Loss of TREM2 Confers Resilience to Synaptic and Cognitive Impairment in Aged Mice

Triggering receptor expressed on myeloid cells 2 (TREM2), a receptor exclusively expressed by microglia in the brain, modulates microglial immune homeostasis. Human genetic studies have shown that the loss-of-function mutations in TREM2 signaling are strongly associated with an elevated risk of age-related neurodegenerative diseases including Alzheimer''s disease (AD). Numerous studies have investigated the impact of TREM2 deficiency in the pathogenic process of AD. However, the role of TREM2 in shaping neuronal and cognitive function during normal aging is underexplored. In the present study, we employed behavioral, electrophysiological, and biochemical approaches to assess cognitive and synaptic function in male and female young and aged TREM2-deficient (Trem2−/−) mice compared with age-matched, sex-matched, and genetic background-matched wild-type (WT) C57BL/6J controls. Young Trem2−/− mice exhibited normal cognitive function and synaptic plasticity but had increased dendritic spine density compared with young WT. Unexpectedly, aged Trem2−/− mice showed superior cognitive performance compared with aged WT controls. Consistent with the behavioral data, aged Trem2−/− mice displayed significantly enhanced hippocampal long-term potentiation (LTP) and increased dendritic spine density and synaptic markers compared with aged WT mice. Taken together, these findings suggest that loss of TREM2 affects the neuronal structure and confers resilience to age-related synaptic and cognitive impairment during non-pathogenic aging.SIGNIFICANCE STATEMENT Microglia are innate immune cells of the brain that orchestrates neurodevelopment, synaptic function, and immune response to environmental stimuli. Microglial triggering receptor expressed on myeloid cells 2 (TREM2) signaling plays pivotal roles in regulating these functions and loss of TREM2 signaling leads to increased risk of developing age-related neurologic disorders. However, the neurologic role of TREM2 in normal aging is poorly understood. The results of the present study unveil the positive impacts of TREM2 deficiency on cognitive and synaptic function during aging and suggest that TREM2 may exert detrimental effects on neuronal function. The possibility of age-related negative impacts from TREM2 is critically important since TREM2 has emerged as a major therapeutic target for Alzheimer''s dementia.     

GABA Attenuates Amyloid Toxicity by Downregulating its Endocytosis and Improves Cognitive Impairment

GABA (gamma-aminobutyric acid) receptor modulators have been investigated as a potential treatment strategy in Alzheimer's disease (AD). In the present study, we found that GABA levels were different in wild type (WT) and AβPP/PS1 mouse brains. GABA downregulated amyloid-β (Aβ) uptake in neurons through the receptor for advanced glycation end-products. Therefore, relative high levels of GABA decreased cytotoxicity induced by Aβ in WT mice. GABA treatment decreased basal levels of cell death and the cell death induced by hydrogen peroxide in WT and AβPP/PS1 neurons. Application of GABA during early life before 2 months of age can improve cognitive function significantly in AβPP/PS1 mice. However, GABA treatment at 6 and 8 months of age cannot improve water maze performance. Activating or suppressing GABAA receptors by optogenetic methods also confirmed that GABA activation before 2 months of age increased water maze performance in AβPP/PS1 mice. Our data suggest that GABA administration during early life can be a potential treatment for AD.     

Proteomic CNS Profile of Delayed Cognitive Impairment in Mice Exposed to Gulf War Agents

Gulf War Illness (GWI) is a chronic multisymptom condition with a central nervous system (CNS) component, for which there is no treatment available. It is now believed that the combined exposure to Gulf War (GW) agents, including pyridostigmine bromide (PB) and pesticides, such as permethrin (PER), was a key contributor to the etiology of GWI. In this study, a proteomic approach was used to characterize the biomolecular disturbances that accompany neurobehavioral and neuropathological changes associated with combined exposure to PB and PER. Mice acutely exposed to PB and PER over 10 days showed an increase in anxiety-like behavior, psychomotor problems and delayed cognitive impairment compared to control mice that received vehicle only. Proteomic analysis showed changes in proteins associated with lipid metabolism and molecular transport in the brains of GW agent-exposed mice compared to controls. Proteins associated with the endocrine and immune systems were also altered, and dysfunction of these systems is a prominent feature of GWI. The presence of astrogliosis in the GW agent-exposed mice compared to control mice further suggests an immune system imbalance, as is observed in GWI. These studies provide a broad perspective of the molecular disturbances driving the late pathology of this complex illness. Evaluation of the potential role of these biological functions in GWI will be useful in identifying molecular pathways that can be targeted for the development of novel therapeutics against GWI.     

皮质下脑梗死所致血管性认知障碍患者认知功能与脑白质病变的相关性研究

目的 分析皮层下脑梗死所致血管性认知障碍 （subcorticalvascular cognitive impairment, SVCI） 脑白质 变性与认知功能评分的相关性。 方法 连续入组皮层下脑梗死患者91例, 根据神经心理学蒙特利尔认知评估 （Montreal Cognitive Assessment, MOCA） 分为皮层下脑梗死所致血管性认知障碍 （subcortical vascular cognitive impairment, SVCI） 组 （49例） 和无认知障碍的皮质下梗死 （subcortical infarcts, SI） 组 （42例） , 分析其临床、 认知 障碍、 神经影像学特征, 并探讨认知障碍与白质损伤的相关性。 结果 SVCI组糖尿病发病率高于SI组 （38.78% vs 16.67%, P =0.02） , SVCI组脑白质病变患者37 例 （75.51%） 。 脑白质损害程度与MOCA执行功能 （ Rs =-0.415, P =0.028） 、 瞬时记忆 （ Rs =-0.577, P =0.001） 、 注意 （ Rs =-0.382, P =0.001） 、 延迟记忆 （ Rs =-0.389, P =0.041） 等4个分量表以及MOCA 量表总分 （ Rs =-0.495, P =0.002） 成负相关。 结论 SVCI患者糖尿病比例高于SI患者, 白质病变多见, 且白质病变的程度可以反映不同程度的认知 损害。     

Thalamic Shape and Cognitive Performance in Amnestic Mild Cognitive Impairment

ObjectiveThis study aimed to investigate thalamic shape alterations and their relationships with various episodic memory impairments in subjects with amnestic mild cognitive impairment (aMCI).MethodsWe compared volumes and morphological alterations of the thalamus between aMCI subjects and healthy controls. In addition, we investigated the correlation between thalamic deformations and various memory impairments in aMCI subjects using a comprehensive neuropsychological battery.ResultsThe normalized left thalamic volumes of the aMCI group were significantly smaller than those of the healthy control group (p<0.0001). aMCI subjects exhibited significant thalamic deformations in the left thalamic dorso-medial and antero-medial areas compared with healthy individuals. CERAD-K Word List Memory scores were significantly correlated with the left dorso-medial areas in aMCI subjects. There were no significant correlations between verbal fluency, Boston naming test, constructional praxis, Word List Recognition, and Visuospatial Recall scores and thalamic shape in aMCI subjects. Verbal delayed recall scores were also significantly correlated with the left dorso-medial areas in the aMCI group.ConclusionStructural alterations in the thalamic deformations in the left dorso-medial and antero-medial areas might be core underlying neurobiological mechanisms of thalamic dysfunction related to Word List Memory and delayed verbal recall in individuals with aMCI.     

轻度认知功能障碍患者认知损害与血清脑源性神经营养因子水平的相关性

目的 研究轻度认知功能障碍（mild cognitive impairment,MCI）患者认知损害与血清脑源性神经营养因子（brain derived neurotrophic factor,BDNF）水平的关系。 方法 从认知障碍门诊筛选MCI患者30例,正常对照老年人32例,采用酶联免疫吸附法（enzyme linked immunosorbent assay,ELISA）检测MCI患者的血清BDNF水平。 结果 MCI的血清BDNF水平较正常对照组显著升高（P=0.025）,MCI组中血清BDNF与简明精神状态量表（Mini-Mental State Examination Scale,MMSE）中的记忆力（r=-0.494,P=0.009）、语言能力（r=-0.399,P=0.039）呈负相关,与定向力、注意力和计算力、回忆能力无相关性;与临床痴呆量表（Clinical Dementia Rating Scale,CDR）总分呈正相关（r=0.476,P=0.012）;与MMSE总分、全面衰退量表（Global Deterioration Scale,GDS）总分无相关性。 结论 MCI患者的BDNF水平显著升高,提示BDNF可能参与MCI认知损害的病理生理过程     

Neurotropic Infectious Agents and Cognitive Impairment in Schizophrenia

The links between infectious agents and risk for schizophrenia have been widely debated, but few investigations have focused on “epidiagnostic” effects, eg, whether exposures to infectious agents alter key clinical aspects of the disorder, such as cognitive impairment. The present theme issue evaluates epidiagnostic cognitive effects of two common infectious agents, namely Herpes Simplex Virus, type 1 and Toxoplasma gondii.Key words: schizophrenia, cognition, herpes, virus, Toxoplasma gondiiThe first article of the theme issue indicates that exposure to Herpes Simplex Virus, type 1 (HSV-1) may not be entirely benign for patients with SZ, even though it has not been implicated as a risk factor for schizophrenia (SZ) per se. The word herpes, derived from the Greek “herpein” (“to creep”), describes an unusual characteristic of HSV-1, ie, its proclivity to “creep” along sensory nerves following primary infection in mucosal membranes or in the skin.¹ The retrograde transport takes it to sensory nerve ganglia as well as cortical regions, where it establishes lifelong infection. HSV-1 evades and even hijacks the body’s cellular processes to lie in a relatively dormant state in the nuclei of host neurons. Sporadic reactivation culminates in anterograde transport to sensory nerve endings in mucosal and skin membranes, where typical lytic eruptions reappear. Thus, HSV-1 establishes persistent, ineradicable, lifelong cycles of latency and lytic reactivation. The infection has wide ranging clinical effects, including asymptomatic states, mucosal lesions or devastating encephalitis in immune-compromised individuals and rarely, in otherwise immune competent persons. Whether the repeated latency/reactivation cycles impair neuronal survival, particularly in the brain is not known. In the first article of the theme issues, Prasad et al suggest ominous effects of persistent infection that are particularly notable in SZ patients exposed to HSV-1: (1) structural damage in the cortical gray matter; (2) cognitive impairment; (3) cognitive deterioration over time. The review suggests small to medium effect sizes for the associations between exposure and cognitive impairment, but the population attributable fraction is likely to be 15% or higher, based on a recent association study² and exposure rates over 70% even in middle-aged US adults (http://www.cdc.gov/nchs/nhanes.htm).Genome-wide association studies (GWAS) indicate that HLA variants are associated with SZ risk predominantly in Caucasian ancestry samples, but the basis for the associations is uncertain.³ In the second article of this issue, Bamne et al report nominal associations with the Caucasian-GWAS SNPS in an African American case-control sample. As HLA molecules play a critical role in host immune responses to infection, Bamne and colleagues also investigated the SZ associated SNPs in relation to HSV-1 exposure. No significant associations were found, apart from a curious nominal association with rs3130297. One allele of this SNP elevates risk for SZ, while the other allele is associated with HSV-1 exposure. Analysis of additional replicative samples could clarify whether the epidiagnostic effects reviewed by Prasad et al are related to such host genetic variation. Toxoplama gondii (TOX), the focus of the third theme issue article is a protozoan with unusual clinical features. It infects diverse warm-blooded animals (including rodents), with cats serving as the definitive host for sexual reproduction of the parasite. Presumably to facilitate transfer from rodents to feline species, TOX reduces feline fear in infected rodents.^4,5 TOX infections also occur in 10%–20% of US adults, with exposure rates that approach 50% in other countries. Humans are considered accidental hosts for TOX as further transmission of the parasite to feline species ceases, except for unlikely but plausible cases of infected humans becoming preys of tigers and lions. Reminiscent of its effects on rodent behavior, TOX exposure has also been associated with elevated risk for accidents in humans in addition to its well-known devastating prenatal effects.^6,7 More important for SZ research, meta-analysis of over 30 case-control studies indicates elevated SZ risk in association with TOX infection.⁸ The basis for the association is not known. Kannan and Pletnikov (this issue) show that TOX infection impairs measures of spatial learning and memory in rodents. Because analogous variables are also impaired in SZ patients, it would be important to see whether TOX exposure explains some of the cognitive impairments in SZ patients.The associations discussed in the theme issue do not conclusively prove causal links between HSV-1 or TOX exposure and cognitive impairment. Cohort-based studies and treatment studies are needed. Recently, a double-blind placebo-controlled study of HSV-1 exposed SZ patients revealed significant improvement in verbal memory, working memory, and visual object learning following treatment with valacylcovir, a drug used to treat reactivated HSV-1 infection.⁹ Such studies may indicate novel remedies for cognitive impairment in SZ. They will also establish paradigms that may help us sift through the trove of data that are being generated by the NIH-funded Human Microbiome Project, which aims to characterize trillions of microorganisms harbored in the human body (http://commonfund.nih.gov/hmp/index.aspx).     

帕金森病认知功能损害

帕金森病（Parkinson’s disease,PD）认知功能损害近年来受到人们的关注,PD认知损害严重影响患者的日常生活能力,早期诊断和干预PD认知损害将有助于延缓PD痴呆的发生。本文就PD认知功能损害的发生率、诊断标准及治疗等方面进行简要综述。     

脑微出血及其与血管性认知功能障碍的关系

脑微出血是血管性认知功能障碍 （vascular cognitiveimpairment, VCI） 的独立危险因素之一, 在VCI形成过程中扮演着重要角色。 本文就脑微出血的相关危险因素、 病理基础, 以及导致血管性认 识功能障碍的可能机制、 相关治疗进行介绍。     

Effects of Virtual Reality-Based Cognitive Training in the Elderly with and without Mild Cognitive Impairment

ObjectiveThis study aimed to introduce a 4-week long fully immersive virtual reality-based cognitive training (VRCT) program that could be applied for both a cognitively normal elderly population and patients with mild cognitive impairment (MCI). In addition, we attempted to investigate the neuropsychological effects of the VRCT program in each group. MethodsA total of 56 participants, 31 in the MCI group and 25 in the cognitively normal elderly group, underwent eight sessions of VRCT for 4 weeks. In order to evaluate the effects of the VRCT, the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet was administered before and after the program. The program’ s safety was assessed using a simulator sickness questionnaire (SSQ), and availability was assessed using the presence questionnaire. ResultsAfter the eighth session of the VRCT program, cognitive improvement was observed in the ability to learn new information, visuospatial constructional ability, and frontal lobe function in both groups. At the baseline evaluation, based on the SSQ, the MCI group complained of disorientation and nausea significantly more than the cognitively normal elderly group did. However, both groups showed a reduction in discomfort as the VRCT program progressed. ConclusionWe conclude that our VRCT program helps improve cognition in both the MCI group and cognitively normal elderly group. Therefore, the VRCT is expected to help improve cognitive function in elderly populations with and without MCI.     

Racial/Ethnic Differences in Correspondence Between Subjective Cognitive Ratings and Cognitive Impairment

ObjectivesResponding to racial/ethnic disparities in dementia diagnosis and care, we examined the role of race/ethnicity in the correspondence between subjective and objective ratings of cognitive impairment. Our examination focused on the two types of discordance: (1) positive ratings in the presence of cognitive impairment and (2) negative ratings in the absence of cognitive impairment.Design and ParticipantsA cross-sectional assessment was conducted using the data from the Harmonized Cognitive Assessment Protocol project, a sub-study of the Health and Retirement Study. Our analytic sample included 3,096 participants: 2,257 non-Hispanic Whites, 498 Blacks, and 341 Hispanics.MeasurementsDiscordant groups were identified based on self-ratings of cognition (positive versus negative) and the Langa–Weir classification of cognitive impairment (normal versus impaired).ResultsBlacks and Hispanics were more prone to falsely positive perceptions of their cognitive function in the presence of cognitive impairment than non-Hispanic Whites. On the other hand, non-Hispanic Whites were more likely to manifest negative ratings even in the absence of cognitive impairment.ConclusionOur findings demonstrate the critical role of race/ethnicity in determining discordance between subjective and objective measures of cognition and highlight the importance of a tailored effort to promote dementia diagnosis and care.     

轻度认知功能障碍的认识

轻度认知功能障碍（MCI）是指介于痴呆和正常衰老之间的认知功能损害状态。由于概念的混淆、方法的差异及标准的不同,MCI在临床实践中存在着不少困惑。本文回顾了认知功能损害的研究历史,讨论了MCI的概念、诊断标准、临床分型、与正常老化和痴呆的鉴别以及临床预后,探讨了MCI与阿尔茨海默病的关系。