Journal of Alzheimer's Disease - Volume 50, issue 4

Authors: Eustache, Pierre | Nemmi, Federico | Saint-Aubert, Laure | Pariente, Jeremie | Péran, Patrice

Article Type: Research Article

Abstract: One objective of modern neuroimaging is to identify markers that can aid in diagnosis, monitor disease progression, and impact long-term drug analysis. In this study, physiopathological modifications in seven subcortical structures of patients with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) were characterized by simultaneously measuring quantitative magnetic resonance parameters that are sensitive to complementary tissue characteristics (e.g., volume atrophy, shape changes, microstructural damage, and iron deposition). Fourteen MCI patients and fourteen matched, healthy subjects underwent 3T-magnetic resonance imaging with whole-brain, T1-weighted, T2* -weighted, and diffusion-tensor imaging scans. Volume, shape, mean R2* , mean diffusivity (MD), and mean …fractional anisotropy (FA) in the thalamus, hippocampus, putamen, amygdala, caudate nucleus, pallidum, and accumbens were compared between MCI patients and healthy subjects. Comparisons were then performed using voxel-based analyses of R2* , MD, FA maps, and voxel-based morphometry to determine which subregions showed the greatest difference for each parameter. With respect to the micro- and macro-structural patterns of damage, our results suggest that different and distinct physiopathological processes are present in the prodromal phase of AD. MCI patients had significant atrophy and microstructural changes within their hippocampi and amygdalae, which are known to be affected in the prodromal stage of AD. This suggests that the amygdala is affected in the same, direct physiopathological process as the hippocampus. Conversely, atrophy alone was observed within the thalamus and putamen, which are not directly involved in AD pathogenesis. This latter result may reflect another mechanism, whereby atrophy is linked to indirect physiopathological processes. Show more

Keywords: Alzheimer’s disease, brain, diffusion tensor imaging, iron, magnetic resonance imaging, mild cognitive impairment, multimodal, shape, subcortical structures, volumetry

DOI: 10.3233/JAD-150353

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1035-1050, 2016

Authors: Lacalle-Aurioles, María | Navas-Sánchez, Francisco Javier | Alemán-Gómez, Yasser | Olazarán, Javier | Guzmán-De-Villoria, Juan Adán | Cruz-Orduña, Isabel | Mateos-Pérez, José María | Desco, Manuel

Article Type: Research Article

Abstract: According to the so-called disconnection hypothesis, the loss of synaptic inputs from the medial temporal lobes (MTL) in Alzheimer’s disease (AD) may lead to reduced activity of target neurons in cortical areas and, consequently, to decreased cerebral blood flow (CBF) in those areas. The aim of this study was to assess whether hypoperfusion in parietotemporal and frontal cortices of patients with mild cognitive impairment who converted to AD (MCI-c) and patients with mild AD is associated with atrophy in the MTL and/or microstructural changes in the white matter (WM) tracts connecting these areas. We assessed these relationships by investigating correlations …between CBF in hypoperfused areas, mean cortical thickness in atrophied regions of the MTL, and fractional anisotropy (FA) in WM tracts. In the MCI-c group, a strong correlation was observed between CBF of the superior parietal gyri and FA in the parahippocampal tracts (left: r  = 0.90, p  <  0.0001; right: r  = 0.597, p  = 0.024), and between FA in the right parahippocampal tract and the right precuneus (r  = 0.551, p  = 0.041). No significant correlations between CBF in hypoperfused regions and FA in the WM tract were observed in the AD group. These results suggest an association between perfusion deficits and altered WM tracts in prodromal AD, while microvasculature impairments may have a greater influence in more advanced stages. We did not find correlations between cortical thinning in the medial temporal lobes and decreased FA in the WM tracts of the limbic system in either group. Show more

Keywords: Alzheimer’s disease, diffusion tensor imaging, disconnection hypothesis, magnetic resonance imaging, mild cognitive impairment, perfusion weighted imaging

DOI: 10.3233/JAD-150288

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1051-1064, 2016

Authors: Wruck, Wasco | Schröter, Friederike | Adjaye, James

Article Type: Research Article

Abstract: Although the incidence of Alzheimer’s disease (AD) is continuously increasing in the aging population worldwide, effective therapies are not available. The interplay between causative genetic and environmental factors is partially understood. Meta-analyses have been performed on aspects such as polymorphisms, cytokines, and cognitive training. Here, we propose a meta-analysis approach based on hierarchical clustering analysis of a reliable training set of hippocampus biopsies, which is condensed to a gene expression signature. This gene expression signature was applied to various test sets of brain biopsies and iPSC-derived neuronal cell models to demonstrate its ability to distinguish AD samples from control. Thus, …our identified AD-gene signature may form the basis for determination of biomarkers that are urgently needed to overcome current diagnostic shortfalls. Intriguingly, the well-described AD-related genes APP and APOE are not within the signature because their gene expression profiles show a lower correlation to the disease phenotype than genes from the signature. This is in line with the differing characteristics of the disease as early-/late-onset or with/without genetic predisposition. To investigate the gene signature’s systemic role(s), signaling pathways, gene ontologies, and transcription factors were analyzed which revealed over-representation of response to stress, regulation of cellular metabolic processes, and reactive oxygen species. Additionally, our results clearly point to an important role of FOXA1 and FOXA2 gene regulatory networks in the etiology of AD. This finding is in corroboration with the recently reported major role of the dopaminergic system in the development of AD and its regulation by FOXA1 and FOXA2. Show more

Keywords: Alzheimer’s disease, energy metabolism, forkhead box proteins, gene expression, induced pluripotent stem cells, meta-analysis, microarray analysis, transcription factors

DOI: 10.3233/JAD-150733

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1065-1082, 2016

Authors: Li, Hsin-Hua | Lin, Shi-Lung | Huang, Chien-Ning | Lu, Fung-Jou | Chiu, Pai-Yi | Huang, Wen-Nung | Lai, Te-Jen | Lin, Chih-Li

Article Type: Research Article

Abstract: Deficiency of insulin signaling has been linked to diabetes and ageing-related neurodegenerative diseases such as Alzheimer’s disease (AD). In this regard, brains exhibit defective insulin receptor substrate-1 (IRS-1) and hence result in alteration of insulin signaling in progression of AD, the most common cause of dementia. Consequently, dysregulation of insulin signaling plays an important role in amyloid-β (Aβ)-induced neurotoxicity. As the derivation of induced pluripotent stem cells (iPSC) involves cell reprogramming, it may provide a means for regaining the control of ageing-associated dysfunction and neurodegeneration via affecting insulin-related signaling. To this, we found that an embryonic stem cell (ESC)-specific microRNA, …miR-302, silences phosphatase and tensin homolog (PTEN) to activate Akt signaling, which subsequently stimulates nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) elevation and hence inhibits Aβ-induced neurotoxicity. miR-302 is predominantly expressed in iPSCs and is known to regulate several important biological processes of anti-oxidative stress, anti-apoptosis, and anti-aging through activating Akt signaling. In addition, we also found that miR-302-mediated Akt signaling further stimulates Nanog expression to suppress Aβ-induced p-Ser307 IRS-1 expression and thus enhances tyrosine phosphorylation and p-Ser 473-Akt/p-Ser 9-GSK3β formation. Furthermore, our in vivo studies revealed that the mRNA expression levels of both Nanog and miR-302-encoding LARP7 genes were significantly reduced in AD patients’ blood cells, providing a novel diagnosis marker for AD. Taken together, our findings demonstrated that miR-302 is able to inhibit Aβ-induced cytotoxicity via activating Akt signaling to upregulate Nrf2 and Nanog expressions, leading to a marked restoration of insulin signaling in AD neurons. Show more

Keywords: Alzheimer’s disease, amyloid-β, insulin signaling, miR-302, Nanog, phosphatase and tensin homolog

DOI: 10.3233/JAD-150741

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1083-1098, 2016

Authors: Kuźma, Elżbieta | Soni, Maya | Littlejohns, Thomas J. | Ranson, Janice M. | van Schoor, Natasja M. | Deeg, Dorly J.H. | Comijs, Hannie | Chaves, Paulo H.M. | Kestenbaum, Bryan R. | Kuller, Lewis H. | Lopez, Oscar L. | Becker, James T. | Langa, Kenneth M. | Henley, William E. | Lang, Iain A. | Ukoumunne, Obioha C. | Llewellyn, David J.

Article Type: Research Article

Abstract: Background: Vitamin D deficiency has been linked with dementia risk, cognitive decline, and executive dysfunction. However, the association with memory remains largely unknown. Objective: To investigate whether low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with memory decline. Methods: We used data on 1,291 participants from the US Cardiovascular Health Study (CHS) and 915 participants from the Dutch Longitudinal Aging Study Amsterdam (LASA) who were dementia-free at baseline, had valid vitamin D measurements, and follow-up memory assessments. The Benton Visual Retention Test (in the CHS) and Rey’s Auditory Verbal Learning Test (in the LASA) were used …to assess visual and verbal memory, respectively. Results: In the CHS, those moderately and severely deficient in serum 25(OH)D changed -0.03 SD (95% CI: –0.06 to 0.01) and –0.10 SD (95% CI: –0.19 to –0.02) per year respectively in visual memory compared to those sufficient (p  = 0.02). In the LASA, moderate and severe deficiency in serum 25(OH)D was associated with a mean change of 0.01 SD (95% CI: –0.01 to 0.02) and –0.01 SD (95% CI: –0.04 to 0.02) per year respectively in verbal memory compared to sufficiency (p  = 0.34). Conclusions: Our findings suggest an association between severe vitamin D deficiency and visual memory decline but no association with verbal memory decline. They warrant further investigation in prospective studies assessing different memory subtypes. Show more

Keywords: Cognition, memory, prospective studies, vitamin D

DOI: 10.3233/JAD-150811

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1099-1108, 2016

Authors: Eketjäll, Susanna | Janson, Juliette | Kaspersson, Karin | Bogstedt, Anna | Jeppsson, Fredrik | Fälting, Johanna | Haeberlein, Samantha Budd | Kugler, Alan R. | Alexander, Robert C. | Cebers, Gvido

Article Type: Research Article

Abstract: A growing body of pathological, biomarker, genetic, and mechanistic data suggests that amyloid accumulation, as a result of changes in production, processing, and/or clearance of brain amyloid-β peptide (Aβ) concentrations, plays a key role in the pathogenesis of Alzheimer’s disease (AD). Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid-β protein precursor (AβPP) to Aβ peptides, with the soluble N terminal fragment of AβPP (sAβPPβ) as a direct product, and BACE1 inhibition is an attractive target for therapeutic intervention to reduce the production of Aβ. Here, we report the in vitro and in vivo pharmacological …profile of AZD3293, a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. The in vitro potency of AZD3293 was demonstrated in several cellular models, including primary cortical neurons. In vivo in mice, guinea pigs, and dogs, AZD3293 displayed significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aβ40 , Aβ42 , and sAβPPβ. The in vitro potency of AZD3293 in mouse and guinea pig primary cortical neuronal cells was correlated to the in vivo potency expressed as free AZD3293 concentrations in mouse and guinea pig brains. In mice and dogs, the slow off-rate from BACE1 may have translated into a prolongation of the observed effect beyond the turnover rate of Aβ. The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293. Show more

Keywords: Alzheimer’s disease, amyloid-β, drug therapy, pharmacology, preclinical drug evaluation

DOI: 10.3233/JAD-150834

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1109-1123, 2016

Authors: Jung, Na-Yeon | Han, Cheol E. | Kim, Hee Jin | Yoo, Sang Wook | Kim, Hee-Jong | Kim, Eun-Joo | Na, Duk L. | Lockhart, Samuel N. | Jagust, William J. | Seong, Joon-Kyung | Seo, Sang Won

Article Type: Research Article

Abstract: The white matter tract-specific correlates of neuropsychological deficits are not fully established in patients with subcortical vascular cognitive impairment (SVCI), where white matter tract damage may be a critical factor in cognitive impairment. The purpose of this study is to investigate the tract-specific correlates of neuropsychological deficits in SVCI patients using tract-specific statistical analysis (TSSA). We prospectively recruited 114 SVCI patients, and 55 age-, gender-, and education-matched individuals with normal cognition (NC). All participants underwent diffusion weighted imaging and neuropsychological testing. We classified tractography results into fourteen major fiber tracts and analyzed group comparison and correlation with cognitive impairments. Relative …to NC subjects, SVCI patients showed decreased fractional anisotropy values in bilateral anterior-thalamic radiation, cingulum, superior-longitudinal fasciculus, uncinate fasciculus, corticospinal tract, and left inferior-longitudinal fasciculus. Focal disruptions in specific tracts were associated with specific cognitive impairments. Our findings suggest that disconnection of specific white matter tracts, especially those neighboring and providing connections between gray matter regions important to certain cognitive functions, may contribute to specific cognitive impairments in SVCI. Show more

Keywords: Diffusion-tensor imaging, neuropsychological correlation, subcortical vascular cognitive impairment, tract-specific statistical analysis, white matter connectivity

DOI: 10.3233/JAD-150841

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1125-1135, 2016

Authors: Luo, Xiao | Qiu, Tiantian | Xu, Xiaojun | Huang, Peiyu | Gu, Quanquan | Shen, Zhujing | Yu, Xinfeng | Jia, YunLu | Guan, Xiaojun | Song, Ruirui | Zhang, Minming | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The apolipoprotein E (APOE) ɛ 4 allele is the best-known genetic risk factor for developing sporadic Alzheimer’s disease (AD). According to neuroimaging studies, the APOE ɛ 4 allele is associated with localized altered brain function. However, in long-range circuitry, APOE ɛ 4 allele-related alterations in functional communication between hemispheres have rarely been directly investigated. We examined the alteration of resting-state functional connectivity (RSFC) between inter-hemispheric homotopic regions in cognitively intact, elderly APOE ɛ 4 carriers. The voxel-mirrored homotopic connectivity method was used to assess the inter-hemispheric RSFC. The current study included 13 cognitively intact, elderly APOE ɛ 4 carriers (with …at least one copy of APOE ɛ 4 allele) and 22 well-matched ɛ 3 homozygotes. Comparisons between the two groups were conducted, and subsequently, the correlation between the differential inter-hemispheric RSFC and cognitive ability was analyzed. Compared with ɛ 3 homozygotes, APOE ɛ 4 carriers showed decreased inter-hemispheric RSFC in the bilateral medial temporal lobe (MTL) and orbital frontal cortex (OFC). Moreover, in APOE ɛ 4 carriers, the inter-hemispheric RSFC of the MTL correlated with the Wechsler Memory Scale-Logical Memory (WMS-LM) (immediate and delayed performance, r  = 0.64, p  <  0.05; r  = 0.65, p  <  0.05, respectively), and the inter-hemispheric RSFC of the OFC correlated with the WMS-LM delayed performance (r  = 0.71, p  <  0.05). In our study, the presence of the APOE ɛ 4 allele was linked with decreased inter-hemispheric RSFC, which was attributed to memory performance in carriers. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, corpus callosum, functional magnetic resonance imaging, memory

DOI: 10.3233/JAD-150989

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1137-1148, 2016

Authors: Zhu, Mingming | Huang, Cong | Ma, Xiao | Wu, Rui | Zhu, Weiwei | Li, Xiaoting | Liang, Zhaofeng | Deng, Feifei | Zhu, Jianyun | Xie, Wei | Yang, Xue | Jiang, Ye | Wang, Shijia | Wu, Jieshu | Geng, Shanshan | Xie, Chunfeng | Zhong, Caiyun

Article Type: Research Article

Abstract: Neuronal cell death is an important feature of neurodegeneration. Aluminum is associated with neurodegenerative disorders, particularly Alzheimer’s disease. However, the underlying mechanisms by which aluminum induces neuronal apoptosis remain to be elucidated. miR-19 is a key miRNA implicated in regulating cell survival process, while the role of miR-19 in Alzheimer’s disease has not been investigated. In the present study, we showed that Aluminum maltolate (Al-malt), a lipophilic Al complex which is a common component of human diet with the ability to facilitate the entry of Al into the brain, induced apoptosis in human neuroblastoma SH-SY5Y cells, along with downregulation of …miR-19a/miR-19b, upregulation of miR-19-targeted PTEN, and alterations of its downstream apoptosis related proteins including AKT, p53, Bax, and Bcl-2. miR-19 overexpression attenuated Al-malt-induced apoptosis as well as changes in the expression of apoptosis related proteins in SH-SY5Y cells. We further revealed that exposure of rats to Al-malt for 12 weeks at doses relevant to human exposure significantly elevated Al concentrations in serum and brain tissues. Al-malt dose-dependently induced apoptosis in rat brain, as evidenced by increased caspase activation and increased TUNEL staining. Consistent with in vitro results, Al-malt reduced miR-19 expression and altered the expression of apoptotic related proteins in rat brain. Taken together, our data suggest for the first time that miR-19 modulation is critically involved in Al-induced neural cell apoptosis. Findings from this study could provide new insight into the molecular mechanisms of Al-associated neurodegenerative pathogenesis. Show more

Keywords: Aluminum, apoptosis, miR-19, modulation, neurodegenerative diseases

DOI: 10.3233/JAD-150763

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1149-1162, 2016

Authors: Zhang, Yudong | Wang, Shuihua | Phillips, Preetha | Yang, Jiquan | Yuan, Ti-Fei

Article Type: Research Article

Abstract: Background: Considering that Alzheimer’s disease (AD) is untreatable, early diagnosis of AD from the healthy elderly controls (HC) is pivotal. However, computer-aided diagnosis (CAD) systems were not widely used due to its poor performance. Objective: Inspired from the eigenface approach for face recognition problems, we proposed an eigenbrain to detect AD brains. Eigenface is only for 2D image processing and is not suitable for volumetric image processing since faces are usually obtained as 2D images. Methods: We extended the eigenbrain to 3D. This 3D eigenbrain (3D-EB) inherits the fundamental strategies in either eigenface or 2D eigenbrain …(2D-EB). All the 3D brains were transferred to a feature space, which encoded the variation among known 3D brain images. The feature space was named as the 3D-EB, and defined as eigenvectors on the set of 3D brains. We compared four different classifiers: feed-forward neural network, support vector machine (SVM) with linear kernel, polynomial (Pol) kernel, and radial basis function kernel. Results: The 50x10-fold stratified cross validation experiments showed that the proposed 3D-EB is better than the 2D-EB. SVM with Pol kernel performed the best among all classifiers. Our “3D-EB + Pol-SVM” achieved an accuracy of 92.81% ± 1.99% , a sensitivity of 92.07% ± 2.48% , a specificity of 93.02% ± 2.22% , and a precision of 79.03% ± 2.37% . Based on the most important 3D-EB U 1 , we detected 34 brain regions related with AD. The results corresponded to recent literature. Conclusions: We validated the effectiveness of the proposed 3D-EB by detecting subjects and brain regions related to AD. Show more

Keywords: Alzheimer’s disease, classification, detection, eigenbrain, machine learning, magnetic resonance imaging, polynomial kernel, prediction, support vector machine

DOI: 10.3233/JAD-150988

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1163-1179, 2016