The impact of cerebrovascular aging on vascular cognitive impairment and dementia

As human life expectancy rises, the aged population will increase. Aging is accompanied by changes in tissue structure, often resulting in functional decline. For example, aging within blood vessels contributes to a decrease in blood flow to important organs, potentially leading to organ atrophy and loss of function. In the central nervous system, cerebral vascular aging can lead to loss of the integrity of the blood-brain barrier, eventually resulting in cognitive and sensorimotor decline. One of the major of types of cognitive dysfunction due to chronic cerebral hypoperfusion is vascular cognitive impairment and dementia (VCID). In spite of recent progress in clinical and experimental VCID research, our understanding of vascular contributions to the pathogenesis of VCID is still very limited. In this review, we summarize recent findings on VCID, with a focus on vascular age-related pathologies and their contribution to the development of this condition.     

轻度认知功能障碍患者的语义记忆损害与神经调控

文题释义：轻度认知障碍：是介于正常衰老与痴呆的过渡状态,是相对于年龄与教育程度的记忆或其他认知功能减退,记忆力、语言功能、注意力、执行能力等不同认知领域的减退,以记忆力减退为最常见的临床表现。国际轻度认知功能障碍工作组在2003年制定了轻度认知障碍的诊断标准：①有认知主诉,本人或知情者提供的认知功能障碍线索;②有认知功能损害的客观证据,选用蒙特利尔认知评估量表进行评分,高中及以上文化程度者≤26分,初中及以下文化程度者≤25分,且主要表现为记忆项异常者;③日常生活能力正常或仅有复杂日常能力轻度减退;④简易认知状态量表≥24分,不符合精神疾病的诊断和统计手册第四版诊断为痴呆的标准。语义记忆：包括对词语的意义、概念与事实的记忆。语义记忆涉及概念和实际知识是储存。广义上语义记忆包括对世界的所有认识。严格意义上的语义记忆,则是根据命名、分类任务判定。语义记忆障碍的患者表现为对熟悉的物品命名障碍。轻度的可能表现为语义分类词生成的减少,而严重的语义记忆障碍则表现为告知物品用途也不能进行命名,或给予名称也不能说出物品的用途,严重者可能表现为常识的缺失。 背景：阿尔茨海默病是一种进行性神经系统退化疾病,以认知下降为主要特点。认知力下降会导致老年人逐渐失去自我照料的能力,影响日常生活和活动。轻度认知障碍作为阿尔茨海默病的前驱状态,尽早对轻度认知障碍进行诊断和治疗,对预防阿尔茨海默病发展有重大的意义。 目的：针对轻度认知障碍语义记忆障碍评估与治疗的发展及未来前景做一综述。 方法：应用计算机在PubMed、Web of Science和中国知网、万方等数据库检索轻度认知障碍语义记忆评估、治疗的相关研究,检索关键词为“mild cognitive impairment,semantic memory impairment,semantic memory deficit,语义记忆,轻度认知功能障碍,轻度认知损害”,检索时间为2009年1月至2019年11月。结果与结论：语义记忆障碍为轻度认知障碍的主要临床症状之一,有一定的特异性。目前有不同类型的记忆量表可作为轻度认知障碍语义记忆障碍的神经心理学测量,颞叶、额叶和前运动区可能参与语义记忆环路。针对性的语义记忆神经生理学及辅助检查,靶向进行语义记忆康复训练,可利于早期识别轻度认知障碍的发生与转化。 ORCID: 0000-0002-2121-1523(关汉添) 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

Structural and functional neural correlates of visuospatial information processing in normal aging and amnestic mild cognitive impairment

Our understanding of cognitive changes related to human aging and their underlying neural processes is challenged by the distinction between normal and pathological aging. In our study, the neural correlates of visuospatial working memory (VSWM) in young persons (YC), healthy older adults (HC) and patients with amnestic mild cognitive impairment (aMCI) were investigated. Effects of the genetic risk factor apolipoprotein E (ApoE) ε4 on a VSWM task were analyzed for HC and aMCI patients. Higher cortical activation in extrastriate occipital regions and significantly decreased brain volumes in frontoparietal areas were observed in HC compared with young persons. Also, reduced cortical activation in the right middle frontal gyrus and superior frontal gyrus was observed in aMCI-patients compared with HC. Thus, attenuated cortical activation during VSWM tasks is related to the formation of aMCI and may serve as an early marker for cognitive decline. In contrast to previous studies, no significant apolipoprotein E-linked differences were found between HC and aMCI groups.     

Executive dysfunction and gray matter atrophy in amnestic mild cognitive impairment

Recent studies have shown that impairment in executive function (EF) is common in patients with amnestic mild cognitive impairment (aMCI). However, the neuroanatomic basis of executive impairment in patients with aMCI remains unclear. In this study, multiple regression voxel-based morphometry analyses were used to examine the relationship between regional gray matter volumes and EF performance in 50 patients with aMCI and 48 healthy age-matched controls. The core EF components (response inhibition, working memory and task switching, based on the EF model of Miyake et al) were accessed with computerized tasks. Atrophic brain areas related to decreases in the three EF components in patients with aMCI were located in the frontal and temporal cortices. Within the frontal cortex, the brain region related to response inhibition was identified in the right inferior frontal gyrus. Brain regions related to working memory were located in the left anterior cingulate gyrus, left premotor cortex, and right inferior frontal gyrus, and brain regions related to task shifting were distributed in the bilateral frontal cortex. Atrophy in the right inferior frontal gyrus was most closely associated with a decrease in all three EF components in patients with aMCI. Our data, from the perspective of brain morphology, contribute to a better understanding of the role of these brain areas in the neural network of EF.     

Increased fMRI responses during encoding in mild cognitive impairment

Structural and functional magnetic resonance imaging (fMRI) was performed on 21 healthy elderly controls, 14 subjects with mild cognitive impairment (MCI) and 15 patients with mild Alzheimer's disease (AD) to investigate changes in fMRI activation in relation to underlying structural atrophy. The fMRI paradigm consisted of associative encoding of novel picture-word pairs. Structural analysis of the brain was performed using voxel-based morphometry (VBM) and hippocampal volumetry. Compared to controls, the MCI subjects exhibited increased fMRI responses in the posterior hippocampal, parahippocampal and fusiform regions, while VBM revealed more atrophy in MCI in the anterior parts of the left hippocampus. Furthermore, the hippocampal volume and parahippocampal activation were negatively correlated in MCI, but not in controls or in AD. We suggest that the increased fMRI activation in MCI in the posterior medial temporal and closely connected fusiform regions is compensatory due to the incipient atrophy in the anterior medial temporal lobe.     

Activation of caspase-6 in aging and mild cognitive impairment

Active caspase-6 (Csp6) and Tau cleaved by Csp6 (TauDeltaCsp6) are abundant in neuritic plaques (NPs), neuropil threads (NPTs), and neurofibrillary tangles (NFTs) in end-stage Alzheimer's disease (AD) (Guo H, Albrecht S, Bourdeau M, Petzke T, Bergeron C, LeBlanc AC: Active caspase-6 and caspase-6 cleaved Tau in neuropil threads, neuritic plaques and neurofibrillary tangles of Alzheimer's disease. Am J Pathol 2004, 165:523-531). The goal of this study was to determine whether active Csp6 is present in young and aged noncognitively impaired (NCI); aged mild cognitively impaired (MCI); and aged mild, moderate, severe, and very severe AD individuals. Csp6 activity was assessed with anti-p20Csp6 and TauDeltaCsp6 immunoreactivity. Active Csp6 is present in NFTs, NPTs, and NPs at all stages of AD. Active Csp6 is present in NFTs of all MCI cases and present in NPTs and NPs of some MCI cases. Active Csp6 is present in NFTs and NPTs of all NCI cases but is absent in younger cases. The level of TauDeltaCsp6-positive NFTs and NPTs correlates inversely with global cognitive scores in NCI individuals. Therefore, Csp6 activity can occur with aging in the absence of AD and is always associated with clinical and pathological features of confirmed AD cases. Given the ability of active Csp6 to increase amyloid-beta peptide production and cleave Tau and several synaptic proteins (LeBlanc AC, Liu H, Goodyer C, Bergeron C, Hammond J: Caspase-6 role in apoptosis of human neurons, amyloidogenesis and Alzheimer's disease. J Biol Chem 1999, 274:23426-23436; Petzke TL, Rousselet E, Goodyer C, LeBlanc AC: Substrates of caspase-6 in human primary neurons: a proteomic study. Program No. 80.9. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience. Online), we suggest that active Csp6 could be an early instigator of neuronal dysfunction.     

Extracellular superoxide dismutase overexpression protects against aging-induced cognitive impairment in mice

Extracellular superoxide dismutase (EC-SOD) controls the availability of extracellular superoxide and appears to play a role in controlling oxidative stress and intercellular signaling. Whether EC-SOD overexpression would help or hinder neurobehavioral function appears to depend on the age of the individual. In young adult mice, we have found that EC-SOD overexpression can interfere with learning on the radial-arm maze, possibly by reducing control over nitric oxide neurotransmission. In aged mice, we found, in the current study, that EC-SOD overexpression greatly improves learning on the radial-arm maze. Control (N = 17) and EC-SOD overexpressing mice (N = 13) acquired the 8-arm radial maze over 21 sessions of training. The EC-SOD overexpressing mice had significantly better choice accuracy than the control mice (p < 0.005). The EC-SOD overexpressing mice averaged 6.34 ± 0.22 correct arm entries before an error (entries to repeat) during the acquisition phase, while the control mice averaged 5.18 ± 0.22 entries to repeat. EC-SOD genotype did not cause a main effect on response latency. The advantage held by the EC-SOD overexpressing mice persisted during the eight-session post-acquisition phase of testing (p < 0.01). When there was a shift from high to low levels of motivation by reducing the period of food restriction before testing, the EC-SOD overexpression-induced improvement was reduced slightly, but it was still significant compared with the wild-type controls (p < 0.025). Then, after 4 months of no testing, the mice were tested for retention and reacquisition of performance on the radial-arm maze. The EC-SOD overexpressing mice maintained their significantly better choice accuracy (p < 0.05). Enhancement of EC-SOD activity appears to improve learning and memory performance, specifically in aging mice. EC-SOD mimetic treatment during the course of aging may hold promise for aging-induced cognitive impairment.     

Sensitivity to expectancy violations in healthy aging and mild cognitive impairment

In this study, individuals with mild cognitive impairment (MCI) were tested to see if executive dysfunction impacts their implementation of expectancy biases in a priming task. Young adults, healthy older adults, and individuals with MCI made speed-related decisions to sequentially presented word pairs. The proportion of category related (e.g., apple-fruit) versus coordinate related (apple-pear) pairs was varied to create different expectancy biases. When the proportion of category pairs was high (80%), the control groups showed an expectancy bias: Significant inhibition was observed for coordinate pairs compared with category pairs. The MCI group also demonstrated an expectancy bias but with much larger costs for unexpected targets. The findings suggest that individuals with MCI are inordinately sensitive to expectancy violations, and these findings are discussed in terms of possible executive dysfunction.     

Recollection- and familiarity-based memory in healthy aging and amnestic mild cognitive impairment

Little is known about the cognitive mechanisms of the memory impairment associated with amnestic mild cognitive impairment (aMCI). We explored recollection and familiarity in 27 healthy young adults, 45 healthy older adults, and 17 individuals with aMCI. Relative to the younger adults, recollection was reduced in the older adults, especially among those with aMCI. Familiarity did not differ among groups. In the healthy younger and older adults, better performance on a set of clinical memory measures that are sensitive to medial temporal lobe functioning was associated with greater recollection. In addition, among the healthy older adults better executive functioning was also associated with greater recollection. These results are consistent with the notion that recollection is a product of strategic processes mediated by the prefrontal cortex that suppport the retrieval of context-dependent memories from the hippocampus. Hippocampal atrophy associated with aMCI may disrupt this brain network, and thereby interfere with recollection.     

Conceptual implicit memory impaired in amnestic mild cognitive impairment patient

Explicit memory has been well proven to be impaired in amnestic mild cognitive impairment (aMCI), and conceptual implicit memory is impaired in Alzheimer's disease. However, it is unclear whether implicit memory is affected in aMCI. In the present study, 35 patients with aMCI and 35 healthy elderly subjects were administered a neuropsychological battery of tests including conceptual and perceptual implicit memory tasks (category exemplar generation, image identification) as well as explicit memory tasks. Patients with aMCI exhibited impairment in explicit memory tasks and selective impairment in conceptual priming tasks, while the effect of perceptual priming was preserved. More importantly, category exemplar generation task priming, but not perceptual priming, was positively correlated with verbal fluency test performance in the aMCI group. The dissociation between the 2 components of implicit priming suggests that conceptual priming impairment in aMCI patients may be related to frontal lobe dysfunction.     

Associations between sleep duration and cognitive impairment in mild cognitive impairment

The prevalence of mild cognitive impairment (MCI) increases among elderly people and is associated with a high risk of dementia. Identifying factors that may contribute to the progress of MCI to dementia is critical. The objective of this study was to examine the association of objective sleep with cognitive performance in MCI patients. A subsample of 271 participants with a diagnosis of probable Alzheimer's disease (AD; N = 50) or mild cognitive impairment (MCI; N = 121) and 100 persons who were not cognitively impaired (NI) were recruited from a large population‐based cohort in the island of Crete, Greece (3140 older adults aged >60 years). All participants underwent extensive neuropsychiatric/neuropsychological evaluation and a 3‐day 24‐hr actigraphy. Objective sleep variables and their association with neuropsychological performance were examined across the three groups, controlling for demographics, body mass index, depression, sleep apnea symptoms and psychotropic medications. Patients with AD had significantly longer 24‐hr total sleep time (TST) compared to the MCI and NI groups. Long 24‐hr TST was associated with reduced performance on tasks that placed significant demands on attention and processing speed in the MCI group and the AD group. Elderly patients with MCI have similar objective sleep duration to normal controls, whereas AD patients sleep longer. Long sleep duration in patients with multidomain subtypes of MCI is associated with critical non‐memory cognitive domains. It appears that within the MCI group those that sleep longer have more severe cognitive impairment.     

Progression of tau pathology in cholinergic Basal forebrain neurons in mild cognitive impairment and Alzheimer's disease

Tau is a microtubule-associated protein that forms neurofibrillary tangles (NFTs) in the selective vulnerable long projection neurons of the cholinergic basal forebrain (CBF) in Alzheimer's disease (AD). Although CBF neurodegeneration correlates with cognitive decline during AD progression, little is known about the temporal changes of tau accumulation in this region. We investigated tau posttranslational modifications during NFT evolution within the CBF neurons of the nucleus basalis (NB) using tissue from subjects with no cognitive impairment, mild cognitive impairment, and AD. The pS422 antibody was used as an early tau pathology marker that labels tau phosphorylated at Ser422; the TauC3 antibody was used to detect later stage tau pathology. Stereologic evaluation of NB tissue immunostained for pS422 and TauC3 revealed an increase in neurons expressing these tau epitopes during disease progression. We also investigated the occurrence of pretangle tau events within cholinergic NB neurons by dual staining for the cholinergic cell marker, p75(NTR), which displays a phenotypic down-regulation within CBF perikarya in AD. As pS422+ neurons increased in number, p75(NTR)+ neurons decreased, and these changes correlated with both AD neuropathology and cognitive decline. Also, NFTs developed slower in the CBF compared with previously examined cortical regions. Taken together, these results suggest that changes in cognition are associated with pretangle events within NB cholinergic neurons before frank NFT deposition.     

Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer's disease

Neurofibrillary degeneration in the nucleus basalis and a loss of its cortical cholinergic projections are prominent components of the neuropathology in Alzheimer's disease (AD). The AD brain is also associated with a degeneration of the noradrenergic projections arising from the nucleus locus coeruleus (LC), but the time course of this lesion is poorly understood. To determine whether the LC displays neurofibrillary abnormalities early in the course of events leading to AD, we examined tissue specimens from seven cognitively normal controls and five subjects at the stages of mild cognitively impairment (MCI) or early AD. Tyrosine hydroxylase immunochemistry was used as a marker of LC neurons while AT8 immunolabeling visualized abnormal tau associated with neurofibrillary tangles and their precursors. Thioflavine-S was used as a marker for fully developed tangles. We found that AT8-positive labeling and thioflavine-S positive tangles were present in both groups of specimens. However, the percentage of neurons containing each of these markers was significantly higher in the cognitively impaired group. The MMSE scores displayed a negative correlation with both markers of cytopathology. These results indicate that cytopathology in the LC is an early event in the age-MCI-AD continuum and that it may be listed among the numerous factors that mediate the emergence of the cognitive changes leading to dementia.     

Perturbations of neural circuitry in aging,mild cognitive impairment,and Alzheimer's disease

Alzheimer's disease (AD) is a global public health threat that continues to rise as the proportion of the population over the age of 60 rapidly increases. Aging and dementia are both associated with cognitive decline and share some features in terms of structural and functional alterations in neural circuitry. In this review, we attempt to highlight the network perturbations that occur in “typical” aging and emphasize how they may differ from those that manifest in dementia. We focus in particular on neuroimaging studies of the medial temporal lobe (MTL) network, which is involved in episodic memory and is known to change both with age and with AD pathology. We propose a temporal model of structural and functional alterations in the MTL along the aging-dementia continuum. The earliest changes are synaptic in nature and are detectable in particularly vulnerable white matter pathways such as the perforant path. These are followed by structural degradation in the transentorhinal region and subsequently neurodegeneration of the hippocampus as a result of accumulating pathology as well as deafferentation from entorhinal input. We believe that testing this model explicitly is an important direction for future research, particularly in the context of biomarker discovery and clinical trial design.     

Sensory cortical interactions in aging, mild cognitive impairment, and Alzheimer's disease.

Progressive declines in memory function accompany normal aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD). Neuropathological studies suggest that damage to neurons providing connections between cortical areas may contribute to memory impairments in AD. Because AD develops slowly, similar neuropathological changes, to a lesser degree, may be present in MCI and some asymptomatic elderly subjects. In this study we tested the hypothesis that corticocortical interactions between sensory regions are impaired in aging, MCI, and AD, as compared with young subjects. When sensory cortical evoked potentials are elicited by pairs of stimuli the amplitudes of potentials to the second stimulus are attenuated. Corticocortical interactions were assessed by presenting stimulus pairs in different modalities (auditory/visual). There were significant group differences in the degree that a visual stimulus attenuated subsequent auditory potentials (young > healthy elderly > MCI > AD). Control experiments indicated equivalent amplitude reductions for all groups to the second stimulus for stimulus pairs having the same modality. These findings are compatible with progressive declines in corticocortical processing in aging, MCI, and AD.     

Hippocampal and ventricular changes in Parkinson's disease mild cognitive impairment

We analyzed T1-weighted brain magnetic resonance imaging data of 100 cognitively normal elderly controls (NC), 127 cognitively normal Parkinson's disease (PD; PDCN) and 31 PD-associated mild cognitive impairment (PDMCI) subjects from the Norwegian ParkWest study. Using automated segmentation methods, followed by the radial distance technique and multiple linear regression we studied the effect of clinical diagnosis on hippocampal and ventricular radial distance while adjusting for age, education, and scanning site. PDCN subjects had significantly smaller bilateral hippocampal radial distance relative to NC. Nonamnestic PDMCI subjects showed smaller right hippocampal radial distance relative to NC. PDMCI subjects showed significant enlargement of all portions of the lateral ventricles relative to NC and significantly larger bilateral temporal and occipital and left frontal lateral ventricular expansion relative to PDCN subjects. Nonamnestic PDMCI subjects showed significant ventricular enlargement spanning all parts of the lateral ventricle while those with amnestic PDMCI showed changes localized to the left occipital horn. Hippocampal atrophy and lateral ventricular enlargement show promise as structural biomarkers for PD.     

A meta-analysis of diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease

We reviewed case-control studies of diffusion tensor imaging (DTI) in patients with Alzheimer's dementia (AD) and mild cognitive impairment (MCI), in order to establish the relative severity and location of white matter microstructural changes. EMBASE and MEDLINE were searched using the keywords, ([“diffusion tensor”] and [“Alzheimer*” or “mild cognitive impairment”]), as were reference lists of relevant papers. Forty-one diffusion tensor imaging studies contained data that were suitable for inclusion. Group means and standard deviations for fractional anisotropy and mean diffusivity, or p values from 2-sample tests, were extracted and pooled, using standard methods of meta-analysis and metaregression. Fractional anisotropy was decreased in AD in all regions except parietal white matter and internal capsule, while patients with MCI had lower values in all white matter regions except parietally and occipitally. Mean diffusivity was increased in AD in all regions, and in MCI in all but occipital and frontal regions.     

Combined rCBF and CSF biomarkers predict progression from mild cognitive impairment to Alzheimer's disease

This study aimed to identify preclinical Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) using measurements of both regional cerebral blood flow (rCBF) and cerebrospinal fluid (CSF) biomarkers. Baseline rCBF assessments ((133)Xe method) were performed in 70 patients with MCI who were cognitively stable for 4-6 years, 69 patients with MCI who subsequently developed AD, and 33 healthy individuals. CSF was collected at baseline and analyzed for beta-amyloid(1-42), total tau and phophorylated tau. In contrast to patients with stable MCI, those who subsequently developed AD had decreased rCBF in the temporo-parietal cortex already at baseline. The relative risk of future progression to AD was particularly increased in MCI patients with decreased rCBF in parietal cortex (hazard ratio 3.1, P<0.0001). Subjects with pathological levels of both CSF tau and beta-amyloid(1-42) were also at high risk of developing AD (hazard ratio 13.4, P<0.0001). The MCI patients with a combination of decreased parietal rCBF and pathological CSF biomarkers at baseline had a substantially increased risk of future development of AD, with a hazard ratio of 24.3 (P<0.0001), when compared to those with normal CSF biomarkers. Moreover, decreased parietal rCBF (but not CSF biomarkers) was associated with a more rapid progression to AD. In conclusion, the combination of rCBF and CSF biomarkers improves the risk assessment of progression to AD in patients with MCI.