Effects of demographic factors on cortical thickness in Alzheimer's disease

The aim of this study was to investigate the effect of demographic factors (age of onset, sex and years of education) on the distribution of cortical thickness in a large sample of patients with Alzheimer's disease (AD). The study participants consisted of 193 AD patients and 142 controls with no cognitive impairment (NCI) that were measured with cortical thickness across the entire brain. The effects of demographic factors on cortical thickness were analyzed by applying linear regression after controlling confounding factors. Older individuals in NCI group showed more cortical thinning in frontal, temporal association cortices and insula than younger participants. Early onset AD was associated with cortical thinning in the parietal lobe, whereas late onset AD was associated with cortical thinning in the medial temporal region. The NCI group demonstrated sex-related differences in cortical thickness, although those differences were not present in the AD group. While the education effect was absent in NCI individuals, high levels of education in the AD group correlated with cortical thinning in the frontal and temporoparietal association cortices. Our results show that AD with earlier onset and higher education had suffered more pronounced cortical atrophy in specific parts of the brain than their counterparts, which may be related to cognitive reserve theory.     

Voxel-based assessment of gray and white matter volumes in Alzheimer's disease

Using the study-specific templates and optimized voxel-based morphometry (VBM), this study investigated abnormalities in gray and white matter to provide depiction of the concurrent structural changes in 13 patients with Alzheimer's disease (AD) compared with 14 age- and sex-matched normal controls. Consistent with previous studies, patients with AD exhibited significant gray matter volume reductions mainly in the hippocampus, parahippocampal gyrus, insula, superior/middle temporal gyrus, thalamus, cingulate gyrus, and superior/inferior parietal lobule. In addition, white matter volume reductions were found predominately in the temporal lobe, corpus callosum, and inferior longitudinal fasciculus. Furthermore, a number of additional white matter regions such as precentral gyrus, cingulate fasciculus, superior and inferior frontal gyrus, and sub-gyral in parietal lobe were also affected. The pattern of gray and white matter volume reductions helps us understand the underlying pathologic mechanisms in AD and potentially can be used as an imaging marker for the studies of AD in the future.     

Alzheimer's pathology in primary progressive aphasia

Primary progressive aphasia (PPA) is a neurodegenerative disorder with language impairment as the primary feature. Different subtypes have been described and the 3 best characterized are progressive nonfluent aphasia (PNFA), semantic dementia (SD) and logopenic/phonological aphasia (LPA). Of these subtypes, LPA is most commonly associated with Alzheimer's disease (AD) pathology. However, the features of PPA associated with AD have not been fully defined. Here we retrospectively identified 14 patients with PPA and either pathologically confirmed AD or cerebrospinal fluid (CSF) biomarkers consistent with AD. Analysis of neurological and neuropsychological features revealed that all patients had a syndrome of LPA with relatively nonfluent spontaneous speech, phonemic errors, and reduced digit span; most patients also had impaired verbal episodic memory. Analysis of the pattern of cortical thinning in these patients revealed left posterior superior temporal, inferior parietal, medial temporal, and posterior cingulate involvement and in patients with more severe disease, increasing involvement of left anterior temporal and frontal cortices and right hemisphere areas in the temporo-parietal junction, posterior cingulate, and medial temporal lobe. We propose that LPA may be a “unihemispheric” presentation of AD, and discuss this concept in relation to accumulating evidence concerning language dysfunction in AD.     

Visual attention deficits in Alzheimer's disease: an fMRI study

Cognitive and neuroscience studies indicate that attentional operations are impaired in Alzheimer's disease (AD). Our goal was to define the anatomical areas of activation associated with visual attention processing and to define deficits or changes that may occur in AD patients compared with control group. Thirteen AD patients and 13 age- and education-matched normal controls were tested in two visual search tasks (one was a conjunction task, where feature binding is required. The other was a subset task, where group stimuli is needed without feature binding) using fMRI techniques. After stereotactical normalization, voxel-by-voxel t statistics was used to compare activated brain areas between patients and control subjects. Our findings suggest that both search tasks are controlled by partially overlapping cerebral networks, including parietal, frontal and occipital-temporal cortical regions and primary visual cortex. The AD patient group showed less activation in both parietal lobes and the left frontal regions, while increased activation was found in the right frontal lobes and the right occipito-temporal cortical regions with the conjunction task. In the subset task, decreased activation in AD patients was seen in the left parietal lobe and bilateral frontal lobes, while increased activation was seen in both medial temporal lobes. In addition, for the comparison between tasks, The difference is very small for AD patients. Control group showed a higher amplitude in the right prefrontal region, temporal cortical regions and parietal lobe. These results indicate that attention deficits in AD patients may be attributed to both binding problem and grouping inefficiency.     

Elevation of Cystatin C in Susceptible Neurons in Alzheimer’s Disease

A common polymorphism in the cystatin C gene is associated with increased risk of developing Alzheimer's disease (AD). To explore possible neuropathological consequences of this genetic association, we examined expression of cystatin C in brains from 22 AD and 11 control patients by immunohistochemistry. In the temporal cortex of all AD brains, there was strong cystatin C immunostaining of neurons and activated glia, whereas staining was absent or minimal in 7 of the 11 control brains. Neuronal staining of cystatin C in AD brains was primarily limited to pyramidal neurons in cortical layers III and V, which are the neurons most susceptible to cell death in AD. The increase in cystatin C staining in AD was independent of cystatin C genotype. Immunostaining of cystatin C within neurons showed a punctate distribution, which co-localized with the endosomal/lysosomal proteinase, cathepsin B. A primarily glial source for cystatin C was suggested by parallel studies using in situ hybridization of mouse brain. In human AD brain, there was little co-localization of cystatin C with parenchymal Abeta deposits, although a small fraction of cerebral blood vessels and neurofibrillary tangles were cystatin C-positive. The regional distribution of cystatin C neuronal immunostaining also duplicated the pattern of neuronal susceptibility in AD brains: the strongest staining was found in the entorhinal cortex, in the hippocampus, and in the temporal cortex; fewer pyramidal neurons were stained in frontal, parietal, and occipital lobes. These neuropathological observations reinforce the association between cystatin C and AD, and support a model of cystatin C involvement in the process of neuronal death in 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).     

Volumetric correlates of memory and executive function in normal elderly, mild cognitive impairment and Alzheimer's disease

In Alzheimer's disease (AD), atrophy negatively impacts cognition while in healthy adults, inverse relationships between brain volume and cognition may occur. We investigated correlations between gray matter volume and cognition in elderly controls, AD and mild cognitive impairment (MCI) patients with memory and executive deficits. AD demonstrated substantial loss in temporal, parietal and frontal regions while MCI exhibited moderate volume loss in temporal and frontal regions. In controls, memory and executive function were negatively correlated with frontal regions, while in AD, memory was positively correlated with temporal and frontal gyri, and executive function with frontal regions. The combination of the two patterns may explain the lack of correlations in MCI. Developmental versus pathological contributions to these relationships are discussed.     

Patterns of cortical thinning in Alzheimer's disease and frontotemporal dementia

In vivo measurement of cortical thickness is a sensitive representation of pathology in neurodegenerative disorders which primarily target the gray mantle. In this study we used magnetic resonance images to describe the patterns of cortical thinning in 11 frontotemporal dementia (FTD), 38 Alzheimer's disease (AD) and 34 healthy elderly (H(E)) subjects. AD and FTD displayed significant thinning of the cortical mantle compared to the H(E) group, but with distinctive distributions. AD subjects had significantly thinner cortex in all lobes whereas FTD compared to H(E) showed significant differences only in specific regions of frontal and temporal lobes. When compared to AD, the FTD subjects had a trend of thinner cortex in the anterior cingulate region and in selective regions of anterior frontal and temporal regions. In conclusion, the cortical thinning in dementia when compared to H(E), is disease specific whereby FTD subjects display a pattern distinct than that seen in Alzheimer's disease.     

Homocysteine and electroencephalographic rhythms in Alzheimer disease: a multicentric study

High plasma concentration of homocysteine is an independent risk factor for Alzheimer’s disease (AD), due to microvascular impairment and consequent neural loss [Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, Wilson PW, Wolf PA (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 346(7):476–483]. Is high plasma homocysteine level related to slow electroencephalographic (EEG) rhythms in awake resting AD subjects, as a reflection of known relationships between cortical neural loss and these rhythms? To test this hypothesis, we enrolled 34 mild AD patients and 34 subjects with mild cognitive impairment (MCI). Enrolled people were then subdivided into four sub-groups of 17 persons: MCI and AD subjects with low homocysteine level (MCI− and AD−, homocysteine level <11 μmol/l); MCI and AD subjects with high homocysteine level (MCI+ and AD+, homocysteine level ≥11 μmol/l). Resting eyes-closed EEG data were recorded. EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–10.5 Hz), alpha 2 (10.5–13 Hz), beta 1 (13–20 Hz), and beta 2 (20–30 Hz). EEG cortical sources were estimated by low-resolution brain electromagnetic tomography (LORETA). Results showed that delta (frontal and temporal), theta (central, frontal, parietal, occipital, and temporal), alpha 1 (parietal, occipital, and temporal), and alpha 2 (parietal and occipital) sources were stronger in magnitude in AD+ than AD− group. Instead, no difference was found between MCI− and MCI+ groups. In conclusion, high plasma homocysteine level is related to unselective increment of cortical delta, theta, and alpha rhythms in mild AD, thus unveiling possible relationships among that level, microvascular concomitants of advanced neurodegenerative processes, and synchronization mechanisms generating EEG rhythms.     

Differential effects of aging and Alzheimer's disease on medial temporal lobe cortical thickness and surface area

The volume of parcellated cortical regions is a composite measure related to both thickness and surface area. It is not clear whether volumetric decreases in medial temporal lobe (MTL) cortical regions in aging and Alzheimer's disease (AD) are due to thinning, loss of surface area, or both, nor is it clear whether aging and AD differ in their effects on these properties. Participants included 28 Younger Normals, 47 Older Normals, and 29 patients with mild AD. T1-weighted MRI data were analyzed using a novel semi-automated protocol (presented in a companion article) to delineate the boundaries of entorhinal (ERC), perirhinal (PRC), and posterior parahippocampal (PPHC) cortical regions and calculate their mean thickness, surface area, and volume. Compared to Younger Normals, Older Normals demonstrated moderately reduced ERC and PPHC volumes, which were due primarily to reduced surface area. In contrast, the expected AD-related reduction in ERC volume was produced by a large reduction in thickness with minimal additional effect (beyond that of aging) on surface area. PRC and PPHC also showed large AD-related reductions in thickness. Of all these MTL morphometric measures, ERC and PRC thinning were the best predictors of poorer episodic memory performance in AD. Although the volumes of MTL cortical regions may decrease with both aging and AD, thickness is relatively preserved in normal aging, while even in its mild clinical stage, AD is associated with a large degree of thinning of MTL cortex. These differential morphometric effects of aging and AD may reflect distinct biologic processes and ultimately may provide insights into the anatomic substrates of change in memory-related functions of MTL cortex.     

成人大脑皮质老化形态学改变的MRI研究

目的 探讨成人大脑正常衰老过程中大脑皮质体积、厚度及表面积改变的区域性差异及侧化差异MRI的表现。方法 采用前瞻性研究。2017年9月—2018年1月山东省立医院影像科及寿光市人民医院CT磁共振室招募18~85岁右利手汉族健康成年志愿者109人,其中男性56人、女性53人,年龄(53.13±15.61)岁,均行3.0 T MRI颅脑扫描原始数据。使用FreeSurfer脑成像软件分析,获取左右大脑半球、各脑叶的感兴趣区脑皮质的体积、厚度及表面积的具体数值并进行标准化处理,分析其与年龄的相关关系,以及大脑皮质老化的区域性差异及侧化差异。结果 线性回归分析显示,大脑皮质体积、厚度及表面积随年龄增长而下降(P＜0.01),表现出与年龄相关的皮质体积减少较多的区域为海马旁回、额下回岛盖部、额中回、额下回三角部、舌回、颞中回(最大为-0.653%/岁,P＜0.01),皮质厚度减少较多的区域主要在颞上回、后扣带回、额中回、外眶额回、顶下缘角回、颞极、海马旁回(最大-0.009 mm/岁,P<0.01),皮质表面积减少较多的区域主要是在海马旁回、舌回、颞下回、额中回、额下回岛盖部(最大-0.402%/岁,P＜ 0.01)。大脑左右半球皮质体积年龄效应不对称的区域为额上回、额下回岛盖部及三角部、中眶额回、额极、顶下缘角回、缘上回、梭状回、颞极、海马旁回、前扣带回、内嗅皮层(P＜0.05),皮质厚度年龄效应不对称的区域为额上回、额下回岛盖部、中眶额回、楔叶、颞下回、颞极、前扣带回、后扣带回(P＜0.05),皮质表面积年龄效应不对称的区域为额上回、额中回、额下回岛盖部及三角部、中眶额回、额极、顶下缘角回、缘上回、梭状回、颞极、海马旁回、前扣带回、后扣带回、内嗅皮层(P＜0.05)。结论 在人脑的正常老化过程中,大脑皮质体积、厚度及表面积与年龄呈现线性负相关性改变,不同脑区皮质与年龄呈不同程度的线性负相关关系,部分脑回皮质的年龄效应存在侧化差异,皮质体积、厚度、表面积三个形态学指标是相互关联的。     

Decreased brain levels of 2',3'-cyclic nucleotide-3'-phosphodiesterase in Down syndrome and Alzheimer's disease.

In Down syndrome (DS) as well as in Alzheimer's disease (AD) oligodendroglial and myelin alterations have been reported. 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) and carbonic anhydrase II (CA II) are widely accepted as markers for oligodendroglia and myelin. However, only data on CNPase activity have been available in AD and DS brains so far. In our study we determined the protein levels of CNPase and CA II in DS, AD and in control post mortem brain samples in order to assess oligodendroglia and myelin alterations in both diseases. We used two dimensional electrophoresis to separate brain proteins that were subsequently identified by matrix assisted laser desorption and ionization mass-spectroscopy (MALDI-MS). Seven brain areas were investigated (frontal, temporal, occipital and parietal cortex, cerebellum, thalamus and caudate nucleus). In comparison to control brains we detected significantly decreased CNPase protein levels in frontal and temporal cortex of DS patients. The level of CA II protein in DS was unchanged in comparison to controls. In AD brains levels of CNPase were decreased in frontal cortex only. The level of CA II in all brain areas in AD group was comparable to controls. Changes of CNPase protein levels in DS and AD are in agreement with the previous finding of decreased CNPase activity in DS and AD brain. They probably reflect decreased oligodendroglial density and/or reduced myelination. These can be secondary to disturbances in axon/oligodendroglial communication due to neuronal loss present in both diseases. Alternatively, reduced CNPase levels in DS brains may be caused by impairment of glucose metabolism and/or alterations of thyroid functions.     

Expression of somatostatin receptor subtypes (SSTR1-5) in Alzheimer's disease brain: an immunohistochemical analysis

Somatostatin, widely distributed in human cortical brain regions, acts through specific high affinity somatostatin receptors (SSTR1-5) to exert profound effects on motor, sensory, behavioral, cognitive and autonomic functions. Somatostatin levels are consistently decreased in the cortex of Alzheimer's disease (AD) brain and in cerebrospinal fluid, and have become reproducible markers of this disease. In the present study, the distributional pattern of SSTR1-5 antigens in the frontal cortex of AD and age-matched control brains was studied using antipeptide polyclonal rabbit antibodies directed against the five human somatostatin receptor subtypes. All five SSTRs were differentially expressed as membrane and cytoplasmic proteins in cortical neurons with significant variations in control vs. AD brain. In AD cortical brain region, somatostatin and neuropeptide-Y-positive neurons decreased (>70%), and glial fibrillary acidic protein-positive astrocytes significantly increased (>130%) in comparison to control brain. SSTR2 and 4 were the predominant subtypes followed by SSTR1, 3 and 5. AD cortex showed a marked reduction in neuronal expression of SSTR4 and 5 and a modest decrease in SSTR2-like immunoreactivity without any changes in SSTR1 immunoreactive neurons. In contrast, SSTR3 was the only receptor subtype that increased in AD cortex. In AD cortex, SSTR1-, 3- and 4-like immunoreactivities were strongly expressed in glial cells but not SSTR2 and 5. These findings suggest the differential loss of immunoreactivity of SSTR2, 4 and 5 but not SSTR1, and increased SSTR3 in frontal cortex of AD brain as well as subtype-selective glial expression in AD brain. In summary, subtype-selective changes in the expression of SSTRs at protein levels in AD cortical regions suggest that somatostatin and SSTR-containing neurons are pathologically involved in AD and could possibly be used as markers of this disease.     

Identifying severely atrophic cortical subregions in Alzheimer's disease

The present study analyses the pattern of atrophy in anatomically discrete brain regions in prospectively-studied pathologically-confirmed patients with Alzheimer's disease (AD) and controls. Standard volumetric measurements were made of the entire cortex subdivided into 23 anatomical regions. Analyses determined regions of significant atrophy in AD and differences between the severity and rates of atrophy. Two levels of severity were found. Atrophy concentrated in medial temporal lobe structures as well as in inferior temporal and superior and middle frontal cortices. The degree of atrophy in these regions related to disease duration, consistent with an early and sustained disease process. The rate of atrophy was significantly greater for the fusiform gyrus. The inferior frontal lobes were entirely spared at all AD stages, while atrophy of other cortical regions was less marked and not related to disease duration, suggesting late involvement. Our findings show that the fusiform gyrus is particularly affected by AD, and suggest two levels of atrophy that correspond with published neurofibrillary tangle (most atrophic) and senile plaque (less atrophic) densities.     

2',3'-cyclic nucleotide-3'-phosphodiesterase activity as an index of myelin in the post-mortem brains of patients with Alzheimer's disease

The activity of 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) was determined as an index of myelin in the post-mortem brain samples of 16 patients with Alzheimer's disease (AD) and of 14 controls. The CNPase activity was mildly increased in the temporal, hippocampal and parietal cortex in AD subjects pointing to a relative sparing of myelin as compared to the neuron loss within cortex in AD. In the hippocampus the CNPase activity was decreased in AD patients indicating loss of myelin and thus myelinated axons in this area in AD.     

Increased glyceraldehyde 3-phosphate dehydrogenase levels in the brain of patients with Down's syndrome

Impaired glucose metabolism in Down's syndrome (DS) has been well-documented in vivo, although information on the underlying biochemical defect is limited and no biochemical studies on glucose handling enzymes have been carried out in the brain. In a previous study, we found by gene hunting in DS brain an overexpressed sequence homologous to the glyceraldehyde 3-phosphate dehydrogenase (G3PD) gene. Here we studied G3PD activity and expression levels, using two-dimensional gel analysis, in five brain regions of patients with DS and Alzheimer's disease (AD). The protein expression levels in four brain areas were approximately 1.5-fold higher in patients with DS in comparison with the controls. G3PD activity was significantly elevated in the frontal, parietal, occipital and temporal lobe of DS as well, but not in the corresponding AD brain regions. We conclude that our biochemical findings complement previously published data of impaired brain glucose metabolism in DS evaluated by positron emission tomography in clinical studies.     

Senile dementia and Alzheimer's disease: lack of changes of the cortical content of quinolinic acid

The content of Quinolinic Acid (QUIN) was fragmentographically measured in the frontal, parietal and temporal cortex obtained at autopsy from patients affected by Alzheimer's disease-senile dementia Alzheimer type (AD/SDAT) or matched controls. The density of large cholinergic neurons in the nucleus basalis magnocellularis and the density of plaques in the hippocampal formation, parietal and frontal cortex of these patients was also evaluated in order to obtain a quantitative estimation of the Alzheimer type changes. In the three cortical areas studied, the content of QUIN was similar in AD/SDAT patients and age matched controls. The AD/SDAT patients had an important reduction of the number of large cholinergic neurons in the nucleus basalis magnocellularis and a much higher density of plaques in cortex and in hippocampus than age matched controls. The data reported here do not support the possibility than an accumulation of QUIN plays a role in the neuronal degeneration occurring in the cortex of patients affected by AD/SDAT.     

Caspase-cleaved amyloid precursor protein in Alzheimer's disease

Caspase-3 mediated cleavage of the amyloid precursor protein (APP) has been proposed as a putative mechanism underlying amyloidosis and neuronal cell death in Alzheimer's disease (AD). We utilized an antibody that selectively recognizes the neo epitope generated by caspase-3 mediated cleavage of APP (alphadeltaC(csp)-APP) to determine if this proteolytic event occurs in senile plaques in the inferior frontal gyrus and superior temporal gyrus of autopsied AD and age-matched control brains. Consistent with a role for caspase-3 activation in AD pathology, alphadeltaC(csp)-APP immunoreactivity colocalized with a subset of TUNEL-positive pyramidal neurons in AD brains. AlphadeltaC(csp)-APP immunoreactivity was found in neurons and glial cells, as well as in small- and medium-size particulate elements, resembling dystrophic terminals and condensed nuclei, respectively, in AD and age-matched control brains. There were a larger number of alphadeltaC(csp)-APP immunoreactive elements in the inferior frontal gyrus and superior temporal gyrus of subjects with AD pathology than age-matched controls. AlphadeltaC(csp)-APP immunoreactivity in small and medium size particulate elements were the main component colocalized with 30% of senile plaques in the inferior frontal gyrus and superior temporal gyrus of AD brains. In some control brains, alphadeltaC(csp)-APP immunoreactivity appeared to be associated with a clinical history of metabolic encephalopathy. Our results suggest that apoptosis contributes to cell death resulting from amyloidosis and plaque deposition in AD.     

Cortical rhythms reactivity in AD, LBD and normal subjects: a quantitative MEG study

The present study evaluated the reactivity of cortical rhythms in 15 Alzheimer's disease (AD) patients, 7 Lewy body dementia (LBD) patients and 9 control subjects using a 165 SQUID whole-head MEG system. The absolute power values of the rhythms recorded over different areas over the brain (frontal, parietal, temporal, occipital) were analysed in the 3-47Hz frequency range. The cortical reactivity of the alpha (9-14Hz) and pre-alpha rhythms (7-9Hz) during open and closed eyes conditions differentiated the control group from the patient groups and moderate AD from severe AD and LBD groups, respectively. The cortical reactivity of the slow-band (3-7Hz) obtained by comparing a simple mental task and the rest discriminated the severe AD group from the other groups. In addition, spectral coherence analysis in the alpha band showed that the loss of coherence in AD and LBD patients mainly involved long connections. These results suggest that investigations on rhythms reactivity and spectral coherence might help on the study of the dementias with different etiology.