基于体素的形态测量学在阿尔茨海默病及轻度认知功能障碍研究中的应用

阿尔茨海默病(Alzheimer's disease,AD)是发生于老年和老年前期、以进行性认知功能障碍和行为异常为特征的中枢神经系统退行性疾病,是老年痴呆中最常见类型。轻度认知功能障碍(mild cognitive impairment,MCI)是介于正常衰老和痴呆之间的一种中间状态,指有轻度的记忆或认知损伤,但尚未达到痴呆程度的一种状态,日常生活和社会功能不受影响,其中很大一部分患者最终进展为AD。临床诊断AD患者多已达中晚期,为了能早期诊断AD及预测MCI的转归,有关AD的生物学标注物的研究成为近年来的科研热点。AD患者颅脑的大体病理特征为脑萎缩,其萎缩有别于正常老龄化所致的退行性改变,有其自身特点,这种特定形式的萎缩有可能成为AD早期诊断的生物学标志物。基于体素的形态测量学(voxel-based morphometry,VBM)是一种基于像素水平对脑核磁图像进行自动、全面、客观分析的技术,可以定量分析全脑结构、刻画出局部脑区结构特征,是一种较好的脑形态分析工具,广泛用于阿尔茨海默病及轻度认知功能障碍的研究中,本文综述了近年来其研究进展,期望为临床及科研提供参考。     

Selenium and cognitive impairment: a brief-review based on results from the EVA study

Preventing cognitive impairment and dementia in the elderly is a major public health challenge for our century and all hypotheses should be explored. Selenium (Se) is one of the factors that may affect the risk of cognitive decline. Its importance in the health and aging process has been documented. Because of the potential of selenoproteins to protect against oxidative stress, Se raises significant expectations for the prevention of chronic diseases including cancer, cardiovascular disease, and type 2 diabetes conditions commonly associated with oxidative stress. Thus, the relationships between Se and cognitive impairment or dementia can be examined through vascular risk factors for dementia, with particular interest in diabetes and dyslipidemia. In addition, in cases of Se deficiency, the brain is the organ that remains Se replete the longest suggesting that Se plays an important role in brain functions. This article presents results obtained in the frame of a longitudinal study on Se and cognitive impairment. They are consistent with the hypothesis that low Se status is a risk factor for cognitive decline even after taking into account vascular risk factors. The concomitant evolution between plasma Se decrease over a 9-year period and cognitive decline suggested that optimal Se status is potentially important to maintain neuropsychological functions in aging people. However, as our understanding of Se biology is incomplete, epidemiological studies are needed to define the groups of population that could benefit from Se supplementation.     

Epidemiological Pathology of Dementia: Attributable-Risks at Death in the Medical Research Council Cognitive Function and Ageing Study

Background

Dementia drug development aims to modulate pathological processes that cause clinical syndromes. Population data (epidemiological neuropathology) will help to model and predict the potential impact of such therapies on dementia burden in older people. Presently this can only be explored through post mortem findings. We report the attributable risks (ARs) for dementia at death for common age-related degenerative and vascular pathologies, and other factors, in the MRC Cognitive Function and Ageing Study (MRC CFAS).

Methods and Findings

A multicentre, prospective, longitudinal study of older people in the UK was linked to a brain donation programme. Neuropathology of 456 consecutive brain donations assessed degenerative and vascular pathologies. Logistic regression modelling, with bootstrapping and sensitivity analyses, was used to estimate AR at death for dementia for specific pathologies and other factors. The main contributors to AR at death for dementia in MRC CFAS were age (18%), small brain (12%), neocortical neuritic plaques (8%) and neurofibrillary tangles (11%), small vessel disease (12%), multiple vascular pathologies (9%), and hippocampal atrophy (10%). Other significant factors include cerebral amyloid angiopathy (7%) and Lewy bodies (3%).

Conclusions

Such AR estimates cannot be derived from the living population; rather they estimate the relative contribution of specific pathologies to dementia at death. We found that multiple pathologies determine the overall burden of dementia. The impact of therapy targeted to a specific pathology may be profound when the dementia is relatively “pure,” but may be less impressive for the majority with mixed disease, and in terms of the population. These data justify a range of strategies, and combination therapies, to combat the degenerative and vascular determinants of cognitive decline and dementia. Please see later in the article for the Editors'' Summary     

Peripheral ethanolamine plasmalogen deficiency: a logical causative factor in Alzheimer's disease and dementia

Although dementia of the Alzheimer's type (DAT) is the most common form of dementia, the severity of dementia is only weakly correlated with DAT pathology. In contrast, postmortem measurements of cholinergic function and membrane ethanolamine plasmalogen (PlsEtn) content in the cortex and hippocampus correlate with the severity of dementia in DAT. Currently, the largest risk factor for DAT is age. Because the synthesis of PlsEtn occurs via a single nonredundant peroxisomal pathway that has been shown to decrease with age and PlsEtn is decreased in the DAT brain, we investigated potential relationships between serum PlsEtn levels, dementia severity, and DAT pathology. In total, serum PlsEtn levels were measured in five independent population collections comprising >400 clinically demented and >350 nondemented subjects. Circulating PlsEtn levels were observed to be significantly decreased in serum from clinically and pathologically diagnosed DAT subjects at all stages of dementia, and the severity of this decrease correlated with the severity of dementia. Furthermore, a linear regression model predicted that serum PlsEtn levels decrease years before clinical symptoms. The putative roles that PlsEtn biochemistry play in the etiology of cholinergic degeneration, amyloid accumulation, and dementia are discussed.     

The decline and resurgence of vascular dementia.

Arteriosclerotic narrowing of cerebral arteries was once viewed as the key to mental decline. As Alzheimer''s disease gained recognition and the concept of multi-infarct dementia achieved acceptance, vascular dementia came to be regarded as uncommon. The changing nature of cerebral vascular disease, the aging of the population and the widespread use of brain imaging techniques have brought new prominence to vascular dementia, chiefly in the form of an epidemic of "Binswanger''s disease". Growing evidence suggests that not only grey matter lesions but also white matter lesions contribute to dementia, that vascular factors commonly coexist and interact with Alzheimer changes and that Alzheimer''s disease has a vascular and potentially treatable component. Vascular dementia needs to be redefined, reappraised and reinvestigated.     

Emerging Role of microRNAs in Dementia

MicroRNAs are small non-coding RNAs regulating mRNA translation. They play a crucial role in regulating homeostasis in neurons, especially in regulating local and stimulation dependent protein synthesis. Since activity-mediated protein synthesis in neurons is critical for memory and cognition, microRNAs have become key players in modulating these processes. Dementia is a broad term used for symptoms involving decline of memory and cognition. Several studies have implicated the dysregulation of microRNAs in many brain diseases like neurodegenerative diseases, neurodevelopmental disorders, brain injuries and dementia. In this review, we give an overview of microRNA-mediated regulation of proteins and cellular processes affected in dementia pathology, hence illustrating the importance of microRNAs in normal functioning. We also focus on a relatively less explored area in dementia pathology—the importance of activity-mediated protein synthesis at the synapse and the role of microRNAs in modulating this. Overall, this review will be helpful in looking at the significance of microRNAs in dementia from the perspective of defective regulation of protein synthesis and synaptic dysfunction.     

Tau is central in the genetic Alzheimer-frontotemporal dementia spectrum

In contrast to the common and genetically complex senile form of Alzheimer's disease (AD), the molecular genetic dissection of inherited presenile dementias has given important mechanistic insights into the pathogenesis of degenerative brain disease. Here, we focus on recent genotype-phenotype correlative studies in presenile AD and the frontotemporal dementia (FTD) complex of disorders. Together, these studies suggest that AD and FTD are linked in a genetic spectrum of presenile degenerative brain disorders in which tau appears to be the central player.     

Vascular Cognitive Disorder. A Biological and Clinical Overview

Although vascular dementia (VaD) represents the second most common cause of dementia after Alzheimer’s disease (AD) in the elderly, and is referred as the “silent epidemic of the twenty-first century”, there is still a controversy on terminology, classification and diagnostic criteria of VaD. The diagnosis of VaD resides in clinical criteria determining a cognitive impairment, the presence of cerebrovascular disease and, only in the case of post-stroke dementia or multi-infarct dementia, a temporal relationship between these. The search for a reliable biochemical tests helping in the diagnosis of VaD is so far not available. Several vascular risk factors have a role in the development of VaD and their identification and treatment are among the major aspects of management of VaD. A new line of research in this field is the study of genetic factors underlying vascular cognitive impairment which are: (1) genes predisposing to cerebrovascular disease, and (2) genes that influence brain tissue responses to cerebrovascular lesions. Evidence in favour of a coexistence of vascular and degenerative components in the pathogenesis of dementia in an elderly population comes from neuropathological and epidemiological studies. There is now a great debate whether VaD and AD are more than common coexisting unrelated pathologies and, instead, represent different results of synergistic pathological mechanisms. Preventive approaches aiming at reducing incident VaD by targeting patients at risk of cerebrovascular disease (primary prevention), or acting on patients after a stroke (secondary prevention) to prevent stroke recurrence and the progression of brain changes associated with cognitive impairment are mandatory therapeutic strategies.     

Blood markers of oxidative stress in Alzheimer's disease

Alzheimer's disease (AD) represents a highly common form of dementia, but can be diagnosed in the earlier stages before dementia onset. Early diagnosis is crucial for successful therapeutic intervention. The introduction of new diagnostic biomarkers for AD is aimed at detecting underlying brain pathology. These biomarkers reflect structural or biochemical changes related to AD. Examination of cerebrospinal fluid has many drawbacks; therefore, the search for sensitive and specific blood markers is ongoing. Investigation is mainly focused on upstream processes, among which oxidative stress in the brain is of particular interest. Products of oxidative stress may diffuse into the blood and evaluating them can contribute to diagnosis of AD. However, results of blood oxidative stress markers are not consistent among various studies, as documented in this review. To find a specific biochemical marker for AD, we should concentrate on specific metabolic products formed in the brain. Specific fluorescent intermediates of brain lipid peroxidation may represent such candidates as the composition of brain phospholipids is unique. They are small lipophilic molecules and can diffuse into the blood stream, where they can then be detected. We propose that these fluorescent products are potential candidates for blood biomarkers of AD.     

Unchanged levels of interleukins, neopterin, interferon-gamma and tumor necrosis factor-alpha in cerebrospinal fluid of patients with dementia of the Alzheimer type.

Several histopathological studies suggest that amyloidogenesis in dementia of the Alzheimer type is accompanied by activated glia and glia-derived cytokines, leading to chronic, self-propagating, cytokine-mediated molecular and cellular reactions. As studies regarding inflammatory changes in cerebrospinal fluid of patients with dementia of the Alzheimer type has been inconclusive, we set up a prospective study to assess cerebrospinal fluid levels of interleukin-1beta, interleukin-6, interleukin-10, interleukin-12, soluble interleukin-2 receptor, interferon-gamma, tumor necrosis factor-alpha and neopterin in 20 patients with dementia of the Alzheimer type and 20 age- and sex-matched controls. Comparing both groups, no significant differences in concentrations and specific activities could be revealed. An additional 22 patients were included to enlarge the study population. No statistically significant differences were shown comparing patients (n=42) with the control group (n=20). We conclude that the immune-mediated inflammatory changes found in histopathological studies are not reflected in cerebrospinal fluid of patients with dementia of the Alzheimer type. Probably, cytokine production appears very localized in the central nervous system, not allowing representative detection in cerebrospinal fluid. Further studies assessing cytokine levels in various regions of central nervous system of patients with dementia of the Alzheimer type will be of interest to confirm this hypothesis.     

Hyperamylinemia as a risk factor for accelerated cognitive decline in diabetes

Type II diabetes increases the risk for cognitive decline via multiple traits. Amylin is a pancreatic hormone that has amyloidogenic and cytotoxic properties similar to the amyloid-β peptide. The amylin hormone is overexpressed in individuals with pre-diabetic insulin resistance or obesity leading to amylin oligomerization and deposition in pancreatic islets. Amylin oligomerization was implicated in the apoptosis of the insulin-producing β-cells. Recent studies showed that brain tissue from diabetic patients with cerebrovascular dementia or Alzheimer’s disease contains significant deposits of oligomerized amylin. It has also been reported that the brain amylin deposition reduced exploratory drive, recognition memory and vestibulomotor function in a rat model that overexpresses human amylin in the pancreas. These novel findings are reviewed here and the hypothesis that type II diabetes is linked with cognitive decline by amylin accumulation in the brain is proposed. Deciphering the impact of hyperamylinemia on the brain is critical for both etiology and treatment of dementia.     

Literature review on the role of dietary protein and amino acids in cognitive functioning and cognitive decline

As the population of elderly people is growing rapidly, the number of individuals with dementia and cognitive impairment is also increasing. One of the preventive measures against cognitive decline is diet and different dietary factors have already been investigated. This review provides an overview of studies on dietary protein and cognitive functioning and cognitive decline. Also studies on the individual amino acids that are related to brain function, tryptophan and tyrosine, are discussed. Overall, the role of dietary protein intake on cognitive functioning as well as cognitive decline has hardly been studied; we found eight observational studies and three intervention studies. More studies investigated the role of tryptophan (14 studies) and tyrosine (nine studies) in relation to cognitive functioning, but all these studies were performed in young adult populations and mostly under special conditions. Research in elderly populations, in particular, is warranted. Also more research is needed to come to definitive conclusions and specific recommendations regarding protein intake or intake of specific amino acids for maintaining optimal cognitive functioning.     

Multi factorial interactions in the pathogenesis pathway of Alzheimer’s disease: a new risk charts for prevention of dementia

Background

The population longitudinal study named “The Conselice Study” has been the focus of the present investigation. 65 years old or older participants of this population study on brain aging were followed up for 5 years: 937 subjects completed the follow-up. Relationships of 46 genetic, phenotypic, clinical and nutritional factors on incident cognitive decline and incident dementia cases were investigated.

Results

A new statistical approach, called the Auto Contractive Map (AutoCM) was applied to find relationship between variables and a possible hierarchy in the relevance of each variable with incident dementia. This method, based on an artificial adaptive system, was able to define the association strength of each variable with all the others. Moreover, few variables resulted to be aggregation points in the variable connectivity map related to cognitive decline and dementia. Gene variants and cognate phenotypic variables showed differential degrees of relevance to brain aging and dementia. A risk map for age associated cognitive decline and dementia has been constructed and will be presented and discussed.

Conclusion

This map of variables may be use to identify subjects with increased risk of developing cognitive decline end/or dementia and provide pivotal information for early intervention protocols for prevention of dementia.

     

Cerebral small vessel disease: A glymphopathy?

Small vessel disease (SVD) is a common instigator of dementia in the aging population. The hallmarks of SVD are enlargement of the perivascular spaces and white matter hyperintensities. The latter represents local fluid accumulation in white matter that either subsides or develops into lacunar infarcts. We here propose that failure of brain fluid transport—via the glymphatic system—plays a key role in initiation and progression of SVD. Our major case for this concept is that perivascular spaces are utilized as waterways for influx of cerebrospinal fluid. Stagnation of glymphatic transport may drive loss of brain fluid homeostasis leading to transient white matter edema, perivascular dilation, and ultimately demyelination. This review will discuss how glymphatic rodent studies of hypertension and diabetes have provided new insight into the pathogenesis of SVD.     

Tau function and dysfunction in neurons: its role in neurodegenerative disorders

Alzheimer’s disease (AD) is the most usual neurodegenerative disorder leading to dementia in the aged human population. It is characterized by the presence of two main brain pathological hallmarks: senile plaques and neurofibrillary tangles (NFTs). NFTs are composed of fibrillar polymers of the abnormally phosphorylated cytoskeletal protein tau.     

Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer's disease: potential role in disease pathogenesis

In addition to pathology in the gray matter, there are also abnormalities in the white matter in Alzheimer's disease (AD). Sulfatide species are a class of myelin-specific sphingolipids and are involved in certain diseases of the central nervous system. To assess whether sulfatide content in gray and white matter in human subjects is associated with both the presence of Alzheimer's disease (AD) pathology as well as the stage of dementia, we analyzed the sulfatide content of brain tissue lipid extracts by electrospray ionization mass spectrometry from 22 subjects whose cognitive status at time of death varied from no dementia to very severe dementia. All subjects with dementia had AD pathology. The results demonstrate that: (i) sulfatides were depleted up to 93% in gray matter and up to 58% in white matter from all examined brain regions from AD subjects with very mild dementia, whereas all other major classes of lipid (except plasmalogen) in these subjects were not altered in comparison to those from age-matched subjects with no dementia; (ii) there was no apparent deficiency in the biosynthesis of sulfatides in very mild AD subjects as characterized by the examination of galactocerebroside sulfotransferase activities in post-mortem brain tissues; (iii) the content of ceramides (a class of potential degradation products of sulfatides) was elevated more than three-fold in white matter and peaked at the stage of very mild dementia. The findings demonstrate that a marked decrease in sulfatides is associated with AD pathology even in subjects with very mild dementia and that these changes may be linked with early events in the pathological process of AD.     

Prevalencia de demencia en adultos mayores de América Latina: revisión sistemática

Background and objectiveDementia is a growing public health problem. It involves the impairment of several cognitive functions, generating mental and physical disability, and therefore greater functional dependence. There is limited epidemiological information which reveals an approximate prevalence in older adults from Latin America. The objective of this study was to determine the prevalence of dementia in the older adult population of Latin America, and its distribution according to geographic area and gender.Materials and methodsA systematic review was carried out in databases: PubMed, Ovid, Lilacs, Cochrane, Scielo and Google Scholar, in order to identify studies that estimate the prevalence of dementia in urban and / or rural population over 65 years of age.ResultsOn February 2018, the literature search yielded 357 publications. The overall prevalence of dementia in the older adult population of Latin America was found to be 11%, prevailing more in female gender and urban people.ConclusionThe prevalence of dementia in Latin America is higher than registered previously, and even than in other continents.     

Imaging the default mode network in aging and dementia

Although in the last decade brain activation in healthy aging and dementia was mainly studied using task-activation fMRI, there is increasing interest in task-induced decreases in brain activity, termed deactivations. These deactivations occur in the so-called default mode network (DMN). In parallel a growing number of studies focused on spontaneous, ongoing ‘baseline’ activity in the DMN. These resting state fMRI studies explored the functional connectivity in the DMN. Here we review whether normal aging and dementia affect task-induced deactivation and functional connectivity in the DMN. The majority of studies show a decreased DMN functional connectivity and task-induced DMN deactivations along a continuum from normal aging to mild cognitive impairment and to Alzheimer's disease (AD). Even subjects at risk for developing AD, either in terms of having amyloid plaques or carrying the APOE4 allele, showed disruptions in the DMN. While fMRI is a useful tool for detecting changes in DMN functional connectivity and deactivation, more work needs to be conducted to conclude whether these measures will become useful as a clinical diagnostic tool in AD. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.