertensive patients: −2.3 ± 2.7 vs in normotensive patients 0.3 ± 5.0, p = 0.02). Furthermore, there was no correlation between changes in ADAS-cog and in vascular variables. Conclusions: A 7-month multidomain training slows, though modestly, cognitive decline, especially in hypertensive individuals. This effect is accompanied by improved systemic endothelial function and preserved carotid distensibility and it is significant only in the hypertensive subgroup.

Mild Cognitive Impairment (MCI) is an intermediate condition between normal aging and dementia, associated with an increased risk of progression into the latter within months or years. Olfactory impairment, a well-known biomarker for neurodegeneration, might be present in the condition early, possibly representing a signal for future pathological onset. Our study aimed at evaluating olfactory function in MCI and healthy controls in relation to neurocognitive performance and endothelial function. A total of 85 individuals with MCI and 41 healthy controls, matched for age and gender, were recruited. Olfactory function was assessed by Sniffin' Sticks Extended Test (Burghart, Medizintechnik, GmbH, Wedel, Germany). A comprehensive neurocognitive assessment was performed. Endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery by ultrasound. MCI individuals showed an impaired olfactory function compared to controls. The overall olfactory score is able to predict MCI with a good sensitivity and specificity (70.3 and 77.4% respectively). In MCI, olfactory identification score is correlated with a number of neurocognitive abilities, including overall cognitive status, dementia rating, immediate and delayed memory, visuospatial ability and verbal fluency. FMD was reduced in MCI (2.90 +/- 2.15 vs. 3.66 +/- 1.96%, P = 0.016) and was positively associated with olfactory identification score (rho(s)=0.219, P = 0.025). The association remained significant after controlling for age, gender, and smoking. In conclusion, olfactory evaluation is able to discriminate between MCI and healthy individuals. Systemic vascular dysfunction might be involved, at least indirectly, in olfactory dysfunction in MCI.

An inflammatory episode during brain development is discussed as first hit which could trigger a higher susceptibility for epilepsy or development of mental disorders. We addressed the early developmental actions of an IL-6 type pro-inflammatory cytokine, leukemia inhibitory factor (LIF) on cortical maturation both in vivo and in slice cultures. A rather modest enhancement of LIF signaling was used as a proxy for an early postnatal inflammation. It resulted in a dramatic interneuron synaptopathy. Our results indicate that LIF impairs development of cortical interneuron subsets and causes a lasting imbalance of excitation and inhibition. In particular, LIF not only downregulates the expression of the TrkB receptor ligand NT4, but concurrently prevents the neurotrophins from activating the MAP kinase pathway. As a consequence, strictly TrkB-dependent cortical inhibitory GABA-ergic interneurons, in particular fast-spiking basket (B) and chandelier (C) neurons are severely affected. They display an underdevelopment of the somatodendritic domain, less and smaller presynaptic boutons, a reduced expression of the calcium buffer parvalbumin, the voltage-gated potassium channel Kv3.2, the ultrafast vesicular calcium sensor synaptotagmin-2, and glutamate decarboxylase isoform GAD-65 which synthesized GABA for phasic inhibition. These presynaptic proteins are essential for the fast-spiking properties and a highly synchronous GABA release, both being critical determinants for neuronal oscillations in the cognitive gamma frequency band. Also pyramidal cells are altered: dendritic spines are lower in density and less mature, GABAARα1 at basket cell terminals and α2 at chandelier cell terminals are reduced in expression, the axon initial segment is shorter and its core scaffolding protein ßIV-spectrin is reduced. The presynaptic deficits (outlined in the graphical abstract with left: healthy; right: LIF / inflammation) suggest a serious impairment of inhibition, and calcium imaging indeed reveals a hyperexcitable network. A set of recovery experiments reveals a surprisingly slow recovery of the affected proteins, and intriguingly, synaptotagmin-2 entirely fails to recover. In summary, our study suggests LIF as a negative upstream modulator of TrkB signaling. The impaired trophic support results in a maldevelopment in particular of fast-spiking interneurons, a deficit of inhibition and cortical hyperexcitability.