Pages 341-361
Review
Pravir Kumar, Niraj Kumar Jha, Saurabh Kumar Jha, Karunya Ramani, Rashmi K. Ambasta
Tau Phosphorylation, Molecular Chaperones, and Ubiquitin E3 Ligase: Clinical Relevance in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is characterized by dementia, cognitive disabilities, and tauopathy. Tau is a microtubule associated protein that helps maintain the neuronal network. While phosphorylation of tau protein causes disruption of the microtubular network, dephosphorylation allows reconstitution of the microtubule network. Several kinases, e.g., MARK, MAPK, and protein kinase C, are known to hyperphosphorylate tau, leading to disruption of the microtubular network and formation of neurofibrillary tangles (NFTs), which are further glycosylated, glycated, and have lipid peroxide adducts that impair the neuronal transport system and affect memory formation and retention. Moreover, intracerebral administration of amyloid-β oligomers causes hyperphosphorylation of tau, but whether it is involved in the formation of NFTs is still unclear. Further, amyloid burden activates AMP-activated protein kinase that increases phosphorylation of tau at position Ser262/Ser356 and Ser396. Several phosphatases are present at low levels in AD brains indicating that their down regulation results in abnormal hyperphosphorylation of tau. However, evidence strengthens a possible link between tau phosphorylation and molecular chaperone mediated tau metabolism for the clearance of toxic tau accumulation and has a crucial role in tauopathy. Furthermore, accumulation of phosphorylated tau protein and the possibility of removing the toxic phosphorylated tau protein from the milieu indicates that the chaperone interacts with phosphorylated tau and promotes its degradation. For instance, Hsp90 and cdc37 regulate tau stability and phosphorylation dynamics whereas Hsp27 is able to modulate neuronal plasticity, while 14-3-3 is involved in the interaction of tau with small HSPs. Hsp70 ATPase acts as a modulator in AD therapeutics while Hsc70 rapidly engages tau after microtubular destabilization. Herein, we highlight the various causes of tauopathy and HSP-E3 ligase mediated therapeutics in AD.
Pages 363-367
Short Communication
Mª Ascensión Zea-Sevilla, Pedro Bermejo-Velasco, Regino Serrano-Heranz, Miguel Calero
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) associated with a Novel C82R Mutation in the NOTCH3 Gene
Abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare inherited cerebrovascular disease associated with mutations in the NOTCH3 gene on chromosome 19, and represents the most common hereditary stroke disorder. We describe a pedigree, which suffered the classical clinical CADASIL pattern of migraine headaches, recurrent subcortical infarcts, and subcortical dementia, associated with a previously undescribed missense mutation (c.[244T>C], p.[C82R]) in NOTCH3. This new mutation extends the list of known pathogenic mutations responsible for CADASIL, which are associated with an odd number of cysteine residues within any of the epidermal growth factor-like repeats of Notch3 receptor protein.
Pages 369-374
Short Communication
Bernadette Schreiner*, Louise Hedskog*, Birgitta Wiehager, Maria Ankarcrona (Handling Associate Editor: Russell Swerdlow) *These authors contributed equally to this work.
Amyloid-β Peptides are Generated in Mitochondria-Associated Endoplasmic Reticulum Membranes
Abstract: Extracellular aggregates of amyloid-β peptides (Aβ) are a hallmark in Alzheimer’s disease (AD) brains. Recent findings suggest that Aβ is generated intracellularly and potential production sites include endosomes and trans-Golgi network. We determined the production of Aβ in subcellular fractions isolated from mouse brain. We found that a considerable amount of Aβ is produced at mitochondria-endoplasmic reticulum (ER) contact sites including outer mitochondrial membrane and mitochondria-associated ER membranes. Enhanced Aβ production at this site may disturb ER, mitochondrial and mitochondria-ER contact site function. This may be one key step in the cascade of events eventually leading to neurodegeneration in AD.
Pages 375-379
Short Communication
Emanuela Maderna, Cristina Cattaneo, Francesca Cacciatore, Marcella Catania, Giuseppe Di Fede, Fabrizio Tagliavini, Giorgio Giaccone
Divergent Cognitive Status with the Same Braak Stage of Neurofibrillary Pathology: Does the Pattern of Amyloid-β Deposits Make the Difference?
Abstract: The neuropathological hallmark of Alzheimer’s disease (AD) is the co-occurrence of extracellular amyloid-β (Aβ) deposition and intraneuronal neurofibrillary changes composed of abnormal tau. Over the last decades, the concept emerged that neurofibrillary changes progress in a hierarchical manner from mesial temporal structures through the associative neocortex to primary sensory and motor fields, paralleling cognitive deterioration closer than Aβ. The observation that two patients (one cognitively normal, one with dementia) exhibited neurofibrillary changes closely overlapping as regards their entity and topographic distribution but differed for characteristics of Aβ deposition suggests that the latter may directly contribute in determining cognitive impairment in AD.
Pages 381-384
Short Communication
Timothy J. Shakespeare, Keir X.X. Yong, David Foxe, John Hodges, Sebastian J. Crutch (Handling Associate Editor: Carlo Abbate)
Pronounced Impairment of Everyday Skills and Self-Care in Posterior Cortical Atrophy
Abstract: Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive visual dysfunction and parietal, occipital, and occipitotemporal atrophy. The aim of this study was to compare the impact of PCA and typical Alzheimer’s disease (tAD) on everyday functional abilities and neuropsychiatric status. The Cambridge Behavioural Inventory-Revised was given to carers of 32 PCA and 71 tAD patients. PCA patients showed significantly greater impairment in everyday skills and self-care while the tAD group showed greater impairment in aspects of memory and orientation, and motivation. We suggest that PCA poses specific challenges for those caring for people affected by the condition.
Pages 385-395
Chiara Cerami, Chiara Crespi, Pasquale Anthony Della Rosa, Alessandra Dodich, Alessandra Marcone, Giuseppe Magnani, Elisabetta Coppi, Andrea Falini, Stefano F. Cappa, Daniela Perani (Handling Associate Editor: Christine Bastin)
Brain Changes within the Visuo-Spatial Attentional Network in Posterior Cortical Atrophy
Abstract: Posterior cortical atrophy (PCA) is characterized by basic visual and high order visual-spatial dysfunctions. In this study, we investigated long-distance deafferentation processes within the frontal-parietal-occipital network in ten PCA patients using a MRI-PET combined approach. Objective voxel-based [18F]FDG-PET imaging measured metabolic changes in single patients. Comprehensive investigation of diffusion tensor imaging (DTI) metrics and grey-matter density with voxel-based morphometry were obtained in a subgroup of 6 patients. Fractional anisotropy in the superior longitudinal fasciculus correlated with the PET metabolic changes within the inferior parietal and frontal eye field regions. [18F]FDG-PET analysis showed in each PCA case the typical bilateral hypometabolic pattern, involving posterior temporal, parietal, and occipital cortex, with additional hypometabolic foci in the frontal eye fields. Voxel-based morphometry showed right-sided atrophy in the parieto-occipital cortex, as well as a limited temporal involvement. DTI revealed extensive degeneration of the major anterior-posterior connecting fiber bundles and of commissural frontal lobe tracts. Microstructural measures in the superior longitudinal fasciculus were correlated with the PET metabolic changes within the inferior parietal and frontal eye field regions. Our results confirmed the predominant occipital-temporal and occipital-parietal degeneration in PCA patients. [18F]FDG-PET and DTI-MRI combined approaches revealed neurodegeneration effects well beyond the classical posterior cortical involvement, most likely as a consequence of deafferentation processes within the occipital-parietal-frontal network that could be at the basis of visuo-perceptual, visuo-spatial integration and attention deficits in PCA.
Pages 397-413
Klaus Maria Perrar*, Holger Schmidt*, Yvonne Eisenmann, Bernadette Cremer, Raymond Voltz (Handling Associate Editor: Jenny van der Steen) *These authors contributed equally to this work
Needs of People with Severe Dementia at the End-of-Life: A Systematic Review
Abstract: Background: Epidemiological data shows an increasing number of people affected by dementia. It is mentioned that people with severe dementia have special care needs which are intensified at the end-of-life. Objective: This paper offers a systematic analysis of the current status of research on the needs of people with severe dementia in the last phase of their lives. Methods: A systematic review of the MEDLINE, CINAHL, Cochrane Library, PsycINFO, and AMED databases performed up to April 2014 was further expanded by contacting experts, conducting internet searches, and screening relevant reference lists. Studies were screened according to defined criteria and appraised for methodological quality. Findings were then synthesized using a narrative thematic approach to identify and categorize relevant needs into thematic categories and subcategories. Results: A total of ten studies published from 1993-2013 were identified, encompassing qualitative (n=7), quantitative (n=2), and a mixed-methods study (n=1). Data synthesis yielded seven themes, with physical, social, and psychological needs the categories most frequently mentioned. Other categories were spiritual, supportive, and environmental needs and needs related to individuality. Needs were often named, but what they entailed operationally was not highlighted in detail. Conclusion: This systematic review shows the paucity of empirical findings on the needs of people with severe dementia. The structured presentation of thematic categories points to a clearer delineation of these needs. Thus, this overview emphasizes the topics for future research and can likewise serve as an orientation for care provision.
Pages 415-424
Joel Ramirez, Courtney Berezuk, Alicia A. McNeely, Christopher J.M. Scott, Fuqiang Gao, Sandra E. Black (Handling Associate Editor: Sang Won Seo)
Visible Virchow-Robin Spaces on Magnetic Resonance Imaging of Alzheimer’s Disease Patients and Normal Elderly from the Sunnybrook Dementia Study
Abstract: Background: Visible Virchow-Robin spaces (VRS) are commonly used markers for small vessel disease in aging and dementia. Objective: However, as previous reports were based on subjective visual ratings, the goal of this project was to validate and apply an MRI-based quantitative measure of VRS as a potential neuroimaging biomarker. Methods: A modified version of Lesion Explorer was applied to MRIs from Alzheimer’s disease patients (AD: n=203) and normal elderly controls (NC: n=94). Inter-rater reliability, technique validity, group/gender differences, and correlations with other small vessel disease markers were examined (lacunes and white matter hyperintensities, WMH). Results: Inter-rater reliability and spatial congruence was excellent (ICC=0.99, SI=0.96), and VRS volumes were highly correlated with established rating scales (CS: ρ=0.84, p<0.001; BG: ρ=0.75, p<0.001). Compared to NC, AD had significantly greater volumes of WMH (p<0.01), lacunes (p<0.001), and VRS in the white matter (p<0.01), but not in the basal ganglia (n.s.). Compared to women, demented and non-demented men had greater VRS in the white matter (p<0.001), but not in the basal ganglia (n.s.). Additionally, VRS were correlated with lacunes and WMH, but only in AD (r=0.3, p<0.01). Conclusion: Compared to women, men may be more susceptible to greater volumes of VRS, particularly in the white matter. Results support the hypothesis that VRS in the white matter may be more related to AD-related vascular pathology compared to VRS found in the basal ganglia. Future work using this novel VRS segmentation tool will examine its potential utility as an imaging biomarker of vascular rather than parenchymal amyloid.
Pages 425-433
Gehad M. Subaiea, Aseef H. Ahmed, Lina I. Adwan, Nasser H. Zawia (Handling Associate Editor: Debomoy Lahiri)
Reduction of Amyloid-β Deposition and Attenuation of Memory Deficits by Tolfenamic Acid
Abstract: We have previously reported that tolfenamic acid treatment decreases the amyloidogenic proteins in C57BL/6 and in old hemizygous R1.40 transgenic mice via the degradation of the transcription factor specificity 1 protein (Sp1). The lowering of amyloid-β protein precursor (AβPP) and amyloid-β (Aβ) in hemizygous R1.40 transgenic mice was accompanied by reversal of the identified spatial reference and working memory deficits observed in the mouse model. In this study, we examined the ability of tolfenamic acid to reduce the amyloid plaque burden, as well as to ameliorate spatial learning and memory deficits in homozygous R1.40 mice. Results from immunohistochemical analysis indicated that tolfenamic acid treatment resulted in a profound decrease in cerebral Aβ plaque burden that was accompanied by improvements in spatial working memory assessed by spontaneous alternation ratio in the Y-maze. These results provide further evidence that tolfenamic acid could be utilized as a repurposed drug to modify Alzheimer’s disease pathogenesis.
Pages 435-441
Lucas Simieli, Fabio Augusto Barbieri, Diego Orcioli-Silva, Ellen Lirani-Silva, Florindo Stella, Lilian Teresa Bucken Gobbi
Obstacle Crossing with Dual Tasking is a Danger for Individuals with Alzheimer’s Disease and for Healthy Older People
Abstract: Background/Objective: The aim of this study was to analyze the effects of dual tasking on obstacle crossing during walking by individuals with Alzheimer’s disease (AD) and by healthy older people. Methods: Thirty four elderly individuals (16 healthy subjects and 18 individuals with AD) were recruited to participate in this study. Three AD individuals and one control participant were excluded due to exclusion criteria. The participants were instructed to walk barefoot at their own speed along an 8 m long pathway. Each participant performed five trials for each condition (unobstructed walking, unobstructed walking with dual tasking, and obstacle crossing during walking with dual tasking). The trials were completely randomized for each participant. The mid-pathway stride was measured in the unobstructed walking trials and the stride that occurred during the obstacle avoidance was measured in the trials that involved obstacle crossing. Results/Conclusion: The behavior of the healthy elderly subjects and individuals with AD was similar for obstacle crossing during walking with dual tasking. Both groups used the “posture first” strategy to prioritize stability and showed decreased attention to executive tasking while walking. Additionally, AD had a strong influence on the modifications that are made by the elderly while walking under different walking conditions.
Pages 443-449
Thomas Benke, Günter Sanin, Anita Lechner, Peter Dal-Bianco, Gerhard Ransmayr, Margarete Uranüs, Josef Marksteiner, Maren Gaudig, Reinhold Schmidt on behalf of the PRODEM Study Group
Predictors of Patient Dependence in Mild-to-Moderate Alzheimer’s Disease
Abstract: Background: Patient dependence has rarely been studied in mild-to-moderate Alzheimer’s disease (AD). Objective: To identify factors which predict patient dependence in mild-to-moderate AD. Methods: We studied 398 non-institutionalized AD patients (234 females) of the ongoing Prospective Registry on Dementia (PRODEM) in Austria. The Dependence Scale (DS) was used to assess patient dependence. Patient assessment comprised functional abilities, neuropsychiatric symptoms and cognitive functions. A multiple linear regression analysis was performed to identify predictors of patient dependence. Results: AD patients were mildly-to-moderately impaired (mean scores and SDs were: CDR 0.84 ± 0.43; DAD 74.4 ± 23.3, MMSE = 22.5 ± 3.6). Psychopathology and caregiver burden were in the low range (mean NPI score 13.2, range 0 to 98; mean ZBI score 18, range 0-64). Seventy five percent of patients were classified as having a mild level of patient dependence (DS sum score 0 to 6). Patient dependence correlated significantly and positively with age, functional measures, psychopathology and depression, disease duration, and caregiver burden. Significant negative, but low correlations were found between patient dependence, cognitive variables, and global cognition. Activities of daily living, patient age, and disease severity accounted for 63% of variance in patient dependence, whereas cognitive variables accounted for only 11%. Conclusion: Dependence in this cohort was mainly related to age and functional impairment, and less so to cognitive and neuropsychiatric variables. This differs from studies investigating patients in more advanced disease stages which found abnormal behavior and impairments of cognition as main predictors of patient dependence.
Pages 451-463
Yongfu Wang, Long Wu, Du Fang, Changjia Zhong, John Xi Chen, Shirley ShiDu Yan (Handling Associate Editor: Hemachandra Reddy)
Synergistic Exacerbation of Mitochondrial and Synaptic Dysfunction and Resultant Learning and Memory Deficit in a Mouse Model of Diabetic Alzheimer’s Disease
Abstract: Diabetes is considered to be a risk factor in Alzheimer’s disease (AD) pathogenesis. Although recent evidence indicates that diabetes exaggerates pathologic features of AD, the underlying mechanisms are not well understood. To determine whether mitochondrial perturbation is associated with the contribution of diabetes to AD progression, we characterized mouse models of streptozotocin (STZ)-induced type 1 diabetes and transgenic AD mouse models with diabetes. Brains from mice with STZ-induced diabetes revealed significantly increase of cyclophilin D (CypD) expression, reduced respiratory function, and decreased hippocampal long-term potentiation (LTP); these animals had impaired spatial learning and memory. Hyperglycemia exacerbated the upregulation of CypD, mitochondrial defects, synaptic injury, and cognitive dysfunction in the brains of transgenic AD mice overexpressing amyloid-β as shown by decreased mitochondrial respiratory complex I and IV enzyme activity and greatly decreased mitochondrial respiratory rate. Concomitantly, hippocampal LTP reduction and spatial learning and memory decline, two early pathologic indicators of AD, were enhanced in the brains of diabetic AD mice. Our results suggest that the synergistic interaction between effects of diabetes and AD on mitochondria may be responsible for brain dysfunction that is in common in both diabetes and AD.
Pages 465-477
Ju Wang*, Zi-Qi Shi*, Mu Zhang, Gui-Zhong Xin, Tao Pang, Ping Zhou, Jun Chen, Lian-Wen Qi, Hua Yang, Xiaojun Xu, Ping Li (Handling Associate Editor: Yi Zhun Zhu) *These authors contributed equally to this work.
Camptothecin and its Analogs Reduce Amyloid-β Production and Amyloid-β42-Induced IL-1β Production
Abstract: Compounds derived from natural products are becoming promising alternative drugs/tools in Alzheimer’s disease (AD) therapeutics. From an in-house natural products library, seventeen hits were selected for their inhibitory effect on the production of amyloid-β (Aβ) with IC50 lower than 10 μM without causing obvious toxicity. Among these compounds, camptothecin (CPT) and its analogs showed inhibitory effects on amyloid-β 1-42 (Aβ42) with the IC50 value in nanomolar range in HEKsw cells and SHSY5Ysw cells. Further studies showed that CPT and its analogs inhibited Aβ42 via a p53 dependent pathway. Meanwhile, CPT and its analogs could also inhibit Aβ42 induced IL-1β production in the THP-1 cells. Taken together, our results indicate that CPT and its analogs would be the promising therapeutic candidates for AD.
Pages 479-489
Jing Zhou, Jin-Tai Yu, Hui-Fu Wang, Xiang-Fei Meng, Chen-Chen Tan, Jun Wang, Chong Wang, Lan Tan
Association between Stroke and Alzheimer’s Disease: Systematic Review and Meta-Analysis
Abstract: Alzheimer’s disease (AD) and stroke are common disorders of aging, but the relationship between these two disorders remains uncertain. Recent evidence recognized that they frequently co-occur and are influenced by each another, while other studies have produced inconsistent results. We conducted this systematic review and meta-analysis of stroke on risk for AD and AD on risk for stroke subtypes to clarify the relation between these two disorders on the basis of the studies published from 1975 to November 2013 in the PubMed, EMBASE, and Cochrane Library databases. In total, 7 cohort studies and 2 nested case-control studies met the inclusion criteria for meta-analysis. For stroke, the pooled effect size for AD risk was 1.59 (95% CI 1.25-2.02; z=3.76; p=0.000). For AD dementia, it was not associated with risk of all strokes or ischemic stroke (IS), but the risk of intracerebral hemorrhage (ICH was higher among persons with AD. The pooled RR for AD in relation to incident IS did not indicate a significant association (RR: 1.13; 95% CI 0.75–1.70; z=0.58; p=0.565). The pooled effect size for AD and ICH risk was 1.41 (95% CI 1.21–1.66; z=4.27; p<0.001). Stroke significantly and independently increased risk for AD and in turn AD increased risk for ICH. These results confirm that AD and ICH may have common pathogenesis and share preventive treatment measures.
Pages 491-509
Tapan K. Khan, Abhik Sen, Jarin Hongpaisan, Chol S. Lim, Thomas J. Nelson, Daniel L. Alkon
PKCε Deficits in Alzheimer’s Disease Brains and Skin Fibroblasts
Abstract: In Alzheimer’s disease (AD) transgenic mice, activation of synaptogenic protein kinase C ε (PKCε) was found to prevent synaptotoxic amyloid-β (Aβ)-oligomer elevation, PKCε deficits, early synaptic loss, cognitive deficits, and amyloid plaque formation. In humans, to study the role of PKCε in the pathophysiology of AD and to evaluate its possible use as an early AD-biomarker, we examined PKCε and Aβ in the brains of autopsy-confirmed AD patients (n=20) and age-matched controls (AC, n=19), and in skin fibroblast samples from AD (n=14), non-AD dementia patients (n=14), and AC (n=22). Intraneuronal Aβ levels were measured immunohistochemically (using an Aβ-specific antibody) in hippocampal pyramidal cells of human autopsy brains. PKCε was significantly lower in the hippocampus and temporal pole areas of AD brains, whereas Aβ levels were significantly higher. The ratio of PKCε to Aβ in individual CA1 pyramidal cells was markedly lower in the autopsy AD brains versus controls. PKCε was inversely correlated with Aβ levels in controls, whereas in AD patients, PKCε showed no significant correlation with Aβ. In autopsy brains, PKCε decreased as the Braak score increased. Skin fibroblast samples from AD patients also demonstrated a deficit in PKCε compared to controls and an AD-specific change in the Aβ-oligomer effects on PKCε. Together, these data demonstrate that the relationship between Aβ levels and PKCε is markedly altered in AD patients’ brains and skin fibroblasts, reflecting a loss of protective effect of PKCε against toxic Aβ accumulation. These changes of PKCε levels in human skin fibroblasts may provide an accurate, non-invasive peripheral AD biomarker.
Pages 511-518
Fan Zeng*, Wan-Ting Xie*, Yan-Jiang Wang, Hong-Bo Luo, Xiang-Qun Shi, Hai-Qiang Zou, Yue-Qing Zeng, Ya-Fei Li, Shao-Rong Zhang, Yan Lian * These authors contribute equally to this work.
General Public Perceptions and Attitudes toward Alzheimer’s Disease from Five Cities in China
Abstract: Alzheimer’s disease (AD) is the most common type of dementia affecting the aged population worldwide, yet its social perceptions have been less studied. To investigate the perceptions and attitudes toward AD in the Chinese population, a cross-sectional face-to-face survey of 2,000 randomly selected adults was conducted in five representative cities of China. This survey focused on the fear of AD, and the relationship between this variable and each studied factor was analyzed using univariate analysis and multivariate regression analysis. In general, 76.6% of the total respondents had personal fear of developing AD, and such fear was closely related to the proximity to AD and perceived severity of AD, as well as other factors such as gender and self-perceived health. The results strongly suggested that more attention should be paid to public health education of AD, which can only achieved with the cooperation of government, media, medical institutions, and the community so as to eliminate people’s confusion about AD, relieve their psychological burden, and optimize their health-seeking behavior.
Pages 519-534
Dayong Wang*, Yang Hui* , Yahui Peng*, Lu Tang,Jianfeng Jin, Rongzhang He, Yanze Li, Shuai Zhang, Lisha Li, You Zhou, Jing Li, Ning Ma, Jihong Li, Sijia Li, Xu Gao, Shanshun Luo (Handling Associate Editor: Wolff Kirsch) *These authors contributed equally to this work.
Overexpression of Heme Oxygenase 1 Causes Cognitive Decline and Affects Pathways for Tauopathy in Mice
Abstract: The stress protein heme oxygenase-1 (HO-1) is upregulated and co-localizes to pathological features, including tauopathies in the brains of individuals with Alzheimer’s disease. However, the relationship between HO-1 and Alzheimer’s disease remains unclear. In our previous research, the long-term overexpression of HO-1 was shown to promote tau aggregation by inducing tau phosphorylation in the mouse brain. In this study, we found that the long-term overexpression of HO-1 led to cognitive decline in transgenic mice, as determined by the water maze test, and that HO-1 can affect two pathways for tauopathy. Through one pathway, HO-1 promotes the expression of CDK5 by accumulating reactive oxygen species, which are produced by HO-1 downstream products of iron in neuro2a cell lines and mouse brain. Through the second pathway, HO-1 induces tau truncation at D421 in vivo and in vitro. Clearly, there is a HO-1-dependent mechanism responsible for tau protein phosphorylation and tau truncation in vivo and in vitro. Taken together, our results suggest that HO-1 plays an important role in the disease process of tauopathies in AD.
Pages 535-548
Jiang-chao Li*, Lu Han*, Yin-xin Wen, Yong-xia Yang, Shuai Li, Xue-song Li, Chang-jiang Zhao, Ting-yu Wang, Hui Chen, Ying Liu, Cui-ling Qi, Xiao-dong He, Qu-liangGu, Yu-xiang Ye, Ren Huang, Yu-e Wu, Xiao-yu Song, Liu Cao, Li-jing Wang *These authors contributed equally to this work.
Increased Permeability of the Blood-Brain Barrier and Alzheimer’s Disease-Like Alterations in Slit-2 Transgenic Mice
Abstract: Alzheimer’s disease (AD) is a progressive neurological disorder that primarily affects memory, and its prevalence is rising. Increasing evidence suggests that dysfunction of the blood-brain barrier (BBB) may be involved in AD and other neurodegenerative diseases. Herein, we report that the permeability of the BBB is increased and that AD-like alterations are present in Slit-2 overexpressing transgenic mice. We found that behavioral change and the corresponding molecular diagnostic markers of AD, such as hippocampal neuron apoptosis, amyloid-β (Aβ) protein deposition, and acetylcholinesterase expression, were increased in the Slit-2 transgenic mice. Moreover, the endothelial cells were dysfunctional, the size of the lateral ventricle cavity increased, and the permeability of the BBB increased. Additionally, there was an increased serum level of glutamate indicating that the BBB is related to AD. Finally, histopathological analysis of other organs in the Slit-2 overexpressing mice did not show any marked abnormalities. These findings demonstrate that Slit2 overexpression may be responsible for AD-like alterations and the increased BBB permeability in these mice. Our study provides a potential novel mechanism for the development of AD.
Pages 549-563
Xuemei Zhao, Serguei Lejnine, Jeffrey Spond, Chunsheng Zhang, T C Ramaraj, Daniel J. Holder, Hongyue Dai, Russell Weiner, Omar F. Laterza (Handling Associate Editor: Gary Arendash)
A Candidate Plasma Protein Classifier to Identify Alzheimer’s Disease
Abstract: Biomarkers currently used in the aid for the diagnosis of Alzheimer’s disease (AD) are cerebrospinal fluid (CSF) protein markers and brain neuroimaging markers. These biomarkers, however, either involve semi-invasive procedures or are costly to measure. Thus, AD biomarkers from more easily accessible body fluids, such as plasma, are very enticing. Using an aptamer-based proteomic technology, we profiled 1,129 plasma proteins of AD patients and non-demented control individuals. A 5-protein classifier for AD identification was constructed in the discovery study with excellent 10-fold cross-validation performance (90.1% sensitivity, 84.2% specificity, 87.9% accuracy, and AUC as 0.94). In an independent validation study, the classifier was applied and correctly predicted AD with 100.0% sensitivity, 80.0% specificity, and 90.0% accuracy, matching or outperforming the CSF Aβ42 and tau biomarkers whose performance were assessed in individual-matched CSF samples obtained at the same visit as plasma sample collection. Moreover, the classifier also correctly predicted mild cognitive impairment, an early pre-dementia state of the disease, with 96.7% sensitivity, 80.0% specificity, and 92.5% accuracy. These studies demonstrate that plasma proteins could be used effectively and accurately to contribute to the clinical diagnosis of AD. Although additional and more diverse cohorts are needed for further validation of the robustness, including the support of postmortem diagnosis, the 5-protein classifier appears to be a promising blood test to contribute diagnosis of AD.
Pages 565-573
Henna Martiskainen*, Seppo Helisalmi*, Jayashree Viswanathan, Mitja Kurki, Anette Hall, Sanna-Kaisa Herukka, Timo Sarajärvi, Teemu Natunen, Kaisa M. A. Kurkinen, Jaakko Huovinen, Petra Mäkinen, Marjo Laitinen, Anne M. Koivisto, Kari M. Mattila, Terho Lehtimäki, Anne M. Remes, Ville Leinonen, Annakaisa Haapasalo, Hilkka Soininen, Mikko Hiltunen (Handling Associate Editor: Henrik Zetterberg) *These authors contributed equally to this work.
Effects of Alzheimer’s Disease-Associated Risk Loci on Cerebrospinal Fluid Biomarkers and Disease Progression: A Polygenic Risk Score Approach
Abstract: Background: Several risk loci for Alzheimer’s disease (AD) have been identified during recent years in large-scale genome-wide association studies. However, little is known about the mechanisms by which these loci influence AD pathogenesis. Objective: To investigate the individual and combined risk effects of the newly identified AD loci. Methods: Association of 12 AD risk loci with AD and AD-related cerebrospinal fluid (CSF) biomarkers was assessed. Furthermore, a polygenic risk score combining the effect sizes of the top 22 risk loci in AD was calculated for each individual among the clinical and neuropathological cohorts. Effects of individual risk loci and polygenic risk scores were assessed in relation to CSF biomarker levels as well as neurofibrillary pathology and different biochemical measures related to AD pathogenesis obtained from the temporal cortex. Results: Polygenic risk scores associated with CSF amyloid-β42 (Aβ42) levels in the clinical cohort, and with soluble Aβ42 levels and γ-secretase activity in the neuropathological cohort. The γ-secretase effect was independent of APOE. APOE-ε4 associated with CSF Aβ42 (p<0.001) levels. For the other risk loci, no significant associations with AD risk or CSF biomarkers were detected after multiple testing correction. Conclusions: AD risk loci polygenically contribute to Aβ pathology in the CSF and temporal cortex, and this effect is potentially associated with increased γ-secretase activity.
Pages 575-588
Stina Tucker, Christer Möller, Karin Tegerstedt, Anna Lord, Hanna Laudon, Johan Sjödahl, Linda Söderberg, Erika Spens, Charlotte Sahlin, Erik Rollman Waara, Andrew Satlin, Pär Gellerfors, Gunilla Osswald, Lars Lannfelt (Handling Associate Editor: Thomas Bayer)
The Murine Version of BAN2401 (mAb158) Selectively Reduces Amyloid-β Protofibrils in Brain and Cerebrospinal Fluid of tg-ArcSwe Mice
Abstract: Amyloid-β (Aβ) immunotherapy for Alzheimer’s disease (AD) has good preclinical support from transgenic mouse models and clinical data suggesting that a long-term treatment effect is possible. Soluble Aβ protofibrils have been shown to exhibit neurotoxicity in vitro and in vivo, and constitute an attractive target for immunotherapy. Here, we demonstrate that the humanized antibody BAN2401 and its murine version mAb158 exhibit a strong binding preference for Aβ protofibrils over Aβ monomers. Further, we confirm the presence of target by showing that both antibodies efficiently immunoprecipitate soluble Aβ aggregates in human AD brain extracts. mAb158 reached the brain and reduced the brain protofibril levels by 42% in an exposure-dependent manner both after long-term and short-term treatment in tg-ArcSwe mice. Notably, a 53% reduction of protofibrils/oligomers in cerebrospinal fluid (CSF) that correlated with reduced brain protofibril levels was observed after long-term treatment, suggesting that CSF protofibrils/oligomers could be used as a potential biomarker. No change in native monomeric Aβ42 could be observed in brain TBS extracts after mAb158-treatment in tg-ArcSwe mice. By confirming the specific ability of mAb158 to selectively bind and reduce soluble Aβ protofibrils, with minimal binding to Aβ monomers, we provide further support in favor of its position as an attractive new candidate for AD immunotherapy. BAN2401 has undergone full Phase 1 development, and available data indicate a favorable safety profile in AD patients.
Pages 589-603
Meng-Shan Tan, Jin-Tai Yu, Chen-Chen Tan, Hui-Fu Wang, Xiang-Fei Meng, Chong Wang, Teng Jiang, Xi-Chen Zhu, Lan Tan (Handling Associate Editor: Francesco Panza)
Efficacy and Adverse Effects of Ginkgo biloba for Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis
Abstract: Background: Research into Ginkgo biloba has been ongoing for many years, while the benefit and adverse effects of Ginkgo biloba extract EGb761 for cognitive impairment and dementia has been discussed controversially. Objective: To discuss new evidence on the clinical and adverse effects of standardized Ginkgo biloba extract EGb761for cognitive impairment and dementia. Methods: MEDLINE, EMBASE, Cochrane, and other relevant databases were searched in March 2014 for eligible randomized controlled trials of Ginkgo biloba EGb761 therapy in patients with cognitive impairment and dementia. Results: Nine trials met our inclusion criteria. Trials were of 22-26 weeks duration and included 2,561 patients in total. In the meta-analysis, the weighted mean differences in change scores for cognition were in favor of EGb761 compared to placebo (-2.86, 95%CI -3.18; -2.54); the standardized mean differences in change scores for activities in daily living (ADLs) were also in favor of EGb761 compared to placebo (-0.36, 95%CI -0.44; -0.28); Peto OR showed a statistically significant difference from placebo for Clinicians’ Global Impression of Change (CGIC) scale (1.88, 95%CI 1.54; 2.29). All these benefits are mainly associated with EGb761 at a dose of 240 mg/day. For subgroup analysis in patients with neuropsychiatric symptoms, 240 mg/day EGb761 improved cognitive function, ADLs, CGIC, and also neuropsychiatric symptoms with statistical superiority than for the whole group. For the Alzheimer’s disease subgroup, the main outcomes were almost the same as the whole group of patients with no statistical superiority. Finally, safety data revealed no important safety concerns with EGb761. Conclusions: EGb761 at 240 mg/day is able to stabilize or slow decline in cognition, function, behavior, and global change at 22-26 weeks in cognitive impairment and dementia, especially for patients with neuropsychiatric symptoms.
Pages 605-611
Commentary
Vincenzo Solfrizzi* and Francesco Panza* *These authors contributed equally to this work.
Plant-Based Nutraceutical Interventions against Cognitive Impairment and Dementia: Meta-Analytic Evidence of Efficacy of a Standardized Gingko biloba Extract
Abstract: Among nutraceuticals and nutritional bioactive compounds, the standardized Ginkgo biloba extract EGb 761 is the most extensively clinically tested herbal-based substance for cognitive impairment, dementia, and Alzheimer’s disease (AD). In the last three years, notwithstanding negative meta-analytic findings and the discouraging results of preventive trials against AD, some randomized controlled trials focusing particularly on dementia, AD, and mild cognitive impairment (MCI) subgroups with neuropsychiatric symptoms (NPS) and some recent meta-analyses have suggested a renowned role for EGb 761 for cognitive impairment and dementia. Meta-analytic findings suggested overall benefits of EGb 761 for stabilizing or slowing decline in cognition of subjects with cognitive impairment and dementia. The safety and tolerability of EGb 761 appeared to be excellent at different doses. Subgroup analyses showed that these clinical benefits of EGb 761 were mainly associated with the 240 mg/day dose, and also confirmed in the AD subgroup. More importantly, one of these meta-analyses showed clinical benefits in cognition, behavior, functional status, and global clinical change of EGb 761 at a dose of 240 mg/day in the treatment of patients with dementia, AD, and MCI with NPS. The inclusion of the recent randomized controlled trials focusing on dementia, AD, and MCI subgroups with NPS may partly explain the conflicting results of these recent meta-analyses and previous pooled findings.
Pages 613-624
Diana Pisa*, Ruth Alonso*, Angeles Juarranz, Alberto Rábano, Luis Carrasco *These authors contributed equally to this work.
Direct Visualization of Fungal Infection in Brains from Patients with Alzheimer’s Disease
Abstract: Recently, we have reported the presence of fungal infections in patients with Alzheimer’s disease (AD). Accordingly, fungal proteins and DNA were found in brain samples, demonstrating the existence of infection in the central nervous system. In the present work, we raised antibodies to specific fungal species and performed immunohistochemistry to directly visualize fungal components inside neurons from AD patients. Mice infected with Candida glabrata were initially used to assess whether yeast can be internalized in mammalian tissues. Using polyclonal rabbit antibodies against C. glabrata, rounded immunopositive cells could be detected in the cytoplasm of cells from liver, spleen, and brain samples in infected, but not uninfected, mice. Immunohistochemical analyses of tissue from the frontal cortex of AD patients revealed the presence of fungal material in a small percentage (~10%) of cells, suggesting the presence of infection. Importantly, this immunopositive material was absent in control samples. Confocal microscopy indicated that this fungal material had an intracellular localization. The specific morphology of this material varied between patients; in some instances, disseminated material was localized to the cytoplasm, whereas small punctate bodies were detected in other patients. Interestingly, fungal material could be revealed using different anti-fungal antibodies, suggesting multiple infections. In summary, fungal infection can only be observed using specific anti-fungal antibodies and only a small percentage of cells contain fungi. Our findings provide an explanation for the hitherto elusive detection of fungi in AD brains, and are consistent with the idea that fungal cells are internalized inside neurons.
Pages 625-630
Claire Boutoleau-Bretonnière, Agnès Camuzat, Isabelle Le Ber, Kawtar Bouya-Ahmed, Rita Guerreiro, Anne-Laure Deruet, Christelle Evrard, José Bras, Estelle Lamy, Elisabeth Auffray-Calvier, Amandine Pallardy, John Hardy, Alexis Brice, Pascal Derkinderen, Martine Vercelletto
A Phenotype of Atypical Apraxia of Speech in a Family Carrying SQSTM1 Mutation
Abstract: SQSTM1 mutations, coding for the p62 protein, were identified as a monogenic cause of Paget disease of bone and of amyotrophic lateral sclerosis. More recently, SQSTM1 mutations were identified in few families with frontotemporal dementia. We report a new family carrying SQSTM1 mutation and presenting with a clinical phenotype of speech apraxia or atypical behavioral disorders, associated with early visuo-contructional deficits. This study further supports the implication of SQSTM1 in frontotemporal dementia, and enlarges the phenotypic spectrum associated with SQSTM1 mutations.
Pages 631-647
Jesús Cespón, Santiago Galdo-Álvarez, Arturo X. Pereiro, Fernando Díaz (Handling Associate Editor: Claudio Babiloni)
Differences between Mild Cognitive Impairment Subtypes as Indicated by Event-Related Potential Correlates of Cognitive and Motor Processes in a Simon Task
Abstract: Mild cognitive impairment (MCI) may represent a prodromal stage of Alzheimer’s disease (AD), although the clinical manifestations of MCI are heterogeneous. Consequently, MCI subtypes are differentiated since amnestic decline (particularly when combined with decline on multiple cognitive domains) increases the probability of progression to AD. In the present study, event-related potential (ERP) correlates of stimulus evaluation (N2), visuospatial attention (negativity posterior-contralateral, N2pc), stimulus categorization (P3b), executive control (pre-response positivity, PP, and medial frontal negativity), and motor (lateralized readiness potential, LRP) processes were studied in 53 participants while they performed a Simon task. Participants were divided into control group (CG), multiple-domain non-amnestic MCI (mdnaMCI), single-domain amnestic MCI (sdaMCI), and multiple-domain amnesic MCI (mdaMCI). Although there were no differences in reaction times and percentage of errors in the performed Simon-type task, a differential pattern of electrophysiological correlates was observed in MCI compared to CG. Concretely, amnestic MCI (sdaMCI and mdaMCI) showed reduced motor activity (LRP amplitude; AUC: 0.84); impairment in executive control (PP amplitude; AUC: 0.80) was observed in multiple-domain MCI (mdaMCI and mdnaMCI); finally, stimulus evaluation (N2 latency; AUC: 0.86) and visuospatial attention (N2pc amplitude; AUC: 0.78) was affected in mdaMCI. Overall, results linked the poorer prognosis of the mdaMCI subtype with a greater number of differences in ERP correlates regarding CG. Therefore, the present results enable us to suggest possible ERP biomarkers for specific MCI subtypes.
Pages 649-655
Xingbin Wang, Oscar L. Lopez, Robert A. Sweet, James T. Becker, Steven T. DeKosky, Mahmud M. Barmada, F. Yesim Demirci, M. Ilyas. Kamboh
Genetic Determinants of Disease Progression in Alzheimer’s Disease
Abstract: There is a strong genetic basis for late-onset Alzheimer’s disease (LOAD); thus far 22 genes/loci have been identified that affect the risk of LOAD. However, the relationships among the genetic variations at these loci and clinical progression of the disease have not been fully explored. In the present study, we examined the relationships of 22 known LOAD genes to the progression of AD in 680 AD patients recruited from the University of Pittsburgh Alzheimer’s Disease Research Center. Patients were classified as “rapid progressors” if the Mini-Mental State Examination (MMSE) changed ≥3 points in 12 months and “slow progressors” if the MMSE changed ≤2 points. We also performed a genome-wide association study in this cohort in an effort to identify new loci for AD progression. Association analysis between single nucleotide polymorphisms (SNPs) and the progression status of the AD cases was performed using logistic regression model controlled for age, gender, dementia medication use, psychosis, and hypertension. While no significant association was observed with either APOE*4 (p=0.94) or APOE*2 (p=0.33) with AD progression, we found multiple nominally significant associations (p<0.05) either within or adjacent to seven known LOAD genes (INPP5D, MEF2C, TREM2, EPHA1, PTK2B, FERMT2, and CASS4) that harbor both risk and protective SNPs. Genome-wide association analyses identified four suggestive loci (PAX3, CCRN4L, PIGQ, and ADAM19) at p<1E-05. Our data suggest that short-term clinical disease progression in AD has genetic basis. Better understanding of these genetic factors could help to improve clinical trial design and potentially affect the development of disease modifying therapies.
Pages 657-668
Jiu Chen, Hao Shu, Zan Wang, Duan Liu, Yongmei Shi, Xiangrong Zhang, Zhijun Zhang
The Interaction of APOE Genotype by Age in Amnestic Mild Cognitive Impairment: A Voxel-Based Morphometric Study
Abstract: The apolipoprotein E (APOE) gene has been confirmed as the major genetic risk factor for the conversion of amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD). The present study was to assess whether there was a specific interaction of APOE by the aging process on brain morphology in aMCI. The analysis of gray matter (GM) voxel-based morphometry was performed in 85 aMCI and 100 healthy controls (HC). A significant interaction of APOE genotype by age on GM volume was found in the left calcarine, the left insula, and the left medial frontal gyrus in aMCI. GM volume in aMCI decreased significantly with ε2-carriers < ε3/ε3 < ε4-carriers in above brain regions (except the left insula) while there was only a reduced tendency in HC. The multivariate regression analysis showed the well-known negative relationship for ε4-carriers and the positive relationship for ε2-carriers (except the left insula), while no correlations were found for ε3/ε3 between age and GM volumes on above brain regions. Moreover, the reduced GM volumes in the left calcarine and insula correlated with the impairment of visuo-spatial cognition and episodic memory in ε4- and ε2-carriers but not ε3/ε3, respectively. These results suggest that the APOE ε4 and ε2 alleles have the opposing effects on brain morphology across the spectrum of cognitive aging. Moreover, the interaction of APOE by age on brain morphology may accelerate the pathological progression of late-life cognitive decline in aMCI with ε4-carriers and delay the possible conversion from aMCI with ε2-carriers to AD.
Pages 669-675
Xin Xu, Shifu Xiao, Tri Budi Rahardjo, Eef Hogervorst
Tofu Intake is Associated with Poor Cognitive Performance among Community-Dwelling Elderly in China
Abstract: Tofu is a soy product which is commonly consumed in Asian countries, such as China and Indonesia. Several studies found negative associations of high tofu consumption with cognitive function in older Asian populations. However, the effect of tofu on cognitive function remains disputed as it was not found in Western populations. In the present study, the effect of weekly tofu intake on cognitive performance was investigated in an observational cross sectional study of 517 Chinese elderly from Shanghai. Similar to earlier studies, results showed that a higher weekly intake of tofu was associated with worse memory performance using the Hopkins Verbal Learning Test (β=-0.10, p=0.01) after controlling for age, gender, education, being vegetarian, and weekly intake of fruit/juice, green vegetables, and orange/red vegetables. Furthermore, among older elderly (≥68 years of age), high tofu intake increased the risk of cognitive impairment indicative of dementia (OR=1.27, 95% CI= 0.99-1.64, p=0.04), after adjusting for all covariates. Consumption of meat and green vegetables independently also reduced risk of dementia. To conclude, high intake of tofu was negatively related to cognitive performance among community-dwelling elderly in China. Similar findings were reported in Indonesia and in Japanese Americans in the US. These findings suggest that the effect of tofu on cognition in elderly should be further investigated.
Pages 677-686
Simone Hollands, Yen Ying Lim, Rachel Buckley, Robert H. Pietrzak, Peter J. Snyder, David Ames, Kathryn A. Ellis, Karra Harrington, Nicola Lautenschlager, Ralph N. Martins, Colin L. Masters, Victor L. Villemagne, Christopher C. Rowe, Paul Maruff for the AIBL Research Group (Handling Associate Editor: Mark Bondi)
Amyloid-β Related Memory Decline is not associated with Subjective or Informant Rated Cognitive Impairment in Healthy Adults
Abstract: Background: The detection of early Alzheimer’s disease (AD) can rely on subjective and informant reports of cognitive impairment. However, relationships between subjective cognitive impairment, objectively measured cognitive function, and amyloid-β (Aβ) biomarkers remain unclear. Objective: To determine the extent to which impairment or decline in subjective and informant rated cognitive impairment was associated with memory in healthy older adults with high Aβ. Methods: Healthy older adults (n=289) enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were studied at baseline. Pittsburgh Compound B was used to determine Aβ status at baseline. At baseline and 18 months assessments, subjective memory impairment was assessed using the Memory Complaint Questionnaire and the Short Form of the Informant Questionnaire on Cognitive Decline in the Elderly. Cognition was measured using the Cogstate Brief Battery. Results: At baseline, there were no differences between low and high Aβ groups in subjective or informant-rated cognitive impairment, depressive and anxiety symptoms, or cognitive function. Longitudinal analyses showed moderate decline in learning and working memory over the 18 months in the high Aβ group. However there was no change over time in subjective or informant-rated cognitive impairment, depressive and anxiety symptoms, or cognition in either Aβ group. Conclusions: Although healthy older adults with high Aβ levels show decline in learning and working memory over 18 months, subjective or informant ratings of cognitive impairment do not change over the same period suggesting subjective cognitive impairment may have limited utility for the very early identification of AD.
Pages 687-697
Bing Zhang1, Xin Zhang1, Fang Zhang, Ming Li, Christopher G. Schwarz, Jiange Zhang, Zhenyu Yin, Lai Qian, Hui Zhao, Kun Wang, Chuanshuai Tian, Haiping Yu, Weibo Chen, Fangfei Lu, Wenbo Wu, Qing X. Yang, Yun Xu*, Bin Zhu* (Handling Associate Editor: Yong He) 1These authors contributed equally to this work. *These authors contributed equally to this work.
Characterizing Topological Patterns in Amnestic Mild Cognitive Impairment by Quantitative Water Diffusivity
Abstract: Mean diffusivity (MD) derived from diffusion tensor imaging has shown its ability to assess the microscopic structural integrity damage of gray matter in amnestic mild cognitive impairment (aMCI), a prodromal stage of Alzheimer’s disease (AD). However, little is known about the small world topology networks constructed by cortical MD in cognitive disease. In this work, we measured the cortical MD in the entire brain in patients with aMCI (n = 30) and AD (n = 30) compared with cognitive-normal (CNs) controls (n = 30), and then constructed the cortical diffusivity network by using graph-theoretical analysis. Compared with CNs, patients with aMCI and AD showed abnormal small-world property of cortical diffusivity networks (higher degree of clustering and longer path length), reflecting a less optimal topological organization. Moreover, the mean degree of connections of network in aMCI patients was characterized by lower than CNs but higher than AD. In addition, 11 hub regions were identified by negative correlations between MD and the score of Montreal Cognitive Assessment after multiple regression analysis, including bilateral hippocampi and related limbic system. Among those hub regions, the connectivity of the right olfactory cortex and middle orbital gyrus to the rest of brain regions were disrupted earlier than the other 9 regions in aMCI when compared to CN. In conclusion, the change of cortical diffusivity in topological network organization, mean degree of connections, and disrupted hub regions in aMCI may serve to identify patients in the prodromal stage of AD and reflect microstructural deterioration of neurodegeneration.
