Serum levels of inflammation factors and cognitive performance in amnestic mild cognitive impairment: a Chinese clinical study

Early diagnosis of Alzheimer's disease (AD) is important for initiating timely therapy to block or slow the rate of disease progression. This study was designed to investigate the potential of inflammation-related biomarkers in peripheral blood to accurately reflect AD onset and progression. Individuals (n=150) with amnestic mild cognitive impairment (aMCI) were divided into two subgroups (low- and high-risk) based on APOEε4 allele carrier status, and administered a battery of neuropsychological tests and tested for serum levels of IL-6, IL-10, TNF-α, and IFN-γ by using specific enzyme-linked immunosorbent assays. Results were compared with those from age-matched healthy controls (n=150). The levels of IL-6 were significantly higher in the aMCI group than in controls (P<0.01). When the aMCI group was stratified by APOEε4 status, significant differences were found between the low- and high-risk groups and controls in the levels of IL-6 and IFN-γ (P<0.01 and P=0.041, respectively). Moreover, the IL-6 level in the low-risk aMCI group was higher than that in the high-risk aMCI group (P=0.028). A weak but significant negative correlation was found between IL-6 and cognitive performance. Taken together, these findings indicate that IL-6, while not useful alone, has potential in combination with other biomarkers to support early diagnosis of aMCI due to its association with the progression of cognitive impairment.     

Microstructural White Matter Changes,Not Hippocampal Atrophy,Detect Early Amnestic Mild Cognitive Impairment

Background

Alzheimer’s disease (AD) is generally considered to be characterized by pathology in gray matter of the brain, but convergent evidence suggests that white matter degradation also plays a vital role in its pathogenesis. The evolution of white matter deterioration and its relationship with gray matter atrophy remains elusive in amnestic mild cognitive impairment (aMCI), a prodromal stage of AD.

Methods

We studied 155 cognitively normal (CN) and 27 ‘late’ aMCI individuals with stable diagnosis over 2 years, and 39 ‘early’ aMCI individuals who had converted from CN to aMCI at 2-year follow up. Diffusion tensor imaging (DTI) tractography was used to reconstruct six white matter tracts three limbic tracts critical for episodic memory function - the fornix, the parahippocampal cingulum, and the uncinate fasciculus; two cortico-cortical association fiber tracts - superior longitudinal fasciculus and inferior longitudinal fasciculus; and one projection fiber tract - corticospinal tract. Microstructural integrity as measured by fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) was assessed for these tracts.

Results

Compared with CN, late aMCI had lower white matter integrity in the fornix, the parahippocampal cingulum, and the uncinate fasciculus, while early aMCI showed white matter damage in the fornix. In addition, fornical measures were correlated with hippocampal atrophy in late aMCI, whereas abnormality of the fornix in early aMCI occurred in the absence of hippocampal atrophy and did not correlate with hippocampal volumes.

Conclusions

Limbic white matter tracts are preferentially affected in the early stages of cognitive dysfunction. Microstructural degradation of the fornix preceding hippocampal atrophy may serve as a novel imaging marker for aMCI at an early stage.     

Functional Neural Correlates of Attentional Deficits in Amnestic Mild Cognitive Impairment

Although amnestic mild cognitive impairment (aMCI; often considered a prodromal phase of Alzheimer’s disease, AD) is most recognized by its implications for decline in memory function, research suggests that deficits in attention are present early in aMCI and may be predictive of progression to AD. The present study used functional magnetic resonance imaging to examine differences in the brain during the attention network test between 8 individuals with aMCI and 8 neurologically healthy, demographically matched controls. While there were no significant behavioral differences between groups for the alerting and orienting functions, patients with aMCI showed more activity in neural regions typically associated with the networks subserving these functions (e.g., temporoparietal junction and posterior parietal regions, respectively). More importantly, there were both behavioral (i.e., greater conflict effect) and corresponding neural deficits in executive control (e.g., less activation in the prefrontal and anterior cingulate cortices). Although based on a small number of patients, our findings suggest that deficits of attention, especially the executive control of attention, may significantly contribute to the behavioral and cognitive deficits of aMCI.     

Bayesian Network Analysis Reveals Alterations to Default Mode Network Connectivity in Individuals at Risk for Alzheimer's Disease

Alzheimer''s disease (AD) is associated with abnormal functioning of the default mode network (DMN). Functional connectivity (FC) changes to the DMN have been found in patients with amnestic mild cognitive impairment (aMCI), which is the prodromal stage of AD. However, whether or not aMCI also alters the effective connectivity (EC) of the DMN remains unknown. We employed a combined group independent component analysis (ICA) and Bayesian network (BN) learning approach to resting-state functional MRI (fMRI) data from 17 aMCI patients and 17 controls, in order to establish the EC pattern of DMN, and to evaluate changes occurring in aMCI. BN analysis demonstrated heterogeneous regional convergence degree across DMN regions, which were organized into two closely interacting subsystems. Compared to controls, the aMCI group showed altered directed connectivity weights between DMN regions in the fronto-parietal, temporo-frontal, and temporo-parietal pathways. The aMCI group also exhibited altered regional convergence degree in the right inferior parietal lobule. Moreover, we found EC changes in DMN regions in aMCI were correlated with regional FC levels, and the connectivity metrics were associated with patients'' cognitive performance. This study provides novel sights into our understanding of the functional architecture of the DMN and adds to a growing body of work demonstrating the importance of the DMN as a mechanism of aMCI.     

Aberrant hippocampal subregion networks associated with the classifications of aMCI subjects: a longitudinal resting-state study

Background

Altered hippocampal structure and function is a valuable indicator of possible conversion from amnestic type mild cognitive impairment (aMCI) to Alzheimer''s disease (AD). However, little is known about the disrupted functional connectivity of hippocampus subregional networks in aMCI subjects.

Methodology/Principal Findings

aMCI group-1 (n = 26) and controls group-1 (n = 18) underwent baseline and after approximately 20 months follow up resting-state fMRI scans. Integrity of distributed functional connectivity networks incorporating six hippocampal subregions (i.e. cornu ammonis, dentate gyrus and subicular complex, bilaterally) was then explored over time and comparisons made between groups. The ability of these extent longitudinal changes to separate unrelated groups of 30 subjects (aMCI-converters, n = 6; aMCI group-2, n = 12; controls group-2, n = 12) were further assessed. Six longitudinal hippocampus subregional functional connectivity networks showed similar changes in aMCI subjects over time, which were mainly associated with medial frontal gyrus, lateral temporal cortex, insula, posterior cingulate cortex (PCC) and cerebellum. However, the disconnection of hippocampal subregions and PCC may be a key factor of impaired episodic memory in aMCI, and the functional index of these longitudinal changes allowed well classifying independent samples of aMCI converters from non-converters (sensitivity was 83.3%, specificity was 83.3%) and controls (sensitivity was 83.3%, specificity was 91.7%).

Conclusions/Significance

It demonstrated that the functional changes in resting-state hippocampus subregional networks could be an important and early indicator for dysfunction that may be particularly relevant to early stage changes and progression of aMCI subjects.     

Autophagy Is Involved in the Sevoflurane Anesthesia-Induced Cognitive Dysfunction of Aged Rats

Autophagy is associated with regulation of both the survival and death of neurons, and has been linked to many neurodegenerative diseases. Postoperative cognitive dysfunction is commonly observed in elderly patients following anesthesia, but the pathophysiological mechanisms are largely unexplored. Similar effects have been found in aged rats under sevoflurane anesthesia; however, the role of autophagy in sevoflurane anesthesia-induced hippocampal neuron apoptosis of older rats remains elusive. The present study was designed to investigate the effects of autophagy on the sevoflurane-induced cognitive dysfunction in aged rats, and to identify the role of autophagy in sevoflurane-induced neuron apoptosis. We used 20-month-old rats under sevoflurane anesthesia to study memory performance, neuron apoptosis, and autophagy. The results demonstrated that sevoflurane anesthesia significantly impaired memory performance and induced hippocampal neuron apoptosis. Interestingly, treatment of rapamycin, an autophagy inducer, improved the cognitive deficit observed in the aged rats under sevoflurane anesthesia by improving autophagic flux. Rapamycin treatment led to the rapid accumulation of autophagic bodies and autophagy lysosomes, decreased p62 protein levels, and increased the ratio of microtubule-associated protein light chain 3 II (LC3-II) to LC3-I in hippocampal neurons through the mTOR signaling pathway. However, administration of an autophagy inhibitor (chloroquine) attenuated the autophagic flux and increased the severity of sevoflurane anesthesia-induced neuronal apoptosis and memory impairment. These findings suggest that impaired autophagy in the hippocampal neurons of aged rats after sevoflurane anesthesia may contribute to cognitive impairment. Therefore, our findings represent a potential novel target for pro-autophagy treatments in patients with sevoflurane anesthesia-induced neurodegeneration.     

轻度认知损伤患者的联系记忆损伤特征

遗忘型轻度认知损伤患者(aMCI)在项目记忆和联系记忆上都有损伤．本文通过临床记忆量表中的项目记忆和联系记忆测验,研究aMCI的联系记忆是否比项目记忆有更显著的损伤．另外,通过分析配对联想学习测验,进一步研究aMCI联系记忆损伤的特点．25名aMCI和28名健康老人参与了两个联系记忆测验(配对联想学习测验和联想回忆测验)和两个项目记忆测验(图像自由回忆和无意义图形再认),aMCI患者在联系记忆测验上表现出了更显著的损伤,即使控制了项目记忆的损伤,aMCI的联系记忆仍然比健康老人显著降低．另外,ROC分析表明联系记忆测验比项目记忆测验对aMCI病人有更高的区分度．对配对联想学习测验的分析表明,相对于健康老人,aMCI患者在记忆有语言联系的词对要比记忆无语义联系的词对更为困难．本研究进一步表明aMCI患者的联系记忆比项目记忆有更大的损伤．相对于健康老人,aMCI患者不仅难以在两个无关项目间创建记忆连接,而且在有效利用项目间本身的语义联系方面存在更大的损伤．联系记忆测验比项目记忆测验对aMCI患者有更高的区分度．在神经心理评估中增加联系记忆测验,能更加有效地识别aMCI患者．     

Forced running exercise attenuates hippocampal neurogenesis impairment and the neurocognitive deficits induced by whole-brain irradiation via the BDNF-mediated pathway

Cranial radiotherapy induces progressive and debilitating cognitive deficits, particularly in long-term cancer survivors, which may in part be caused by the reduction of hippocampal neurogenesis. Previous studies suggested that voluntary exercise can reduce the cognitive impairment caused by radiation therapy. However, there is no study on the effect of forced wheel exercise and little is known about the molecular mechanisms mediating the effect of exercise. In the present study, we investigated whether the forced running exercise after irradiation had the protective effects of the radiation-induced cognitive impairment. Sixty-four Male Sprague–Dawley rats received a single dose of 20 Gy or sham whole-brain irradiation (WBI), behavioral test was evaluated using open field test and Morris water maze at 2 months after irradiation. Half of the rats accepted a 3-week forced running exercise before the behavior detection. Immunofluorescence was used to evaluate the changes in hippocampal neurogenesis and Western blotting was used to assess changes in the levels of mature brain-derived neurotrophic factor (BDNF), phosphorylated tyrosine receptor kinase B (TrkB) receptor, protein kinase B (Akt), extracellular signal-regulated kinase (ERK), calcium-calmodulin dependent kinase (CaMKII), cAMP-calcium response element binding protein (CREB) in the BDNF–pCREB signaling. We found forced running exercise significantly prevented radiation-induced cognitive deficits, ameliorated the impairment of hippocampal neurogenesis and attenuated the down-regulation of these proteins. Moreover, exercise also increased behavioral performance, hippocampal neurogenesis and elevated BDNF–pCREB signaling in non-irradiation group. These results suggest that forced running exercise offers a potentially effective treatment for radiation-induced cognitive deficits.     

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Enhances Hippocampal Synaptic Plasticity and Improves Memory Performance in Huntington’s Disease

Deficits in hippocampal synaptic plasticity result in cognitive impairment in Huntington’s disease (HD). Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that exerts neuroprotective actions, mainly through the PAC1 receptor. However, the role of PACAP in cognition is poorly understood, and no data exists in the context of Huntington’s disease (HD). Here, we investigated the ability of PACAP receptor stimulation to enhance memory development in HD. First, we observed a hippocampal decline of all three PACAP receptor expressions, i.e., PAC1, VPAC1, and VPAC2, in two different HD mouse models, R6/1 and HdhQ7/Q111, from the onset of cognitive dysfunction. In hippocampal post-mortem human samples, we found a specific decrease of PAC1, without changes in VPAC1 and VPAC2 receptors. To determine whether activation of PACAP receptors could contribute to improve memory performance, we conducted daily intranasal administration of PACAP38 to R6/1 mice at the onset of cognitive impairment for seven days. We found that PACAP treatment rescued PAC1 level in R6/1 mice, promoted expression of the hippocampal brain-derived neurotrophic factor, and reduced the formation of mutant huntingtin aggregates. Furthermore, PACAP administration counteracted R6/1 mice memory deficits as analyzed by the novel object recognition test and the T-maze spontaneous alternation task. Importantly, the effect of PACAP on cognitive performance was associated with an increase of VGlut-1 and PSD95 immunolabeling in hippocampus of R6/1 mice. Taken together, these results suggest that PACAP, acting through stimulation of PAC1 receptor, may have a therapeutic potential to counteract cognitive deficits induced in HD.     

Dysregulated daily rhythmicity of neuronal resting-state networks in MCI patients

In young healthy participants, the degree of daily rhythmicity largely varies across different neuronal resting-state networks (RSNs), while it is to date unknown whether this temporal pattern of activity is conserved in healthy and pathological aging. Twelve healthy elderly (mean age?=?65.1?±?5.7 years) and 12 patients with amnestic mild cognitive impairment (aMCI; mean age?=?69.6?±?6.2 years) underwent four resting-state functional magnetic resonance imaging scans at fixed 2.5?h intervals throughout a day. Time courses of a RSN were extracted by a connectivity strength and a spatial extent approach performed individually for each participant. Highly rhythmic RSNs included a sensorimotor, a cerebellar and a visual network in healthy elderly; the least rhythmic RSNs in this group included a network associated with executive control and an orbitofrontal network. The degree of daily rhythmicity in aMCI patients was reduced and dysregulated. For healthy elderly, the findings are in accordance with results reported for young healthy participants suggesting a comparable distribution of daily rhythmicity across RSNs during healthy aging. In contrast, the reduction and dysregulation of daily rhythmicity observed in aMCI patients is presumably indicative of underlying neurodegenerative processes in this group.     

Development of Biomarkers Based on DNA Methylation in the NCAPH2/LMF2 Promoter Region for Diagnosis of Alzheimer’s Disease and Amnesic Mild Cognitive Impairment

From the standpoint of early interventions for dementia, a convenient method of diagnosis using biomarkers is required for Alzheimer’s disease (AD) in the early stage as well as amnesic mild cognitive impairment (aMCI). Focusing on differences in DNA methylation due to AD and aMCI, in the present study, we first conducted genome-wide screening, measuring blood DNA methylation levels by the Illumina Infinium HD Methylation Assay in 3 small age-and gender-matched groups consisting of 4 subjects each: normal controls (NC), aMCI and AD. The genome-wide analysis produced 11 DNA methylation loci that distinguished the 3 groups. For confirmation, we increased group sizes and examined samples by pyrosequencing which revealed that DNA methylation in the NCAPH2/LMF2 promoter region was significantly decreased in the AD (n = 30) and aMCI (n = 28) groups as compared to the NC group (n = 30) (P < 0.0001, ANCOVA). No association was found between methylation levels and APOE genotype. NCAPH2/LMF2 methylation levels were considered to potentially be a convenient and useful biomarker for diagnosis of AD and aMCI.     

Association study of candidate gene polymorphisms with amnestic mild cognitive impairment in a chinese population

To investigate the relationship between amnestic mild cognitive impairment (aMCI) and candidate gene polymorphisms in a Chinese population, 116 aMCI patients and 93 normal controls were recruited. Multi-dimensional neuropsychological tests were used to extensively assess the cognitive functions of the subjects. MassARRAY and iPLEX systems were used to measure candidate single nucleotide polymorohisms (SNPs) and analyse allelic, genotypic or haplotypic distributions. The scores of the neuropsychological tests were significantly lower for the aMCI patients than for the normal controls. The distributions of SNPs relating to the amyloid cascade hypothesis (TOMM40 rs157581 G and TOMM40 rs2075650 G), to the cholesterol metabolism hypothesis (ApoE rs429358 C, LDLR rs11668477 G and CH25H rs7091822 T and PLAU rs2227564 CT) and to the tau hypothesis (MAPT/STH rs242562 GG) in aMCI were significantly different than those in normal controls. Interactions were also found in aMCI amongst SNPs in LDLR rs11668477, PLAU rs2227564, and TOMM40 rs157581, between SNPs in TOMM40 rs157580 and BACE2 rs9975138. The study suggests that aMCI is characterised by memory impairment and associated with SNPs in three systems relating to the pathogenesis of AD-those of the amyloid cascade, tau and cholesterol metabolism pathways. Interactions were also observed between genes in the amyloid pathway and between the amyloid and cholesterol pathways.     

Specifically progressive deficits of brain functional marker in amnestic type mild cognitive impairment

Background

Deficits of the default mode network (DMN) have been demonstrated in subjects with amnestic type mild cognitive impairment (aMCI) who have a high risk of developing Alzheimer’s disease (AD). However, no longitudinal study of this network has been reported in aMCI. Identifying links between development of DMN and aMCI progression would be of considerable value in understanding brain changes underpinning aMCI and determining risk of conversion to AD.

Methodology/Principal Findings

Resting-state fMRI was acquired in aMCI subjects (n = 26) and controls (n = 18) at baseline and after approximately 20 months follow up. Independent component analysis was used to isolate the DMN in each participant. Differences in DMN between aMCI and controls were examined at baseline, and subsequent changes between baseline and follow-up were also assessed in the groups. Posterior cingulate cortex/precuneus (PCC/PCu) hyper-functional connectivity was observed at baseline in aMCI subjects, while a substantial decrement of these connections was evident at follow-up in aMCI subjects, compared to matched controls. Specifically, PCC/PCu dysfunction was positively related to the impairments of episodic memory from baseline to follow up in aMCI group.

Conclusions/Significance

The patterns of longitudinal deficits of DMN may assist investigators to identify and monitor the development of aMCI.     

Neurogenesis in a rat model of age-related cognitive decline

Age-related decrements in hippocampal neurogenesis have been suggested as a basis for learning impairment during aging. In the current study, a rodent model of age-related cognitive decline was used to evaluate neurogenesis in relation to hippocampal function. New hippocampal cell survival was assessed approximately 1 month after a series of intraperitoneal injections of 5-bromo-2'-deoxyuridine (BrdU). Correlational analyses between individual measures of BrdU-positive cells and performance on the Morris water maze task provided no indication that this measure of neurogenesis was more preserved in aged rats with intact cognitive abilities. On the contrary, among aged rats, higher numbers of BrdU-positive cells in the granule cell layer were associated with a greater degree of impairment on the learning task. Double-labelling studies confirmed that the majority of the BrdU+ cells were of the neuronal phenotype; the proportion of differentiated neurons was not different across a broad range of cognitive abilities. These data demonstrate that aged rats that maintain cognitive function do so despite pronounced reductions in hippocampal neurogenesis. In addition, these findings suggest the interesting possibility that impaired hippocampal function is associated with greater survival of newly generated hippocampal neurons at advanced ages.     

Effects of positive AMPA receptor modulators on calpain-mediated spectrin degradation in cultured hippocampal slices

Positive modulators of AMPA receptors (AMPAr), also known as ampakines, are allosteric effectors of the receptors and have been extensively studied in past years due to their potential use as treatment for various diseases and ailments of the central nervous system such as mild cognitive impairment, schizophrenia, and Alzheimer's disease. Ampakines have been shown to improve performance on memory tasks in animals and in human subjects, an effect linked to their ability to increase agonist-mediated ion influx through AMPAr, thus leading to enhanced synaptic responses and facilitation of long-term potentiation (LTP) induction at glutamatergic synapses. As LTP is associated with calpain activation and spectrin degradation, we determined the effects of ampakine treatment of cultured hippocampal slices on spectrin degradation. Calpain activation was evaluated by determining the levels of the 145-150kDa degradation products of spectrin. Our data indicated that incubation of hippocampal slices with some, but not all positive modulators of AMPA receptors resulted in enhanced spectrin degradation, an effect that was blocked by a calpain inhibitor. In addition, an antagonist of AMPAr but not of NMDAr blocked ampakine-induced spectrin degradation. These results indicate that prolonged treatment with selected ampakines leads to spectrin degradation mediated by activation of the calcium-dependent protease calpain.     

Detecting subtle changes in visuospatial executive function and learning in the amnestic variant of mild cognitive impairment

Background and Purpose

Amnestic mild cognitive impairment (aMCI) is a putative prodromal stage of Alzheimer''s disease (AD) characterized by deficits in episodic verbal memory. Our goal in the present study was to determine whether executive dysfunction may also be detectable in individuals diagnosed with aMCI.

Methods

This study used a hidden maze learning test to characterize component processes of visuospatial executive function and learning in a sample of 62 individuals with aMCI compared with 94 healthy controls.

Results

Relative to controls, individuals with aMCI made more exploratory/learning errors (Cohen''s d = .41). Comparison of learning curves revealed that the slope between the first two of five learning trials was four times as steep for controls than for individuals with aMCI (Cohen''s d = .64). Individuals with aMCI also made a significantly greater number of rule-break/error monitoring errors across learning trials (Cohen''s d = .21).

Conclusions

These results suggest that performance on a task of complex visuospatial executive function is compromised in individuals with aMCI, and likely explained by reductions in initial strategy formulation during early visual learning and “on-line” maintenance of task rules.     

Analysis of lipophilic fluorescent products in blood of Alzheimer's disease patients

Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by cognitive decline. Prodromal stage of AD, also called mild cognitive impairment (MCI), especially its amnestic type (aMCI), precedes dementia stage of AD. There are currently no reliable diagnostic biomarkers of AD in the blood. Alzheimer's disease is accompanied by increased oxidative stress in brain, which leads to oxidative damage and accumulation of free radical reaction end‐products. In our study, specific products of lipid peroxidation in the blood of AD patients were studied. Lipophilic extracts of erythrocytes (AD dementia = 19, aMCI = 27, controls = 16) and plasma (AD dementia = 11, aMCI = 17, controls = 16) were analysed by fluorescence spectroscopy. The level of these products is significantly increased in erythrocytes and plasma of AD dementia and aMCI patients versus controls. We concluded that oxidative stress end‐products are promising new biomarkers of AD, but further detailed characterisation of these products is needed.     

Short-Term Delayed Recall of Auditory Verbal Learning Test Is Equivalent to Long-Term Delayed Recall for Identifying Amnestic Mild Cognitive Impairment

Delayed recall of words in a verbal learning test is a sensitive measure for the diagnosis of amnestic mild cognitive impairment (aMCI) and early Alzheimer’s disease (AD). The relative validity of different retention intervals of delayed recall has not been well characterized. Using the Auditory Verbal Learning Test–Huashan version, we compared the differentiating value of short-term delayed recall (AVL-SR, that is, a 3- to 5-minute delay time) and long-term delayed recall (AVL-LR, that is, a 20-minute delay time) in distinguishing patients with aMCI (n = 897) and mild AD (n = 530) from the healthy elderly (n = 1215). In patients with aMCI, the correlation between AVL-SR and AVL-LR was very high (r = 0.94), and the difference between the two indicators was less than 0.5 points. There was no difference between AVL-SR and AVL-LR in the frequency of zero scores. In the receiver operating characteristic curves analysis, although the area under the curve (AUC) of AVL-SR and AVL-LR for diagnosing aMCI was significantly different, the cut-off scores of the two indicators were identical. In the subgroup of ages 80 to 89, the AUC of the two indicators showed no significant difference. Therefore, we concluded that AVL-SR could substitute for AVL-LR in identifying aMCI, especially for the oldest patients.     

Intrahippocampal administration of a domain antibody that binds aggregated amyloid-β reverses cognitive deficits produced by diet-induced obesity

BackgroundThe prevalence of high fat diets (HFD), diet-induced obesity (DIO) and Type 2 diabetes continues to increase, associated with cognitive impairment in both humans and rodent models. Mechanisms transducing these impairments remain largely unknown: one possibility is that a common mechanism may be involved in the cognitive impairment seen in obese and/or diabetic states and in dementia, specifically Alzheimer's disease (AD). DIO is well established as a risk factor for development of AD. Oligomeric amyloid-β (Aβ) is neurotoxic, and we showed that intrahippocampal oligomeric Aβ produces cognitive and metabolic dysfunction similar to that seen in DIO or diabetes. Moreover, animal models of DIO show elevated brain Aβ, a hallmark of AD, suggesting that this may be one source of cognitive impairment in both conditions.MethodsIntrahippocampal administration of a novel anti-Aβ domain antibody for aggregated Aβ, or a control domain antibody, to control or HFD-induced DIO rats. Spatial learning measured in a conditioned contextual fear (CCF) task after domain antibody treatment; postmortem, hippocampal NMDAR and AMPAR were measured.ResultsDIO caused impairment in CCF, and this impairment was eliminated by intrahippocampal administration of the active domain antibody. Measurement of hippocampal proteins suggests that DIO causes dysregulation of hippocampal AMPA receptors, which is also reversed by acute domain antibody administration.ConclusionsOur findings support the concept that oligomeric Aβ within the hippocampus of DIO animals may not only be a risk factor for development of AD but may also cause cognitive impairment before the development of dementia.General Significance and InterestOur work integrates the engineering of domain antibodies with conformational- and sequence-specificity for oligomeric amyloid beta with a clinically relevant model of diet-induced obesity in order to demonstrate not only the pervasive effects of obesity on several aspects of brain biochemistry and behavior, but also the bioengineering of a successful treatment against the long-term detrimental effects of a pre-diabetic state on the brain. We show for the first time that cognitive impairment linked to obesity and/or insulin resistance may be due to early accumulation of oligomeric beta-amyloid in the brain, and hence may represent a pre-Alzheimer's state.     

The effects of cyclophosphamide on hippocampal cell proliferation and spatial working memory in rat

Cyclophosphamide (CP) is a chemotherapy used in combinations that are associated with cognitive impairment. In the present study male Lister-hooded rats (n = 12) were used to investigate the effects of chronic administration of CP (30mg/kg, 7 i.v. doses, or an equivalent volume of saline) on performance in the novel location recognition (NLR) task and on the proliferation and survival of hippocampal cells. The survival of hippocampal cells dividing at the beginning of treatment was significantly reduced by CP. However, no difference was seen between CP treated and control groups for the number of cells proliferating 7 days after the final injection and both groups performed equally well in the NLR task. These results indicate that the given dose of CP acutely reduces the survival of newly born hippocampal cells. However, it does not have a longer term effect on spatial working memory or hippocampal proliferation, suggesting that CP is less neurotoxic than other chemotherapies with which it is used in combination.