Early Cognitive Deficits Research Articles

In Addition to Poor Glycemic Control, a High Level of Irisin in the Plasma Portends Early Cognitive Deficits Clinically in Chinese Patients With Type 2 Diabetes Mellitus.

Background and Objectives: Irisin plays an important role in the metabolism and homeostasis of energy balance, which is involved in cognitive impairment. This study aimed to investigate the role of irisin in mild cognitive impairment (MCI) among Chinese patients with type 2 diabetes mellitus (T2DM).Methods: We recruited 133 Chinese patients with T2DM, and divided them according to the Montreal Cognitive Assessment score. Demographic data were collected and the level of irisin in the plasma was determined. In addition, the results of neuropsychological testing were examined. The concentration of irisin in the plasma was measured using an enzyme immunoassay.Results: A total of 59 patients were diagnosed with MCI and 74 patients were included as healthy-cognition controls. The level of irisin in the plasma (p = 0.043) and homeostasis model of assessment for insulin resistance (p = 0.032) in diabetic patients with MCI were higher than those observed in the healthy controls. A higher level of irisin in the plasma was associated with impaired overall cognition, specifically executive function. Linear regression analysis suggested that irisin (p = 0.017) and glycosylated hemoglobin (p = 0.036) were independent factors of diabetic MCI.Conclusions: The level of irisin in the plasma correlated with cognitive impairment in T2DM patients, particularly with executive function. These results further suggest that, in addition to poor glycemic control, a high level of irisin in the plasma portends early cognitive deficits clinically in Chinese patients with T2DM.

Dorsal hippocampal changes in T2 relaxation times are associated with early spatial cognitive deficits in 5XFAD mice

T2 relaxation time (T2) alterations may serve as markers for early detection and disease progression monitoring by reflecting brain microstructural integrity in Alzheimer’s disease (AD). However, the characteristics of T2 alterations during the early stage of AD remain elusive. We explored T2 alterations and their possible correlations with cognitive function in 5XFAD mice at early ages (1, 2, 3, and 5 months of age). Voxel-based analysis (VBA) and region of interest (ROI) analysis showed a decreased T2 in the hippocampus of 2-, 3-, and 5-month-old 5XFAD mice compared to those of controls. The dorsal hippocampal T2 decreased earlier than the ventral hippocampus T2. A significant correlation was observed between Morris water maze (MWM) test cognitive behavior and the dorsal hippocampus T2 in 5XFAD mice. These results indicated that the microstructural integrity of brain tissues, particularly the hippocampus, was impaired early and the impairment became more extensive and severe during disease progression. Furthermore, the dorsal hippocampus is a crucial component involved in spatial cognition impairment in young 5XFAD mice.

P.015 Long-term progression and prognosis in different subtypes of Parkinson’s disease: validation of a new multi-domain subtyping method

Background: Parkinson’s disease (PD) varies in clinical manifestations and course of progression from person to person. Identification of distinct PD subtypes is of great priority to develop personalized care approaches. We aimed to compare long-term progression and prognosis between different PD subtypes. Methods: Data on 421 individuals with de novo early-onset PD was retrieved from Parkinson’s Progression Markers Initiative (PPMI). Using a newly developed multi-domain subtyping method (based on motor phenotype, RBD, autonomic disturbance, early cognitive deficit), we divided PD population into three subtypes at baseline: “mild motor-predominant”, “Diffuse malignant” and “Intermediate”. Rate of global progression (mixed motor and non-motor features) and developing dementia were compared between the subtypes. Results: Patients with “diffuse malignant” PD experienced 0.5 z-score further worsening of global composite outcome (p=0.017) and 2.2 further decline in MOCA score (p=0.001) after 6-years of follow-up. Hazard for MCI/dementia was significantly higher in “diffuse malignant” (HR=3.2, p<0.001) and “intermediate” (HR=1.8, p<0.001) subtypes. Individuals with “diffuse malignant” PD had the lowest level of CSF amyloid-beta (p=0.006) and SPECT striatal binding ratio (p=0.001). Conclusions: This multi-domain subtyping is a valid method to predict subgroups of PD with distinct patterns of long-term progression at drug-naïve early-stage with potential application in real-life clinical practice.

Hydroxyurea Improves Spatial Memory and Cognitive Plasticity in Mice and Has a Mild Effect on These Parameters in a Down Syndrome Mouse Model.

Down syndrome (DS), a genetic disorder caused by partial or complete triplication of chromosome 21, is the most common genetic cause of intellectual disability. DS mouse models and cell lines display defects in cellular adaptive stress responses including autophagy, unfolded protein response, and mitochondrial bioenergetics. We tested the ability of hydroxyurea (HU), an FDA-approved pharmacological agent that activates adaptive cellular stress response pathways, to improve the cognitive function of Ts65Dn mice. The chronic HU treatment started at a stage when early mild cognitive deficits are present in this model (∼3 months of age) and continued until a stage of advanced cognitive deficits in untreated mice (∼5–6 months of age). The HU effects on cognitive performance were analyzed using a battery of water maze tasks designed to detect changes in different types of memory with sensitivity wide enough to detect deficits as well as improvements in spatial memory. The most common characteristic of cognitive deficits observed in trisomic mice at 5–6 months of age was their inability to rapidly acquire new information for long-term storage, a feature akin to episodic-like memory. On the background of severe cognitive impairments in untreated trisomic mice, HU-treatment produced mild but significant benefits in Ts65Dn by improving memory acquisition and short-term retention of spatial information. In control mice, HU treatment facilitated memory retention in constant (reference memory) as well as time-variant conditions (episodic-like memory) implicating a robust nootropic effect. This was the first proof-of-concept study of HU treatment in a DS model, and indicates that further studies are warranted to assess a window to optimize timing and dosage of the treatment in this pre-clinical phase. Findings of this study indicate that HU has potential for improving memory retention and cognitive flexibility that can be harnessed for the amelioration of cognitive deficits in normal aging and in cognitive decline (dementia) related to DS and other neurodegenerative diseases.

Regulation of Neprilysin Activity and Cognitive Functions in Rats After Prenatal Hypoxia.

The amyloid-degrading enzyme neprilysin (NEP) is one of the therapeutic targets in prevention and treatment of Alzheimer's disease (AD). As we have shown previously NEP expression in rat parietal cortex (Cx) and hippocampus (Hip) decreases with age and is also significantly reduced after prenatal hypoxia. Following the paradigms for enhancement of NEP expression and activity developed in cell culture, we analysed the efficacy of various compounds able to upregulate NEP using our model of prenatal hypoxia in rats. In addition to the previous data demonstrating that valproic acid can upregulate NEP expression both in neuroblastoma cells and in rat Cx and Hip we have further confirmed that caspase inhibitors can also restore NEP expression in rat Cx reduced after prenatal hypoxia. Here we also report that administration of a green tea catechin epigallocatechin-3-gallate (EGCG) to adult rats subjected to prenatal hypoxia increased NEP activity in blood plasma, Cx and Hip as well as improved memory performance in the 8-arm maze and novel object recognition tests. Moreover, EGCG administration led to an increased number of dendritic spines in the hippocampal CA1 area which correlated with memory enhancement. The data obtained allowed us to conclude that the decrease in the activity of the amyloid-degrading enzyme NEP, as well as a reduction in the number of labile interneuronal contacts in the hippocampus, contribute to early cognitive deficits caused by prenatal hypoxia and that there are therapeutic avenues to restore these deficits via NEP activation which could also be used for designing preventive strategies in AD.

Treatment with the glutamate modulator riluzole prevents early life stress-induced cognitive deficits and impairments in synaptic plasticity in APPswe/PS1dE9 mice

BackgroundEnvironmental factors like stress affect age-related cognitive deficits and promote Alzheimer's disease (AD)-related pathology in mice. Excess glutamate has been proposed as a possible mediator underlying these effects in the hippocampus, a vulnerable brain region implicated in learning and memory. MethodsHere, we examined a) whether stress applied during a sensitive developmental period early in life affects later synaptic plasticity, learning and memory and plaque load in the APPswe/PS1dE9 mouse model for Alzheimer's disease and b) whether these effects could be rescued using long-term treatment with the glutamate modulator riluzole. ResultsOur results demonstrate that ELS impairs synaptic plasticity in 6-month-old mice and increases plaque load in 12-month-old APPswe/PS1dE9 mice, while impairing flexible spatial learning in the Barnes maze at this age. Notably, spatial learning correlated well with hippocampal expression of the transporter EAAT2, which is important for extracellular glutamate uptake. The changes in LTP, plaque load and cognition after ELS were all prevented by riluzole treatment that started from post-weaning. ConclusionThese results suggest that normalising glutamate signalling may be a viable therapeutic strategy for treating vulnerable individuals at risk of developing stress-aggravated AD, particularly in relation to adverse early life experiences.

Structural Correlates of Personality Dimensions in Healthy Aging and MCI.

The revised NEO Personality Inventory (NEOPI-R), popularly known as the five-factor model, defines five personality factors: Neuroticism, Extraversion, Openness to Experience, Agreeableness, and Conscientiousness. The structural correlates of these personality factors are still a matter of debate. In this work, we examine the impact of subtle cognitive deficits on structural substrates of personality in the elderly using DTI derived white matter (WM) integrity measure, Fractional Anisotropy (FA). We employed canonical correlation analysis (CCA) to study the relationship between personality factors of the NEOPI-R and FA measures in two population groups: healthy controls and MCI. Agreeableness was the only personality factor to be associated with FA patterns in both groups. Openness was significantly related to FA data in the MCI group and the inverse was true for Conscientiousness. Furthermore, we generated saliency maps using bootstrapping strategy which revealed a larger number of positive correlations in healthy aging in contrast to the MCI status. The MCI group was found to be associated with a predominance of negative correlations indicating that higher Agreeableness and Openness scores were mostly related to lower FA values in interhemispheric and cortico-spinal tracts and a limited number of higher FA values in cortico-cortical and cortico-subcortical connection. Altogether these findings support the idea that WM microstructure may represent a valid correlate of personality dimensions and also indicate that the presence of early cognitive deficits led to substantial changes in the associations between WM integrity and personality factors.

Galantamine reversed early postoperative cognitive deficit via alleviating inflammation and enhancing synaptic transmission in mouse hippocampus

Postoperative cognitive dysfunction (POCD) is commonly seen in patients undergoing major surgeries and may persist. Although neuroinflammation is one of the important contributors to the development of POCD, the mechanisms underlying POCD remain unclear. We performed stabilized tibial fracture operation in male mice. In comparison with sham mice (anesthesia only), the surgery mice exhibited cognitive deficits in a fear conditioning paradigm at postsurgery day 3-7, and increased numbers of microglia and elevated levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) without change of anti-inflammatory cytokines (IL-4 and IL-10) in the hippocampus. Electrophysiological recordings from CA1 hippocampal neurons revealed that POCD mice exhibited impairment in AMPA receptor-mediated evoked excitatory postsynaptic currents (eEPSCs) without alteration in the rectification property of AMPA receptors. Interestingly, daily intraperitoneal administration of galantamine, an inhibitor of acetylcholinesterase, reversed cognitive dysfunction in surgery mice and attenuated accumulation of microglia and protein levels of IL-1β, IL-6 and TNF-α in the hippocampus. Additionally, galantamine potentiated AMPA receptor-mediated eEPSCs in the hippocampus more prominent in surgery mice than in sham mice. Therefore, enhancement of cholinergic tone in the hippocampus might be a therapeutic strategy for early POCD in terms of suppression of inflammation and normalization of excitatory synaptic transmission.

Phenotypic variability and neuropsychological findings associated with C9orf72 repeat expansions in a Bulgarian dementia cohort.

BackgroundThe GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in several European populations. The objective of this study was to determine the frequency of C9orf72 repeat expansions in a Bulgarian dementia cohort and to delineate the associated clinical features.Methods and findingsPCR-based assessments of the C9orf72 hexanucleotide repeat expansion in all study samples (including 82 FTD, 37 Alzheimer’s disease (AD), and 16 other neurodegenerative/dementia disorder cases) were performed. We report the clinical, neuropsychological, and neuroimaging findings obtained for the C9orf72 repeat expansion carriers. Of the 135 cases screened, 3/82 (3.7%) of all FTD cases and 1/37 (2.7%) of all clinical AD cases had a C9orf72 repeat expansion. In this cohort, the C9orf72 pathological expansion was found in clinical diagnoses bridging the FTD, parkinsonism, ALS and AD spectrum. Interestingly, we showed early writing errors without aphasia in two subjects with C9orf72 expansions.ConclusionsThis study represents the first genetic screening for C9orf72 repeat expansions in a Bulgarian dementia cohort. The C9orf72 repeat expansion does not appear to be a common cause of FTD and related disorders. This report confirms the notion that C9orf72 repeat expansions underlie a broad spectrum of neurodegenerative phenotypes. Relatively isolated agraphia in two cases with C9orf72 repeat expansions is a strong motivation to provide detailed and sophisticated oral and written language assessments that can be used to more precisely characterize early cognitive deficits in these heterogeneous conditions.

Do cognitive and neuropsychological functioning deficits coincide with hippocampal alteration during first-psychotic episode?

Numerous studies shown that structural hippocampal alterations are present in subjects at high risk of developing psychosis or schizophrenia. These findings indicate that in a subset of patients undergoing first-psychosis episode (FPE), hippocampal volume alterations are accompanied by associated cognitive and neuropsychological deficits. The combination of psychological deficits and neuroanatomical alterations, in turn, appears to increase treatment complexity and worsen clinical outcomes. We aim to determine whether cognitive and neuropsychological functioning deficits precede or follow hippocampal alterations during early onset psychosis. This cross-sectional study describes 3 case-studies of adolescent subjects, ages 16-17, admitted at the child and adolescent inpatient psychiatric unit in lieu of first psychotic episode. We conducted detailed structured clinical psychiatric interviews, anatomical-structural magnetic resonance imaging (MRI), sleep-deprived electroencephalogram (EEG) recordings, laboratory testing, and a comprehensive battery of psychological testing to better understand their clinical pictures. Psychological testing in each patient demonstrated the presence of low to borderline intellectual functioning coupled with neuropsychological deficits in different psychiatric domains. Interestingly, these changes coincided with structural MRI alterations in the hippocampal area. Our case report adds to the armamentarium of literature signifying that radiologically detectable alterations of the hippocampus may occur either concomitantly or closely following the development of early cognitive deficits in patients with FPE.

TrpV1 receptor activation rescues neuronal function and network gamma oscillations from Aβ-induced impairment in mouse hippocampus in vitro.

Amyloid-β peptide (Aβ) forms plaques in Alzheimer's disease (AD) and is responsible for early cognitive deficits in AD patients. Advancing cognitive decline is accompanied by progressive impairment of cognition-relevant EEG patterns such as gamma oscillations. The endocannabinoid anandamide, a TrpV1-receptor agonist, reverses hippocampal damage and memory impairment in rodents and protects neurons from Aβ-induced cytotoxic effects. Here, we investigate a restorative role of TrpV1-receptor activation against Aβ-induced degradation of hippocampal neuron function and gamma oscillations. We found that the TrpV1-receptor agonist capsaicin rescues Aβ-induced degradation of hippocampal gamma oscillations by reversing both the desynchronization of AP firing in CA3 pyramidal cells and the shift in excitatory/inhibitory current balance. This rescue effect is TrpV1-receptor-dependent since it was absent in TrpV1 knockout mice or in the presence of the TrpV1-receptor antagonist capsazepine. Our findings provide novel insight into the network mechanisms underlying cognitive decline in AD and suggest TrpV1 activation as a novel therapeutic target.

Cerebral inoculation of human A53T α-synuclein reduces spatial memory decline and amyloid-β aggregation in APP/PS1 transgenic mice of Alzheimer’s disease

Amyloid-β (Aβ) peptide and α-synuclein (α-syn) are major components of senile plaques in Alzheimer’s disease (AD) and Lewy bodies in Parkinson’s disease (PD), respectively. Co-occurrence of Aβ and α-syn in the senile brains of AD and LB diseases suggests interactions between the two proteins. However, the significance of the overlapping deposition, especially the effects of α-syn on the Aβ aggregation, still remains to be clarified. In the present study, we investigated the effects of α-syn pre-formed fibrils (PFFs) injection on the cognitive behaviors and Aβ deposition in the brain of APP/PS1 transgenic AD mice by using Morris water maze (MWM) test, immunohistochemistry and western blot techniques. We found that APP/PS1 transgenic mice exhibited an obvious elevation in the α-syn load, as well as Aβ deposition in the brain compared with wild type of C57 BL littermates. 5 months after cerebral injection of exogenous α-syn, MWM tests showed an alleviation in cognitive impairments in APP/PS1 mice; western blot and immunohistochemistry experiments also exhibited a significant reduction in Aβ level in the brain of APP/PS1 mice injected with α-syn. These results suggest that α-syn aggregated in the brain of AD may act as a protective factor and defend the brain tissue from early Aβ deposition and cognitive deficits.

The motor and cognitive features of Parkinson\u2019s disease in patients with concurrent Gaucher disease over 2 years: a case series

We report the cognitive features and progression of Parkinson’s disease (PD) in five patients with concurrent Gaucher disease. The patients presented at an earlier age than patients with sporadic PD, as previously noted by others; but in contrast to many previous reports, our patients followed a variable clinical course. While two patients developed early cognitive deficits and dementia, three others remained cognitively intact over the follow-up period. Thus, in this small case series, PD in the context of GD more closely resembles idiopathic PD in terms of its clinical heterogeneity in contrast to PD associated with GBA heterozygote mutations.

Evidence for altered dendritic spine compartmentalization in Alzheimer's disease and functional effects in a mouse model.

Alzheimer's disease (AD) is associated with a progressive loss of synapses and neurons. Studies in animal models indicate that morphological alterations of dendritic spines precede synapse loss, increasing the proportion of large and short ("stubby") spines. Whether similar alterations occur in human patients, and what their functional consequences could be, is not known. We analyzed biopsies from AD patients and APP x presenilin 1 knock-in mice that were previously shown to present a loss of pyramidal neurons in the CA1 area of the hippocampus. We observed that the proportion of stubby spines and the width of spine necks are inversely correlated with synapse density in frontal cortical biopsies from non-AD and AD patients. In mice, the reduction in the density of synapses in the stratum radiatum was preceded by an alteration of spine morphology, with a reduction of their length and an enlargement of their neck. Serial sectioning examined with electron microscopy allowed us to precisely measure spine parameters. Mathematical modeling indicated that the shortening and widening of the necks should alter the electrical compartmentalization of the spines, leading to reduced postsynaptic potentials in spine heads, but not in soma. Accordingly, there was no alteration in basal synaptic transmission, but long-term potentiation and spatial memory were impaired. These results indicate that an alteration of spine morphology could be involved in the early cognitive deficits associated with AD.

Chronic Hippocampal Expression of Notch Intracellular Domain Induces Vascular Thickening, Reduces Glucose Availability, and Exacerbates Spatial Memory Deficits in a Rat Model of Early Alzheimer.

The specific roles of Notch in progressive adulthood neurodegenerative disorders have begun to be unraveled in recent years. A number of independent studies have shown significant increases of Notch expression in brains from patients at later stages of sporadic Alzheimer's disease (AD). However, the impact of Notch canonical signaling activation in the pathophysiology of AD is still elusive. To further investigate this issue, 2-month-old wild-type (WT) and hemizygous McGill-R-Thy1-APP rats (Tg(+/-)) were injected in CA1 with lentiviral particles (LVP) expressing the transcriptionally active fragment of Notch, known as Notch Intracellular Domain (NICD), (LVP-NICD), or control lentivirus particles (LVP-C). The Tg(+/-) rat model captures presymptomatic aspects of the AD pathology, including intraneuronal amyloid beta (Aβ) accumulation and early cognitive deficits. Seven months after LVP administration, Morris water maze test was performed, and brains isolated for biochemical and histological analysis. Our results showed a learning impairment and a worsening of spatial memory in LVP-NICD- as compared to LVP-C-injected Tg(+/-) rats. In addition, immuno histochemistry, ELISA multiplex, Western blot, RT-qPCR, and 1H-NMR spectrometry of cerebrospinal fluid (CSF) indicated that chronic expression of NICD promoted hippocampal vessel thickening with accumulation of Aβ in brain microvasculature, alteration of blood-brain barrier (BBB) permeability, and a decrease of CSF glucose levels. These findings suggest that, in the presence of early Aβ pathology, expression of NICD may contribute to the development of microvascular abnormalities, altering glucose transport at the BBB with impact on early decline of spatial learning and memory.

P.2.023 - Impairment of learning and memory in mice overexpressing α- and γ-synuclein in dopaminergic neurons- implication in Parkinson’s disease

Introduction Idiopathic Parkinson’s disease (PD) is characterized by progressive brain pathology affecting several neurotransmitter systems, leading to a diverse profile of autonomic, motor, cognitive and psychiatric dysfunctions. Multiple convergent lines of evidence implicate the aggregation and accumulation of α-synuclein in the PD pathogenesis [1]. Moreover, post-translational changes of γ-synuclein increase the α-synuclein aggregation [2]. α- and γ-synuclein are members of the synuclein family of small cytoplasmic neuron-specific proteins, and have been suggested to modulate the function of monoamine transporters (DAT, SERT, NET) [3]. Previously, we reported that α-synuclein knockdown mice showed increased extracellular dopamine and serotonin levels –compared to control mice– in caudate-putamen (CPu) and medial prefrontal cortex (mPFC) after DAT or SERT blockade with nomifensine or citalopram, respectively (Alarcon-Aris et al., in review). Aims Given the role of monoamine neurotransmission in cognitive processes, in the present study we assessed the effects of over-expressing α- and γ-synuclein in mouse dopaminergic neurons on spatial and working memory. Methods We generated a mouse model overexpressing human wild-type α-synucleinor endogenous γ-synuclein in dopaminergic neurons from the substantia nigra compacta (SNc) and ventral tegmental area (VTA) using adeno-associated virus type-5 (AAV5-human-α-synuclein) or type-10 (AAV10-mouse-γ-synuclein) unilaterally injected in SNc/VTA. Behavioral tests were performed in mice at 4, 8 and 16 weeks post-infection using cognitive (novel object recognition, Morris water maze, passive avoidance tests) and motor paradigms (cylinder test, rotarod). Extracellular striatal dopamine levels were measured by in vivo microdialysis after implanting concentric dialysis probes, and analyzed by high precision liquid chromatography with electrochemical detection (+0.75 V). In situ hybridization was performed on fixed mice tissues, with 33P-dATP labeled probes in order to detect α- and γ-synuclein transcripts through autoradiography. Results AAV5-α-synuclein mice showed increased human α-synuclein mRNA levels in the ipsilateral SNc over time reaching a 278% of sham mice at 8 weeks post-infection. Similarly, AAV10-γ-synuclein mice reached to a maximal of 250% of sham mice. Overexpression of α- or γ-synuclein led to lower extracellular dopamine levels in CPu and mPFC compared to sham mice after local veratridine (sodium chanel activator agent, 50 µM) or nomifensine (DAT inhibitor, 1-10-50 µM) administration at 4 weeks post-infection. Moreover, overexpression of α- or γ-synuclein led to the impairment of working memory in mice as revealed by passive avoidance test (retention memory 35.5% and 45.9% shorter in AAV5-α-synuclein andAAV10-γ-synuclein mice, respectively) and novel object recognition test (reduction of 10% in time spent exploring novel object in both infected models) at 4-8 weeks post-infection. Likewise, these mice showed deficits in the spatial learning using the Morris water maze (F(1,28)=5.711, P=0.02 in AAV5-α-synuclein; F(1,28)=11.43, P=0.0021 in AAV10-γ-synuclein). These non-motor symptoms appeared earlier than motor deficits assessed by the cylinder test and rotarod. Conclusions Overall, these findings indicate that 1) α- and γ-synuclein are directly involved in the regulation of cognitive functions, likely through changes in monoamine functions, and 2) overexpression of α- or γ-synuclein in dopaminergic neurons mimics the temporal progression of clinical symptoms in PD, with early cognitive deficits appearing before motor symptoms.

Eye Movement Abnormalities in Multiple Sclerosis: Pathogenesis, Modeling, and Treatment.

Multiple sclerosis (MS) commonly causes eye movement abnormalities that may have a significant impact on patients’ disability. Inflammatory demyelinating lesions, especially occurring in the posterior fossa, result in a wide range of disorders, spanning from acquired pendular nystagmus (APN) to internuclear ophthalmoplegia (INO), among the most common. As the control of eye movements is well understood in terms of anatomical substrate and underlying physiological network, studying ocular motor abnormalities in MS provides a unique opportunity to gain insights into mechanisms of disease. Quantitative measurement and modeling of eye movement disorders, such as INO, may lead to a better understanding of common symptoms encountered in MS, such as Uhthoff’s phenomenon and fatigue. In turn, the pathophysiology of a range of eye movement abnormalities, such as APN, has been clarified based on correlation of experimental model with lesion localization by neuroimaging in MS. Eye movement disorders have the potential of being utilized as structural and functional biomarkers of early cognitive deficit, and possibly help in assessing disease status and progression, and to serve as platform and functional outcome to test novel therapeutic agents for MS. Knowledge of neuropharmacology applied to eye movement dysfunction has guided testing and use of a number of pharmacological agents to treat some eye movement disorders found in MS, such as APN and other forms of central nystagmus.

Cerebrospinal fluid from Dementia with Lewy body patients suppresses neuronal network activity

Cerebrospinal fluid from Dementia with Lewy body patients suppresses neuronal network activity

Combined corticosterone treatment and chronic restraint stress lead to depression associated with early cognitive deficits in mice.

Many models, such as chronic mild stress, chronic stress or chronic corticosterone injections are used to induce depression associated with cognitive deficits. However, the induction period in these different models is still long and face constraints when it is short such as in the chronic mild stress done in a minimum period of 21days. This study aimed to characterize a model of depression with early onset cognitive deficit. 14days combined chronic injection of corticosterone followed by 2h restraint stress using a restrainer was used to induce depression with early cognitive deficit onset. The forced swim test, sucrose test and plasma corticosterone concentration were used to assess depression-like characteristics. The Morris water maze, novel object recognition task, as well as hippocampal acetylcholinesterase activity were used to assess cognitive deficit. The combined corticosterone injection + chronic restraint stress group presented with marked depression-like behaviour and a higher plasma corticosterone concentration compared to corticosterone injection alone and restraint stress alone. It also showed an alteration in the learning process, memory deficit as well as increased acetylcholinesterase activity compared to corticosterone injection and restraint stress alone groups. These findings suggest that the combined corticosterone administration and chronic restraint stress can be used not only as an animal model for severe depression, but also for depression with early onset cognitive deficit.

Endocannabinoid-Specific Impairment in Synaptic Plasticity in Striatum of Huntington's Disease Mouse Model.

Huntington's disease (HD) is an inherited neurodegenerative disease affecting predominantly striatum and cortex that results in motor and cognitive disorders. Before a motor phenotype, animal models of HD show aberrant cortical-striatal glutamate signaling. Here, we tested synaptic plasticity of cortical excitatory synapses onto striatal spiny projection neurons (SPNs) early in the YAC128 mouse model of HD. High-frequency stimulation-induced long-term depression, mediated by the endocannabinoid anandamide and cannabinoid receptor 1 (CB1), was significantly attenuated in male and female YAC128 SPNs. Indirect pathway SPNs, which are more vulnerable in HD, were most affected. Our experiments show metabotropic glutamate receptor and endocannabinoid 2-arachidonoylglycerol-dependent plasticity, as well as direct CB1 activation by agonists, was similar in YAC128 and FVB/N wild-type SPNs suggesting that presynaptic CB1 is functioning normally. These results are consistent with a specific impairment in postsynaptic anandamide synthesis in YAC128 SPN. Strikingly, although suppression of degradation of anandamide was not effective, elevating 2-arachidonoylglycerol levels restored long-term depression in YAC128 striatal neurons. Together, these results have potential implications for neuroprotection and ameliorating early cognitive and motor deficits in HD.SIGNIFICANCE STATEMENT Huntington's disease (HD) is an inherited neurodegenerative disease with no cure. Recent studies find impairment of the endocannabinoid system in animal models but the functional implication for synaptic plasticity in HD remains unclear. Sepers et al. show a selective deficit in synaptic plasticity mediated by the endocannabinoid anandamide, but not 2-arachidonoylglycerol in a mouse model of HD. The deficit is rescued by selectively elevating levels of 2-arachidonoylglycerol produced on-demand. This mechanism could be targeted in the development of future therapeutics for HD.