Acceleration of cortical thinning in familial Alzheimer's disease

Background

MRI in presymptomatic autosomal dominant Alzheimer's disease mutation carriers (MC) provides an opportunity to detect changes that pre-date symptoms or clinical diagnosis. We used automated cortical thickness (CTh) measurement to compare the grey matter of such a group with cognitively normal controls.

Methods

9 presymptomatic mutation carriers (4 PSEN1, 5 APP) and 25 healthy, age and sex-matched controls underwent longitudinal volumetric MRI brain imaging. CTh measurement was performed across the whole brain using a validated, automated technique. Four regions of interest (ROI) (entorhinal cortex (ERC), parahippocampal gyrus (PHG), posterior cingulate cortex and precuneus) and two control regions (paracentral and pericalcarine) were selected on the basis of imaging data in existing Alzheimer's disease (AD) literature. Linear mixed models were used to describe normal ageing in controls and the extent to which mean CTh in cases differed from controls according to time since clinical diagnosis, adjusting for normal ageing.

Results

An accelerating decline in CTh was observed across all ROI in the MC group. No such decline was demonstrated in the control regions for the MC group. Relative to controls, and adjusting for normal ageing, there was evidence (p = 0.05, one-sided test) of lower CTh in the posterior cingulate up to 1.8 years prior to diagnosis and in the precuneus up to 4.1 years prior to diagnosis in the MC group.

Discussion

Automated CTh analysis is a relatively practical, rapid and effective technique for assessing subtle structural change in AD. There is evidence that cortical thickness is reduced in mutation carriers a number of years prior to clinical diagnosis.     

Longitudinal changes of cortical thickness in early- versus late-onset Alzheimer's disease

Early-onset Alzheimer's disease (EOAD) has been shown to progress more rapidly than late-onset Alzheimer's disease (LOAD). However, no studies have compared the topography of brain volume reduction over time. The purpose of this 3-year longitudinal study was to compare EOAD and LOAD in terms of their rates of decline in cognitive testing and topography of cortical thinning. We prospectively recruited 36 patients with AD (14 EOAD and 22 LOAD) and 14 normal controls. All subjects were assessed with neuropsychological tests and with magnetic resonance imaging at baseline, Year 1, and Year 3. The EOAD group showed more rapid decline than the LOAD group in attention, language, and frontal-executive tests. The EOAD group also showed more rapid cortical thinning in widespread association cortices. In contrast, the LOAD group presented more rapid cortical thinning than the EOAD group only in the left parahippocampal gyrus. Our study suggests that patients with EOAD show more rapid cortical atrophy than patients with LOAD, which accounts for faster cognitive decline on neuropsychological tests.     

Cortical thickness and voxel-based morphometry in posterior cortical atrophy and typical Alzheimer's disease

A significant minority of Alzheimer's disease patients present with posterior cortical atrophy (PCA). PCA is characterized by visuospatial and visuoperceptual deficits, and relatively preserved memory, whereas patients with typical Alzheimer's disease (tAD) mostly present with early episodic memory deficits. We used two unbiased image analysis techniques to assess atrophy patterns in 48 PCA, 30 tAD, and 50 healthy controls. FreeSurfer was used to measure cortical thickness, and volumetric grey matter differences were assessed using voxel-based morphometry (VBM). Both PCA and tAD showed widespread reductions compared with controls using both techniques. Direct comparison of PCA and tAD revealed thinner cortex predominantly in the right superior parietal lobe in the PCA group compared with tAD, whereas the tAD group showed thinning in the left entorhinal cortex compared with PCA. Similar results were obtained in the VBM analysis. These distinct patterns of atrophy may have diagnostic utility. In a clinical context, a relatively spared medial temporal lobe in the presence of posterior parietal atrophy may imply PCA, and should not discount AD.     

Variations in cortical thickness with dementia severity in Alzheimer's disease

Previous magnetic resonance imaging (MRI) studies have used volumetric methods to investigate cerebral atrophy and showed its linear pattern with the measure of dementia severity in Alzheimer's disease (AD). This study analyzed the phase- and region-specific changes in cortical thickness with dementia severity. In 43 normal controls and 60 AD patients with clinical dementia rating (CDR) (0.5, n=21; 1, n=28; 2, n=11), the cortical thickness was measured using automated surface-based analysis of MRI data. Statistical analyses were performed to investigate overall the hemispheric mean thicknesses as well as the topography of cortical atrophy based on vertices in the groups. No significant difference in cortical thickness was observed for the mild (from CDR=0.5 to 1) stage of dementia. In contrast, a significant reduction of cortical thickness occurred from CDR=1 to 2. Topographic analysis of cortical atrophy showed that the significant cortical thinning in CDR=0.5 relative to normal was found in most association cortices, with this being more extensive than previously reported. There were significant cortical atrophies between CDR=1 and 2 in the frontal, inferolateral temporal, inferior parietal lobule, medial occipital, and posterior-cingulated regions. Our results confirm and extend previous findings, suggesting that widespread cortical thinning occurs before the onset of dementia (from normal to CDR=0.5), and that once dementia starts, cortical atrophy in association cortices accelerates in moderate AD (from CDR=1 to 2).     

Age-related neuropathology, cognitive decline, and Alzheimer's disease

In the last 20 years, there have been tremendous strides made in the understanding of the molecular and cellular processes that occur during brain aging, as well as our understanding of age-related disorders of the central nervous system (CNS). Aging is associated with a decline in cognitive performance, and is the biggest risk factor for the development of Alzheimer's disease (AD), although the underlying basis for both of these observations is poorly defined. Both normal aging and AD are associated with overlapping and increased levels of pathology. Numerous reports have now linked elevations in pathology as potential mediators of cognitive decline in the elderly, with most studies focusing on the role of AD-related pathology. However, it is important to point out that there are numerous other pathological features observed in the aging brain including corpora amylacea, argyrophilic grains, neuromelanin, and lipofuscin. In this review, I discuss the decreased cognitive performance observed during normal aging, the potential for pathology to alter neuronal function and neuronal viability during normal brain aging, and the potential for common pathologies to either inhibit or promote the development of age-related disorders such as AD.     

Dimensionality reduced cortical features and their use in the classification of Alzheimer's disease and mild cognitive impairment

Features defined on the cortical surface derived from magnetic resonance imaging provide important information to distinguish normal controls from Alzheimer's disease (AD) and mild cognitive impairment (MCI). We adopted cortical thickness and sulcal depth, parameterized by three dimensional meshes, as our feature. The cortical feature is high dimensional and direct use of it is problematic in a modern classifier due to small sample size problem. We applied manifold learning to reduce the dimensionality of the feature and then tested the usage of the dimensionality reduced feature with a support vector machine classifier. A leave-one-out cross-validation was adopted for quantifying classifier performance. We chose principal component analysis (PCA) as the manifold learning method. We applied PCA to a region of interest within the cortical surface. Our classification performance was at least on par for the AD/normal and MCI/normal groups and significantly better for the AD/MCI groups compared to recent studies. Our approach was tested using 25 AD, 25 MCI, and 50 normal control patients from the OASIS database.     

Increased hippocampal quinone reductase 2 in Alzheimer's disease

Quinone reductase 2 (QR2), a detoxifying cytosolic flavoenzyme, is thought to play an important role in the acquisition and loss of memory [3]. We determined the amount of QR2 in the hippocampus, amygdala, and superior frontal gyrus of Alzheimer's disease (AD) patients with dementia by using western blot analysis. The level of QR2 was significantly higher in the hippocampus of AD patients than in that of the control subjects. The relation between QR2 and AD has not yet been determined; however, our results suggest that the increase in hippocampal QR2 might be a cause of AD or might promote the progression of AD by causing an increase in the toxic quinone levels and consequent loss of cognitive function.     

Changes in vascular factors 28 years from midlife and late-life cortical thickness

We assessed midlife blood pressure (BP), body mass index, total cholesterol, and their changes over time in relation to cortical thickness on magnetic resonance imaging 28 years later in 63 elderly at risk of dementia. Participants in the population-based Cardiovascular Risk Factors, Aging, and Dementia study were first examined at midlife. A first follow-up was conducted after 21 years, and a second follow-up after an additional 7 years. Magnetic resonance images from the second follow-up were analyzed using algorithms developed at McGill University, Montreal, Canada. Midlife hypertension was related to thinner cortex in several brain areas, including insular, frontal, and temporal cortices. In elderly with thinner insular cortex, there was a continuous decline in systolic BP and an increase in pulse pressure after midlife, while in elderly with thicker insular cortex the decline in systolic BP started at older ages, paralleled by a decline in pulse pressure. No associations were found between body mass index, cholesterol, or apolipoprotein E ε4 allele and cortical thickness in this group of elderly at risk individuals.     

不同年龄段成人大脑皮质厚度偏侧性的MRI研究

目的 探讨不同年龄段成人大脑皮质厚度的偏侧性差异。方法 前瞻性研究。2017年9月—2018年12月寿光市人民医院CT磁共振室招募右利手汉族21~80岁的健康志愿者360人,分为青年组(21~40岁)、中年组(41~60岁)、老年组(61~80岁)三个年龄段组,采用3.0 T MR对志愿者行颅脑扫描,获取原始数据。使用FreeSurfer脑成像软件分析,获得左右大脑半球、各感兴趣区脑回皮质的厚度。观察不同年龄组左右大脑半球的皮质厚度是否存在偏侧性。观察不同年龄组间,各脑回的皮质厚度是否存在偏侧性,对有偏侧性的脑区计算侧化指数;统计有偏侧性的脑区的数量及偏侧程度。结果 青年组全脑、左右大脑半球皮质厚度分别为(2.506±0.027)mm、(2.508±0.015)mm、(2.504±0.015)mm,中年组分别为(2.372±0.012)mm、(2.372±0.007)mm、(2.373±0.008)mm,老年组分别为(2.264±0.021)mm、(2.264±0.015)mm、(2.263±0.014)mm。同一年龄组中,左、右大脑半球皮质厚度差异均无统计学意义(P值均＞0.05)。不同年龄组间,全脑、左右大脑半球的皮质厚度均随着年龄的增加逐渐减少,差异均有统计学意义(F=64.907、34.843、34.863,P值均＜0.01)。青年组、中年组、老年组大脑皮质厚度的偏侧性及侧化指数各不相同:3组中出现了侧化区域的保留(如外侧枕回、舌回、后扣带回、内嗅皮层等)、增加(如额下回三角部、中央前回、颞下回、颞极等)及减少(如额上回、额下回岛盖部、中眶额回、楔叶、前扣带回等)的现象;中年组侧化脑区数量多于青年组、老年组,呈倒“U”型模式;部分脑区皮质厚度偏侧性贯穿三个年龄段,但其偏侧程度有着明显的差异(外侧枕回、舌回呈现“大-小-大”模式,而后扣带回、内嗅皮层呈现“小-大-小”模式)。结论 成人大脑左右半球皮质厚度是不对称的,大脑皮质厚度的偏侧性及偏侧程度随年龄的变化而呈现不同模式的改变,为神经行为、神经生理疾病的认知提供了新的视角。     

Age-related effects on cortical thickness patterns of the Rhesus monkey brain

The Rhesus monkey is a useful model for examining age-related as well as other neurological and developmental effects on the brain, because of the extensive neuroanatomical homology to the human brain, the reduced occurrence of neurological diseases such as Alzheimer's disease, and the possibility of obtaining relevant behavioral data and post-mortem tissue for histological analyses. In this study, cortical thickness measurements based on a cortical surface modeling technique were applied for the first time to investigate cortical thickness patterns in the rhesus monkey brain, and were used to evaluate regional age related effects across a wide range of ages. Age related effects were observed in several cortical areas, in particular in the somato-sensory and motor cortices, where a robust negative correlation of cortical thickness with age was observed, similar to that found in humans. In contrast, results for monkeys compared with humans show significant interspecies differences in cortical thickness patterns in the frontal and the inferior temporal regions.     

Everyday memory deficits in very mild Alzheimer's disease

Memory complaints of patients sometimes are not verified via standard cognitive testing. Acquisition of information in everyday life requires memorization in complex three-dimensional environments. The authors mimicked this with a photorealistic virtual environment (VE). Memory for verbal material and spatial scenery was tested in healthy controls (HC) and patients with mild Alzheimer's disease (AD); mini-mental state evaluation (MMSE) 25.7 ± 1.8 (mean ± standard deviation). The number of memorized items increased to 90% in both classical list learning and for items memorized in VE in HC. In contrast, only 40% of items were recalled in list learning and 20% in VE in AD patients. Unlike the gender difference favoring female HC on list learning, performance was alike for both genders in VE. We conclude that verbal learning abilities in healthy elderly subjects are alike in standard settings and under virtual reality conditions. In AD patients memory deficits that are relevant to everyday life yet not detectable with list learning are unmasked in virtual reality. In future, this may aid objective appraisal of interventions with regard to their everyday relevance.     

阿尔茨海默病关于年龄因素的差异基因表达分析

目的 分析阿尔茨海默病（AD）随年龄增长表达变化的基因。方法 通过Qlucore Omics Explorer（QOE）软件分析数据库Gene Expression Omnibus（GEO）中的GSE36980和GSE53890数据集,在严格的统计学设定前提下,以两组比较和线性回归方式,选出阿尔茨海默病和年龄相关的基因,并用在线工具DAVID进行Gene Ontology (GO)功能富集分析。 结果 筛选出20个和年龄相关的阿尔茨海默病差异基因。GO功能富集分析表明,这些基因涉及的生物学过程有蛋白质代谢、细胞周期和神经代谢调控;涉及的细胞组成包括轴突,质膜,突触,细胞骨架,胞内无膜结构细胞器;涉及的分子功能为嘌呤核苷酸结合蛋白和金属离子结合蛋白。结论 PDE2A等20个基因随个体年龄增高,其基因表达降低,提示其不仅与神经系统的衰老程度相关,而且可能与阿尔茨海默病的发病机理相关。     

人参皂甙对Alzheimer病模型大鼠海马生长抑素mRNA表达的影响

目的：研究人参皂甙（GS）对Alzheimer病（AD）模型大鼠海马内生长抑素（SS）mRNA表达的影响。方法：本实验以D-半乳糖致衰老合并鹅膏蕈氨酸脑内Meynert核注射建立AD大鼠模型,运用原位杂交方法结合图像分析检测各组大鼠海马SSmRNA表达。结果：模型组大鼠海马各区SSmRNA表达阳性神经元平均灰度值比正常对照组明显升高,平均密度显著降低;而预防组、治疗组阳性神经元灰度值则比模型组显著降低,平均密度明显升高;正常对照组与人参皂甙对照组大鼠的CA4及DG区中,此两项指标差异显著。结论：GS对AD模型大鼠海马SSmRNA表达减弱有预防及治疗作用。     

Alzheimer基因研究现状

阿尔茨海默病(AD)目前临床无客观性生化检测手段,仅靠精神量表,且常在临床症状出现后才能诊断。近年来,一系列新的基因研究有助于阿尔茨海默病的早期识别。这些基因的改变往往先于阿尔茨海默病的病理变化和临床表现,对其早期诊断有重要意义。本文就这些基因的研究现状作一综述。     

Chromosome fragility in Alzheimer's disease

We present cytogenetic findings for 12 patients with Alzheimer's Disease (AD) mean age 75.8 ± 6.01 years and 35 normal age and sex matched controls (mean age 74.8 ± 4.04 years). The study, undertaken due to reports of increased fragments and chromosome breakage in individuals with AD, was performed blind on coded peripheral blood specimens and the allocation of AD or control was not known to the cytogenetic staff until the end of the study. Both the AD group and the controls have been very carefully selected and both underwent the same clinical assessment and screening procedures which included CT scanning.
Chromosomes were analysed after 72 h cultures, using deprived medium TC199 which is known to enhance the appearance of fragile sites. A minimum of 50 cells was examined in each case and any rearrangement found was classified as ctg, csg, ctb, csb and the chromosome in which it occurred was recorded. Analysis of results showed that there was no statistically significant difference between the AD group and the controls for either the total occurrence of breaks, the type of aberration or the chromosome(s) involved. In both groups the commonest break was in 3p.     

Oscillations in cerebral blood flow and cortical oxygenation in Alzheimer's disease

In Alzheimer's disease (AD) cerebrovascular function is at risk. Transcranial Doppler, near-infrared spectroscopy, and photoplethysmography are noninvasive methods to continuously measure changes in cerebral blood flow velocity (CBFV), cerebral cortical oxygenated hemoglobin (O₂Hb), and blood pressure (BP). In 21 patients with mild to moderate AD and 20 age-matched controls, we investigated how oscillations in cerebral blood flow velocity (CBFV) and O₂Hb are associated with spontaneous and induced oscillations in blood pressure (BP) at the very low (VLF = 0.05 Hz) and low frequencies (LF = 0.1 Hz). We applied spectral and transfer function analysis to quantify dynamic cerebral autoregulation and brain tissue oxygenation. In AD, cerebrovascular resistance was substantially higher (34%, AD vs. control: Δ = 0.69 (0.25) mm Hg/cm/second, p = 0.012) and the transmission of very low frequency (VLF) cerebral blood flow (CBF) oscillations into O₂Hb differed, with increased phase lag and gain (Δ phase 0.32 [0.15] rad; Δ gain 0.049 [0.014] μmol/cm/second, p both < 0.05). The altered transfer of CBF to cortical oxygenation in AD indicates that properties of the cerebral microvasculature are changed in this disease.     

Cortical senile plaques in coronary artery disease, aging and Alzheimer's disease

Mild alterations in cognitive function are present in normal aging and severe cognitive alterations are a hallmark of Alzheimer's disease (AD). The cognitive change in AD has been correlated to the characteristic pathologic lesions in the brain, senile plaques (SP) and neurofibrillary tangles. Senile plaques are the most consistent correlative marker in AD. We present preliminary data indicating that abundant SP are found in the brains of nondemented patients dying with or as a result of critical coronary artery disease (cCAD) compared to nonheart disease (non-HD) subjects; 15 of 20 cCAD patients contained SP and only two of 16 non-HD patients contained SP.     

PSEN1 polymorphisms alter the rate of cognitive decline in sporadic Alzheimer's disease patients

Mutations in amyloid precursor protein (APP) and presenilin (PSEN) genes are known to cause familial early-onset Alzheimer's disease (AD), which account for around 5% of AD cases. Genetic associations for the remaining “sporadic” cases, other than the risks associated with the apolipoprotein (APOE) 4 allele are currently not fully established. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in PSEN1 are associated with a modified risk for sporadic AD or a modified disease phenotype. Eight tag SNPs were identified using linkage disequilibrium (LD) data from the International HapMap project providing coverage of the entire PSEN1 gene. These SNPs were investigated for AD susceptibility in a case-control haplotype association study (N = 714) and for genotype-specific effects on cognitive performance in AD patients (N = 169) using non-linear mixed effects modelling. Replication of a mild associated-risk of an intronic PSEN1 polymorphism with AD was achieved (P = 0.03). No other single SNPs or haplotypes were associated with AD risk. However, 3 SNPs were associated with an altered rate of cognitive decline underlining their role as genetic modifiers of disease.     

阿尔茨海默病的免疫治疗研究新进展

阿尔茨海默病（AD）是痴呆最常见的原因。根据淀粉样蛋白级联假说,AD的疫苗治疗成为该病的治疗方法。虽然AD的主动免疫治疗的Ⅱ期临床试验由于一些病人出现了脑膜脑炎而停止,但被治疗病人的临床和病理研究都表明疫苗治疗是有效的。为了避免AB疫苗诱发的脑膜脑炎,研究者试偿了各种各样的方法,其中包括发展短的免疫原、使用新的佐剂、改变给药途径、研制DNA非病毒载体的疫苗和应用催化性抗体。一些在转基因小鼠上的实验研究表明,上述的方法是AD的安全有效的治疗方法。     

小RNA与阿尔茨海默病发病机制研究进展

小RNA(miRNA)是一类非编码的小RNA,通过转录后水平调控细胞蛋白质的表达,在神经系统的生长发育、分化及功能执行中发挥重要的作用.脑组织内miRNA的异常表达可通过多种途径影响阿尔茨海默病的发生和发展.对于miRNA的研究将有助于深入了解阿尔茨海默病的发病机制.